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Myeloid-derived suppressor cells (MDSCs) mobilize and migrate from bone marrow to peripheral tissues or immune organs, which is associated with poor prognosis in sepsis. Intervention of MDSCs might be a potential target for the effective treatment of sepsis. In the present study, we demonstrated that IL-1R1 blockade with either recombinant human IL-1R antagonist Anakinra or IL-1R1 deficiency had a protective effect on the liver injury in septic mice. The possible mechanism was that Anakinra treatment and IL-1R1 knockout inhibited the migration of MDSCs to the liver in sepsis, thus attenuating the immune suppression of MDSCs on effector T cells characterized with the decrease in proportion of CD4+ and CD8+ T cells. Furthermore, the switch from pro-inflammatory M1 macrophage to anti-inflammatory M2 phenotype and the ability of bacterial clearance in the liver of septic mice were enhanced obviously by Anakinra and IL-1R1 deficiency, which contributes to the attenuated liver injury. Taken together, these findings provide new ideas for revealing the relationship between IL-1R1 and MDSCs in sepsis, thereby providing a potentially effective target for ameliorating septic liver injury. • The blockade of IL-1R1 signaling showed a protective effect on the liver injury of septic mice. • IL-1R1 signaling blockade reduced the proportion of MDSCs in liver of septic mice. • The IL-1R1 blockade attenuated the immune suppression of MDSCs on T cells by inhibiting the migration of MDSCs to the liver. • The IL-1R1 blockade enhanced the ability of bacterial clearance in the liver of septic mice. The IL-1R1 blockade attenuated liver injury by promoting the switch of macrophages from M1 to M2 phenotype. [ABSTRACT FROM AUTHOR]

• Meta -analysis of 36 studies links certain chemokines to glioma risk. • Elevated CXCR4, CXCL12, CCL2, CCL18 correlate with high-grade gliomas. • CXCR4 expression linked to lower survival in glioma patients. • Study shows chemokines' role in glioma pathogenesis and prognosis. • Chemokine pathways in glioma may lead to new treatment options. Glioma is a primary tumor originating from the central nervous system, and despite ongoing efforts to improve treatment, its overall survival rate remains low. There are a limited number of reports regarding the clinical grading, prognostic impact, and utility of chemokines. Therefore, conducting a meta -analysis is necessary to obtain convincing and conclusive results. A comprehensive literature search was conducted using various databases, including PubMed, Web of Science, The Cochrane Library, Embase, Ovid Medline, CNKI, Wanfang Database, VIP, and CBM. The search encompassed articles published from the inception of the databases until March 2024. The estimated odds ratio (ORs), standard mean difference (SMDs), and hazard ratio (HR) with their corresponding 95% confidence intervals (95% CI) were calculated to assess the predictive value of chemokine and receptor levels in glioma risk. Additionally, heterogeneity tests and bias tests were performed to evaluate the reliability of the findings. This meta -analysis included a total of 36 studies, involving 2,480 patients diagnosed with glioma. The results revealed a significant association between the expression levels of CXCR4 (n = 8; OR = 22.28; 95 % CI = 11.47–43.30; p = 0.000), CXCL12 (n = 4; OR = 10.69; 95 % CI = 7.03–16.24; p = 0.000), CCL2 (n = 6; SMD = -0.83; 95 % CI = -0.98‐-0.67; p = 0.000), CXCL8 (n = 3; SMD = 0.75; 95 % CI = 0.47–1.04; p = 0.000), CXCR7 (n = 3; OR = 20.66; 95 % CI = 10.20–41.82; p = 0.000), CXCL10 (n = 2; SMD = 3.27; 95 % CI = 2.91–3.62; p = 0.000) and the risk of glioma. Additionally, a significant correlation was observed between CXCR4 (n = 8; OR = 4.39; 95 % CI = 3.04–6.32; p = 0.000), (n = 6; SMD = 1.37; 95 % CI = 1.09–1.65; p = 0.000), CXCL12 (n = 6; OR = 6.30; 95 % CI = 3.87–10.25; p = 0.000), (n = 5; ES = 2.25; 95 % CI = 1.15–3.34; p = 0.041), CCL2 (n = 3; OR = 9.65; 95 % CI = 4.55–20.45; p = 0.000), (n = 4; SMD = -1.47; 95 % CI = -1.68--1.26; p = 0.000), and CCL18 (n = 3; SMD = 1.62; 95 % CI = 1.30–1.93; p = 0.000) expression levels and high-grade glioma (grades 3-4). Furthermore, CXCR4 (HR = 2.38, 95 % CI = 1.66–3.40; p = 0.000) exhibited a strong correlation with poor overall survival (OS) rates in glioma patients. The findings of this study showed a robust association between elevated levels of CXCR4, CXCL12, CCL2, CXCL8, CXCL10 and CXCR7 with a higher risk of glioma. Furthermore, the WHO grading system was validated by the strong correlation shown between higher expression of CXCR4, CXCL12, CCL2, and CCL18 and WHO high-grade gliomas (grades 3-4). Furthermore, the results of the meta -analysis suggested that CXCR4 might be a helpful biomarker for predicting the worse prognosis of glioma patients. [ABSTRACT FROM AUTHOR]

