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Microarray and Single-Molecule Molecular Inversion Probe (smMIP)-based targeted RNA sequencing are two RNA profiling platforms for identifying disease-associated biomarkers. The microarray uses a GeneChip array with oligonucleotide probes to measure expression levels across thousands of genes, while smMIPs capture and quantify RNA transcripts and transcript variants via next-generation sequencing. To evaluate the strengths and weaknesses of both platforms, a comparative gene expression profiling study was conducted using RNA samples from 52 prostate tissues (normal, benign prostatic hyperplasia (BPH) and various prostate cancer (PCa) grades). Of all genes covered by both platforms, only 35% of the expression levels aligned, with 45% showing discrepancies. Both platforms identified the same 17 genes as potential PCa biomarkers. Microarray analysis identified an additional 253 genes that were not covered or not identified by smMIP technology, while smMIP technology identified eight markers not covered or not identified in the microarray core gene analysis, including fusion genes and splice variants. For high-grade prostate cancer (HG-PCa), the smMIP-method identified 8 markers, and the microarray identified 17 markers, with FOLH1, FAP and CLDN3 being common across both platforms. The choice of RNA expression analysis technology depends on research objectives; microarray technology is useful for the evaluation of a wide range of genes but has low throughput. In contrast, smMIP-based RNA sequencing enables sensitive analysis with minimal RNA in a medium- to high-throughput setting. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) is a complex clonal disorder characterized by clinical, genetic, metabolomic, and epigenetic heterogeneity resulting in the uncontrolled proliferation of aberrant blood-forming precursor cells. Despite advancements in the understanding of the genetic, metabolic, and epigenetic landscape of AML, it remains a significant therapeutic challenge. Functional profiling techniques, such as BH3 profiling (BP), gene expression profiling (GEP), proteomics, metabolomics, drug sensitivity/resistance testing (DSRT), CRISPR/Cas9, and RNAi screens offer valuable insights into the functional behavior of leukemia cells. BP evaluates the mitochondrial response to pro-apoptotic BH3 peptides, determining a cell's apoptotic threshold and its reliance on specific anti-apoptotic proteins. This knowledge can pinpoint vulnerabilities in the mitochondria-mediated apoptotic pathway in leukemia cells, potentially informing treatment strategies and predicting therapeutic responses. GEP, particularly RNA sequencing, evaluates the transcriptomic landscape and identifies gene expression alterations specific to AML subtypes. Proteomics and metabolomics, utilizing mass spectrometry and nuclear magnetic resonance (NMR), provide a detailed view of the active proteins and metabolic pathways in leukemia cells. DSRT involves exposing leukemia cells to a panel of chemotherapeutic and targeted agents to assess their sensitivity or resistance profiles and potentially guide personalized treatment strategies. CRISPR/Cas9 and RNAi screens enable systematic disruption of genes to ascertain their roles in leukemia cell survival and proliferation. These techniques facilitate precise disease subtyping, uncover novel biomarkers and therapeutic targets, and provide a deeper understanding of drug-resistance mechanisms. Recent studies utilizing functional profiling have identified specific mutations and gene signatures associated with aggressive AML subtypes, aberrant signaling pathways, and potential opportunities for drug repurposing. The integration of multi-omics approaches, advances in single-cell sequencing, and artificial intelligence is expected to refine the precision of functional profiling and ultimately improve patient outcomes in AML. This review highlights the diverse landscape of functional profiling methods and emphasizes their respective advantages and limitations. It highlights select successes in how these methods have further advanced our understanding of AML biology, identifies druggable targets that have improved outcomes, delineates challenges associated with these techniques, and provides a prospective view of the future where these techniques are likely to be increasingly incorporated into the routine care of patients with AML. [ABSTRACT FROM AUTHOR]

The member of trace-amine associated receptor family, TAAR5 receptor was suggested to recognize tertiary amines, mostly in the olfactory system; however, knocking out the receptor TAAR5 in mice showed an enhancing effect on adult neurogenesis and dopamine neurotransmission in the striatum. To estimate the role of the TAAR5, we performed gene expression profiling of striatal samples from TAAR5 knockout (KO) mice and their wild-type littermates. The higher expression of several genes involved in dopaminergic signaling and the downregulation of genes associated with gliogenesis were revealed in TAAR5-KO mice. Meanwhile, the upregulating effect of TAAR5 knockout on genes was associated with neurogenesis and synaptogenesis. The estimation of cell-type relative abundance through the deconvolution of RNA sequencing data demonstrated that TAAR5-KO striatum samples contain more D2 dopamine receptor-expressing medium spiny neurons but fewer astrocytes than wild-type mice. Our findings indicate that previously identified improvement in cognitive functions and motor coordination in TAAR5-KO mice may activate genes involved in neurogenesis, synaptogenesis, and synapse organization in the striatum. These data suggest that the pharmaceutical targeting of TAAR5 may improve striatum-dependent cognitive or motor functions. At the same time, a more detailed investigation of future TAAR5 antagonists' effect on glia development is necessary. [ABSTRACT FROM AUTHOR]

Honeybee larvae and pupae form the cornerstone of colony survival, development, and reproduction. Azoxystrobin is an effective strobilurin fungicide that is applied during the flowering stage for controlling plant pathogens. The contaminated nectar and pollen resulting from its application are collected by forager bees and impact the health of honeybee larvae and pupae. The current study evaluated the survival, development, and physiological effects of azoxystrobin exposure on the larvae and pupae of Apis mellifera worker bees. The field-recommended concentrations of azoxystrobin were found to suppress the survival indices and lifespan in the larval as well as pupal stages; moreover, the rates of the survival and pupation of larvae as well as the body weights of the pupae and newly-emerged adult bees were significantly reduced upon long-term exposure to azoxystrobin. In addition, azoxystrobin ingestion induced changes in the expression of genes critical for the development, immunity, and nutrient metabolism of larvae and pupae, although the expression profile of these genes differed between the larval and pupal stages. Results indicated the chronic toxicity of azoxystrobin on the growth and development of honeybee larvae and pupae, which would affect their sensitivity to pathogens and other external stresses during the development stage and the study will provide vital information regarding the pollination safety and rational use of pesticides. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with limited effective therapies. Interstitial macrophages (IMs), especially those derived from monocytes, play an unknown role in IPF pathogenesis. By using single-cell RNA sequencing (scRNA-seq), bleomycin (BLM)-induced pulmonary fibrosis mouse lungs were analyzed to characterize the cellular landscape and heterogeneity of macrophages in this model. scRNA-seq was used to identify distinct interstitial macrophage subpopulations in fibrotic lungs, with monocyte-derived macrophages exhibiting a pro-fibrotic gene expression profile enriched in wound healing, extracellular matrix (ECM) remodeling, and pro-fibrotic cytokine production functions. A pseudotime analysis revealed that IMs originated from monocytes and differentiated along a specific trajectory. A cell–cell communication analysis demonstrated strong interactions between monocyte-derived interstitial macrophages (Mo-IMs) and fibroblasts through the transforming growth factor beta (TGFβ), secreted phosphoprotein 1 (SPP1), and platelet-derived growth factor (PDGF) signaling pathways. Flow cytometry validated the presence and expansion of Mo-IMs subpopulations in BLM-treated mice. This study reveals the cellular heterogeneity and developmental trajectory of lung macrophages in early BLM-induced pulmonary fibrosis, highlighting the crucial role of Mo-IMs with a pro-fibrotic phenotype in IPF pathogenesis via interactions with fibroblasts. Targeting these specific macrophage subpopulations and associated signaling pathways may provide novel therapeutic strategies for IPF. [ABSTRACT FROM AUTHOR]

Alcohol use disorder's complexity arises from genetic and environmental factors, with alcohol metabolism genes and neurotransmitter pathways being critical. This study aims to analyze synaptic plasticity gene expression changes in individuals with AUD in order to study their contribution to AUD development and to identify potential biomarkers of treatment response. RNA was extracted from whole peripheral blood (20 patients, 10 healthy controls), before and after treatment (Qiagen AllPrep RNA/DNA Mini Kit), and the gene expression of 84 genes related to neuroplasticity was studied using the RT2 Profiler for Human Synaptic Plasticity RT-PCR Array (PAHS-126ZA, Qiagen), comparing AUD patients to control and responders to non-responders. The potential prognostic/predictive biomarkers were searched using machine learning models. A total of 35 dysregulated genes were found in AUD patients. EPHB2, EGR, and AKT1 were increased, while TIMP1, NCAM1, and GRM2 were decreased. Responders showed distinct gene expression profiles at baseline. After treatment, the expression of 57 genes was normalized, while NCAM1, GRM2, and BDNF showed the most significant recovery. EGR4, INHBA, and NCAM1 emerged as potential biomarkers to predict treatment success. These results indicate that gene profiles in peripheral blood can serve as prognostic markers for the prognosis and treatment of AUD, although further validation is required. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 30% of acute myeloid leukemias are genetically defined by alteration in the FMS-like tyrosine kinase 3 (FLT3). Tyrosine kinase inhibitors targeting FLT3 improved the prognosis of patients with AML but also increased infection rates. Dendritic cells are professional antigen-presenting cells inducing robust immune responses. Therefore, we investigated the immunomodulatory effect of three different FLT3 inhibitors, midostaurin, gilteritinib and quizartinib, on normal dendritic cells in vitro. In this study, we unveil the immunosuppressive effect of midostaurin on DCs by flow cytometry, RNA sequencing and western blotting. The effect of gilteritinib was less pronounced, while quizartinib exerted almost no immunosuppression. Our data may provide an explanation for increased infection rates observed in clinical trials and will help to choose the optimal compound for therapy. Background: FMS-like tyrosine kinase 3 (FLT3) mutations or internal tandem duplication occur in 30% of acute myeloid leukemia (AML) cases. In these cases, FLT3 inhibitors (FLT3i) are approved for induction treatment and relapse. Allogeneic hematopoietic stem cell transplantation (alloHSCT) remains the recommended post-induction therapy for suitable patients. However, the role of FLT3i therapy after alloHSCT remains unclear. Therefore, we investigated the three currently available FLT3i, gilteritinib, midostaurin, and quizartinib, in terms of their immunosuppressive effect on dendritic cells (DCs). DCs are professional antigen-presenting cells inducing T-cell responses to infectious stimuli. Highly activated DCs can also cause complications after alloHSCT, such as triggering Graft versus Host disease, a serious and potentially life-threatening complication after alloHSCT. Methods: To study the immunomodulatory effects on DCs, we differentiated murine and human DCs in the presence of FLT3i and performed immunophenotyping by flow cytometry and cytokine measurements and investigated gene and protein expression. Results: We detected a dose-dependent immunosuppressive effect of midostaurin, which decreased the expression of costimulatory markers like CD86, and found a reduced secretion of pro-inflammatory cytokines such as IL-12, TNFα, and IL-6. Mechanistically, we show that midostaurin inhibits TLR and TNF signaling and NFκB, PI3K, and MAPK pathways. The immunosuppressive effect of gilteritinib was less pronounced, while quizartinib did not show truncation of relevant signaling pathways. Conclusions: Our results suggest different immunosuppressive effects of these three FLT3i and may, therefore, provide an additional rationale for optimal maintenance therapy after alloHSCT of FLT3-positive AML patients to prevent infectious complications and GvHD mediated by DCs. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is a deadly form of cancer, affecting areas like the mouth, throat, and larynx. This review explores the complex molecular pathways involved in HNSCC development and progression, focusing on the role of microRNAs (miRNAs)—small molecules that regulate gene expression. We aim to provide a comprehensive overview of how miRNAs influence HNSCC, their potential as diagnostic and prognostic markers, and their use in developing new targeted therapies. We also discuss promising nanotechnology-based approaches for delivering miRNA therapies more effectively. By synthesizing the current knowledge on miRNAs in HNSCC, this research may help identify new biomarkers for early detection and prognosis, as well as novel therapeutic targets. Ultimately, these insights could lead to improved personalized treatments and better outcomes for HNSCC patients. This paper presents a comprehensive comparative analysis of biomarkers for head and neck cancer (HNC), a prevalent but molecularly diverse malignancy. We detail the roles of key proteins and genes in tumourigenesis and progression, emphasizing their diagnostic, prognostic, and therapeutic relevance. Our bioinformatic validation reveals crucial genes such as AURKA, HMGA2, MMP1, PLAU, and SERPINE1, along with microRNAs (miRNA), linked to HNC progression. OncomiRs, including hsa-miR-21-5p, hsa-miR-31-5p, hsa-miR-221-3p, hsa-miR-222-3p, hsa-miR-196a-5p, and hsa-miR-200c-3p, drive tumourigenesis, while tumour-suppressive miRNAs like hsa-miR-375 and hsa-miR-145-5p inhibit it. Notably, hsa-miR-155-3p correlates with survival outcomes in addition to the genes RAI14, S1PR5, OSBPL10, and METTL6, highlighting its prognostic potential. Future directions should focus on leveraging precision medicine, novel therapeutics, and AI integration to advance personalized treatment strategies to optimize patient outcomes in HNC care. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous melanoma is a malignancy of melanocytes with increasing global incidence. While most early-stage cases have favorable outcomes, melanomas can unexpectedly progress, highlighting the need for better risk prediction methods. This review examined the 31-gene expression profile (31-GEP) test, which analyzes the activity of 31 genes in melanoma tumors to predict the risk of metastasis. Data from multiple studies was systematically reviewed and analyzed to assess the 31-GEP test's efficacy in predicting melanoma patient outcomes. Our findings suggest that the 31-GEP test may improve risk prediction when used alongside standard clinical and pathological assessments. By using 31-GEP, physicians may be better able to make more informed decisions about treatment and follow-up care, potentially improving outcomes for melanoma patients. Background: Cutaneous melanoma is an increasingly common and potentially lethal form of skin cancer. Current staging systems based on clinical and pathological features have limitations in accurately predicting outcomes, particularly for early-stage disease. The 31-gene expression profile (31-GEP) test has emerged as a promising tool for improving risk stratification in melanoma patients. Methods: We conducted a systematic review and meta-analysis of studies evaluating the prognostic performance of the 31-GEP test in cutaneous melanoma. A comprehensive literature search was performed in multiple databases. Studies reporting survival outcomes stratified by 31-GEP class were included. Random-effects models were used to determine survival estimates across studies. Results: Thirteen studies comprising 14,760 patients were included in the meta-analysis. The 31-GEP test consistently stratified patients into risk groups with significantly different outcomes. The 5-year melanoma-specific survival rates were 99.8% (95% CI: 98–100%) for Class 1A, 97.6% (95% CI: 92.4–99.3%) for Class 1B/2A, and 83.4% (95% CI: 66.5–92.7%) for Class 2B. Similar trends were observed for recurrence-free and distant metastasis-free survival. Conclusions: This meta-analysis supports the prognostic utility of the 31-GEP test in cutaneous melanoma prognostication. The test consistently stratified patients into clinically meaningful risk groups across multiple survival metrics. These findings support the potential clinical utility of the 31-GEP test in enhancing current staging systems and informing personalized management strategies for melanoma patients. [ABSTRACT FROM AUTHOR]

