Correlation Between Immunohistochemistry and Sequencing in H3G34-Mutant Gliomas

ola Kala shared this article with you from Inoreader Correlation Between Immunohistochemistry and Sequencing in H3G34-Mutant Gliomas Μέσω The American Journal of Surgical Pathology - Current Issue Recurrent glycine-to-arginine/valine alterations at codon 34 (G34R/V) within H3F3A gene characterize a subset of hemispheric high-grade gliomas (HGG) affecting children and young adults. These tumors, defined as G34R/V-mutant gliomas, are histologically heterogenous, with microscopic features of either HGG or embryonal tumors (primitve neuroectodermal tumor-like features). To assess the value of immunohistochemistry (IHC) to detect G34R/V-mutated cases, we tested anti-histone G34V (clone 329E5) and anti-histone G34R (clone RM240) antibodies in a series of 28 formalin-fixed and paraffin-embedded samples. A total of 28 cases of hemis pheric, IDH-wt HGG mainly affecting children and young adults were evaluated by IHC and by sequencing. The median age of patients at diagnosis was 17 years (0.1 to 26 y). By IHC, 10 of the 28 cases showed nuclear positivity for G34R and 3 of the 28 cases for G34V. Molecular analysis of G34R/V-mutation status was successful in 24 of the 28 cases. Mutation at glycine 34 of the H3F3A gene was identified in 9 of the 24 tumors (37%) by direct sequencing, revealing 7 of 9 positive case by sequencing and 2 of 9 false negative cases by IHC. Two of 15 negative case by sequencing demonstrated a false positivity by IHC. In total, in 4 (16.6%) of 24 cases, IHC and mutational results were discordant: 2 tumors were negative by IHC (false negative) but harbored G34R mutation by sequencing, and 2 cases were positive by IHC (false positive by IHC) but wild type by sequencing. Moreover, most mutated cases showed loss of ATRX expression and/or p53 expression. The positivity by IHC with specific anti body tested is not highly predictive for presence of G34R/V mutation, but confirmation by sequencing is mandatory; G34R/V mutations should be suspected in all hemispheric tumor IDH1/2 wild type, showing loss of OLIG2 and ATRX and/or p53 expression. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

INSM1 Is Less Sensitive But More Specific Than Synaptophysin in Gynecologic High-grade Neuroendocrine Carcinomas: An Immunohistochemical Study of 75 Cases With Specificity Test and Literature Review

ola Kala shared this article with you from Inoreader INSM1 Is Less Sensitive But More Specific Than Synaptophysin in Gynecologic High-grade Neuroendocrine Carcinomas: An Immunohistochemical Study of 75 Cases With Specificity Test and Literature Review Μέσω The American Journal of Surgical Pathology - Current Issue Insulinoma-associated protein 1 (INSM1) has emerged as a promising diagnostic marker for high-grade neuroendocrine carcinomas (HGNECs); however, it is controversial whether INSM1 is more sensitive than conventional markers chromogranin, synaptophysin, and CD56. Here, we investigated immunohistochemical expression of INSM1 in 75 gynecologic HGNECs using full tissue sections (30 small-cell carcinomas [SmCCs], 34 large-cell neuroendocrine carcinomas [LCNECs], and 11 mixed SmCC and LCNEC), with specificity analysis in 422 gynecologic non-neuroendocrine tumors (410 in tissue microarrays and 12 full sections) and comparison with conven tional neuroendocrine markers for their sensitivity and specificity. Positive INSM1 staining was seen in 69 (92%) HGNECs, whereas chromogranin, synaptophysin, and CD56 staining was seen in 61 (81%), 72 (96%), and 44 (69%) tumors, respectively (INSM1 vs. chromogranin, P=0.09; INSM1 vs. synaptophysin, P=0.4942; and INSM1 vs. CD56, P View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations

ola Kala shared this article with you from Inoreader Two Cases With Features of Lymphocyte Variant Hypereosinophilic Syndrome With STAT3 SH2 Domain Mutations Μέσω The American Journal of Surgical Pathology - Current Issue Lymphocyte variant hypereosinophilic syndrome (LV-HES) is a rare cause of eosinophilia that is due to eosinophilipoietic cytokine production by an immunophenotypically abnormal T-cell clone. The molecular pathogenesis of this disorder is largely unknown and only 1 case of LV-HES with a pathogenic STAT3 mutation has been described thus far. Here we report 2 cases of LV-HES with STAT3 SH2 domain mutations. These cases further support the model that activation of STAT3 signaling through STAT3 SH2 domain mutations is a recurrent event in LV-HES. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Malignant Diffuse Mesothelioma in Women: A Study of 354 Cases