In the present paper, we establish two Erdélyi-type integrals for Saran's hypergeometric function F K , which has applications in specific branches of applied physics and statistics (see below). We employ methods based on the k-dimensional fractional integration by parts to obtain our main integral identities. The first integral generalizes Koschmieder's result and the second integral extends one of Erdélyi's classical hypergeometric integral. Some useful special cases and important remarks are also discussed. [ABSTRACT FROM AUTHOR]

Genomic alterations are important biological markers for cancer diagnosis and prognosis, disease classification, risk stratification, and treatment selection. Chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are superb new tools for evaluating cancer genomes. These state-of-the-art technologies offer highthroughput, highly accurate, targeted and whole-genome evaluation of genomic alterations in tumor tissues. The application of CMA and NGS technologies in cancer research has generated a wealth of useful information about the landscape of genomic alterations in cancer and their implications in cancer care. As the knowledge base in cancer genomics and genome biology grows, the focus of research is now shifting toward the clinical applications of these technologies to improve patient care. Although not yet standard of care in cancer, there is an increasing interest among the cancer genomics communities in applying these new tech-nologies to cancer diagnosis in the Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories. Many clinical laboratories have already started adopting these technologies for cancer genomic analysis. We anticipate that CMA and NGS will soon become the major diagnostic means for cancer genomic analysis to meet the increasing demands of precision cancer care. [ABSTRACT FROM AUTHOR]

Immunosuppressive myeloid-derived suppressor cells (MDSCs) continuously expand and lead to poor outcome during sepsis. The activation of liver X receptor (LXR) can mitigate sepsis-induced liver and myocardial damage. This study aims to determine whether LXR plays a protective role in sepsis by regulating MDSCs. Cecal ligation and puncture(CLP)was used to induce sepsis in mice. The mice were then treated with LXR agonist GW3965 (3 mg/kg) or vehicle 1 h, 6 h, 12 h, 24 h, 48 h, 72 h postoperatively. The effect of LXR on the survival rate and multi-organ injury induced by sepsis was evaluated by survival analysis, histological staining, biochemical analysis and ELISAs. The percentages of MDSCs and T cells were detected using flow cytometry. The mRNA expressions of LXR and ATP-binding cassette transporter A1 (ABCA1) were measured using real-time quantitative PCR (RT-qPCR). ABCA1 protein level was determined using immunofluorescence staining. LXR agonist GW3965 treatment improved the survival of septic mice, accompanied by reduced multi-organ injury and a decreased level of inflammatory cytokines. Furthermore, GW3965 treatment decreased MDSCs abundance in spleen by boosting the apoptosis of spleen MDSCs, therefore ameliorating their immunosuppressive activity. Meanwhile, bacteria clearance in tissues was enhanced after the GW3965 administration in septic mice. Mechanistically, GW3965 activated LXRβ and its downstream target ABCA1 to initiate the apoptosis of spleen MDSCs. These findings provide new insights into the relationship between LXR and MDSCs in sepsis, thus revealing a potentially effective approach to target the immunosuppression of sepsis. [ABSTRACT FROM AUTHOR]