Simple Summary: CD59 prevents the formation of membrane attack complex, enabling tumor cells to escape complement-mediated cytotoxicity. It appears that the expression of CD59 significantly impacts survival outcomes due to its interaction with immune cells. The associations between CD59 and immune suppressive cells such as T-regulatory cells, myeloid derived suppressor cells, and macrophage create an immune suppressive environment in cervical, brain, head and neck, and stomach cancers. However, kidney cancer has less or no association, leading to better survival outcomes. Thus, assessing the levels of CD59 and its immune cell associations is crucial as it plays a predictive role in deciding prognostic outcomes. Background: CD59, a GPI-anchored membrane protein, protects cancer cells from complement-dependent cytotoxicity (CDC) by inhibiting the formation of the membrane attack complex (MAC). It has been demonstrated to be overexpressed in most solid tumors, where it facilitates tumor cell escape from complement surveillance. The role of CD59 in cancer growth and interactions between CD59 and immune cells that modulate immune evasion has not been well explored. Methods: Using cancer patient database from The Cancer Genome Atlas (TCGA) and other public databases, we analyzed CD59 expression, its prognostic significance, and its association with immune cell infiltration in the tumor microenvironment, identifying associated genomic and functional networks and validating findings with invitro cell-line experimental data. Results: This article describes the abundant expression of CD59 in multiple tumors such as cervical squamous cell carcinoma (CESC), kidney renal cell carcinoma (KIRC), glioblastoma multiforme (GBM), head and neck squamous cell carcinoma (HNSC), and stomach adenocarcinoma (STAD), as well as in pan-cancer, using The Cancer Genome Atlas (TCGA) database and confirmed using multiple cancer cell lines. The expression of CD59 significantly alters the overall survival (OS) of patients with multiple malignancies such as CESC, GBM, HNSC, and STAD. Further, the correlation between CD59 and Treg and/or MDSC in the tumor microenvironment (TME) has shown to be strongly associated with poor outcomes in CESC, GBM, HNSC, and STAD as these tumors express high FOXP3 compared to KIRC. Moreover, unfavorable outcomes were strongly associated with the expression of CD59 and M2 tumor-associated macrophage infiltration in the TME via the IL10/pSTAT3 pathway in CESC and GBM but not in KIRC. In addition, TGFβ1-dominant cancers such as CESC, GBM, and HNSC showed a high correlation between CD59 and TGFβ1, leading to suppression of cytotoxic T cell activity. Conclusion: Overall, the correlation between CD59 and immune cells predicts its prognosis as unfavorable in CESC, GBM, HNSC, and STAD while being favorable in KIRC. [ABSTRACT FROM AUTHOR]

Simple Summary: While tumor cell invasion beyond the surgically resectable "margin" of glioblastoma is thought to be associated with nearly 100% of recurrences and poor survival, no reliable methods exist for mapping the location of invading tumor cells within the human brain. Building on prior work demonstrating the ability of Q-space magnetic resonance imaging (QSI) to highlight structural alterations in tissue architecture, we hypothesized that using this imaging method to construct tumor-associated tractography might identify tumor-specific structures that underlie cellular invasion. Our results demonstrate that such tractography patterns can be observed in a tumor-specific manner, and provide preliminary evidence that those patterns may colocalize with invading tumor cells, and metrics derived from them may be associated with patient survival time. Background: The invasion of glioblastoma cells beyond the visible tumor margin depicted by conventional neuroimaging is believed to mediate recurrence and predict poor survival. Radiomic biomarkers that are associated with the direction and extent of tumor infiltration are, however, non-existent. Methods: Patients from a single center with newly diagnosed glioblastoma (n = 7) underwent preoperative Q-space magnetic resonance imaging (QSI; 3T, 64 gradient directions, b = 1000 s/mm2) between 2018 and 2019. Tumors were manually segmented, and patterns of inter-voxel coherence spatially intersecting each segmentation were generated to represent tumor-associated tractography. One patient additionally underwent regional biopsy of diffusion tract- versus non-tract-associated tissue during tumor resection for RNA sequencing. Imaging data from this cohort were compared with a historical cohort of n = 66 glioblastoma patients who underwent similar QSI scans. Associations of tractography-derived metrics with survival were assessed using t-tests, linear regression, and Kaplan–Meier statistics. Patient-derived glioblastoma xenograft (PDX) mice generated with the sub-hippocampal injection of human-derived glioblastoma stem cells (GSCs) were scanned under high-field conditions (QSI, 7T, 512 gradient directions), and tumor-associated tractography was compared with the 3D microscopic reconstruction of immunostained GSCs. Results: In the principal enrollment cohort of patients with glioblastoma, all cases displayed tractography patterns with tumor-intersecting tract bundles extending into brain parenchyma, a phenotype which was reproduced in PDX mice as well as in a larger comparison cohort of glioblastoma patients (n = 66), when applying similar methods. Reconstructed spatial patterns of GSCs in PDX mice closely mirrored tumor-associated tractography. On a Kaplan–Meier survival analysis of n = 66 patients, the calculated intra-tumoral mean diffusivity predicted the overall survival (p = 0.037), as did tractography-associated features including mean tract length (p = 0.039) and mean projecting tract length (p = 0.022). The RNA sequencing of human tissue samples (n = 13 tumor samples from a single patient) revealed the overexpression of transcripts which regulate cell motility in tract-associated samples. Conclusions: QSI discriminates tumor-specific patterns of inter-voxel coherence believed to represent white matter pathways which may be susceptible to glioblastoma invasion. These findings may lay the groundwork for future work on therapeutic targeting, patient stratification, and prognosis in glioblastoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Understanding neural crest stem cells as the cells of origin for a series of tumors expands the potential strategies for treatment, especially for rare tumor types. The shared properties and signatures of stem-like tumor cells, also called cancer stem cells (CSCs), are reviewed for neural crest-originated tumors. Scrutinizing the relationship between neural crest stem cells and CSCs in NF1-associated tumors can allow for earlier detection and treatment in NF1 patients. Previously identified CSC markers can be the key to NF1 tumor pathogenesis and therapeutic targets. Targeting CD44, for example, can potentially reduce CSC-related tumor progression, relapse, and even metastasis. This review delineates the reported CSCs in tumors of neural crest origin and highlights their potential relevance in NF1-associated tumors. Neurofibromatosis type 1 (NF1) is a genetic disorder that predisposes individuals to develop benign and malignant tumors of the nerve sheath. Understanding the signatures of cancer stem cells (CSCs) for NF1-associated tumors may facilitate the early detection of tumor progression. Background: Neural crest cells, the cell of origin of NF1-associated tumors, can initiate multiple tumor types, including melanoma, neuroblastoma, and schwannoma. CSCs within these tumors have been reported; however, identifying and targeting CSC populations remains a challenge. Results: This study aims to leverage existing studies on neural crest-derived CSCs to explore markers pertinent to NF1 tumorigenesis. By focusing on the molecular and cellular dynamics within these tumors, we summarize CSC signatures in tumor maintenance, progression, and treatment resistance. Conclusion: A review of these signatures in the context of NF1 will provide insights into NF1 tumor biology and pave the way for developing targeted therapies and improving treatment outcomes for NF1 patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study examined PD-L1 expression in advanced Thyroid Cancer (TC) and its relationship with histological subtypes, molecular mutations, and progression-free survival (PFS). Analyzing data from 176 patients with advanced TC, our study found significant variability in PD-L1 expression with Oncocytic Thyroid Cancer (OTC) and Anaplastic Thyroid Cancer (ATC) exhibiting the highest frequencies of PD-L1 expression, while Medullary TC (MTC) and Papillary TC Follicular Variant (PTCFV) did not show any PD-L1 expression. Notably, PD-L1 positivity correlated with shorter progression-free survival (PFS) in ATC and was associated with TP53 mutation. These findings suggest that PD-L1 expression, combined with genetic profiling could inform personalized immunotherapy strategies for aggressive forms of TC, emphasizing the need for further research to validate these biomarkers and enhance treatment efficacy. Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC. [ABSTRACT FROM AUTHOR]

