Oncocytic Intraductal Carcinoma of Salivary Glands: A Distinct Variant with TRIM33‐RET Fusions and BRAF V600E mutations

alwin shared this article with you from Inoreader Oncocytic Intraductal Carcinoma of Salivary Glands: A Distinct Variant with TRIM33‐RET Fusions and BRAF V600E mutations Via Histopathology Abstract Aims Salivary gland intraductal carcinoma (IDC) is a complex ductal neoplasm surrounded by a layer of myoepithelial cells. Recent insights have shown that there are 3 different types: intercalated duct‐like, with frequent NCOA4‐RET fusions; apocrine, with salivary duct carcinoma‐like mutations; and mixed intercalated duct‐like/apocrine with RET fusions including TRIM27‐RET. In addition, an oncocytic IDC was described, but it remains unclear if it represents a fourth variant or simply oncocytic metaplasia of another IDC type. Methods and Results Six IDCs with oncocytic changes were retrieved from the authors' archives, from 3 men and 3 women ranging from 45‐75 years (mean, 63). Five arose in the parotid, with one in an accessory parotid gland. Four patients with follow‐up were free of disease after 1‐23 months. Several immunostains (S100, mammaglobin, androgen receptor, p63/p40) and molecular tools (RNA sequencing, RET fluorescence in situ hybridization, BRAF V600E VE1 immunohistochemistry and Sanger sequencing) were performed. Histologically, tumors were variably cystic with solid intracystic nodules often difficult to recognize as intraductal. In all, tumor ducts were positive for S100 and mammaglobin, negative for androgen receptor, and completely surrounded by myoepithelial cells positive for p63/p40. Molecular analysis revealed TRIM33‐RET in 2/6, NCOA4‐RET in 1/6, and BRAF V600E in 2/6 cases. One case had no identifiable alterations. Conclusions Oncocytic IDC shares similarities with intercalated duct‐like IDC. While additional verification is needed, the oncocytic variant appears to be sufficiently unique to be regarded now as the fourth distinct subtype of IDC. Because of its indolent nature, oncocytic IDC should be distinguished from histologic mimickers. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

A Network Pharmacology to Explore the Mechanism of Astragalus Membranaceus in the Treatment of Diabetic Retinopathy

alwin shared this article with you from Inoreader A Network Pharmacology to Explore the Mechanism of Astragalus Membranaceus in the Treatment of Diabetic Retinopathy Via eCAM Evidence-Based Complementary and Alternative Medicine IF=2,064 Background. Diabetic retinopathy (DR) includes a series of typical lesions affected by retinal microvascular damage caused by diabetes mellitus (DM), which not only seriously damages the vision, affecting the life's quality of patients, but also brings a considerable burden to the family and society. Astragalus Membranaceus (AM) is a commonly used medicine in clinical therapy of eye disorders in traditional Chinese medicine (TCM). In recent years, it is also used for treating DR, but the specific mechanism is unclear. Therefore, this study explores the potential mechanism of AM in DR treatment by using network pharmacology. Methods. Based on the oral bioavailability (OB) and drug likeness (DL) of two ADME (absorption, distribution, metabolism, excretion) parameters, Traditional Chinese Medicine Systems P harmacology Database (TCMSP), Swiss Target Prediction platform, GeneCards, and OMIM database were used to predict and screen the active compounds of AM, the core targets of AM in DR treatment. The Metascape data platform was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis on the core targets. Results. 24 active compounds were obtained, such as quercetin, kaempferol, and astragaloside IV. There were 169 effective targets of AM in DR treatment, and the targets were further screened and finally, 38 core targets were obtained, such as VEGFA, AKT1, and IL-6. EGFR tyrosine kinase inhibitor resistance, AGE-RAGE signaling pathway in diabetic complications, PI3K-Akt signaling pathway, and other metabolic pathways participated in oxidative stress, cell apoptosis, angiogenesis signal transduction, inflammation, and other biological processes. Conclusion. AM treats DR through multiple compounds, multiple targets, and multiple pat hways. AM may play a role in the treatment of DR by targeting VEGFA, AKT1, and IL-6 and participating in oxidative stress, angiogenesis, and inflammation. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Ethnopharmacology, Phytochemistry, and Pharmacology of Syzygium nervosum