HMGA2::NCOR2 keratin-positive giant cell tumors in children with response to imatinib in an infant [ABSTRACT FROM AUTHOR]

This article discusses a rare form of tumor predisposition called atypical teratoid/rhabdoid tumor (ATRT) that arises in the setting of germline ring chromosome 22. ATRT is a type of embryonal neoplasm characterized by the inactivation of the SMARCB1 gene. Germline ring chromosome 22, although not directly affecting SMARCB1, can lead to somatic mosaicism for monosomy chromosome 22, increasing the risk of ATRT. The article presents two cases of ATRT associated with germline ring chromosome 22 and provides detailed molecular characterization of the tumors. It also highlights the potential clinical manifestations and suggests considering germline karyotype and chromosomal microarray for ATRT patients with dysmorphic features, developmental delay, or disproportionate growth. Additionally, the article reports the first case of multiple meningiomas occurring in a long-term survivor of ATRT with germline ring chromosome 22, which predisposes to both SMARCB1 and NF2 deficient tumors. The authors emphasize the need for clinical monitoring in patients with germline ring chromosome 22 and suggest considering germline chromosomal microarray for all ATRT patients with loss of chromosome 22 observed in the tumor. [Extracted from the article]

Background: Exome sequencing (ES) is a first-tier diagnostic test for many suspected Mendelian disorders. While it is routine to detect small sequence variants, it is not a standard practice in clinical settings to detect germline copy-number variants (CNVs) from ES data due to several reasons relating to performance. In this work, we comprehensively characterized one of the most sensitive ES-based CNV tools, ExomeDepth, against SNP array, a standard of care test in clinical settings to detect genome-wide CNVs. Methods: We propose a modified ExomeDepth workflow by excluding exons with low mappability prior to variant calling to drastically reduce the false positives originating from the repetitive regions of the genome, and an iterative variant calling framework to assess the reproducibility. We used a cohort of 307 individuals with clinical ES data and clinical SNP array to estimate the sensitivity and false discovery rate of the CNV detection using exome sequencing. Further, we performed targeted testing of the STRC gene in 1972 individuals. To reduce the number of variants for downstream analysis, we performed a large-scale iterative variant calling process with random control cohorts to assess the reproducibility of the CNVs. Results: The modified workflow presented in this paper reduced the number of total variants identified by one third while retaining a higher sensitivity of 97% and resulted in an improved false discovery rate of 11.4% compared to the default ExomeDepth pipeline. The exclusion of exons with low mappability removes 4.5% of the exons, including a subset of exons (0.6%) in disease-associated genes which are intractable by short-read next-generation sequencing (NGS). Results from the reproducibility analysis showed that the clinically reported variants were reproducible 100% of the time and that the modified workflow can be used to rank variants from high to low confidence. Targeted testing of 30 CNVs identified in STRC, a challenging gene to ascertain by NGS, showed a 100% validation rate. Conclusions: In summary, we introduced a modification to the default ExomeDepth workflow to reduce the false positives originating from the repetitive regions of the genome, created a large-scale iterative variant calling framework for reproducibility, and provided recommendations for implementation in clinical settings. [ABSTRACT FROM AUTHOR]

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of "CIC-rearranged" sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases. [ABSTRACT FROM AUTHOR]