Simple Summary: This study reports the results of genetic testing to identify germline variants in the main genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, STK11) associated with hereditary polyposis syndromes in 75 index cases with colorectal polyps and a personal/family history of cancer that had been referred to genetic counseling at the Medical Genetics Unit of the National Institute of Gastroenterology "Saverio de Bellis", Castellana Grotte, Bari, Italy. In the screened patients, some of which did not meet the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing, we identified 14 pathogenic variants and 6 variants of uncertain significance. Of note, by combining the results of multigene panel tests with the evaluation of patients' clinical phenotype and family history, we were able to confirm the diagnosis of hereditary polyposis syndrome for pathogenic variant carriers and assign them to specific clinical surveillance and management programs. Background: Hereditary polyposis syndromes are clinically and genetically heterogeneous conditions associated with increased colorectal cancer risk. They are classified based on polyp histology, inheritance mode, causal gene, and colonic and extracolonic manifestations. Their diagnosis is challenging due to overlapping and heterogeneous clinical presentations. Methods: A multigene next-generation sequencing panel was used to screen 75 index cases with colorectal polyps and a personal/family history of cancer for key hereditary polyposis-associated genes (APC, BMPR1A, MUTYH, PTEN, SMAD4, and STK11) in order to identify germline genetic variants. Results: In the screened index cases, we found 14 pathogenic variants involving APC, MUTYH, SMAD4, and STK11 and 6 variants of uncertain significance involving APC, BMPR1A, and SMAD4. In this cohort, four patients not fulfilling the recommended eligibility criteria of current National Comprehensive Cancer Network (NCCN) guidelines for genetic testing were molecularly diagnosed with a hereditary polyposis syndrome. Conclusions: Our findings indicate that stringent NCCN eligibility criteria for molecular screening may lead to missing some of the patients affected by hereditary polyposis syndromes. This highlights the need for a careful evaluation of patients' clinical manifestations, polyp number, age of polyp onset, and family history to select appropriate candidates for molecular diagnosis of these conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: The standard of care for most women with advanced ovarian cancer is primary cytoreduction followed by platinum-based chemotherapy and paclitaxel. However, the use of neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is not inferior, according to prospective randomized trials. Ovarian cancer has a low mutational load but exhibits a high detection rate of molecular alterations in various genes. It remains unclear whether this is an intrinsic feature of ovarian cancer or if it is due to the administration of a platinum combination during NACT. Our study aimed to determine whether NACT affects the tumor's molecular profile. Any modifications in these areas would need to be identified in the initial therapeutic planning, especially in the era of poly (ADP-ribose) polymerase (PARP) inhibitors. Background: Neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy is a therapeutic choice for women with advanced ovarian cancer. Whether NACT affects the tumor's molecular profile has not been determined. Methods: This was a retrospective study of patients with advanced-stage epithelial ovarian cancer treated with NACT at oncology departments affiliated with the Hellenic Cooperative Oncology Group (HeCOG). Tumor molecular profiling was performed on formalin-fixed and paraffin-embedded (FFPE) tumor pre- and post-NACT tissues. Homologous recombination deficiency (HRD), tumor-infiltrating lymphocytes (TILs), tumor molecular alterations, and tumor mutational burden (TMB) via next-generation sequencing analysis were assessed. Results: Overall, tumors from 36 patients were assessed, and molecular profiling was evaluated in 20 paired tumor samples. HRD positivity exhibited no significant change between pre- and post-NACT tumors. The BRCA1/2 mutational status remained constant, irrespective of the treatment administration. Pre-NACT tumors tended to exhibit a lower percentage of intratumoral TILs compared to post-NACT tumors (p = 0.004). Differences in the mutation profile between pre- and post-treatment tissue were observed in 33.33% (6/18) of the cases. The mean tumor cell content (TCC) (p-value: 0.0840) and the mean genomic instability score (p-value: 0.0636) decreased slightly numerically after therapy. A moderate inverse relationship was observed between the pre-NACT TMB and the chemotherapy response score (p-value: 0.038), indicating this correlation is statistically significant. Conclusion: This study provides insights into the effect of NACT on the tumor molecular landscape. While BRCA1/2 and HRD status remained stable, an increase in TIL proportion and changes in the mutational profiles were observed post-treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Endometrial cancer is an important problem and is among the leading causes of reproductive system cancer in women. Every year, the number of cases of the disease only increases, and a high mortality rate from this disease is also recorded. The risk stratification of patients with endometrial carcinoma is based on the severity of the oncological process progression, which makes it necessary to study new diagnostic methods for the more accurate determination of lymph node involvement. Currently, new medical–genetic factors, which may be relevant for assessing the risk of metastasis and disease progression, are actively being studied. Candidate genes, microRNA, and other various biomarkers are being studied, promising the benefit of choosing more effective treatments. Background: According to epidemiological studies, endometrial carcinoma is one of the most frequently diagnosed malignancies of the female reproductive system, with an increasing incidence. Currently, the risk stratification of this neoplasm takes into account the stage, degree of tumor differentiation, histological type and depth of myometrial invasion. Since the publication of the last International Federation of Gynecology and Obstetrics (FIGO) staging system for endometrial cancer in 2009, numerous reports have appeared on the molecular characteristics of different types of endometrial carcinoma. Taking this into account, the FIGO Committee determined in 2023 that changes and updates to the staging system are justified to reflect new information about this tumor. Due to the high prevalence of the disease and mortality from endometrial cancer, an in-depth study of the molecular genetic characteristics of tumor cells is relevant; the results of such studies can be used to improve the efficiency of diagnosis, assess the risk of metastasis and prognosis of the disease. Lymph node assessment is crucial for the choice of treatment strategy for endometrial cancer, since metastatic lymph node involvement is one of the main factors affecting prognosis. At the same time, the criteria for the appropriateness of lymphadenectomy in low-differentiated malignant tumors are not clearly defined. Various molecular methods have been proposed to assess the status of lymph nodes; candidate genes are being studied as potential diagnostic biomarkers, as well as microRNA. The aim of the study was to analyze the literature data on numerous studies of molecular risk factors for progression in endometrioid carcinoma, as well as to preserve the most important marker changes in relation to the prognostic development of this disease. Methods: A literature review was conducted using data from the electronic databases PubMed, Google Scholar, and Wiley Cochrane Library for the period from 2018 to 2023 using the specific keywords. Results: The current scientific genetic studies on metastasis and prognostic factors in uterine cancer were analyzed, and a systematization of the reviewed data from the modern literature was done. Conclusions: To select the most effective treatment - intraoperative, adjuvant or combination therapy, minimize postoperative risks of lymphadenectomy and clearly predict the results - further study of the molecular genetic features of endometrial cancer is necessary. [ABSTRACT FROM AUTHOR]

