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Abstract Chimeric antigen receptor macrophage (CAR-MΦ) represents a significant advancement in immunotherapy, especially for treating solid tumors where traditional CAR-T therapies face limitations. CAR-MΦ offers a promising approach to target and eradicate tumor cells by utilizing macrophages’ phagocytic and antigen-presenting abilities. However, challenges such as the complex tumor microenvironment (TME), variability in antigen expression, and immune suppression limit their efficacy. This review addresses these issues, exploring mechanisms of CAR-MΦ action, optimal construct designs, and interactions within the TME. It also delves into the ex vivo manufacturing challenges of CAR-MΦ, discussing autologous and allogeneic sources and the importance of stringent quality control. The potential synergies of integrating CAR-MΦ with existing cancer therapies like checkpoint inhibitors and conventional chemotherapeutics are examined to highlight possible enhanced treatment outcomes. Furthermore, regulatory pathways for CAR-MΦ therapies are scrutinized alongside established protocols for CAR-T cells, identifying unique considerations essential for clinical trials and market approval. Proposed safety monitoring frameworks aim to manage potential adverse events, such as cytokine release syndrome, crucial for patient safety. Consolidating current research and clinical insights, this review seeks to refine CAR-MΦ therapeutic applications, overcome barriers, and suggest future research directions to transition CAR-MΦ therapies from experimental platforms to standard cancer care options.

The review article titled CD39 Transforming Cancer Therapy by Modulating Tumor Microenvironment published in June 2024 in Cancer Letters provides a comprehensive overview of CD39's multifaceted roles in cancer, particularly its influence on immunoregulation, angiogenesis, and metabolic reprogramming within the tumor microenvironment (TME). This commentary builds on that foundation by incorporating recent advancements in CD39 research, highlighting unresolved issues, and proposing future research directions. We delve into the therapeutic potential of targeting CD39, addressing clinical translation challenges, and exploring the integration of CD39-based strategies into precision oncology.

Leukocyte cell-derived chemotaxin 2 (LECT2) is linked to various immune diseases. Previously, we reported that serum LECT2 levels correlate with disease severity in atopic dermatitis (AD) patients. To investigate the role of LECT2 in AD and elucidate its potential mechanisms, we used LECT2 to treat an AD mouse model induced by 1-Chloro-2,4-dinitrobenzene (DNCB) in LECT2 knockout (KO) and wild-type (WT) mice, and an AD cell model using TNF-α/IFN-γ-induced HaCaT cells. Inflammatory factors and barrier proteins were analyzed by histology, immunohistochemistry, RT-qPCR, ELISA, and Western Blot. Activation of the NF-κB signaling pathway was evaluated by Western Blot and immunofluorescence. In the AD mouse model, LECT2 treatment increased epidermal and dermal thickness, mast cell infiltration, and downregulated barrier proteins. Inflammatory factors were increased in skin lesions and serum. In the AD cell model, LECT2 decreased barrier protein levels and increased inflammatory factor levels, enhancing NF-κB P65 nuclear translocation. These results indicate that LECT2 exacerbates AD-like responses by dysregulating the NF-κB signaling pathway, highlighting its potential as a therapeutic target for AD management.

Thermal conductivity (k), as an important thermal property of nuclear fuels, would be deteriorated due to fission products. Therefore, to investigate the effect of fission products on the thermal conductivity of nuclear fuels is essential. Two typical fission products: Xe and Kr with 0–2 % concentration are considered in this work. The lattice constants (L) of ThO2 increase due to fission products at all testing temperatures. The extent of increase in L due to Xe interstitials is the maximum. The fission products significantly reduce the thermal conductivity of ThO2. The extent of reduction in thermal conductivity of ThO2 by the defects follows the trend Xe (interstitials) > Xe (substitutional defects) > Kr (substitutional defects) > Kr (interstitials). Finally, the full-filled Xe/Kr bubble has a nearly identical thermal conductivity as an empty void or half-filled Xe/Kr bubble. The underlying reason may be that the thorium atoms have a lower mobility than uranium atoms. These calculated values can be used to predict the thermal properties of the irradiated ThO2.