ola Kala shared this article with you from Inoreader Malignant Diffuse Mesothelioma in Women: A Study of 354 Cases Μέσω The American Journal of Surgical Pathology - Current Issue No abstract available View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Male–Female Fertility Differentials

ola Kala shared this article with you from Inoreader Male–Female Fertility Differentials Across 17 High-Income Countries: Insights From A New Data Resource Μέσω Latest Results for European Journal of Population Abstract Obtaining cross-country comparative perspectives on male fertility has long been difficult, as male fertility is usually less well registered than female fertility. Recent methodological advancements in imputing missing paternal ages at childbirth enable us to provide a new database on male fertility. This new resource covers more than 330 million live births and is based on a consistent and well-tested set of methods. These methods allow us to handle missing information on the paternal age, which is missing for roughly 10% of births. The data resource is made available in the Human Fertility Collection and allows for the first time a comparative perspective on male fertility in high-income countries using high-quality birth register data. We analyze trends in male–female fertility quantum and tempo differentials across 17 high-income countries, dating as back as far as the late 1960s for some countries, and with data available for the majority of countries fro m the 1980s onward. Using descriptive and counterfactual analysis methods, we find substantial variation both across countries and over time. Related to the quantum we demonstrate that disparities between male and female period fertility rates are driven to a large degree by the interplay of parental age and cohort size differences. For parental age differences at childbirth, we observe a development toward smaller disparities, except in Eastern Europe. This observation fits with expectations based on gender theories. However, variation across countries also seems to be driven by factors other than gender equality. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Clinical perspectives of BET inhibition in ovarian cancer

Cancer shared this article with you from Inoreader Clinical perspectives of BET inhibition in ovarian cancer Via Latest Results for Cellular Oncology Abstract Background Bromodomain and extra-terminal (BET) proteins are epigenetic readers that bind to acetylated lysines of histones and regulate gene transcription. BET protein family members mediate the expression of various oncogenic drivers in ovarian cancer, such as the MYC and Neuregulin 1 (NRG1) genes. BRD4, the most thoroughly studied member of the BET family, is amplified in a significant subset of high-grade serous carcinomas (HGSC) of the ovary. It has been reported that BET inhibitors can attenuate the proliferation and dissemination of ovarian cancer cells by inhibiting oncogenic pathways, such as the FOXM1 and JAK/STAT pathways. BET inhibition can re-sensitize resistant ovarian cancer cells to already approved anticancer agents, including cisplatin and PARP inhibitors. This synergism was also confirmed in vivo in animal models. These and other preclinical results provide a promising basis for the application of BET inhibitors in ovarian cancer treat ment. Currently, Phase I/II clinical trials explore the safety and efficacy profiles of BET inhibitors in various solid tumors, including ovarian tumors. Here, we review current knowledge on the molecular effects and preclinical activities of BET inhibitors in ovarian tumors. Conclusions BET proteins have emerged as new druggable targets for ovarian cancer. BET inhibitors may enhance antitumor activity when co-administered with conventional treatment regimens. Results from ongoing Phase I/II studies are anticipated to confirm this notion. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Protein arginine methyltransferase 5: a potential cancer therapeutic target

Cancer shared this article with you from Inoreader Protein arginine methyltransferase 5: a potential cancer therapeutic target Via Latest Results for Cellular Oncology Abstract Background PRMT5 is a type II protein arginine methyltransferase that methylates histone or non-histone proteins. Arginine methylation by PRMT5 has been implicated in gene transcription, ribosome biogenesis, RNA transport, pre-mRNA splicing and signal transduction. High expression of PRMT5 has been observed in various cancers and PRMT5 overexpression has been reported to improve cancer cell survival, proliferation, migration and metabolism and to inhibit cancer cell apoptosis. In addition, PRMT5 has been found to be required for cancer stem cell survival, self-renewal and differentiation. Several microRNAs have been shown to regulate PRMT5 expression. As PRMT5 has oncogene-like properties, several PRMT5 inhibitors have been used to explore their efficacy as potential drugs for different types of cancer, and three of them are now being tested in clinical trials. Conclusions In this review, we summarize current knowledge on the role of PRMT5 in cancer development and progression, including its functions and underlying mechanisms. In addition, we highlight the rapid development of PRMT5 inhibitors and summarize ongoing clinical trials for cancer therapy. By affecting both tumor cells and the tumor microenvironment, PRMT5 inhibitors may serve as effective anti-cancer agents, especially when combined with immune therapies. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer

Cancer shared this article with you from Inoreader In silico transcriptomic mapping of integrins and immune activation in Basal-like and HER2+ breast cancer Via Latest Results for Cellular Oncology Abstract Purpose Integrins, transmembrane receptors that mediate cell-extracellular matrix and cell-cell interactions, have been linked to several cancer-associated features. A less explored function of integrins in cancer is their role in leukocyte homing and activation. Understanding their relationship with immune cell infiltrates and immune checkpoints is an area of interest in cancer research. Methods The expression of 33 different integrins was evaluated in relation with breast cancer patient outcome using transcriptomic data (Affymetrix dataset, exploratory cohort) and the METABRIC study (validation cohort). The TIMER online tool was used to assess the association of the identified integrin genes with immune cell infiltration, and the TCGA and METABRIC studies to assess correlations between integrin gene expression and genomic signatures of immune activation. Results We identified 7 genes coding for integrin α and β subunits, i.e., ITGA4, ITGB2, ITGAX, ITGB7, ITGAM, ITGAL and ITGA8, which predict a favorable prognosis in Basal-like and HER2+ breast cancers. Their expression positively correlated with the presence of immune cell infiltrates within the tumor (dendritic cells, CD4+ T-cells, neutrophils, CD8+ T-cells and B-cells), with markers of T-cell activation and antigen presentation, and with gene signatures of immune surveillance (cytotoxic T lymphocyte activation and IFN gamma signature). By contrast, we found that genes coding for integrins that predicted a detrimental outcome (IBSP, ITGB3BP, ITGB6, ITGB1 and ITGAV) were not associated with any of these parameters. Conclusions We identified an integrin signature composed of 7 genes with potential to recognize immune infiltrated and activated Basal-like and HER2+ breast cancers with a favorable prognosis. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB

Cancer shared this article with you from Inoreader Acetylation-stabilized chloride intracellular channel 1 exerts a tumor-promoting effect on cervical cancer cells by activating NF-κB Via Latest Results for Cellular Oncology Abstract Purpose Cervical cancer remains a major cause of cancer-related death in women, especially in developing countries. Previously, we found that the acetylation levels of chloride intracellular channel 1 (CLIC1) at lysine 131 were increased in cervical cancer tissues using a label-free proteomics approach. The aim of this study was to further determine the role of CLIC1 expression and its acetylation in cervical cancer. Methods CLIC1 expression and its implications for the prognosis of cervical cancer were analyzed using primary patient samples and cells, and the Gene Expression Profiling Interactive Analysis (GEPIA) database (gepia.cancer-pku.cn). The effect of CLIC1 on cervical cancer cells was evaluated using Cell Counting Kit (CCK)-8, flow cytometry, scratch wound healing, transwell, Western blotting and co-immunoprecipitation (Co-IP) assays. In vivo tumor growth was assessed using mouse xenograft models. Results We found that CLIC1 expression was increased in cervical cancer tissues and cells and that patients with a high CLIC1 expression tended to have a shorter overall survival time. Knockdown of CLIC1 significantly reduced in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumorigenesis. At the molecular level, we found that nuclear factor kappa B (NF-κB) activity was positively regulated by CLIC1. Pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB, attenuated the tumor-promoting effect of CLIC1. Moreover, we found that CLIC1 acetylation at K131 was upregulated in cervical cancer cells, which stabilized CLIC1 by inhibiting its ubiquitynation. Substitution of K131 inhibited CLIC1 ubiquitynation and promoted in vitro cervical cancer cell proliferation, migration and invasion, and in vivo tumor growth. In addition, we found that acetyltransferase HAT1 was responsible for CLIC1 acetylation at K131. Conclusion Our data indicate that CLIC1 acts as a tumor promoter in cervical cancer, suggesting a potential treatment strategy for cervical cancer by regulating CLIC1 expression and/or acetylation. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer

Cancer shared this article with you from Inoreader CHRNA5 belongs to the secondary estrogen signaling network exhibiting prognostic significance in breast cancer Via Latest Results for Cellular Oncology Abstract Purpose Cholinergic signals can be important modulators of cellular signaling in cancer. We recently have shown that knockdown of nicotinic acetylcholine receptor subunit alpha 5, CHRNA5, diminishes the proliferative potential of breast cancer cells. However, modulation of CHRNA5 expression in the context of estrogen signaling and its prognostic implications in breast cancer remained unexplored. Methods Meta-analyses of large breast cancer microarray cohorts were used to evaluate the association of CHRNA5 expression with estrogen (E2) treatment, estrogen receptor (ER) status and patient prognosis. The results were validated through RT-qPCR analyses of multiple E2 treated cell lines, CHRNA5 depleted MCF7 cells and across a breast cancer patient cDNA panel. We also calculated a predicted secondary (PS) score representing direct/indirect induction of gene expression by E2 based on a public dataset (GSE8597). Co-expression analysis was performed using a weighted gene co-expression network analysis (WGCNA) pipeline. Multiple other publicly available datasets such as CCLE, COSMIC and TCGA were also analyzed. Results Herein we found that CHRNA5 expression was induced by E2 in a dose- and time-dependent manner in breast cancer cell lines. ER− breast tumors exhibited higher CHRNA5 expression levels than ER+ tumors. Independent meta-analysis for survival outcome revealed that higher CHRNA5 expression was associated with a worse prognosis in untreated breast cancer patients. Furthermore, CHRNA5 and its co-expressed gene network emerged as secondarily induced targets of E2 stimulation. These targets were largely downregulated by exposure to CHRNA5 siRNA in MCF7 cells while the response of primary ESR1 targets was dependent on the direction of the PS-score. Moreover, primary and secondary target genes were uncoupled and clustered distinctly based on multiple public datasets. Conclusion Our findings strongly associate increased expression of CHRNA5 and its co-expression network with secondary E2 signaling and a worse prognosis in breast cancer. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The role of capecitabine-based neoadjuvant and adjuvant chemotherapy in early-stage triple-negative breast cancer: a systematic review and meta-analysis

Cancer shared this article with you from Inoreader The role of capecitabine-based neoadjuvant and adjuvant chemotherapy in early-stage triple-negative breast cancer: a systematic review and meta-analysis Via Latest Results for BMC Cancer Abstract Background The role of capecitabine in neoadjuvant and adjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) is highly controversial. Our meta-analysis was designed to further elucidate the effects of capecitabine on survival in early-stage TNBC patients and its safety. Methods PubMed, Embase, and papers presented at several main conferences were searched up to December 19, 2019, to investigate capecitabine-based versus capecitabine-free neoadjuvant and adjuvant chemotherapy in TNBC patients. Heterogeneity was assessed using I2 test, combined with hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CI) computed for disease-free survival (DFS), overall survival (OS), and over grade 3 adverse events (AEs). Results A total of 9 randomized clinical trials and 3842 TNBC patients were included. Overall, the combined capecitabine regimens in neoadjuvant and adjuvant chemotherapy showed significantly improved DFS (HR = 0.75; 95% CI, 0.65–0.86; P < 0.001) and OS (HR = 0.63; 95% CI, 0.53–0.77; P < 0.001). In subgroup analysis, there were improvements in DFS in the groups with addition of capecitabine (HR = 0.64; 95% CI, 0.53–0.78; P < 0.001), adjuvant chemotherapy (HR = 0.73; 95% CI, 0.63–0.85; P < 0.001), and lymph node positivity (HR = 0.62; 95% CI, 0.44–0.86; P = 0.005). Capecitabine regimens were related to higher risks of diarrhea (OR = 2.88, 95% CI 2.23–3.74, P < 0.001), stomatitis (OR = 2.01, 95% CI 1.53–2.64, P < 0.001) and hand–foot syndrome (OR = 8.67, 95% CI 6.70–11.22, P < 0.001). Conclusion This meta-analysis showed that neoadjuvant and adjuvant chemotherapy combined with capecitabine significantly improved both DFS and OS in early-stage TNBC patients with tolerable AEs. There were benefits to DFS in the groups with the addition of capecitabine, adjuvant chemotherapy, and lymph node positivity. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.