Neofusicoccum laricinum is the causal agent of larch shoot blight, a fungal disease affecting several species of larch. It causes severe damage, including stunting and mortality. This study aims to address the severe impact of larch shoot blight by evaluating the effect of farrerol on the inhibition of Neofusicoccum laricinum in Larix olgensis. We used LC-MS/MS and weighted gene co-expression network analysis to investigate farrerol's effects on Neofusicoccum laricinum and identify associated genes in resistant and susceptible larch. Our study identified significant differences in metabolite profiles between resistant and susceptible cultivars, with higher concentrations of farrerol showing complete inhibition of N. laricinum. Additionally, specific genes associated with farrerol content were up-regulated in resistant larch. Farrerol at higher concentrations completely inhibited N. laricinum, showing a strong correlation with increased disease resistance. This research suggests that farrerol enhances disease resistance in larch and provides a foundation for developing disease-resistant larch varieties based on antifungal metabolite traits. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapeutic response and survival outcomes in hepatocellular carcinoma (HCC) patients remain unsatisfactory, with a 5-year survival rate of less than 25%. The lack of molecular analysis of HCC tissue hinders the identification of precise predictors of disease progression and treatment outcomes. Analyzing the hepatic neoangiogenic transcriptomic signature can predict the biological aggressiveness of HCC and its resistance to therapies, offering a valuable diagnostic and prognostic tool that can significantly enhance the management of HCC. Background/Objectives: We evaluated the relationship between the neoangiogenic transcriptomic signature (nTS) and clinical symptoms, treatment outcomes, and survival in hepatocellular carcinoma (HCC) patients. Methods: This study prospectively followed 328 patients in the derivation and 256 in the validation cohort (with a median follow-up of 31 and 22 months, respectively). The nTS was associated with disease presentation, treatments administered, and overall survival rates. Additionally, this study investigated how multiple treatments influenced changes in nTS status and alterations in microRNA expression. Results: The nTS was identified in 27.4% of patients, linked to aggressive features like multifocality and elevated alpha-fetoprotein (AFP), a pattern consistent with that of the validation cohort. Most patients in both cohorts received treatment for HCC. nTS+ patients had limited access to, and benefited less from, liver transplantation or radiofrequency ablation (RFA) compared to nTS− patients. By the end, 78.9% had died, with nTS− patients showing better median survival and response to treatments than their nTS+ counterparts, who had lower survival across all treatment types. Among those who received transarterial chemoembolization (TACE), 31.2% (21/80 patients after the initial treatment and another four following a second TACE) transitioned from an nTS− to an nTS+ status. This shift was associated with lower survival and alterations in microRNA expressions related to oncogenic pathways. Conclusions: The nTS markedly influences treatment eligibility and survival in patients with HCC. Notably, the nTS can develop after repeated TACE procedures, significantly impacting patient survival and altering oncogenic microRNA expression patterns. These findings highlight the critical role of the nTS in guiding treatment decisions and prognostication in HCC management. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) has a rising incidence and poor prognosis due to late diagnosis and limited treatments. Currently, treatment is based solely on TNM staging, without considering molecular tumor characterization. In the present study, we validated a combined amplification refractory mutation system (ARMS) and high-resolution melting analysis (HRMA) technique for detecting mutations in codon 12 of KRAS in PDAC tumor and plasma samples and assessed its prognostic value. We included 88 newly diagnosed PDAC patients, treated with either surgery, chemotherapy, or best supportive treatment only. Both tumor and plasma samples were analyzed, and the most frequent mutations were G12D (36%) and G12V (25%). KRAS mutations G12D and/or G12C in tumors and plasma were associated with lower progression-free survival (PFS) and overall survival (OS) independently of disease stage or treatment performed. ARMS–HRMA offers a rapid, cost-effective method for detecting KRAS mutations and can aid in prognosis and treatment decisions. Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) incidence is rising, and prognosis remains poor due to late diagnosis and limited effective therapies. Currently, patients are treated based on TNM staging, without molecular tumor characterization. This study aimed to validate a technique that combines the amplification refractory mutation system (ARMS) with high-resolution melting analysis (HRMA) for detecting mutations in codon 12 of KRAS in tumor and plasma, and to assess its prognostic value. Methods: Prospective study including patients with newly diagnosed PDAC with tumor and plasma samples collected before treatment. Mutations in codon 12 of KRAS (G12D, G12V, G12C, and G12R) were detected using ARMS–HRMA and compared to Sanger sequencing (SS). Univariate and multivariate analyses were used to evaluate the prognostic significance of these mutations. Results: A total of 88 patients, 93% with ECOG-PS 0–1, 57% with resectable disease. ARMS–HRMA technique showed a higher sensitivity than SS, both in tumor and plasma (77% vs. 51%; 25 vs. 0%, respectively). The most frequent mutation was G12D (n = 32, 36%), followed by G12V (n = 22, 25%). On multivariate analysis, patients with G12D and/or G12C mutations, either in tumor or plasma, had lower PFS (HR 1.792, 95% CI 1.061–3.028, p = 0.029; HR 2.081, 95% CI 1.014–4.272, p = 0.046, respectively) and lower OS (HR 1.757, 95% CI 1.013–3.049, p = 0.045; HR 2.229, 95% CI 1.082–4.594, p = 0.030, respectively). Conclusions: ARMS–HRMA is a rapid and cost-effective method for detecting KRAS mutations in PDAC patients, offering the potential for stratifying prognosis and guiding treatment decisions. The presence of G12D and G12C mutations in both tumor and plasma is associated with a poorer prognosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Intracranial Epidermoid Cysts (IECs) are rare tumors. Despite their benign course, IECs can adhere to critical brain structures resulting in impairment and morbidity. The primary treatment is surgery; however, cyst adherence often complicates complete removal, resulting in notably high progression rates after subtotal resection. Due to the rarity of IECs, there has been limited research focused on understanding the mechanisms of the disease and advancing therapeutic options. As a result, there are currently no effective drug therapies available for treating patients with IECs. Targeted therapy is an effective form of treatment for tumors. It focuses on mutations that turn healthy cells into tumor cells. The mutation profile of IECs has not been investigated. We aimed to investigate the somatic landscape of IECs to gain insights into tumor biology and identify mutations that could potentially serve as targets for additional therapies. Surgery is still the most effective treatment for these patients. Background/Objectives: Intracranial Epidermoid Cysts (IECs) are rare intracranial tumors primarily treated through surgery. Cyst adherence complicates complete removal, leading to high rates of tumor progression after subtotal resection. The molecular drivers of IEC remain unknown. Consequently, advances in treatment have fallen short. Tumor genetic profiling has revealed potential targets for drug development, including FDA-approved options and reshaping treatment. The genetic landscape of IECs has not been explored. We applied Whole Exome Sequencing (WES) to IECs to gain insights into the mechanisms of oncogenesis and identify potential therapeutic targets. Methods: We performed WES on tumor tissue and matched blood samples, when available. Following GATK best practices, we conducted read processing, quality control, somatic variant calling, and copy-number inference. Data analyses and visualization were conducted in R. Results: Top altered genes are associated with the immune system and tumor microenvironment, suggesting a mechanism of immune evasion. Gene and pathway enrichment revealed a high mutation burden in genes associated with Extracellular Matrix (ECM) and PI3K-AKT-mTOR cascades. Recurrent and deleterious alterations in NOTCH2 and USP8 were identified in 50% and 30% of the cohort, respectively. Frequent amplifications in deubiquitinases and beta-defensins strengthened the involvement of immune mechanisms for oncogenic transformation. Conclusions: Top altered genes and recurrent mutations may play a role in shaping the microenvironment and modulating immune evasion in IECs. USP8 and NOTCH2 may serve as clinically relevant target for IECs. Finally, we present evidence that the crosstalk between the PI3K-Akt-mTOR and ECM signaling pathways may play a role in modulating the immune escape mechanism in IECs. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer continues to represent a leading cause of death among women globally. Recent studies have shown a growing link between breast cancer and the living microorganisms from the tumoral breast tissue, known as microbiota. This review looks at how the microbiota is found in healthy breast tissue and the changes observed during cancer development and progression. The microbiota has been shown to affect cancer growth, spread, and resistance to treatments by interacting with the tumor's environment. Moreover, this review explores how different breast cancer types have distinct microbial profiles. Future studies could improve breast cancer care by endowing the microbiota as a diagnostic, prediction and treatment marker. Breast cancer remains one of the leading causes of death among women worldwide, and recent research highlights its growing connection to alterations in the microbiota. This review delves into the intricate relationship between microbiotas and breast cancer, exploring its presence in healthy breast tissue, its changes during cancer progression, and its considerable impact on both the tumor microenvironment (TME) and the tumor immune microenvironment (TIME). We extensively analyze how the microbiota influences cancer growth, invasion, metastasis, resistance to drugs, and the evasion of the immune system, with a special focus on its effects on the TIME. Furthermore, we investigate distinct microbial profiles associated with the four primary molecular subtypes of breast cancer, examining how the microbiota in tumor tissues compares with that in adjacent normal tissues. Emerging studies suggest that microbiotas could serve as valuable diagnostic and prognostic biomarkers, as well as targets for therapy. This review emphasizes the urgent need for further research to improve strategies for breast cancer prevention, diagnosis, and treatment. By offering a detailed examination of the microbiota's critical role in breast cancer, this review aims to foster the development of novel microbiota-based approaches for managing the disease. [ABSTRACT FROM AUTHOR]

Skeletal muscle contusion (SMC) is common in daily life and clinical practice, but the molecular mechanisms underlying SMC healing are unclear. Ferroptosis, a regulated cell death type, has gained attention recently. We observed iron overload in skeletal muscle following contusion through HE and Perls staining. Abnormal iron levels are highly likely to induce ferroptosis. Therefore, we aimed to explore whether iron overload after contusion leads to ferroptosis in skeletal muscle and the underlying mechanisms, which will help us understand the effects of iron abnormalities on skeletal muscle repair. Initially, we searched SMC gene expression profiles from the GEO database and used bioinformatics analysis to reveal ferroptosis occurrence. Then, we identified the gene sat1 plays an important role in this process. We further established a rat SMC model and treated rats with ferroptosis inhibitors (Ferrostatin-1, Deferoxamine). Our findings confirmed iron overload from SMC can lead to ferroptosis in rats. We also demonstrated that SAT1 can regulate ferroptosis by affecting ALOX15. Moreover, we constructed a ferroptosis L6 cell model and found that SAT1 knockdown significantly inhibited ALOX15 expression and reduced cellular lipid peroxidation. In conclusion, these results indicated ferroptosis can occur following SMC, and SAT1, as a key regulator, affects skeletal muscle injury healing by mediating high ALOX15 expression, which in turn regulates lipid peroxidation. [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is the leading cause of visual impairment, particularly in the proliferative form (proliferative DR [PDR]). The impact of the PDR microenvironment on microglia, which are the resident immune cells in the central nervous system, and the specific pathological changes it may induce remain unclear. This study aimed to investigate the role of microglia in the progression of PDR under hypoxic and inflammatory conditions. We performed a comprehensive gene expression analysis using human-induced pluripotent stem cell-derived microglia under different stimuli (dimethyloxalylglycine (DMOG), lipopolysaccharide (LPS), and DMOG + LPS) to mimic the hypoxic inflammatory environment characteristic of PDR. Principal component analysis revealed distinct gene expression profiles, with 76 genes synergistically upregulated under combined stimulation. Notably, prostaglandin-endoperoxide synthase 2 (encoding cyclooxygenase (COX)-2) exhibited the most pronounced increase, leading to elevated prostaglandin E2 (PGE2) levels and driving pathological angiogenesis and inflammation via the COX-2/PGE2/PGE receptor 2 signaling axis. Additionally, the upregulation of the fibrogenic genes snail family transcriptional repressor 1 and collagen type I alpha 1 chain suggested a role for microglia in fibrosis. These findings underscore the critical involvement of microglia in PDR and suggest that targeting both the angiogenic and fibrotic pathways may present new therapeutic strategies for managing this condition. [ABSTRACT FROM AUTHOR]

The glyoxalase pathway, consisting of glyoxalase I (GLYI) and glyoxalase II (GLYII), is an enzymatic system that converts cytotoxic methylglyoxal to non-toxic S-D-lactoylglutathione. Although the GLY gene family has been analyzed in Arabidopsis, rice, grape, cabbage, and soybean, cucumber studies are lacking. Here, we analyzed the cucumber GLY gene family, identifying 13 CsGLYI and 2 CsGLYII genes. Furthermore, we investigated the physicochemical properties, phylogenetic relationships, chromosomal localization and colinearity, gene structure, conserved motifs, cis-regulatory elements, and protein–protein interaction networks of the CsGLY family. They were primarily localized in the cytoplasm, chloroplasts, and mitochondria, with a minor presence in the nucleus. The classification of CsGLYI and CsGLYII genes into five classes closely resembled the homologous genes in Arabidopsis and soybean. Additionally, hormone-responsive elements dominated the promoter region of GLY genes, alongside light- and stress-responsive elements. The predicted interaction proteins of CsGLYIs and CsGLYIIs exerted a significant role in cellular respiration, amino acid synthesis, and metabolism, as well as methylglyoxal catabolism. In addition, the expression profiles of GLY genes were distinct in different tissues of cucumber as well as under diverse abiotic stresses. This study is conducive to the further exploration of the functional diversity among glyoxalase genes and the mechanisms of stress responses in cucumber. [ABSTRACT FROM AUTHOR]

The Domain of Unknown Function 506 (DUF506) belongs to the PD-(D/E) XK nuclease superfamily and has been reported to play critical roles in growth and development as well as responses to abiotic stresses. However, the function of DUF506 genes in Brassica rapa (B. rapa) remains unclear. In this study, a total of 18 BrDUF506 genes were identified and randomly distributed across eight chromosomes, categorized into four subfamilies. Analyzing their promoter sequences has uncovered various stress-responsive elements, such as those for drought, methyl jasmonate (MeJA), and abscisic acid (ABA). Bra000098 and Bra017099 exhibit significantly enhanced expression in response to heat and drought stress. Protein interaction predictions indicate that Bra000098 homolog, At2g38820, is interacting with ERF012 and PUB48 and is involved in abiotic stress regulation. Furthermore, gene expression profiling has identified Bra026262 with a high expression level in flowers and significantly decreased in female sterile mutants. Protein interaction prediction further revealed that its homolog, At4g32480, interacts with MYB and AGL proteins, suggesting the potential roles in female gametophyte development. The current study enhances our understanding of the functional roles of BrDUF506s, providing significant insights that are valuable in investigating sexual reproduction and abiotic stress responses in B. rapa. [ABSTRACT FROM AUTHOR]

Sepsis remains a huge unmet medical need for which no approved drugs, besides antibiotics, are on the market. Despite the clinical impact of sepsis, its molecular mechanism remains inadequately understood. Recent insights have shown that profound hepatic transcriptional reprogramming, leading to fatal metabolic abnormalities, might open a new avenue to treat sepsis. Translation of experimental results from rodents to larger animal models of higher relevance for human physiology, such as pigs, is critical and needs exploration. We performed a comparative analysis of the transcriptome profiles in murine and porcine livers using the following sepsis models: cecal ligation and puncture (CLP) in mice and fecal instillation (FI) in pigs, both of which induce polymicrobial septic peritonitis, and lipopolysaccharide (LPS)-induced endotoxemia in pigs, inducing sterile inflammation. Using bulk RNA sequencing, Metascape pathway analysis, and HOMER transcription factor motif analysis, we were able to identify key genes and pathways affected in septic livers. Conserved upregulated pathways in murine CLP and porcine LPS and FI generally comprise typical inflammatory pathways, except for ER stress, which was only found in the murine CLP model. Conserved pathways downregulated in sepsis comprise almost exclusively metabolic pathways such as monocarboxylic acid, steroid, biological oxidation, and small-molecule catabolism. Even though the upregulated inflammatory pathways were equally induced in the two porcine models, the porcine FI model more closely resembles the metabolic dysfunction observed in the CLP liver compared to the porcine LPS model. This comprehensive comparison focusing on the hepatic responses in mouse CLP versus LPS or FI in pigs shows that the two porcine sepsis models generally resemble quite well the mouse CLP model, with a typical inflammatory signature amongst the upregulated genes and metabolic dysfunction amongst the downregulated genes. The hepatic ER stress observed in the murine model could not be replicated in the porcine models. When studying metabolic dysfunction in the liver upon sepsis, the porcine FI model more closely resembles the mouse CLP model compared to the porcine LPS model. [ABSTRACT FROM AUTHOR]