Prefabricated steel structures are being promoted in China as an important measure to reduce building carbon emissions (CEs). Currently, high-quality carbon emission factors and calculation methods that identify the sources of CEs from construction process are lacking. This study proposed a process-based method for calculating on-site construction CEs and empirically demonstrated its feasibility using a case of a multistory steel structure with typical column-beam systems. Six construction processes comprising 38 subprocesses were first categorized, then the energy and materials consumed for each subprocess were determined to obtain the first-hand CE parameters. The CEs from hoisting the first- and second-section columns were 10.52 kgCO 2 /column and 14.41 kgCO 2 /column, respectively, and the CEs from their installation were in the range 38.16–69.18 kgCO 2 /column. The CEs from hoisting the primary and secondary beams using a car crane were 7.73 kgCO 2 /beam and 4.52 kgCO 2 /beam, respectively, with lower CEs of 2.40 kgCO 2 /beam and 2.22 kgCO 2 /beam, respectively when a tower crane was used for hoisting. The 14 connection types used to install the primary beams and the 11 connection types used to install the secondary beams had CEs of 13.84–125.96 kgCO 2 /beam and 10.39–43.49 kgCO 2 /beam, respectively. The total on-site construction CE was subsequently calculated by summing the CEs from each process. This method was able to track the CE sources for each construction process and their contributions to identify those with high CE intensities. In addition, the case study was evaluated to provide specific feedback on the current national standard for calculating CEs from building construction. • Proposed method for calculating steel construction carbon emissions. • Conducted on-site case study to determine process-specific carbon emissions. • Considered fuel, electricity, and material consumptions. • Evaluated the results to critique the current national calculation standard. • Gave suggestions to improve calculation for on-site construction carbon emissions. [ABSTRACT FROM AUTHOR]

PURPOSE: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion–positive tumors. PATIENTS AND METHODS: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed. RESULTS AND DISCUSSION: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission. CONCLUSION: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer. [ABSTRACT FROM AUTHOR]

Childhood cancers present numerous challenges for variant interpretation in a clinical context due to their rarity, low mutation burden, and diversity of unique molecular alterations, many of which are not found in adult cancers. Consequently, variants associated with childhood tumors are under-represented in public cancer databases. Thus, a focused and directed effort is needed for the structured curation of genetic variant data to document diagnostic, prognostic, therapeutic, and hereditary-risk variants for childhood cancers. The ClinGen Somatic Pediatric Cancer Taskforce (PCT) seeks to address these challenges through multiple initiatives. By extensively analyzing the WHO Classification of Tumours Online: Paediatric Tumours volume and reviewing NCCN Guidelines, the PCT created a master list of key genomic alterations (n=975) in pediatric brain, solid, or hematologic malignancies (>180 ICD-O-3.2 diagnoses) that are drivers or have clinical impact to prioritize genes for curation in the CIViC (civicdb.org) knowledgebase. The PCT developed a pediatric specific curation Standard Operating Procedure for the entry of evidence into CIViC to instruct curators on how to tag pediatric evidence based on age of onset and the selection of the most appropriate ICD-O-3.2 disease. In collaboration with the Human Disease Ontology (DO; disease-ontology.org), 464 hematologic and brain cancer ICD-O-3.2 terms have been added to the DO to aid curated disease selection. To aid curators, the natural language processing methods of CIViCmine (bionlp.bcgsc.ca/civicmine) have been adapted to better recognize publications with pediatric evidence. Our efforts support the public dissemination of high-quality childhood cancer focused variant interpretations in the CIViC knowledgebase. [ABSTRACT FROM AUTHOR]