Nuclear fuel performance would be deteriorated due to radiation defects. Therefore, investigating the effect of irradiation-induced defects on nuclear fuel properties is essential. Thermal conductivity is an important property of nuclear fuel. In this work, the influence of radiation defects on the thermal conductivity of ThO2 within 600–1500 K has been studied using molecular dynamics (MD) method. Three types of point defects have been investigated in the present work: Frenkel pairs, substitutional Xe and vacancies with concentrations from 0 to 1 %. The results indicate that these irradiation-induced point defects increase the lattice parameter (L) at all studied temperatures. The strength of the dependence of Xe atoms on L is the highest. The analytical models for pure ThO2 and defected ThO2 are developed and there is a good agreement between the MD derived results and the model. The thermal conductivity of ThO2 systems is decreased due to Frenkel pairs, substitutional Xe and vacancies. The thermal resistance to thermal conductivity due to three types of defects are different. The degree of reduction in thermal conductivity by Xe is the largest. The dependence of vacancy cluster size on thermal conductivity is analyzed. For the ThO2 system with 0.5 % porosity, the effect of vacancy cluster size on thermal conductivity is weak. For the ThO2 system with a fixed porosity of 2 %, there exists a critical cluster radius of about 0.6 nm, below which the thermal conductivity increases with the cluster size and above which the thermal conductivity almost remains unchanged. Finally, the thermal conductivity of the amorphous ThO2 is calculated and effects of the amorphous structure and Frenkel pairs on thermal conductivity are compared. The result shows that the thermal conductivity of ThO2 systems can be further degraded by the amorphous structure. All these results indicate irradiation-induced defects could degrade the thermal properties of ThO2 systems and should be considered seriously for estimation of radiation damages in nuclear fuels used in nuclear reactors.

Summary: Leukemia-initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches. Here, we show that the RNA-editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T-ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL patient-derived xenograft models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation-associated protein 5 (MDA5). Moreover, we uncover that the cell-intrinsic level of MDA5 dictates the dependency on the ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs.

Receptor tyrosine kinases (RTKs) play a crucial role in cellular signaling and oncogenic progression. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have become the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR-sensitizing mutations, but resistance frequently emerges between 10 to 14 months. A significant factor in this resistance is the role of human EGFR 3 (HER3), an EGFR family member. Despite its significance, effective targeting of HER3 is still developing. This review aims to bridge this gap by deeply examining HER3’s pivotal contribution to EGFR TKI resistance and spotlighting emerging HER3-centered therapeutic avenues, including monoclonal antibodies (mAbs), TKIs, and antibody-drug conjugates (ADCs). Preliminary results indicate combining HER3-specific treatments with EGFR TKIs enhances antitumor effects, leading to an increased objective response rate (ORR) and prolonged overall survival (OS) in resistant cases. Embracing HER3-targeting therapies represents a transformative approach against EGFR TKI resistance and emphasizes the importance of further research to optimize patient stratification and understand resistance mechanisms.

Tumor-associated macrophages (TAMs) are integral to the tumor microenvironment (TME), influencing cancer progression significantly. Attracted by cancer cell signals, TAMs exhibit unparalleled adaptability, aligning with the dynamic tumor milieu. Their roles span from promoting tumor growth and angiogenesis to modulating metastasis. While substantial research has explored the fundamentals of TAMs, comprehending their adaptive behavior, and leveraging it for novel treatments remains challenging. This review delves into TAM polarization, metabolic shifts, and the complex orchestration of cytokines and chemokines determining their functions. We highlight the complexities of TAM-targeted research focusing on their adaptability and potential variability in therapeutic outcomes. Moreover, we discuss the synergy of integrating TAM-focused strategies with established cancer treatments, such as chemotherapy, and immunotherapy. Emphasis is laid on pioneering methods like TAM reprogramming for cancer immunotherapy and the adoption of single-cell technologies for precision intervention. This synthesis seeks to shed light on TAMs’ multifaceted roles in cancer, pinpointing prospective pathways for transformative research and enhancing therapeutic modalities in oncology.

Breast cancer is a heterogeneous disease characterized by distinct molecular subtypes, varied prognoses, and differential treatment responses. Understanding the molecular landscape and identifying therapeutic targets, such as trophoblast cell-surface antigen 2 (TROP2), is vital. TROP2 is notably overexpressed in breast cancer, playing a significant role in tumor growth, invasion, metastasis, and treatment resistance. While significant progress has been made in targeting TROP2 in breast cancer, several challenges and knowledge gaps remain. These challenges include the heterogeneity of TROP2 expression within breast cancer subtypes, resistance to its targeted therapies, potential off-target effects, limited therapeutic agents, and identifying optimal combination treatments. Integrating findings from clinical trials into clinical practice further complicates the landscape. This review article delves deep into TROP2 in breast cancer, highlighting its expression patterns, clinical implications, and therapeutic advancements. By understanding the role of TROP2, we can pave the way for personalized treatments, and transform the landscape of breast cancer care.