The brown planthopper (Nilaparvata lugens, BPH) is a serious insect pest responsible for causing immense economic losses to rice growers around the globe. The development of high-throughput sequencing technologies has significantly improved the research on this pest, and its genome structure, gene expression profiles, and host–plant interactions are being unveiled. The integration of genomic sequencing, transcriptomics, proteomics, and metabolomics has greatly increased our understanding of the biological characteristics of planthoppers, which will benefit the identification of resistant rice varieties and strategies for their control. Strategies like more optimal genome assembly and single-cell RNA-seq help to update our knowledge of gene control structure and cell type-specific usage, shedding light on how planthoppers adjust as well. However, to date, a comprehensive genome-wide investigation of the genetic interactions and population dynamics of BPHs has yet to be exhaustively performed using these next-generation omics technologies. This review summarizes the recent advances and new perspectives regarding the use of omics data for the BPH, with specific emphasis on the integration of both fields to help develop more sustainable pest management strategies. These findings, in combination with those of post-transcriptional and translational modifications involving non-coding RNAs as well as epigenetic variations, further detail intricate host–brown planthopper interaction dynamics, especially regarding resistant rice varieties. Finally, the symbiogenesis of the symbiotic microbial community in a planthopper can be characterized through metagenomic approaches, and its importance in enhancing virulence traits would offer novel opportunities for plant protection by manipulating host–microbe interactions. The concerted diverse omics approaches collectively identified the holistic and complex mechanisms of virulence variation in BPHs, which enables efficient deployment into rice resistance breeding as well as sustainable pest management. [ABSTRACT FROM AUTHOR]

Microglia signatures refer to distinct gene expression profiles or patterns of gene activity that are characteristic of microglia. Advances in gene expression profiling techniques, such as single-cell RNA sequencing, have allowed us to study microglia at a more detailed level and identify unique gene expression patterns that are associated, but not always, with different functional states of these cells. Microglial signatures depend on the developmental stage, brain region, and specific pathological conditions. By studying these signatures, it has been possible to gain insights into the underlying mechanisms of microglial activation and begin to develop targeted therapies to modulate microglia-mediated immune responses in the CNS. Historically, the first two signatures coincide with M1 pro-inflammatory and M2 anti-inflammatory phenotypes. The first one includes upregulation of genes such as CD86, TNF-α, IL-1β, and iNOS, while the second one may involve genes like CD206, Arg1, Chil3, and TGF-β. However, it has long been known that many and more specific phenotypes exist between M1 and M2, likely with corresponding signatures. Here, we discuss specific microglial signatures and their association, if any, with neurodegenerative pathologies and other brain disorders. [ABSTRACT FROM AUTHOR]

This study assessed the efficacy of chitosan, methyl jasmonate, and silicon in the reduction of disease severity and the induction of defense responses in common bean plants against angular leaf spot caused by Pseudocercospora griseola. The expression level of several pathogenesis-related (PR) proteins, PR1, PR2 (β-1,3-glucanase), and PR3 (chitinase), and defense-related enzymes, phenylalanine ammonia-lyase, peroxidase, and lipoxygenase, was analyzed at different time points in common bean plants after different treatments. Elicitor treatments significantly reduced disease severity 21 days after inoculation, with silicon at a 2 mM concentration proving most effective with 38.93% disease control, followed by 1 mM MeJA and 2% chitosan, respectively. Treatments with chitosan, methyl jasmonate, and silicon, regardless of pathogen infection, significantly elevated PR1, PR2, and PR3 gene expressions at 48 h after inoculation (hpi). PAL and POD activities were similarly increased following elicitor treatments and pathogen infection, especially at 48 hpi. Chemical elicitors applied post-inoculation induced PR proteins, PAL, and POD enzyme activities at 48 hpi, while LOX activity exhibited a variable fluctuation with treatments. These findings suggested that chemical elicitors, especially silicon, were effective in reducing ALS disease severity in common beans, with improved resistance associated with the expression of pathogen-responsive genes. This study is the first to analyze the expression profiles of defense-related genes in common beans treated with chemical elicitors prior to P. griseola infection. [ABSTRACT FROM AUTHOR]

Brassinosteroid (BR) signaling is regulated by BRI1-EMS SUPPRESSOR 1 (BES1) transcription factors, which are crucial for plant growth, development, and stress responses. Despite their importance, BES1 gene studies in Medicago sativa L. are limited, hindering our understanding of the BR signaling in this species. This study identified four BES1 genes in M. sativa; characterized their properties, conserved motifs, cis-regulatory elements, and chromosomal location; and explored their functions in development and stress responses. A phylogenetic analysis grouped these genes into two subfamilies. Transcript profiling showed widespread and tissue-specific expression patterns. A qRT-PCR analysis unveiled that most MsBESI genes were upregulated under salt and drought treatments, except MsG0280009980, which was suppressed. This research lays the groundwork for enhancing M. sativa stress resistance and understanding the BES1 gene family's function. [ABSTRACT FROM AUTHOR]

Drought is a primary abiotic stress that inhibits rice (Oryza sativa L.) growth and development, and during the reproductive stage it has a negative impact on the rice seed-setting rate. This research study examined two rice lines, La-96 (drought sensitive) and La-163 (drought resistant), for drought stress treatment (with soil moisture at 20% for 7 days) and control (normal irrigation and kept soil moisture ≥40%). To elucidate the photosynthesis and molecular mechanisms underlying drought tolerance in rice, leaf photosynthetic traits and transcriptome sequencing were used to compare differences between two contrasting recombinant inbred lines (RIL) during drought and subsequent recovery at the booting stage. The rice line La-96 showed a significant decrease in seed-setting rate after being treated for seven days' drought stress (from 86.64% to 22.75%), while La-163 was slightly affected (from 89.04% to 79.33%). The photosynthetic activities of both lines significantly decreased under the drought treatment, and these traits of La-163 recovered to a comparable level with the control after three days of rewatering. The transcriptome of both lines in three treatments (the control, drought stress, and subsequent recovery) were tested, and a total of 16,051 genes were identified, among which 10,566 genes were differentially expressed in various treatments and rice lines. Comprehensive gene expression profiles revealed that the specifically identified DEGs were involved in the ribosome synthesis and the metabolic pathway of photosynthesis, starch, and sucrose metabolism. The DEGs that are activated and respond quickly, as seen during recovery in the tolerant rice line, may play essential roles in regulating subsequent growth and development. This study uncovered the molecular genetic pathways of drought tolerance and extended our understanding of the drought tolerance mechanisms and subsequent recovery regulation in rice. [ABSTRACT FROM AUTHOR]

Laryngeal cancer poses a substantial challenge in head and neck oncology, and there is a growing focus on customized medicine techniques. The present state of gene expression indicators in laryngeal cancer and their potential to inform tailored therapy choices are thoroughly examined in this review. We examine significant molecular changes, such as TP53, CDKN2A, PIK3CA, and NOTCH1 mutations, which have been identified as important participants in the development of laryngeal cancer. The study investigates the predictive and prognostic significance of these genetic markers in addition to the function of epigenetic changes such as the methylation of the MGMT promoter. We also go over the importance of cancer stem cell-related gene expression patterns, specifically CD44 and ALDH1A1 expression, in therapy resistance and disease progression. The review focuses on indicators, including PD-L1, CTLA-4, and tumor mutational burden (TMB) in predicting immunotherapy responses, highlighting recent developments in our understanding of the intricate interactions between tumor genetics and the immune milieu. We also investigate the potential for improving prognosis accuracy and treatment selection by the integration of multi-gene expression panels with clinicopathological variables. The necessity for uniform testing and interpretation techniques is one of the difficulties, in implementing these molecular insights into clinical practice, that are discussed. This review seeks to provide a comprehensive framework for promoting personalized cancer therapy by combining the most recent data on gene expression profiling in laryngeal cancer. Molecularly guided treatment options may enhance patient outcomes. [ABSTRACT FROM AUTHOR]

Background/Objectives: The global SARS-CoV-2 outbreak has escalated into a critical public health emergency, with the spike glycoprotein S1 subunit of SARS-CoV-2 (spike-S1) linked to inflammation in lung tissue and immune cells. Luteolin, a flavone with anti-inflammatory properties, shows promise, but research on its effectiveness against long-COVID-related inflammation and spike protein-induced responses remains limited. This study aims to elucidate the underlying mechanisms of inflammation in THP-1 cells induced by the spike-S1. Additionally, it seeks to assess the potential of luteolin in mitigating inflammatory responses induced by the spike-S1 in a THP-1 macrophage model. Methods: The gene expression profiles of spike-S1 in THP-1 cells were analyzed by transcriptome sequencing. The inhibitory effect of luteolin on ER stress and inflammation in spike-S1-induced THP-1 cells was investigated using Western blotting, RT-PCR, and ELISA. Results: The candidate genes (CAMK2A, SIGLEC7, PPARGC1B, SEC22B, USP28, IER2, and TIRAP) were upregulated in the spike-S1-induced THP-1 group compared to the control group. Among these, calcium/calmodulin-dependent protein kinase II alpha (CAMK2A) was identified as the most promising molecule in spike-S1-induced THP-1 cells. Our results indicate that the spike S1 significantly increased the expression of ER-stress markers at both gene and protein levels. Luteolin significantly reduced ER stress by decreasing the expression of ER-stress marker genes and ER-stress marker proteins (p < 0.01). Additionally, luteolin exhibited anti-inflammatory properties upon spike S1-induction in THP-1 cells by significantly suppressing IL-6, IL-8, and IL-1β cytokine secretion in a dose-dependent manner (p < 0.05). Furthermore, our results revealed that luteolin exhibited the downregulation of the MAPK pathway, as evidenced by modulating the phosphorylation of p-ERK1/2, p-JNK and p-p38 proteins (p < 0.05). Conclusions: The results from this study elucidate the mechanisms by which the spike S1 induces inflammation in THP-1 cells and supports the use of naturally occurring bioactive compounds, like luteolin, against inflammation-related SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