alwin shared this article with you from Inoreader Ethnopharmacology, Phytochemistry, and Pharmacology of Syzygium nervosum Via eCAM Evidence-Based Complementary and Alternative Medicine IF=2,064 Syzygium nervosum, which belongs to the Myrtaceae plant family, is widely distributed and cultivated in South East Asian countries. The decoction of S. nervosum leaves and flower buds has been consumed regularly as a beverage among the Vietnamese and Chinese communities. In addition, it has also been used in traditional medicine for a variety of purposes, notably for influenza, skin diseases, and digestive conditions. To date, there has been a considerable number of publications on chemical profiling and pharmacological activities of S. nervosum crude extract and pure isolated compounds. Our analysis indicated the characteristic chemical scaffolds and potential bioactivities on cancer, diabetes, and inflammatory diseases of this plant. The review aims to summarize up-to-date past study results and suggest future research direction on this species, in order to promote clinical applications of S. nervosum. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Isolation of acetylated and unmodified protein N-terminal peptides by strong cation exchange chromatographic separation of TrypN-digested peptides [Technological Innovation and Resources]

alwin shared this article with you from Inoreader Isolation of acetylated and unmodified protein N-terminal peptides by strong cation exchange chromatographic separation of TrypN-digested peptides [Technological Innovation and Resources] Via MCP Papers in Press We developed a simple and rapid method to enrich protein N-terminal peptides, in which the protease TrypN is first employed to generate protein N-terminal peptides without Lys or Arg and internal peptides with two positive charges at their N-termini, and then the N-terminal peptides with or without N-acetylation are separated from the internal peptides by strong cation exchange chromatography according to a retention model based on the charge/orientation of peptides. This approach was applied to 20 μg of human HEK293T cell lysate pr oteins to profile the N-terminal proteome. On average, 1,550 acetylated and 200 unmodified protein N-terminal peptides were successfully identified in a single LC/MS/MS run with less than 3% contamination with internal peptides, even when we accepted only canonical protein N-termini registered in the Swiss-Prot database. Since this method involves only two steps, protein digestion and chromatographic separation, without the need for tedious chemical reactions, it should be useful for comprehensive profiling of protein N-termini, including proteoforms with neo-N-termini. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Coexistence of a rare type of ectopic kidney with atypical renal vasculature

alwin shared this article with you from Inoreader Coexistence of a rare type of ectopic kidney with atypical renal vasculature Via Anatomical Science International Abstract Knowledge of anatomical anomalies is significant for all specialists in clinical practice and may prevent serious complications following medical procedures. This report presents the rare crossed fused renal ectopia (CFRE) with atypical renal vasculature in cadaver of a 68-year-old man. The ectopic kidney was located on right side with four renal veins, three renal arteries, two ureters, where one of them is double. The embryological background, as well as the potential clinical significance of this morphological variation, is discussed. An interventional radiological and surgical procedure should be appropriately implemented to treat anomalies of vessels and CFRE. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Integrated Genomic Characterization of the Human Immunome in Cancer

alwin shared this article with you from Inoreader Integrated Genomic Characterization of the Human Immunome in Cancer Via Cancer Research current issue Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output across cancer types is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in patients with cancer. To do so, we developed a Network-based Integrative model to Prioritize Potential immune respondER genes (NIPPER). Identified mutations were enriched in essential protein domains and genes identified by NIPPER were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a re source for future functional studies and targeted therapeutics.Significance:This study demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion

alwin shared this article with you from Inoreader Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion Via Cancer Research current issue T-cell exhaustion in cancer is linked to poor clinical outcomes, where evidence suggests T-cell metabolic changes precede functional exhaustion. Direct competition between tumor-infiltrating lymphocytes (TIL) and cancer cells for metabolic resources often renders T cells dysfunctional. Environmental stress produces epigenome remodeling events within TIL resulting from loss of the histone methyltransferase EZH2. Here, we report an epigenetic mechanism contributing to the development of metabolic exhaustion i n TIL. A multiomics approach revealed a Cdkn2a.Arf-mediated, p53-independent mechanism by which EZH2 inhibition leads to mitochondrial dysfunction and the resultant exhaustion. Reprogramming T cells to express a gain-of-function EZH2 mutant resulted in an enhanced ability of T cells to inhibit tumor growth in vitro and in vivo. Our data suggest that manipulation of T-cell EZH2 within the context of cellular therapies may yield lymphocytes that are able to withstand harsh tumor metabolic environments and collateral pharmacologic insults.Significance:These findings demonstrate that manipulation of T-cell EZH2 in cellular therapies may yield cellular products able to withstand solid tumor metabolic–deficient environments.Graphical Abstract:http://cancerres.aacrjournals.org/content/canres/80/21/4707/F1.large.jpg. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Breast Cancer Cell Detection and Characterization from Breast Milk-Derived Cells

