Platinum-Based Chemotherapy Induces Opposing Effects on Immunotherapy Response-Related Spatial and Stromal Biomarkers in the Bladder Cancer Microenvironment.

Purpose: Platinum-based chemotherapy and immune checkpoint inhibitors are key components of systemic treatment for muscle-invasive and advanced urothelial cancer. The ideal integration of these two treatment modalities remains unclear as clinical trials have led to inconsistent results. Modulation of the tumor-immune microenvironment by chemotherapy is poorly characterized.

Homologous recombination repair deficient prostate cancer represents an immunologically distinct subtype.

Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa.

Intratumoral T cell depletion following neoadjuvant chemotherapy in patients with muscle-invasive bladder cancer is associated with poor clinical outcome.

Background: Whereas neoadjuvant cisplatin-based chemotherapy (NAC) followed by a radical cystectomy remains the standard treatment for patients with muscle-invasive bladder cancer (MIBC), increasing evidence suggests that checkpoint inhibitors, either alone or in combination with chemotherapy, are effective in the (neo)adjuvant setting. The major aim of this study was to improve our understanding of the immune-modulating effects of NAC in MIBC.

Methods: Tumor tissue of 81 patients was used, including 60 patients treated with NAC and 21 patients undergoing upfront cystectomy.

Comprehensive Molecular Characterization Reveals Genomic and Transcriptomic Subtypes of Metastatic Urothelial Carcinoma.

Recent molecular characterization of primary urothelial carcinoma (UC) may guide future clinical decision-making. For metastatic UC (mUC), a comprehensive molecular characterization is still lacking. We analyzed whole-genome DNA and RNA sequencing data for fresh-frozen metastatic tumor biopsies from 116 mUC patients who were scheduled for palliative systemic treatment within the context of a clinical trial (NCT01855477 and NCT02925234).

Spatial and Temporal Heterogeneity of Tumor-Infiltrating Lymphocytes in Advanced Urothelial Cancer.

Checkpoint inhibitors targeting PD-(L)1 induce objective responses in 20% of patients with metastatic urothelial cancer (UC). CD8 T cell infiltration has been proposed as a putative biomarker for response to checkpoint inhibitors. Nevertheless, data on spatial and temporal heterogeneity of tumor-infiltrating lymphocytes in advanced UC are lacking.

Whole Blood Transcriptome Profiling Identifies DNA Replication and Cell Cycle Regulation as Early Marker of Response to Anti-PD-1 in Patients with Urothelial Cancer.

Although immune checkpoint inhibitors improve median overall survival in patients with metastatic urothelial cancer (mUC), only a minority of patients benefit from it. Early blood-based response biomarkers may provide a reliable way to assess response weeks before imaging is available, enabling an early switch to other therapies. We conducted an exploratory study aimed at the identification of early markers of response to anti-PD-1 in patients with mUC.

Immunophenotyping Reveals Longitudinal Changes in Circulating Immune Cells During Radium-223 Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer.

Background: Radium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.

Homologous Recombination Repair Deficiency and Implications for Tumor Immunogenicity.

Homologous recombination repair deficiency (HRD) can be observed in virtually all cancer types. Although HRD sensitizes tumors to DNA-damaging chemotherapy and poly(ADP-ribose) polymerase (PARP) inhibitors, all patients ultimately develop resistance to these therapies. Therefore, it is necessary to identify therapeutic regimens with a more durable efficacy.

Prognostic and Predictive Value of Tumor-Infiltrating Immune Cells in Urothelial Cancer of the Bladder.

The prognosis and responsiveness to chemotherapy and checkpoint inhibitors differs substantially among patients with bladder cancer (BC). There is an unmet need for biomarkers that can accurately predict prognosis and treatment outcome. Here, we describe the available literature on the prognostic and predictive value of tumor-infiltrating immune cells in BC.

Lactate dehydrogenase: a marker of diminished antitumor immunity.