Angiosarcomas, clinically aggressive cancers of endothelial origin, are a rare subtype of soft-tissue sarcomas characterized by resistance to chemotherapy and dismal prognosis. In this study, we aim to identify the transcriptomic biomarkers of chemoresistance in angiosarcoma. We examined 72 cases of Asian angiosarcomas, including 35 cases treated with palliative chemotherapy, integrating information from NanoString gene expression profiling, whole transcriptome profiling (RNA-seq), immunohistochemistry, cell line assays, and clinicopathological data. In the chemoresistant cohort (defined as stable disease or progression), we observed the significant overexpression of genes, including SPP1 (log2foldchange 3.49, adj. p = 0.0112), CXCL13, CD48, and CLEC5A, accompanied by the significant enrichment of myeloid compartment and cytokine and chemokine signaling pathways, as well as neutrophils and macrophages. RNA-seq data revealed higher SPP1 expression (p = 0.0008) in tumor tissues over adjacent normal compartments. Immunohistochemistry showed a significant moderate positive correlation between SPP1 protein and gene expression (r = 0.7016; p < 0.00110), while higher SPP1 protein expression correlated with lower chemotherapeutic sensitivity in patient-derived angiosarcoma cell lines MOLAS and ISOHAS. In addition, SPP1 mRNA overexpression positively correlated with epithelioid histology (p = 0.007), higher tumor grade (p = 0.0023), non-head and neck location (p = 0.0576), and poorer overall survival outcomes (HR 1.84, 95% CI 1.07–3.18, p = 0.0288). There was no association with tumor mutational burden, tumor inflammation signature, the presence of human herpesvirus-7, ultraviolet exposure signature, and metastatic state at diagnosis. In conclusion, SPP1 overexpression may be a biomarker of chemoresistance and poor prognosis in angiosarcoma. Further investigation is needed to uncover the precise roles and underlying mechanisms of SPP1. [ABSTRACT FROM AUTHOR]

FOXG1 syndrome is a rare neurodevelopmental disorder of the telencephalon, for which there is no cure. Underlying heterozygous pathogenic variants in the Forkhead Box G1 (FOXG1) gene with resulting impaired or loss of FOXG1 function lead to severe neurological impairments. Here, we report a patient with a de novo pathogenic single nucleotide deletion c.946del (p.Leu316Cysfs*10) of the FOXG1 gene that causes a premature protein truncation. To study this variant in vivo, we generated and characterized Foxg1 c946del mice that recapitulate hallmarks of the human disorder. Accordingly, heterozygous Foxg1 c946del mice display neurological symptoms with aberrant neuronal networks and increased seizure susceptibility. Gene expression profiling identified increased oligodendrocyte- and myelination-related gene clusters. Specifically, we showed that expression of the c946del mutant and of other pathogenic FOXG1 variants correlated with overexpression of proteolipid protein 1 (Plp1), a gene linked to white matter disorders. Postnatal administration of Plp1-targeting antisense oligonucleotides (ASOs) in Foxg1 c946del mice improved neurological deficits. Our data suggest Plp1 as a new target for therapeutic strategies mitigating disease phenotypes in FOXG1 syndrome patients. [ABSTRACT FROM AUTHOR]

The lateral organ boundaries domain (LBD) genes, as the plant-specific transcription factor family, play a crucial role in controlling plant architecture and stress tolerance. However, the functions of AhLBD genes in the peanut plant (Arachis hypogea L.) remain unclear. In this study, 73 AhLBDs were identified in the peanut plant and divided into three groups by phylogenetic tree analysis. Gene structure and conserved protein motif analysis supported the evolutionary conservation of AhLBDs. Tandem and segment duplications contributed to the expansion of AhLBDs. The evolutionary relationship analysis of LBD gene family between A. hypogaea and four other species indicated that the peanut plant had a close relationship with the soybean plant. AhLBDs played a very important role in response to growth and development as well as abiotic stress. Furthermore, gene expression profiling and real-time quantitative qRT-PCR analysis showed that AhLBD16, AhLBD33, AhLBD67, and AhLBD72 were candidate genes for salt stress, while AhLBD24, AhLBD33, AhLBD35, AhLBD52, AhLBD67, and AhLBD71 were candidate genes for drought stress. Our subcellular localization experiment revealed that AhLBD24, AhLBD33, AhLBD67, and AhLBD71 were located in the nucleus. Heterologous overexpression of AhLBD33 and AhLBD67 in Arabidopsis significantly enhanced tolerance to salt stress. Our results provide a theoretical basis and candidate genes for studying the molecular mechanism for abiotic stress in the peanut plant. [ABSTRACT FROM AUTHOR]

Simple Summary: The OncoIndx® platform is an NGS assay designed and developed to identify critical mutations that help in therapeutic decision-making. The OncoIndx® panel targets major exons and a few selected introns of 1080 cancer-associated and actionable genes. The test analyzes complex biomarkers such as single nucleotide variants (SNVs), copy number alterations (CNAs), specific gene fusions, and many more. This study validates the overall sensitivity and efficiency of the test using standard references, clinical samples, and U.S. Food and Drug Administration (FDA)-approved cross-laboratory samples. The ultimate goal of this research is to benchmark the assay against the current guidelines and increase the reliability of the test, thus increasing the confidence of medical professionals for better personalized therapeutic intervention. Comprehensive next-generation sequencing (NGS) assays enable the identification of clinically relevant mutations, enhancing the capability for targeted therapeutic interventions. In addition, genomic alterations driving the oncogenic roadmap and leading to resistance mechanisms are reshaping precision oncology. We report the workflow and clinical and technical validation of the OncoIndx® NGS platform—a comprehensive genomic profiling (CGP)-based assay for pan-cancer investigation. We evaluated the concordance between the OncoIndx® test findings and clinically established hotspot detection using SeraSeq reference standards. OncoIndx is a hybridization capture-based NGS assay for the targeted deep sequencing of all exons and selected introns of 1080 cancer-related genes. We show the outcome in the form of tier I and tier II single nucleotide variants (SNVs), copy number alterations (CNAs), and specific gene fusions. OncoIndx® also informs genome-wide tumor mutational burden (TMB), microsatellite instability (MSI), homologous recombination deficiency (HRD), and genomic loss of heterozygosity (gLOH). A total of 63 samples were utilized for validation with reference standards, clinical samples, and orthogonal assessment for genomic alterations. In addition, 49 cross-laboratory samples were validated for microsatellite instability (MSI), and for the tumor mutation burden (TMB), 18 samples as reference standards, 6 cross-laboratory samples, and 29 TCGA samples were utilized. We show a maximum clinical sensitivity of 98% and a positive predictive value (PPV) of 100% for the clinically actionable genomic variants detected by the assay. In addition, we demonstrate analytical validation with the performance of the assay, limit of detection (LoD), precision, and orthogonal concordance for various types of SVs, CNAs, genomic rearrangements, and complex biomarkers like TMB, MSI, and HRD. The assay offers reliable genomic predictions with the high-precision detection of actionable variants, validated by established reference standards. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The most dangerous breast cancer is triple-negative breast cancer (TNBC). TNBC is very diverse, with 12 underlying subtypes. This great deal of patient diversity, along with the lack of broad-application targetable mechanistic markers (such as ER, PR, and HER2, which are present in other breast cancer subtypes but missing in TNBC), gives TNBC patients the worst outcomes of any breast cancer type. We aim to remedy this by exploring the molecular mechanisms across TNBC samples and subtypes. Molecular mechanisms are potentially targetable for treatment. We explore these options as part of our RNA-sequencing analysis. Our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone). Additionally, we found TNBC subtype-differentiating mechanistic markers, including PDE3B, CFD, IFNG, and ADM, which are targets with known therapeutics and potential for drug repurposing. Background/Objectives: Breast cancer is diagnosed in 2.3 million women each year and kills 685,000 (~30% of patients) worldwide. The prognosis for many breast cancer subtypes has improved due to treatments targeting the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In contrast, patients with triple-negative breast cancer (TNBC) tumors, which lack all three commonly targeted membrane markers, more frequently relapse and have lower survival rates due to a lack of tumor-selective TNBC treatments. We aim to investigate TNBC mechanistic markers that could be targeted for treatment. Methods: We performed a secondary TNBC analysis of 196 samples across 10 publicly available bulk RNA-sequencing studies to better understand the molecular mechanism(s) of disease and predict robust mechanistic markers that could be used to improve the mechanistic understanding of and diagnostic capabilities for TNBC. Results: Our analysis identified ~12,500 significant differentially expressed genes (FDR-adjusted p-value < 0.05), including KIF14 and ELMOD3, and two significantly modulated pathways. Additionally, our novel findings include highly accurate mechanistic markers identified using machine learning methods, including CIDEC (97.1% accuracy alone), CD300LG, ASPM, and RGS1 (98.9% combined accuracy), as well as TNBC subtype-differentiating mechanistic markers, including the targets PDE3B, CFD, IFNG, and ADM, which have associated therapeutics that can potentially be repurposed to improve treatment options. We then experimentally and computationally validated a subset of these findings. Conclusions: The results of our analyses can be used to better understand the mechanism(s) of disease and contribute to the development of improved diagnostics and/or treatments for TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: MicroRNAs (miRNAs) play a significant role as epigenetic regulators in cancer. IsomiRs are miRNA molecules that undergo small modifications during miRNA processing, which can affect their stability and their interaction with mRNA targets. While some isomiRs are linked to specific cancers, many, including those in the lung, remain understudied. To address this, small RNA sequencing data from lung adenocarcinoma (LUAD) and adult non-malignant lung (ANL) samples were analyzed to quantify isomiR expression. This analysis identified 16 A-to-I edited isomiRs, 213 5′ isomiRs, 128 3′ adenylated isomiRs, and 100 3′ uridylated isomiRs. A-to-I editing rates correlated with the expression of editing enzymes ADAR and ADARB1, both deregulated in LUAD. LUAD samples had lower A-to-I editing and 3′ adenylation rates compared to ANL. Machine learning models based on isomiR data effectively distinguished ANL from stage I/II LUAD samples, suggesting that isomiRs hold potential as cancer biomarkers. Background: MicroRNAs (miRNAs) modulate the expression of oncogenes and tumor suppressor genes, functioning as significant epigenetic regulators in cancer. IsomiRs are miRNA molecules that have undergone small modifications during miRNA processing. These modifications can alter an isomiR's binding stability with mRNA targets, and certain isomiRs have been implicated in the development of specific cancers. Still, the isomiRomes of many tissues, including the lung, have not been characterized; Methods: In this study, we analyzed small RNA sequencing data for three cohorts of lung adenocarcinoma (LUAD) and adult non-malignant lung (ANL) samples. Results: We quantified isomiR expression and found 16 A-to-I edited isomiRs expressed in multiple cohorts, as well as 213 5′ isomiRs, 128 3′ adenylated isomiRs, and 100 3′ uridylated isomiRs. Rates of A-to-I editing at editing hotspots correlated with mRNA expression of the editing enzymes ADAR and ADARB1, which were both observed to be deregulated in LUAD. LUAD samples displayed lower overall rates of A-to-I editing and 3′ adenylation than ANL samples. Support vector machines and random forest models were trained on one cohort to distinguish ANL and stage I/II LUAD samples using reads per million (RPM) and frequency data for different types of isomiRs. Models trained on A-to-I editing rates at editing hotspots displayed high accuracy when tested on the other two cohorts and compared favorably to classifiers trained on miRNA expression alone; Conclusions: We have identified isomiRs in the human lung and found that their expression differs between non-malignant and tumor tissues, suggesting they hold potential as cancer biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Pathogenic variants in the PALB2 gene significantly increase the risk of developing breast, ovarian, and pancreatic cancers. However, the prevalence of these mutations in East Asian populations, particularly Koreans, has not been well studied. This research aims to estimate the prevalence of PALB2 variants in these populations by analyzing large-scale genomic databases. Understanding the frequency of PALB2 variants can help in identifying individuals at higher risk for these cancers and guide the development of targeted screening and prevention strategies. The findings from this study provide valuable reference data that can enhance genetic counseling and improve cancer risk management in East Asian populations, ultimately contributing to better health outcomes in these communities. PALB2 is a tumor suppressor gene. Heterozygous germline pathogenic variants of PALB2 significantly increase the lifetime risk of breast cancer and moderately increase the risk of ovarian and pancreatic cancers. This study analyzed the estimated prevalence of PALB2 variants globally, focusing on East Asian and Korean populations, where limited data were previously available. We examined 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9197 East Asians, and additional data from 5305 individuals in the Korean Variant Archive and 1722 in the Korean Reference Genome Database. All PALB2 variants were interpreted according to guidelines from the American College of Medical Genetics and Genomics and the Clinical Genome Resource. The global prevalence of PALB2 variants was 0.18%, with the highest prevalence in Finnish populations (0.41%) and the lowest in Ashkenazi Jewish populations (0.04%). East Asians had a prevalence of 0.09%. By combining data from Korean genome databases and gnomAD totaling 8936 individuals, the overall prevalence of PALB2 variants in the Korean population was determined to be 0.13%. This study is the first comprehensive investigation of PALB2 variant prevalence in East Asians and Koreans using gnomAD and Korean genome databases. These findings provide essential reference data for future research and highlight the importance of region-specific genetic studies that will inform genetic counseling and hereditary cancer risk management. [ABSTRACT FROM AUTHOR]

