Antibody targeting of B7-H4 enhances the immune response in urothelial carcinoma.

Patients with locally advanced and metastatic urothelial carcinoma have a low survival rate (median 15.7 months, 13.1-17.8), with only a 23% response rate to monotherapy treatment with anti-PDL1 checkpoint immunotherapy. To identify new therapeutic targets, we profiled the immune regulatory signatures during murine cancer development using the BBN carcinogen and identified an increase in the expression of the T cell inhibitory protein B7-H4 (VTCN1, B7S1, B7X). B7-H4 expression temporally correlated with decreased lymphocyte infiltration. While the increase in B7-H4 expression within the bladder by CD11

Molecular footprints of muscle-invasive bladder cancer in smoking and nonsmoking patients.

BACKGROUND Bladder cancer is the fifth most common cancer in the United States and smoking is the largest known risk factor. Tobacco-derived carcinogens may induce the accumulation of somatic mutations in urothelial cells, and likely promote tumorigenesis. However, it is still unknown whether smoking-induced bladder carcinogenesis results in tumors with distinctive molecular features that can be therapeutically exploited. METHODS We investigated the genomic alterations of human bladder cancer and examined their association with patient smoking history. We performed bioinformatic analyses and looked at differences in gene expression, somatic mutations, and DNA mutational signatures comparing nonsmokers, reformed smokers, and current smokers. RESULTS We detected a limited set of gene expression and gene mutation differences between smokers and nonsmokers. We also identified a specific mutational signature that is enriched in tumors from smokers. This mutational signature was described before and has been linked to specific DNA repair defects in human bladder tumors, as well as to the direct effect of nitrosamine carcinogens in the BBN murine model of bladder cancer. CONCLUSION We showed associations between smoking status and selected mutational signatures, which could provide insights in the biology of bladder carcinogenesis and tumor progression

ocbe-uio/DIscBIO: DIscBIO universe 1.2.0

<p>This is a timewise match to the release of the DIscBIO R package version 1.2.0 on CRAN. The assets below contain the R package as well as all the other software/documents from this GitHub repo.</p&gt

ocbe-uio/DIscBIO: DIscBIO universe 1.1.0

<p>This is a timewise match to the release of the DIscBIO R package version 1.1.0 on CRAN. The assets below contain the R package as well as all the other software/documents from this GitHub repo.</p&gt

ocbe-uio/DIscBIO: v1.2.2

<p><strong>Full Changelog</strong>: https://github.com/ocbe-uio/DIscBIO/compare/v1.2.1...v1.2.2</p&gt

MutSignatures: an R package for extraction and analysis of cancer mutational signatures

Cancer cells accumulate somatic mutations as result of DNA damage, inaccurate repair and other mechanisms. Different genetic instability processes result in characteristic non-random patterns of DNA mutations, also known as mutational signatures. We developed mutSignatures, an integrated R-based computational framework aimed at deciphering DNA mutational signatures. Our software provides advanced functions for importing DNA variants, computing mutation types, and extracting mutational signatures via non-negative matrix factorization. Specifically, mutSignatures accepts multiple types of input data, is compatible with non-human genomes, and supports the analysis of non-standard mutation types, such as tetra-nucleotide mutation types. We applied mutSignatures to analyze somatic mutations found in smoking-related cancer datasets. We characterized mutational signatures that were consistent with those reported before in independent investigations. Our work demonstrates that selected mutational signatures correlated with specific clinical and molecular features across different cancer types, and revealed complementarity of specific mutational patterns that has not previously been identified. In conclusion, we propose mutSignatures as a powerful open-source tool for detecting the molecular determinants of cancer and gathering insights into cancer biology and treatment

Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2

Damaged DNA-binding protein 2 (DDB2), a nuclear protein, participates in both nucleotide excision repair and mRNA transcription. The transcriptional regulatory function of DDB2 is significant in colon cancer, as it regulates metastasis. To characterize the mechanism by which DDB2 participates in transcription, we investigated the protein partners in colon cancer cells. Here we show that DDB2 abundantly associates with XRCC5/6, not involving CUL4 and DNA-PKcs. A DNA-damaging agent that induces DNA double-stranded breaks (DSBs) does not affect the interaction between DDB2 and XRCC5. In addition, DSB-induced nuclear enrichment or chromatin association of XRCC5 does not involve DDB2, suggesting that the DDB2/XRCC5/6 complex represents a distinct pool of XRCC5/6 that is not directly involved in DNA break repair (NHEJ). In the absence of DNA damage, on the other hand, chromatin association of XRCC5 requires DDB2. We show that DDB2 recruits XRCC5 onto the promoter of SEMA3A, a DDB2-stimulated gene. Moreover, depletion of XRCC5 inhibits SEMA3A expression without affecting expression of VEGFA, a repression target of DDB2. Together our results show that DDB2 is critical for chromatin association of XRCC5/6 in the absence of DNA damage and provide evidence that XRCC5/6 are functional partners of DDB2 in its transcriptional stimulatory activity

ocbe-uio/DIscBIO: DIscBIO universe 1.0.1

<p>This release is a timewise match to the release of the <a href="https://cran.r-project.org/package=DIscBIO">DIscBIO R package on CRAN</a>. Please see the notes about release 1.0.0 concerning the differences between the R package and this release, which contains more assets such as the Jupyter-Binder notebook.</p&gt