Lactate dehydrogenase (LDH) levels are inversely related with response to checkpoint inhibitors. Elevated LDH levels are the product of enhanced glycolytic activity of the tumor and tumor necrosis due to hypoxia, the latter being associated with high tumor burden. In this review, we elucidate the effects of glycolysis and hypoxia on antitumor immunity and set forth ways to improve response to immunotherapy in cancer patients with elevated LDH levels.

Immune checkpoint inhibition-related colitis: symptoms, endoscopic features, histology and response to management.

Background: Immune checkpoint inhibitors are successfully introduced as anticancer treatment. However, they may induce severe immune-related adverse events (irAEs). One of the most frequent irAEs is diarrhoea.

Impact of disease location on fecal calprotectin levels in Crohn's disease.

Objective: The correlation between the Simple Endoscopic Score for Crohn's Disease (SES-CD) and fecal calprotectin is well established in (ileo)colonic Crohn's disease (CD). However, for ileal CD, existing data are conflicting. The aim of this study is to evaluate the biomarker profile in CD patients with varying severity and location of mucosal ulceration.

Role of binding of plectin to the integrin beta4 subunit in the assembly of hemidesmosomes.

We have previously shown that plectin is recruited into hemidesmosomes through association of its actin-binding domain (ABD) with the first pair of fibronectin type III (FNIII) repeats and a small part of the connecting segment (residues 1328-1355) of the integrin beta4 subunit. Here, we show that two proline residues (P1330 and P1333) in this region of the connecting segment are critical for supporting beta4-mediated recruitment of plectin. Additional binding sites for the plakin domain of plectin on beta4 were identified in biochemical and yeast two-hybrid assays.

Specificity of binding of the plectin actin-binding domain to beta4 integrin.

Plectin is a major component of the cytoskeleton and links the intermediate filament system to hemidesmosomes by binding to the integrin beta4 subunit. Previously, a binding site for beta4 was mapped on the actin-binding domain (ABD) of plectin and binding of beta4 and F-actin to plectin was shown to be mutually exclusive. Here we show that only the ABDs of plectin and dystonin bind to beta4, whereas those of other actin-binding proteins do not.

Tom22 is a multifunctional organizer of the mitochondrial preprotein translocase.

Mitochondrial preproteins are imported by a multisubunit translocase of the outer membrane (TOM), including receptor proteins and a general import pore. The central receptor Tom22 binds preproteins through both its cytosolic domain and its intermembrane space domain and is stably associated with the channel protein Tom40 (refs 11-13). Here we report the unexpected observation that a yeast strain can survive without Tom22, although it is strongly reduced in growth and the import of mitochondrial proteins.

Functional complementation analysis of yeast bc1 mutants. A study of the mitochondrial import of heterologous and hybrid proteins.

Previous complementation studies with yeast bc1 mutants, defective in subunit VII or VIII, using heterologous and hybrid subunits, suggested that the requirement for import into mitochondria might significantly restrict the scope of this test for compatible proteins. Prediction algorithms indicate that the N-terminal domain of subunit VII contains all known characteristics of a mitochondrial targeting signal, whereas in subunit VIII such a signal is absent from the N-terminal domain, but possibly present in an internal region of the protein. Despite the fact that the characteristics of a mitochondrial import signal are found in the N-terminus of all known subunit-VII orthologues, in vitro import experiments show that the protein of human origin is not imported into yeast mitochondria.

The preprotein translocase of the mitochondrial inner membrane: function and evolution.

Growing mitochondria acquire most of their proteins by the uptake of mitochondrial preproteins from the cytosol. To mediate this protein import, both mitochondrial membranes contain independent protein transport systems: the Tom machinery in the outer membrane and the Tim machinery in the inner membrane. Transport of proteins across the inner membrane and sorting to the different inner mitochondrial compartments is mediated by several protein complexes which have been identified in the past years.

Expression of genes encoding peroxisomal proteins in Saccharomyces cerevisiae is regulated by different circuits of transcriptional control.

In Saccharomyces cerevisiae induction of the FOX3 gene, encoding peroxisomal 3-oxoacyl-CoA thiolase, by growth on oleate as sole carbon source, is exerted via the cis-acting DNA element designated oleate response element (ORE) (Einerhand et al. (1991) Eur. J.