Simple Summary: Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss is a key factor in diagnosing meningiomas as Central Nervous System (CNS) WHO grade 3 tumors. Typically, detecting this gene loss involves costly and complex techniques like sequencing or FISH. However, the MTAP gene, which is located near CDKN2A/B on the same chromosome, may provide a more accessible way to detect these losses through a simpler, more affordable test called immunohistochemistry (IHC). This study explored different concentrations and antibodies for MTAP and p16 across two institutions to evaluate their potential as surrogate markers for CDKN2A/B loss. The results showed that p16 expression varied and did not align with either MTAP expression or CDKN2A FISH results. This study suggests that IHC for MTAP is a promising, cost-effective method for identifying high-grade meningiomas, offering a quicker and less expensive alternative to existing techniques. Background: Homozygous cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) loss is one of the parameters that support the designation of meningiomas as Central Nervous System (CNS) WHO grade 3 tumors. Evaluation of CDKN2A/B by sequencing or Fluorescence in situ hybridization (FISH) is costly and not always readily accessible. An immunohistochemistry (IHC)-based marker for the evaluation of CDKN2A/B loss would provide faster results at a lower cost. Methods: This retrospective study included patients diagnosed with meningioma at our institution between 2016 and 2019. Archival tumor tissue was used for analysis. MTAP immunohistochemistry (IHC) was performed at various dilutions (1:1200, 1:400, 1:200, 1:100) using two different antibodies, and p16 IHC was conducted simultaneously. These analyses were carried out at two different institutions. To determine the sensitivity and specificity of MTAP and p16 as surrogate markers for CDKN2A/B loss, CDKN2A FISH was utilized as the gold standard. Results: Overall, 46/49 tumors showed strong MTAP staining (94%) at institution 1, and 44/49 (90%) showed either faint positive or positive results at institution 2. One grade 3 meningioma that demonstrated homozygous CDKN2A loss by FISH also showed loss of MTAP expression by IHC. One grade 2 meningioma showed regional CDKN2A loss by FISH and variable MTAP expression under different IHC conditions. MTAP expression evaluation was superior at a dilution of 1:100 with the Abnova Anti-MTAP Monoclonal antibody. Conclusions: P16 expression was variable and did not correlate with either MTAP expression or CDKN2A FISH results. MTAP IHC is a promising surrogate marker for the evaluation of CDKN2A status in meningiomas. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of the GPER in cancer is controversial due to its dual anti and protumor effects. Elevated GPER expression in cervical cancer has been associated with improved survival outcomes. In cervical cancer cell lines, the selective GPER agonist G-1 induces cell cycle arrest and apoptosis, although the precise molecular mechanisms behind these effects are not fully understood. This study explores the impact of GPER activation by G-1 on the transcriptome, cell migration, and invasion in SiHa cells, as well as in non-tumorigenic keratinocytes transduced with HPV16 E6 or E7 oncogenes. G-1 has been shown to exert antitumor effects by activating apoptotic pathways and modulating migration and invasion processes. The findings support the GPER as a promising prognostic marker and suggest that G-1 could be a valuable therapeutic tool for treating cervical cancer. Background/Objectives: Estrogens and HPV are necessary for cervical cancer (CC) development. The levels of the G protein-coupled estrogen receptor (GPER) increase as CC progresses, and HPV oncoproteins promote GPER expression. The role of this receptor is controversial due to its anti- and pro-tumor effects. This study aimed to determine the effect of GPER activation, using its agonist G-1, on the transcriptome, cell migration, and invasion in SiHa cells and non-tumorigenic keratinocytes transduced with the HPV16 E6 or E7 oncogenes. Methods: Transcriptome analysis was performed to identify G-1-enriched pathways in SiHa cells. We evaluated cell migration, invasion, and the expression of associated proteins in SiHa, HaCaT-16E6, and HaCaT-16E7 cells using various assays. Results: Transcriptome analysis revealed pathways associated with proliferation/apoptosis (TNF-α signaling, UV radiation response, mitotic spindle formation, G2/M cell cycle, UPR, and IL-6/JAK/STAT), cellular metabolism (oxidative phosphorylation), and cell migration (angiogenesis, EMT, and TGF-α signaling) in SiHa cells. Key differentially expressed genes included PTGS2 (pro/antitumor), FOSL1, TNFRSF9, IL1B, DIO2, and PHLDA1 (antitumor), along with under-expressed genes with pro-tumor effects that may inhibit proliferation. Additionally, DKK1 overexpression suggested inhibition of cell migration. G-1 increased vimentin expression in SiHa cells and reduced it in HaCaT-16E6 and HaCaT-16E7 cells. However, G-1 did not affect α-SMA expression or cell migration in any of the cell lines but increased invasion in HaCaT-16E7 cells. Conclusions: GPER is a promising prognostic marker due to its ability to activate apoptosis and inhibit proliferation without promoting migration/invasion in CC cells. G-1 could potentially be a tool in the treatment of this neoplasia. [ABSTRACT FROM AUTHOR]

Simple Summary: Nasopharyngeal carcinoma (NPC) is a head and neck cancer that is mainly found in Southeast Asia and North Africa. Most patients with NPC are diagnosed at an advanced stage, which increases the risk of recurrence and metastasis. A cohort of 41 NPC tumor samples from Morocco and North Africa were analyzed using shotgun proteomics. Within the cohort, three proteomically defined clusters were identified. We also examined sex and stage differences from a proteomic perspective. In total, 59 and 26 differentially abundant proteins were identified between male and female patients and patients with early and advanced stages within the cohort. Data were then compared to 21 healthy controls from a prior study. Across the two datasets, 6532 proteins were identified, of which 1507 proteins were differentially abundant between patients and controls. Differentially abundant proteins between tumor and healthy samples included PI3K, MAPK, BCL2, and PPIA proteins, which are involved in various biological pathways related to cell proliferation and growth. This study lays a foundation for both mechanistic and biomarker studies into NPC in Morocco and North African populations. Background: Nasopharyngeal carcinoma (NPC) is a distinct cancer of the head and neck that is highly prevalent in Southeast Asia and North Africa. Though an extensive analysis of environmental and genetic contributors has been performed, very little is known about the proteome of this disease. A proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissues can provide valuable information on protein expression and molecular patterns for both increasing our understanding of the disease and for biomarker discovery. To date, very few NPC proteomic studies have been performed, and none focused on patients from Morocco and North Africa. Methods: Label-free Liquid Chromatography–Tandem Mass Spectrometry (LC-MS/MS) was used to perform a proteomic analysis of FFPE tissue samples from a cohort of 41 NPC tumor samples of Morocco and North Africa origins. The LC-MS/MS data from this cohort were analyzed alongside 21 healthy controls using MaxQuant 2.4.2.0. A differential expression analysis was performed using the MSstats package in R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional annotations were carried out using the DAVID bioinformatic tool. Results: 3341 proteins were identified across our NPC cases, revealing three main clusters and five DEPs with prognostic significance. The sex disparity of NPC was investigated from a proteomic perspective in which 59 DEPs were found between males and females, with significantly enriched terms associated with the immune response and gene expression. Furthermore, 26 DEPs were observed between patients with early and advanced stages of NPC with a significant cluster related to the immune response, implicating up-regulated DEPs such as IGHA, IGKC, and VAT1. Across both datasets, 6532 proteins were quantified between NPC patients and healthy controls. Among them, 1507 differentially expressed proteins (DEPs) were observed. GO and KEGG pathway analyses showed enriched terms of DEPs related to increased cellular activity, cell proliferation, and survival. PI3K and MAPK proteins as well as RAC1 BCL2 and PPIA were found to be overexpressed between cancer tissues and healthy controls. EBV infection was also one of the enriched pathways implicating its latent genes like LMP1 and LMP2 that activate several proteins and signaling pathways including NF-Kappa B, MAPK, and JAK-STAT pathways. Conclusion: Our findings unveil the proteomic landscape of NPC for the first time in the Moroccan population. These studies additionally may provide a foundation for identifying potential biomarkers. Further research is still needed to help develop tools for the early diagnosis and treatment of NPC in Moroccan and North African populations. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck squamous cell carcinoma (HNSCC) is a complex and varied cancer that is difficult to treat due to its biological diversity. Single-cell RNA sequencing (scRNAseq) offers a way to study HNSCC by examining individual cells within tumors. This technology helps identify different cell types and their roles in cancer development, diagnosis, and treatment. By understanding how various cells respond to treatments like chemotherapy and immunotherapy, scRNAseq can enhance the study of cancer biology and improve therapeutic outcomes. This review highlights the significant impact of scRNAseq on HNSCC research and its potential to advance the study of other cancers. Background/Objectives: Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous and the most common form of head and neck cancer, posing significant challenges for disease management. The objective of this review is to assess the utility of single-cell RNA sequencing (scRNAseq) in addressing these challenges by enabling a detailed characterization of the tumor microenvironment (TME) at the cellular level. Methods: This review compiles and analyzes current strategies that utilize scRNAseq and other single-cell technologies in HNSCC research. Results: For HNSCC etiology, scRNAseq allows for the construction of cellular atlases, characterization of different cell types, and investigation of genes and processes involved in cancer initiation, development, and progression within the TME. In terms of HNSCC diagnosis and prognosis, the resolution offered by scRNAseq enables the identification of cell type-specific signatures, enhancing prognostic models and disease stratifiers for patient outcome assessments. Regarding HNSCC treatment, scRNAseq provides insights into cellular responses to various treatments, including radiotherapy, chemotherapy, and immunotherapy, contributing to a better understanding of treatment efficacy and patient outcomes. Conclusions: This review highlights the contributions of scRNAseq to HNSCC research, addressing its cellular and biological complexity, and emphasizes its potential for advancing research and clinical practice in other cancer types. [ABSTRACT FROM AUTHOR]