Nickel (Ni) exposure is a significant risk factor for kidney dysfunction and oxidative stress injury in humans. Thioredoxin reductase 3 (Txnrd3), an important enzyme in animals, plays a role in maintaining cellular homeostasis and regulating oxidative stress. However, its protective effect against kidney injury has been determined. Melatonin (Mel) has antioxidant and anti-apoptotic effects and therefore may be a preventive and therapeutic agent for kidney injury. Our study aimed to investigate the roles of Mel and Txnrd3 in the treatment of nickel-induced renal injury. We divided 80 wild-type mice and 80 Txnrd3 -/- mice (C57BL/6 N) into a control group treated with saline, Ni group treated with 10 mg/kg NiCl2, Mel group treated with 2 mg/kg Mel, and Ni + Mel group given NiCl2 and Mel for 21 days. Histopathological and ultrastructural observation of the kidney showed that nuclei were wrinkled and mitochondrial cristae were broken in the Ni group, and these changes were significantly attenuated by Mel treatment. Mitochondrial and nuclear damage improved significantly in the Ni + Mel and Txnrd3-/- Ni + Mel groups. Furthermore, NiCl2 exposure decreased T-AOC, SOD, and GSH activities in the kidney. The decreases in antioxidant enzyme activity were attenuated by Mel, and these improvements were abolished by Txnrd3 knockout. NiCl2-induced increases in the mRNA and protein levels of apoptosis factors (Bax, Cyt-c, caspase-3, and caspase-9) were attenuated by Mel treatment, and Txnrd3 knockout abolished the repressive effect of Mel on apoptosis genes. Overall, we concluded that Mel improves oxidative stress and apoptosis induced by NiCl2 by regulating Txnrd3 expression in the kidney. Our results provide evidence for the role of Mel in NiCl2-induced kidney injury and identify Txnrd3 as a potential therapeutic target for renal injury.

Neoadjuvant chemotherapy (NACT) was developed with the aims of shrinking tumors or stopping cancer cells from spreading before surgery. Unfortunately, not all breast cancer patients will benefit from NACT, and thus, patients must weigh the risks and benefits of treatment prior to the initiation of therapy. Currently, the data for predicting the efficacy of NACT is limited. Molecular testing, such as Oncotype DX, MammaPrint, and Curebest 95GC, have been developed to assist which breast cancer patients will benefit from the treatment. Patients with an increased level of Human Leukocyte Antigen-DR isotype, tumor-infiltrating lymphocytes, Fizzy-related protein homolog, and a decreased level of tumor-associated macrophages appear to benefit most from NACT.

IntroductionNickel (Ni) is widely used in industrial manufacturing and daily life due to its excellent physical and chemical properties. However, Ni has the potential to harm animals' immune system, and spleen is a typical immune organ. Therefore, it is crucial to understand the mechanism of NiCl2 damage to the spleen. The purpose of this study is to investigate the effects of different concentrations of NiCl2 exposure and intervening with strong antioxidants on spleen lymphocytes to better understand the damage mechanism of Ni on spleen lymphocytes.MethodsIn this experiment, mice spleen lymphocytes were used as the research object. We first measured the degree of oxidative stress, inflammation, and necroptosis caused by different NiCl2 concentrations. Subsequently, we added the powerful antioxidant N-acetyl-L-cysteine (NAC) and used hydrogen peroxide (H2O2) as the positive control in subsequent experiments.ResultsOur findings demonstrated that NiCl2 could cause spleen lymphocytes to produce a large number of reactive oxygen species (ROS), which reduced the mRNA level of antioxidant enzyme-related genes, the changes in GSH-PX, SOD, T-AOC, and MDA, the same to the mitochondrial membrane potential. ROS caused the body to produce an inflammatory response, which was manifested by tumor necrosis factor (TNF-α) in an immunofluorescence experiment, and the mRNA level of related inflammatory genes significantly increased. In the case of caspase 8 inhibition, TNF-α could cause the occurrence of necroptosis mediated by RIP1, RIP3, and MLKL. AO/EB revealed that spleen lymphocytes exposed to NiCl2 had significant necroptosis, and the mRNA and protein levels of RIP1, RIP3, and MLKL increased significantly. Moreover, the findings demonstrated that NAC acted as an antioxidant to reduce oxidative stress, inflammation, and necroptosis caused by NiCl2 exposure.DiscussionOur findings showed that NiCl2 could cause oxidative stress, inflammation, and necroptosis in mice spleen lymphocytes, which could be mitigated in part by NAC. The study provides a point of reference for understanding the toxicological effect of NiCl2. The study suggests that NAC may be useful in reducing the toxicological effect of NiCl2 on the immune system. The research may contribute to the development of effective measures to prevent and mitigate the toxicological effects of NiCl2 on the immune system.