The Sarcoma Working Group of the Cancer Genomics Consortium (CGC) aims to understand the current state of diagnostic testing for pediatric sarcomas and the challenges faced in the field. We conducted a survey of CGC general constituents and American Cytogenetics Forum members (CYTOGN-L@LISTSERV.SC.EDU) in April/May 2022. In total, 46 responses were received, predominantly from university/academic/teaching hospitals (n=45) in the United States (n=41) and Canada (n=5). Respondents reported diverse roles including laboratory directors (n=25), pathologists (n=15), oncologists (n=3), and laboratory technologists (n=3). While most participants reported having in-house FISH (n=40) and/or conventional karyotyping (n=28) assays available for pediatric sarcomas, less than 40% of laboratories offer microarray and/or comprehensive NGS testing clinically. Detailed information on methodology and reported variant types will be discussed. When asked about genetic testing conundrums faced in their practice, the most common response was the scarcity of testing algorithm guidelines (n=12). Additional recurring challenges included: lack of support for new test development and issues with sendout testing (n=6), insufficient knowledge to interpret and act on results (n=4) or when to perform germline testing (n=3), limited tissue for comprehensive testing (n=3), and insurance/reimbursement complications (n=3). To address gaps in guidance for testing, the Workgroup is preparing a manuscript that will report survey results, provide practical scenario-based examples informed by the survey results and supported by literature evidence, and discuss testing options in resource-limited settings for the diagnostic workup of pediatric sarcomas. Areas of focus include but are not limited to NTRK -rearranged tumors and relevant germline testing in pediatric sarcomas. [ABSTRACT FROM AUTHOR]

PURPOSE: Neurotrophic tyrosine receptor kinase (NTRK) fusions have been described as oncogenic drivers in a variety of tumors. However, little is known about the overall frequency of NTRK fusion in unselected pediatric tumors. Here, we assessed the frequency, fusion partners, and clinical course in pediatric patients with NTRK fusion–positive tumors. PATIENTS AND METHODS: We studied 1,347 consecutive pediatric tumors from 1,217 patients who underwent tumor genomic profiling using custom-designed DNA and RNA next-generation sequencing panels. NTRK fusions identified were orthogonally confirmed. RESULTS AND DISCUSSION: NTRK fusions were identified in 29 tumors from 27 patients with a positive yield of 2.22% for all patients and 3.08% for solid tumors. Although NTRK2 fusions were found exclusively in CNS tumors and NTRK1 fusions were highly enriched in papillary thyroid carcinomas, NTRK3 fusions were identified in all tumor categories. The most canonical fusion was ETV6-NTRK3 observed in 10 patients with diverse types of tumors. Several novel NTRK fusions were observed in rare tumor types, including KCTD16-NTRK1 in ganglioglioma and IRF2BP2-NTRK3 in papillary thyroid carcinomas. The detection of an NTRK fusion confirmed the morphologic diagnosis including five cases where the final tumor diagnosis was largely based on the discovery of an NTRK fusion. In one patient, the diagnosis was changed because of the identification of an ETV6-NTRK3 fusion. One patient with infantile fibrosarcoma was treated with larotrectinib and achieved complete pathologic remission. CONCLUSION: NTRK fusions are more frequently seen in pediatric tumors than in adult tumors and involve a broader panel of fusion partners and a wider range of tumors than previously recognized. These results highlight the importance of screening for NTRK fusions as part of the tumor genomic profiling for patients with pediatric cancer. [ABSTRACT FROM AUTHOR]

Congenital brain tumors are rare accounting for 0.5%–1.9% of all pediatric brain tumors. While different criteria have been used to classify a tumor as congenital, those diagnosed prior to 6 months of age are considered to be "probably" congenital in origin. We performed an institutional review of all central nervous system (CNS) tumors (surgical and autopsy specimens from 1990 to 2019) in patients less than 6 months old. Sixty‐four unique cases were identified, and these accounted for 2.0% of all CNS tumor specimens at our institution. The most common tumor types were high‐grade gliomas, low‐grade gliomas and medulloblastomas. Atypical teratoid rhabdoid tumors, choroid plexus tumors and germ cell tumors also accounted for a significant portion of the cohort. Seven tumors were diagnosed prenatally. The most common clinical presentation at diagnosis was increased head circumference. At the conclusion of the study, over half of the patients were alive including all patients with WHO grade I and II tumors. Ninety‐two percent of cases were classifiable using the 2016 WHO system, and when available, molecular findings supported the histologic diagnoses. However, several gliomas had unusual histologic features and did not correspond to a well‐defined entity. Molecular testing was essential for accurate classification of a subset of these tumors, and several high‐grade gliomas exhibited fusions considered unique to infantile gliomas, including those involving the MET, ALK and NTRK genes. To our knowledge, this cohort represents the largest single‐institution study of congenital CNS tumors and highlights many ways in which congenital CNS tumors are distinct from CNS tumors of older pediatric patients and adults. [ABSTRACT FROM AUTHOR]