alwin shared this article with you from Inoreader Breast Cancer Cell Detection and Characterization from Breast Milk-Derived Cells Via Cancer Research current issue Radiologic techniques remain the main method for early detection for breast cancer and are critical to achieve a favorable outcome from cancer. However, more sensitive detection methods to complement radiologic techniques are needed to enhance early detection and treatment strategies. Using our recently established culturing method that allows propagation of normal and cancerous breast epithelial cells of luminal origin, flow cytometry characterization, and genomic sequencing, we show that cancer cells can be detected in breast milk. Cells derived from milk from the breast with cancer were enriched for CD49f+/EpCAM−, CD44+/CD24−, and CD271+ cancer stem–like cells (CSC). These CSCs carried mutations within the cytoplasmic retention domain of HDAC6, stop/gain insertion in MORF4L1, and deletion mutations within SWI/SNF complex component SMARCC2. CSCs were sensitive to HDAC6 inhibitors, BET bromodomain inhibitors, and EZH2 inhibitors, as mutations in SWI/SNF complex components are known to increase sensitivity to these drugs. Among cells derived from breast milk of additional ten women not known to have breast cancer, two of them contained cells that were enriched for the CSC phenotype and carried mutations in NF1 or KMT2D, which are frequently mutated in breast cancer. Breast milk–derived cells with NF1 mutations also carried copy-number variations in CDKN2C, PTEN, and REL genes. The approach described here may enable rapid cancer cell characterization including driver mutation d etection and therapeutic screening for pregnancy/postpartum breast cancers. Furthermore, this method can be developed as a surveillance or early detection tool for women at high risk for developing breast cancer.Significance:These findings describe how a simple method for characterization of cancer cells in pregnancy and postpartum breast cancer can be exploited as a surveillance tool for women at risk of developing breast cancer. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy

alwin shared this article with you from Inoreader FAM46C and FNDC3A Are Multiple Myeloma Tumor Suppressors That Act in Concert to Impair Clearing of Protein Aggregates and Autophagy Via Cancer Research current issue Multiple myeloma is a plasma cell neoplasm characterized by the production of unfolded immunoglobulins, which cause endoplasmic reticulum (ER) stress and sensitivity to proteasome inhibition. The genomic landscape of multiple myeloma is characterized by the loss of several genes rarely mutated in other cancers that may underline specific weaknesses of multiple myeloma cells. One of these is FAM46C that is lost in more than 10% of patients with multiple myeloma. We show here that FAM46C is part of a new complex containing the ER-associated protein FNDC3A, which regulates trafficking and secretion and, by impairing autophagy, exacerbates proteostatic stress. Reconstitution of FAM46C in multiple myeloma cells that had lost it induced apoptosis and ER stress. Apoptosis was preceded by an increase of intracellular aggregates, which was not linked to increased translation of IgG mRNA, but rather to impairment of autophagy. Biochemical analysis showed that FAM46C requires interaction with ER bound protein FNDC3A to reside in the cytoplasmic side of the ER. FNDC3A was lost in some multiple myeloma cell lines. Importantly, depletion of FNDC3A increased the fitness of FAM46C-expressing cells and expression of FNDC3A in cells that had lost it recapitulated the effects of FAM46C, inducing aggregates and apoptosis. FAM46C and FNDC3A formed a complex that modulates secretion routes, increasing lysosome exocytosis. The cellular landscape generated by FAM46C/FNDC3A expression predicted sensitivity to sphingosine kinase inhibition. These results suggest that multiple myeloma cells remodel their trafficking machinery to cope with ER stress.Significance:This study identifies a new multiple myeloma–specific tumor suppressor complex that regulates autophagy and unconventional secretion, highlighting the sensitivity of multiple myeloma cells to the accumulation of protein aggregates. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

CRISPR/Cas9-Mediated Point Mutation in Nkx3.1 Prolongs Protein Half-Life and Reverses Effects Nkx3.1 Allelic Loss