Zearalenone (ZEA) is the most common fungal toxin contaminating livestock and poultry feeding, especially in pigs, causing severe toxic effects and economic losses. However, the mechanism of ZEA damage to the intestine is unknown. We constructed an in vitro model of ZEA toxicity in a porcine small intestinal epithelial cell (IPEC-J2) line. ZEA causes severe oxidative stress in porcine small intestine cells, such as the production of ROS and a significant decrease in the levels of antioxidant enzymes GSH, CAT, SOD, and T-AOC. ZEA also caused apoptosis in porcine small intestine cells, resulting in a significant reduction in protein and/or mRNA expression of apoptosis-related pathway factors such as P53, caspase 3, caspase 9, Bax, and Cyt-c, which in turn caused a significant decrease in protein and/or mRNA expression of inflammatory-related factors such as IL-1β, IL-2, Cox-2, NF-κD, NLRP3, IL-6, and IL -18, which in turn caused a significant increase in protein and/or mRNA expression levels. The final results suggest that ZEA can cause a severe toxic response in porcine small intestine cells, with oxidative stress, apoptotic cell death and inflammatory damage.

Abstract Background Alfalfa, the “queen of forage”, is the most extensively cultivated forage legume in the world. The development and yield of alfalfa are seriously limited by abiotic stress. MADS-box transcription factors are one of the largest gene families and play a pivotal role in plant development and abiotic stress. However, little is known regarding the MADS-box transcription factors in autotetraploid cultivated alfalfa. Results In the present study, we identified 120 MsMADS-box genes in the alfalfa genome. Phylogenetic analysis indicated that 75 type-I MsMADS-box genes were classified into the Mα, Mβ, and Mγ subgroups, and 45 type-II MsMADS-box genes were classified into 11 subgroups. The promoter region of MsMADS-box genes containing several hormone and stress related elements. Chromosomal location analysis revealed that 117 MsMADS-box genes were unevenly distributed on 32 chromosomes, and the remaining three genes were located on unmapped scaffolds. A total of nine pairs of segmental duplications and four groups of tandem duplications were found. Expression analysis showed that MsMADS-box genes were differentially expressed in various tissues and under abiotic stresses. qRT-PCR analysis revealed that the expression profiles of eight selected MsMADS-box genes were distinct under various stresses. Conclusions In this study, MsMADS-box genes were identified in the cultivated alfalfa genome based on autotetraploid level, and further confirmed by Gene Ontology (GO) analysis, phylogenetic analysis, sequence features and expression analysis. Taken together, these findings will provide clues for further study of MsMADS-box functions and alfalfa molecular breeding. Our study is the first to systematically identify and characterize the MADS-box transcription factors in autotetraploid cultivated alfalfa (Medicago sativa L.), and eight MsMADS-box genes were significantly involved in response to various stresses.

Confirmed SARS-CoV-2-caused disease (COVID-19) cases have reached 275.65 million worldwide. Although the majority of COVID-19 patients present mild to moderate symptoms, some have severe complications including death. We first reviewed the pathogenesis on ACE2, a binding receptor of SARS-CoV-2 expressed in multiple organs, and prevalent multinucleate syncytia in the lung tissues of COVID-19 patients. Then, we evaluated the pathological, immunological changes and sequelae in the major organs. Finally, we reviewed the immunological memory after SARS-CoV-2 infection and vaccination. The binding of SARS-Cov-2 to ACE2 receptor results in reduced ACE2 protein levels, which may lead to elevated susceptibility to inflammation, cell death, organ failure, and potentially severe illness. These damages increase the risk of health problems over a long period, which result in many complications. The complications in multiple organs lead to the increased risk of long-term health problems that require additional attention. A multidisciplinary care team is necessary for further management and recovery of the COVID-19 survivors. Many COVID-19 patients will probably make antibodies against SARS-CoV-2 virus for most of their lives, and the immunity against reinfection would last for 3–61 months.