Background: Circulating tumor DNA (ctDNA) offers a convenient way to monitor tumor progression and treatment response. Because tumor mutational profiles are highly variable from person to person, a fixed content panel may be insufficient to track treatment response in all patients.Methods: We design ctDNA fingerprint panels specific to individual patients which are based on whole exome sequencing and target to high frequency clonal population clusters in patients. We test the fingerprint panels in 313 patients who together have eight tumor types (colorectal, hepatocellular, gastric, breast, pancreatic, and esophageal carcinomas and lung cancer and cholangiocarcinoma) and exposed to multiple treatment methods (surgery, chemotherapy, radiotherapy, targeted-drug therapy, immunotherapy, and combinations of them). We also monitor drug-related mutations in the patients using a pre-designed panel with eight hotspot genes.Results: 291 (93.0%) designed fingerprint panels harbor less than ten previously known tumor genes. We detected 7475 ctDNA mutations in 238 (76%) patients and 6196 (96.0%) of the mutations are detected in only one test. Both the level of ctDNA content fraction (CCF) and fold change of CCF (between the definitive and proceeding tests) are highly correlated with clinical outcomes (p-values 1.36e-6 for level and 5.64e-10 for fold change, Kruskal-Wallis test). The CCFs of PD patients are an order of magnitude higher than the CCFs of SD and OR patients (median/mean 2.22%/8.96% for SD, 0.18/0.21% for PD, and 0.31/0.54% for OR; pairwise p-values 7.8e-6 for SD ~ PD, 2.7e-4 for OR ~ PD, and 7.0e-3 for SD ~ OR, Wilcoxon rank sum test). The fold change of CCF distinguishes the patient groups even better, which increases for PD, remains stable for SD, and decreases for OR patients (p-values 0.002, ~ 1, and 0.0001 respectively, Wilcoxon signed-rank test). Eleven drug-related mutations are identified from nine out of the 313 patients.Conclusions: The ctDNA fingerprint method improves both specificity and sensitivity of monitoring treatment response across several tumor types. It can identify tumor relapse/recurrence potentially earlier than imaging-based diagnosis. When augmented with tumor hotspot genes, it can track acquired drug-related mutations in patients. [ABSTRACT FROM AUTHOR]

• MDS evolution to AML can be monitored by periodic leukemia gene panel testing. • MDS does not affect overall survival in patients with MIRAGE syndrome. • SAMD9 genotype impacts overall survival. Gain of function variants in SAMD9 cause MIRAGE syndrome, a rare Mendelian disorder that results in myeloid dysplastic syndrome (MDS), poor immune response, restricted growth, adrenal insufficiency, ambiguous genitalia, feeding difficulties and most often significantly reduced lifespan. In this study, we describe histomorphologic and genetic changes occurring in serial bone marrow measurements in a patient with MIRAGE syndrome and untreated MDS of 9 years. Histomorphological analysis during childhood showed progressive hypocellularity with erythroid and megakaryocytic dysplasia and cytogenetic testing demonstrated monosomy 7. Serial leukemia gene panel testing performed over a seven year period revealed multiple pre-leukemic clones arising at age 7 years followed by sequential mutational events in ETV6 and RUNX1 driving acute myeloid leukemia (AML) at age 9. Comprehensive genotype-phenotype analysis with 28 previously reported patients found the presence of MDS did not impact overall survival, but in silico variant pathogenicity prediction scores for SAMD9 distinguished patients with poor prognosis. Overall, our analysis shows progression of MDS to AML can be monitored by following mutation evolution in leukemia related genes in patients with MIRAGE syndrome, and specific SAMD9 mutations likely influence disease severity and overall survival. [ABSTRACT FROM AUTHOR]