alwin shared this article with you from Inoreader CRISPR/Cas9-Mediated Point Mutation in Nkx3.1 Prolongs Protein Half-Life and Reverses Effects Nkx3.1 Allelic Loss Via Cancer Research current issue NKX3.1 is the most commonly deleted gene in prostate cancer and is a gatekeeper suppressor. NKX3.1 is haploinsufficient, and pathogenic reduction in protein levels may result from genetic loss, decreased transcription, and increased protein degradation caused by inflammation or PTEN loss. NKX3.1 acts by retarding proliferation, activating antioxidants, and enhancing DNA repair. DYRK1B-mediated phosphorylation at serine 185 of NKX3.1 leads to its polyubiquitination and proteasomal degradation. Because NKX3.1 protein levels are reduced, but never entirely lost, in prostate adenocarcinoma, enhancement of NKX3.1 protein levels represents a potential therapeutic strategy. As a proof of principle, we used CRISPR/Cas9-mediated editing to engineer in vivo a point mutation in murine Nkx3.1 to code for a serine to alanine missense at amino acid 186, the target for Dyrk1b phosphorylation. Nkx3.1S186A/−, Nkx3.1+/−, and Nkx3.1+/+ mice were analyzed over one year to determine the levels of Nkx3.1 expression and effects of the mutant protein on the prostate. Allelic loss of Nkx3.1 caused reduced levels of Nkx3.1 protein, increased proliferation, and prostate hyperplasia and dysplasia, whereas Nkx3.1S186A/− mouse prostates had increased levels of Nkx3.1 protein, reduced prostate size, normal histology, reduced proliferation, and increased DNA end labeling. At 2 months of age, when all mice had normal prostate histology, Nkx3.1+/− mice demonstrated indices of metabolic activation, DNA damage response, and stress response. These data suggest that modulation of Nkx3.1 levels alone can exert long-term control over premalignant changes and susceptibility to DNA damage in the prostate.Significance:These findings show that prolonging the half-life of Nkx3.1 reduces proliferation, enhances DNA end-labeling, and protects from DNA damage, ultimately blocking the proneoplastic effects of Nkx3.1 allelic loss. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

The Alternative Splicing Factor, MBNL1, Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness

alwin shared this article with you from Inoreader The Alternative Splicing Factor, MBNL1, Inhibits Glioblastoma Tumor Initiation and Progression by Reducing Hypoxia-Induced Stemness Via Cancer Research current issue Muscleblind-like proteins (MBNL) belong to a family of tissue-specific regulators of RNA metabolism that control premessenger RNA splicing. Inactivation of MBNL causes an adult-to-fetal alternative splicing transition, resulting in the development of myotonic dystrophy. We have previously shown that the aggressive brain cancer, glioblastoma (GBM), maintains stem-like features (glioma stem cell, GSC) through hypoxia-induced responses. Accordingly, we hypothesize here that hypoxia-induced responses in GBM mig ht also include MBNL-based alternative splicing to promote tumor progression. When cultured in hypoxia condition, GSCs rapidly exported muscleblind-like-1 (MBNL1) out of the nucleus, resulting in significant inhibition of MBNL1 activity. Notably, hypoxia-regulated inhibition of MBNL1 also resulted in evidence of adult-to-fetal alternative splicing transitions. Forced expression of a constitutively active isoform of MBNL1 inhibited GSC self-renewal and tumor initiation in orthotopic transplantation models. Induced expression of MBNL1 in established orthotopic tumors dramatically inhibited tumor progression, resulting in significantly prolonged survival. This study reveals that MBNL1 plays an essential role in GBM stemness and tumor progression, where hypoxic responses within the tumor inhibit MBNL1 activity, promoting stem-like phenotypes and tumor growth. Reversing these effects on MBNL1 may therefore, yield potent tumor suppressor activities, uncovering new therapeutic opportunitie s to counter this disease.Significance:This study describes an unexpected mechanism by which RNA-binding protein, MBNL1, activity is inhibited in hypoxia by a simple isoform switch to regulate glioma stem cell self-renewal, tumorigenicity, and progression. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.

Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease

alwin shared this article with you from Inoreader Visualization of Activated T Cells by OX40-ImmunoPET as a Strategy for Diagnosis of Acute Graft-versus-Host Disease Via Cancer Research current issue Graft-versus-host disease (GvHD) is a major complication of allogeneic hematopoietic cell transplantation (HCT), mediated primarily by donor T cells that become activated and attack host tissues. Noninvasive strategies detecting T-cell activation would allow for early diagnosis and possibly more effective management of HCT recipients. PET imaging is a sensitive and clinically relevant modality ideal for GvHD diagnosis, and there is a strong rationale for the use of PET tracers that can monitor T-cell activa tion and expansion with high specificity. The TNF receptor superfamily member OX40 (CD134) is a cell surface marker that is highly specific for activated T cells, is upregulated during GvHD, and mediates disease pathogenesis. We recently reported the development of an antibody-based activated T-cell imaging agent targeting OX40. In the present study, we visualize the dynamics of OX40 expression in an MHC-mismatch mouse model of acute GvHD using OX40-immunoPET. This approach enabled visualization of T-cell activation at early stages of disease, prior to overt clinical symptoms with high sensitivity and specificity. This study highlights the potential utility of the OX40 PET imaging as a new strategy for GvHD diagnosis and therapy monitoring.Significance:OX40-immunoPET imaging is a promising noninvasive strategy for early detection of GvHD, capable of detecting signs of GvHD pathology even prior to the development of overt clinical symptoms. View on the web Inoreader. Take back control of your news feed. Follow us on Twitter and Facebook.