Homeobox (HOX) transcript antisense RNA (Hotair) is elevated in many cancers significantly. However, the oncogenic role of Hotair in human laryngeal squamous cell carcinoma (LSCC) is still unknown. Thus, we explored the expression profile of Hotair and its function in LSCC. We observed high expression levels of Hotair in six LSCC cell lines compared to the human nasopharyngeal epithelial cell line. Knockdown of Hotair inhibited proliferation and enhanced apoptosis of Tu212 and Hep-2 cell lines in vitro. Moreover, the overexpression of hsa-miR-30a-5p inhibited the expression of GRP78 and PD-L1, but Hotair overexpression in LSCC cells rescues both proteins. Furthermore, the impacts of hsa-miR-30a-5p upregulation on the apoptosis and proliferation of LSCC cells were rescued by overexpression of Hotair. Finally, we combined si-Hotair and a VEGF inhibitor to treat LSCC cells in vitro or in vivo and surprisingly observed a significant inhibition of LSCC growth. In summary, these results indicate that Hotair displays an oncogenic role in both malignancy and immune escape in LSCC related to hsa-miR-30a-5p/GRP78/PD-L1 signaling. Therefore, Hotair may be a potential target for treating LSCC.

FeCrAl is regarded as one of the most promising cladding materials for accident-tolerant fuel at nuclear fission reactors due to its comprehensive properties of inherent corrosion resistance, excellent irradiation resistance, high-temperature oxidation resistance, and stress corrosion cracking resistance. In this work, the irradiation response of FeCrAl irradiated by 2.4 MeV He2+ ions with a fluence of 1.1 × 1016 cm−2 at room temperature was studied using X-ray diffraction, transmission electron microscopy, and nanoindentation. The characterization results of structural and mechanical properties showed that only black-dot defects exist in irradiated FeCrAl samples, and that the hardness of the irradiated samples was 11.5% higher than that of the unirradiated samples. Similar to other types of radiation defects, black-dot defects acted as fixed defect obstacles and hindered the movement of slip dislocations moving under the applied load, resulting in a significant increase in the hardness of FeCrAl. Importantly, this work points out that irradiation-induced black-dot defects can significantly affect the mechanical properties of materials, and that their contribution to radiation hardening cannot be ignored.

Abstract Background Effector CD8+ T cell activation and its cytotoxic function to eradicate tumor cells depend on the T cell recognition of tumor neoantigens, and are positively associated with improved survival in breast cancer. Tumor suppressor BRCA1 and cell cycle regulator CCND1 play a critical role in maintaining genome integrity and tumorigenesis, respectively. However, it is still unclear how BRCA1 and CCND1 expression levels affect the effect of T cell activation on breast cancer patient survival. Methods The interactions between T cell activation status and either BRCA1 or CCND1 expression were evaluated using Kaplan-Meier survival curves and multivariate Cox regression models in a public dataset with 1088 breast cancer patients. Results Among the patients with low BRCA1 or CCND1 expression, the Activation group showed better overall survival than the Exhaustion group. Adjusted hazards ratios were 0.43 (95% CI: 0.20–0.93) in patients with a low BRCA1 level, and 0.39 (95% CI: 0.19–0.81) in patients with a low CCND1 level, respectively. There was a significant trend in both subgroups (p-trend = 0.011 in the low BRCA1 group, and p-trend = 0.009 in the low CCND1 group). In contrast, there is no significant association in patients with either high BRCA1 or high CCND1 levels. There is a significant interaction between T cell activation status and BRCA1 level (p = 0.009), but not between T cell activation status and CCND1 level (p = 0.135). Conclusions BRCA1 expression modified the effect of T cell activation status on patient survival in breast cancer, suggesting that the existence of neoantigens and the enhancement of neoantigen presentation in combination with immune checkpoint blockade may have synergistic effects on patient outcome.