• This evidence-based review presents a detailed description of genomic aberrations in all categories of B-lymphoblastic leukemia including clinical outcomes, prognosis, and technical consideration for diagnosis. Clinical management and risk stratification of B-lymphoblastic leukemia/ lymphoma (B-ALL/LBL) depend largely on identification of chromosomal abnormalities obtained using conventional cytogenetics and Fluorescence In Situ Hybridization (FISH) testing. In the last few decades, testing algorithms have been implemented to support an optimal risk-oriented therapy, leading to a large improvement in overall survival. In addition, large scale genomic studies have identified multiple aberrations of prognostic significance that are not routinely tested by existing modalities. However, as chromosomal microarray analysis (CMA) and next-generation sequencing (NGS) technologies are increasingly used in clinical management of hematologic malignancies, these abnormalities may be more readily detected. In this article, we have compiled a comprehensive, evidence-based review of the current B-ALL literature, focusing on known and published subtypes described to date. More specifically, we describe the role of various testing modalities in the diagnosis, prognosis, and therapeutic relevance. In addition, we propose a testing algorithm aimed at assisting laboratories in the most effective detection of the underlying genomic abnormalities. [ABSTRACT FROM AUTHOR]

• Overview of the assessment of genomic findings in the diagnostic workup of CNS neoplasia. • Technical and organizational approaches to genomic assessment of copy number aberrations. • A comprehensive yet concise review of the most important genomic findings in select CNS tumors. • Annotations regarding diagnostic relevance as established by the WHO and other organizations. • Multiple illustrations to demonstrate techniques in the genomic assessment of CNS neoplasia. The period from the 1990s to the 2010s has witnessed a burgeoning sea change in the practice of surgical neuropathology due to the incorporation of genomic data into the assessment of a range of central nervous system (CNS) neoplasms. This change has since matured into the adoption of genomic information into the definition of several World Health Organization (WHO)-established diagnostic entities. The data needed to accomplish the modern diagnosis of CNS neoplasia includes DNA copy number aberrations that may be assessed through a variety of mechanisms. Through a review of the relevant literature and professional practice guidelines, here we provide a condensed and scored overview of the most critical DNA copy number aberrations to assess for a selection of primary CNS neoplasms. [ABSTRACT FROM AUTHOR]

PURPOSE: The diagnosis of cancer predisposition in pediatric patients with cancer is vital for treatment decisions, surveillance, and management of at-risk family members. Somatic tumor testing can identify potential underlying constitutional variants that confer increased cancer risk. Here, we report the characteristics of constitutional variants identified through tumor testing. MATERIALS AND METHODS: Data were abstracted from medical record review of 1,023 patients who received in-house somatic tumor testing over a 28-month period. Patients were identified for testing using referral criteria developed as a collaboration between genomic diagnostics, pathology, and oncology. Characteristics of patients who underwent constitutional testing, including family history and variant loss of heterozygosity, were tracked. RESULTS: From 1,023 patients who underwent somatic tumor sequencing in a 28-month period, 210 variants were identified in 141 patients (13.8%) that were concerning for cancer predisposition syndromes requiring intervention. A total of 73 variants in 41 patients have undergone clinical confirmatory testing thus far. Of these, 26 variants were confirmed to be constitutionally present (35.6%). Among patients tested, 23 (56.1%) of 41 total patients were diagnosed with a cancer predisposition syndrome. CONCLUSION: Our data demonstrate that more than one third of variants in tumor somatic sequencing that were concerning for underlying cancer predisposition were constitutionally confirmed. Overall, somatic tumor testing identified potential cancer predisposition syndromes in pediatric patients, and some would not have been identified on the basis of clinical history alone. [ABSTRACT FROM AUTHOR]

The article focuses on the characterization of a FGFR2-INA fusion gene which was identified during genomic profiling in two cases of mixed neuronal-glial tumors that were not able to be specified as dysembryoplastic neuroepithelial tumors or ganglioglioma.