Simple Summary: Our study aimed to understand why some people with lung adenocarcinoma, a type of lung cancer, survive longer than others, even when their conditions seem similar. By studying the DNA of 1464 patients, we found six specific genetic differences that appear to affect survival. These differences are located in parts of the DNA that do not directly make proteins but might control how certain genes are turned on or off. The goal is to use this information to predict which patients might have better outcomes and to develop more personalized treatment options. Further research is needed to confirm these results and to understand the underlying biological mechanisms, but our findings could eventually improve how we treat lung cancer and understand its outcomes better. Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression of NT5DC2 and NAGK, with high expression associated with the minor alleles. High NT5DC2 and NAGK expression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients with relapsed, refractory, or metastatic osteosarcoma have few therapeutic options. Our findings demonstrated the efficacy of a DC vaccine generated using CD103+ cDC1 cells and OS cell lysates against the primary tumor and lung metastases, as well as its ability to induce a systemic immune response. This cDCV therapy elicited an increase in the infiltration of CD8+ T-cells into the primary and metastatic tumors as well as the TdLNs. cDCV efficacy was increased when combined with anti-CTLA-4. The failure of immunotherapies has been linked to their inability to induce infiltration of T-cells into the tumor. Therefore, our data suggest the potential for this novel immunotherapy using innate immune cells (type 1 CD103+ dendritic cells) alone or in combination with checkpoint blockade for patients with relapsed or metastatic OS, a tumor type that is refractory to the majority of current immunotherapies. Background: We generated a CD103+DC vaccine using K7M3 OS cell lysates (cDCV) and investigated its ability to induce regression of primary tumors, established lung metastases, and a systemic immune response. Methods: A bilateral tumor model was used to assess cDCV therapy efficacy and systemic immunity induction. K7M3 cells were injected into mice bilaterally. Right-sided tumors received PBS (control) or cDCV. Left-sided tumors were untreated. Tumor growth was compared between the vaccine-treated and untreated tumor on the contralateral side and compared to the control group. The immune cell profiles of the tumors, and tumor-draining lymph nodes (TdLNs) and spleen were evaluated. To determine the efficacy of systemic cDCV therapy against established lung metastases, K7M3 cells were injected intratibially. Leg amputation was performed 5 weeks later. Mice were treated intravenously with PBS or cDCV and euthanized 6 weeks later. Lungs, TdLNs and spleen were collected. The number and size of the lung nodules were quantified. The immune cell profile of tumor, and lymph nodes and spleen were also evaluated. Using this same model, we evaluated the effect of cDCV + anti-CTLA-4. Results: cDCV therapy inhibited the treated and untreated tumors and increased the number of T-cells in these tumors and the lymph nodes compared to control-treated mice. Systemic cDCV therapy administered following amputation decreased the size and number of lung metastases, and increased T-cell numbers in the tumor and lymph nodes. Combining anti-CTLA-4 with cDCV therapy increased cDCV efficacy against lung metastases. Conclusions: Intratumor cDCV generated a systemic immune response inhibiting the growth of both the treated and untreated tumors, with increased T-cells in the tumor and lymph nodes. Systemic cDCV was effective against established lung metastases. Efficacy was increased by anti-CTLA4. cDCVs may provide a novel therapeutic approach for relapsed/metastatic OS patients. [ABSTRACT FROM AUTHOR]

Background/Objectives: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, the average survival time is around 15–18 months, underscoring the fatality of GBM. This study aims to investigate the impact of sample heterogeneity on gene expression in GBM, identify key metabolic pathways and gene modules, and explore potential therapeutic targets. Methods: In this study, we analysed GBM transcriptome data derived from The Cancer Genome Atlas (TCGA) using genome-scale metabolic models (GEMs) and co-expression networks. We examine transcriptome data incorporating tumour purity scores (TPSs), allowing us to assess the impact of sample heterogeneity on gene expression profiles. We analysed the metabolic profile of GBM by generating condition-specific GEMs based on the TPS group. Results: Our findings revealed that over 90% of genes showing brain and glioma specificity in RNA expression demonstrate a high positive correlation, underscoring their expression is dominated by glioma cells. Conversely, negatively correlated genes are strongly associated with immune responses, indicating a complex interaction between glioma and immune pathways and non-tumorigenic cell dominance on gene expression. TPS-based metabolic profile analysis was supported by reporter metabolite analysis, highlighting several metabolic pathways, including arachidonic acid, kynurenine and NAD pathway. Through co-expression network analysis, we identified modules that significantly overlap with TPS-correlated genes. Notably, SOX11 and GSX1 are upregulated in High TPS, show a high correlation with TPS, and emerged as promising therapeutic targets. Additionally, NCAM1 exhibits a high centrality score within the co-expression module, which shows a positive correlation with TPS. Moreover, LILRB4, an immune-related gene expressed in the brain, showed a negative correlation and upregulated in Low TPS, highlighting the importance of modulating immune responses in the GBM mechanism. Conclusions: Our study uncovers sample heterogeneity's impact on gene expression and the molecular mechanisms driving GBM, and it identifies potential therapeutic targets for developing effective treatments for GBM patients. [ABSTRACT FROM AUTHOR]

The NITRATE TRANSPORTER 1/PEPTIDE TRANSPORTER (NRT1/PTR) family (NPF) plays an important role in plant nitrate absorption, distribution, and nitrogen use efficiency. Nevertheless, few reports are available regarding Eucalyptus grandis NPF genes and their expression profiles. This study aims to identify and analyze NPF genes and their expression under various nitrogen (N) conditions. In this study, we successfully screened 64 NPF genes within the E. grandis genome. Subsequently, we conducted an extensive analysis, encompassing investigations into chromosome location, gene structure, phylogenetic relationship, promoter region, conserved motif, and gene expression profile. RNA-seq was conducted to analyze the expression profiles of EgNPF genes under different N conditions. The 64 NPF genes were categorized into eight distinct groups, exhibiting an uneven distribution among the 10 chromosomes of E. grandis, and no member was mapped on chromosome (Chr) 9. The examination of cis-regulatory elements revealed that NPF promoters were closely related to light responsive element, MeJA responsiveness, anaerobic induction, gibberellin responsiveness, low-temperature responsiveness, and auxin responsiveness. We used the comparative transcriptome method to identify the 10 differently expressed EgNPF genes of E. grandis under high-nitrogen (N: 119 mg/L) and low-nitrogen (N: 29.25 mg/L) conditions. Expression pattern analyses revealed that EUGRSUZ_G03119 showed an elevated expression in both leaves and roots under high-nitrogen conditions compared to low-nitrogen conditions, suggesting that EUGRSUZ_G03119 might affect nitrogen transport and redistribution, potentially boosting the stress tolerance of E. grandis in response to nitrogen deficiency. These findings may provide valuable insights into the evolutionary development of the NPF gene family in E. grandis and facilitate the clarification of the molecular mechanism underlying EgNPF-mediated N absorption and distribution in E. grandis. [ABSTRACT FROM AUTHOR]

Background and Objectives: Polydeoxyribonucleotides (PDRN), composed of DNA fragments derived from salmon DNA, is widely recognized for its regenerative properties. It has been extensively used in medical applications, such as dermatology and wound healing, due to its ability to enhance cellular metabolic activity, stimulate angiogenesis, and promote tissue regeneration. In the field of dentistry, PDRN has shown potential in promoting periodontal healing and bone regeneration. This study aims to investigate the effects of PDRN on the morphology, survival, and osteogenic differentiation of gingiva-derived stem cell spheroids, with a focus on its potential applications in tissue engineering and regenerative dentistry. Materials and Methods: Gingiva-derived mesenchymal stem cells were cultured and formed into spheroids using microwells. The cells were treated with varying concentrations of PDRN (0, 25, 50, 75, and 100 μg/mL) and cultivated in osteogenic media. Cell morphology was observed over seven days using an inverted microscope, and viability was assessed with Live/Dead Kit assays and Cell Counting Kit-8. Osteogenic differentiation was evaluated by measuring alkaline phosphatase activity and calcium deposition. The expression levels of osteogenic markers RUNX2 and COL1A1 were quantified using real-time polymerase chain reaction. RNA sequencing was performed to assess the gene expression profiles related to osteogenesis. Results: The results demonstrated that PDRN treatment had no significant effect on spheroid diameter or cellular viability during the observation period. However, a PDRN concentration of 75 μg/mL significantly enhanced calcium deposition by Day 14, suggesting increased mineralization. RUNX2 and COL1A1 mRNA expression levels varied with PDRN concentration, with the highest RUNX2 expression observed at 25 μg/mL and the highest COL1A1 expression at 75 μg/mL. RNA sequencing further confirmed the upregulation of genes involved in osteogenic differentiation, with enhanced expression of RUNX2 and COL1A1 in PDRN-treated gingiva-derived stem cell spheroids. Conclusions: In summary, PDRN did not significantly affect the viability or morphology of gingiva-derived stem cell spheroids but influenced their osteogenic differentiation and mineralization in a concentration-dependent manner. These findings suggest that PDRN may play a role in promoting osteogenic processes in tissue engineering and regenerative dentistry applications, with specific effects observed at different concentrations. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to determine the gene expression profiles associated with chemotherapeutic responses in conventional osteosarcomas (COS) within South Africa. We observed a significant downregulation in the ATP binding cassette subfamily C members (ABCC3 and ABCB1-p-glycoprotein), excision repair cross-complimenting group 1 (ERCC 1), replication factor C subunit 1 (RFC1), and tumour protein 53 (p53) genes in the COS tumours compared to the healthy donors. Furthermore, an upregulated ERCC1 gene expression level predicted a poor chemotherapeutic response. Additionally, the predictors of COS chemotherapeutic response comprised age, chondroblastic and osteoblastic histological subtypes, and ABCC3, ERCC1, and RFC1 gene expression. Background: We determined the predictive gene expression profiles associated with chemo-response in conventional osteosarcomas (COS) within South Africa. Materials and methods: In 28 patients, we performed an RNA extraction, cDNA synthesis, and quantitative analysis using the RT-PCR 2−∆∆CT method to determine the fold change in gene expression alongside GAPDH (housekeeping gene). Results: We observed a significant downregulation in the mRNA expression profiles of ABCB1-p-glycoprotein (p = 0.0007), ABCC3 (p = 0.002), ERCC1 (p = 0.007), p-53 (p = 0.007), and RFC1 (p = 0.003) in the COS patients compared to the healthy donors. Furthermore, ABCB1-p-glycoprotein (p = 0.008) and ABCC3 (p = 0.020) exhibited a significant downregulation in the COS tumour tissues when compared to the healthy donors. In our univariate logistic regression, the predictors of chemotherapeutic response comprised ERCC1 [restricted cubic spline (RCS) knot: OR −0.27; CI −0.504 to −0.032; p = 0.036]; osteoblastic subtype [OR −0.36; CI −0.652 to −0.092; p = 0.026); fibroblastic subtype [OR 0.91; CI 0.569 to 1.248; p < 0.001]; and mixed subtype [OR 0.53; CI 0.232 to 0.032; p = 0.032]. In our multivariable logistic regression, the significant predictors of chemotherapeutic response comprised age [RCS knot: OR −2.5; CI −3.616 to −1.378; p = 0.022]; ABCC3 [RCS knot: OR 0.67; CI 0.407 to 0.936, p = 0.016]; ERCC1 [RCS knot: OR 0.57; CI 0.235 to 0.901; p = 0.044]; RFC1 [RCS knot: OR −1.04; CI −1.592 to −0.487; p = 0.035]; chondroblastic subtype [OR −0.83; CI −1.106 to −0.520; p = 0.012]; and osteoblastic subtype [OR −1.28; CI −1.664 to −0.901; p = 0.007]. Conclusions: In this South African cohort, we observed the unique gene expression profiles of osteosarcoma tumourigenesis and chemotherapeutic responses. These may serve as prognostication and therapeutic targets. Larger-scale research is needed on the African continent. [ABSTRACT FROM AUTHOR]