In the present work, the evolution of atomic structures and related changes in energy state, atomic displacement and free volume of symmetrical grain boundaries (GB) under the effects of external strain in body-centered cubic (bcc) iron are investigated by the molecular dynamics (MD) method. The results indicate that without external strain, full MD relaxations at high temperatures are necessary to obtain the lower energy states of GBs, especially for GBs that have lost the symmetrical feature near GB planes following MD relaxations. Under external strain, two mechanisms are explored for the failure of these GBs, including slip system activation, dislocation nucleation and dislocation network formation induced directly by either the external strain field or by phase transformation from the initial bcc to fcc structure under the effects of external strain. Detailed analysis shows that the change in free volume is related to local structure changes in these two mechanisms, and can also lead to increases in local stress concentration. These findings provide a new explanation for the failure of GBs in BCC iron systems.

The identification of novel biomarkers and therapeutic targets in advanced cancer is critical for improving cancer diagnosis and therapeutics. Survivin (SV) is highly expressed predominantly in most cancer cells and tissues but is absent or undetectable in terminally differentiated normal adult tissues. Therefore, it functions as an almost universal tumor antigen. Peptides are short chains of amino acids linked by peptide bonds. To obtain novel SV decamers that are able to induce SV-specific cytotoxic T lymphocytes (CTLs) with a higher cytotoxic efficiency against cancer cells, major histocompatibility complex (MHC) peptide binding algorithms were conducted to predict nine modified SV95 decamers (from SV95–2 to SV95–10) based on the natural SV95–104 peptide sequence of ELTLGEFLKL (here defined as SV95–1). The fluorescent density of each SV95 peptide was determined by a MHC stability assay, followed by the generation of SV95-specific CTLs with each SV95 peptide (from SV95–1 to SV95–10) and human dendritic cells (DCs) loaded with Poly(lactic-co-glycolic) acid (PLGA) nanoparticles encapsulated with SV95 peptide. Finally, IFN-γ ELISpot and CytoTox 96® Non-Radioactive Cytotoxicity Assays were employed to verify their cytotoxic efficiency of the SV95-specific CTLs generated with the corresponding artificial antigen presenting cells (aAPCs) containing SV95 (SV95–1 to SV95–10) peptide. Furthermore, the cytotoxicity of the SV95 specific CTLs generated with nine mutated SV95 peptides was compared to the one generated with natural SV95–1 peptide and TIL2080 cells. The results indicated that the HLA-A2-restricted mutated SV95 epitope decamers (SV95–6 and SV95–7) showed significant higher binding ability compared to natural peptide SV95–1 in MHC stability assay. More importantly, SV95–specific CTLs with higher cytotoxicity were successfully induced with both SV95–6 and SV95–7 peptides, which significantly eliminated target cells (not only SV95–1 peptide pulsed T2 cells, but also both HLA-A2 and SV positive cancer cells) when compared to those generated with natural SV95–1 peptide and TIL2080 cells. These findings suggest that the SV95–6 and SV95–7 peptides are two novel HLA-A2-restricted CTL epitopes and may be useful for the immunotherapy for patients with survivin expressing cancer.

Background Alfalfa is the most widely cultivated forage legume and one of the most economically valuable crops in the world. Its survival and production are often hampered by environmental changes. However, there are few studies on stress-resistance genes in alfalfa because of its incomplete genomic information and rare expression profile data. The MYB proteins are characterized by a highly conserved DNA-binding domain, which is large, functionally diverse, and represented in all eukaryotes. The role of MYB proteins in plant development is essential; they function in diverse biological processes, including stress and defense responses, and seed and floral development. Studies on the MYB gene family have been reported in several species, but they have not been comprehensively analyzed in alfalfa. Methods To identify more comprehensive MYB transcription factor family genes, the sequences of 168 Arabidopsis thaliana, 430 Glycine max, 185 Medicago truncatula, and 130 Oryza sativa MYB proteins were downloaded from the Plant Transcription Factor Database. These sequences were used as queries in a BLAST search against the M. sativa proteome sequences provided by the Noble Research Institute. Results In the present study, a total of 265 MsMYB proteins were obtained, including 50 R1-MYB, 186 R2R3-MYB, 26 R1R2R3-MYB, and three atypical-MYB proteins. These predicted MsMYB proteins were divided into 12 subgroups by phylogenetic analysis, and gene ontology (GO) analysis indicated that most of the MsMYB genes are involved in various biological processes. The expression profiles and quantitative real-time PCR analysis indicated that some MsMYB genes might play a crucial role in the response to abiotic stresses. Additionally, a total of 170 and 914 predicted protein–protein and protein-DNA interactions were obtained, respectively. The interactions between MsMYB043 and MSAD320162, MsMYB253 and MSAD320162, and MsMYB253 and MSAD308489 were confirmed by a yeast two-hybrid system. This work provides information on the MYB family in alfalfa that was previously lacking and might promote the cultivation of stress-resistant alfalfa.

Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies.

Abstract Background: Elevated plasma levels of Lipoprotein(a) [Lp(a)] are recognized as a significant risk factor for atherosclerotic vascular disease. However, there are limited data regarding association between Lp(a) and recurrent heart failure (HF) in patients with chronic HF caused by coronary heart disease (CHD). Objective: Elevated levels of Lp(a) might have a prognostic impact on recurrent HF in patients with chronic HF caused by CHD. Methods: A total of 309 patients with chronic HF caused by CHD were consecutively enrolled in this study. The patients were divided into 2 groups according to whether Lp(a) levels were above or below the median level for the entire cohort (20.6 mg/dL): the high Lp(a) group (n = 155) and the low Lp(a) group (n = 154). A 2-sided p < 0.05 was statistically considered significant. Results: During the median follow-up period of 186 days, 31 cases out of a total of 309 patients (10.03%) could not be reached during follow-up. A Kaplan-Meier analysis demonstrated that patients with higher Lp(a) levels had a higher incidence of recurrent HF than those with lower Lp(a) levels (log-rank < 0.0001). A multivariate Cox regression analysis revealed that Lp(a) levels were independently correlated with the incidence of recurrent HF after adjustment of potential confounders (hazard ratio: 2.720, 95 % confidence interval: 1.730-4.277, p < 0.0001). Conclusions: In Chinese patients with chronic HF caused by CHD, elevated levels of Lp(a) are independently associated with recurrent HF.

Greenblatt and his team have unveiled vertebral skeletal stem cells (vSSCs) as a critical player in the landscape of bone metastasis. This commentary delves into the transformative discoveries surrounding vSSCs, emphasizing their distinct role in bone metastasis compared to other stem cell lineages. We illuminate the unique properties and functions of vSSCs, which may account for the elevated susceptibility of vertebral bones to metastatic invasion. Furthermore, we explore the exciting therapeutic horizons opened by this newfound understanding. These include potential interventions targeting vSSCs, modulation of associated signaling pathways, and broader implications for the treatment and management of bone metastasis. By shedding light on these game-changing insights, we hope to pave the way for novel strategies that could revolutionize the prognosis and treatment landscape for cancer patients with metastatic bone disease. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has emerged as a promising strategy for the treatment of cancer, with the tumor microenvironment (TME) playing a pivotal role in modulating the immune response. CD47, a cell surface protein, has been identified as a crucial regulator of the TME and a potential therapeutic target for cancer therapy. However, the precise functions and implications of CD47 in the TME during immunotherapy for cancer patients remain incompletely understood. This comprehensive review aims to provide an overview of CD47's multifaced role in TME regulation and immune evasion, elucidating its impact on various types of immunotherapy outcomes, including checkpoint inhibitors and CAR T-cell therapy. Notably, CD47-targeted therapies offer a promising avenue for improving cancer treatment outcomes, especially when combined with other immunotherapeutic approaches. The review also discusses current and potential CD47-targeted therapies being explored for cancer treatment and delves into the associated challenges and opportunities inherent in targeting CD47. Despite the demonstrated effectiveness of CD47-targeted therapies, there are potential problems, including unintended effects on healthy cells, hematological toxicities, and the development if resistance. Consequently, further research efforts are warranted to fully understand the underlying mechanisms of resistance and to optimize CD47-targeted therapies through innovative combination approaches, ultimately improving cancer treatment outcomes. Overall, this comprehensive review highlights the significance of CD47 as a promising target for cancer immunotherapy and provides valuable insight into the challenges and opportunities in developing effective CD47-targeted therapies for cancer treatment. [ABSTRACT FROM AUTHOR]