Krüppel-like factors (KLFs) are zinc finger-containing transcription factors that play key roles in the regulation of differentiation and development as well as biological processes central to the development of malignancies. Increasing evidence indicates that Krüppel-like factor 9 (KLF9) plays a critical role in regulating tumorigenesis. However, the biological role and molecular mechanism of KLF9 in glioma progression remain unclear. Herein, we found that KLF9 expression was strongly reduced in gliomas. Reduced KLF9 expression promoted glioma cell proliferation. Importantly, re-constitution of KLF9 expression inhibited glioma cell proliferation and tumor growth in vivo . Furthermore, we determined that KLF9 interacted with the miR-21 promoter, leading to suppression of miR-21 expression and cell cycle arrest. Taken together, our findings indicate a novel mechanism for KLF function in tumorigenesis and may also suggest new targets for clinical intervention in human cancer. [ABSTRACT FROM AUTHOR]

Teriparatide is a commonly used drug indicated for the treatment of osteoporosis in postmenopausal women. Teriparatide can also upregulate Ang-1 expression through the AC/PKA signaling pathway to promote angiogenesis. At present, promoting angiogenesis is a promising but unrealized strategy for the treatment of ischemic cerebral infarction. However, there are few studies on the application of teriparatide in the treatment of cerebral infarction. We used teriparatide to treat ischemic cerebral infarction in rats and obtained three major findings. First, teriparatide can promote angiogenesis, reduce cerebral infarct size, and increase cerebral perfusion by upregulating Ang-1 expression. Second, teriparatide can promote the expression of HO1, SOD2 and inhibit the production of pro-inflammatory cytokines IL-1β, IL-6 by upregulating Nrf2 expression. Third, we further found that teriparatide can mitigate blood-brain barrier disruption and brain edema by downregulating the expressions of MMP9, Ang-2 and AQP4. Our results indicate that teriparatide is neuroprotective through multiple mechanisms of action that include promoting angiogenesis, inhibiting oxidative stress and neuroinflammation, protecting blood-brain barrier, and reducing brain edema. [Display omitted] • Teriparatide promotes angiogenesis by upregulating Ang-1 expression. • Teriparatide plays a crucial role in inhibiting oxidative stress and anti-neuroinflammation. • Teriparatide can mitigate blood-brain barrier disruption and brain edema. [ABSTRACT FROM AUTHOR]

Abstract: Mice that are deficient in p53 exhibit an early onset of multiple types of tumors, especially thymic lymphoma. However, it remains unclear to what extent each of the p53-regulated pathways exerts its tumor suppressor activity. p21Cip1/Waf1, acting down stream of p53, is a major G1/S checkpoint protein that restricts cell cycle progression into S phase in the presence of DNA damage. While at old ages p21−/− mice have a higher incidence of many types of tumors than p21+/+ mice, they are more resistant to thymic lymphomagenesis. In this study, we characterized mutagenesis in vivo in T cells of p21-deficient mice, using loss of heterozygosity (LOH) at Aprt locus as an indicator. We found that the spontaneous Aprt mutant frequency in T cells of p21−/− mice is lower than that in p21+/+ mice. The mutational spectra, however, are similar, with mitotic recombination being the predominant pathway. In contrast to the remarkable induction of LOH events in T cells of p53−/− mice exposed to X-rays, LOH in T cells of p21−/− mice is not significantly induced by X-rays. Correspondingly, lymphoid cells of p21−/− mice are more sensitive to IR-induced apoptosis than those of p21+/+ mice, in contrast to the radioresistance of p53-deficient lymphocytes. Reduction in mutation load in T cell lineages may contribute to the suppression of thymic lymphomagenesis in p21−/− mice. [Copyright &y& Elsevier]