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Prostate cancer (PCa) mortality is driven by highly aggressive tumors characterized by metastasis and resistance to therapy, and this aggressiveness is mediated by numerous factors, including activation of stress survival pathways in the pro-inflammatory tumor microenvironment. LEDGF/p75, also known as the DFS70 autoantigen, is a stress transcription co-activator implicated in cancer, HIV-AIDS, and autoimmunity. This protein is targeted by autoantibodies in certain subsets of patients with PCa and inflammatory conditions, as well as in some apparently healthy individuals. LEDGF/p75 is overexpressed in PCa and other cancers, and promotes resistance to chemotherapy-induced cell death via the transactivation of survival proteins. We report in this study that overexpression of LEDGF/p75 in PCa cells attenuates oxidative stress-induced necrosis but not staurosporine-induced apoptosis. This finding was consistent with the observation that while LEDGF/p75 was robustly cleaved in apoptotic cells into a p65 fragment that lacks stress survival activity, it remained relatively intact in necrotic cells. Overexpression of LEDGF/p75 in PCa cells led to the upregulation of transcript and protein levels of the thiol-oxidoreductase ERp57 (also known as GRP58 and PDIA3), whereas its depletion led to ERp57 transcript downregulation. Chromatin immunoprecipitation and transcription reporter assays showed LEDGF/p75 binding to and transactivating the ERp57 promoter, respectively. Immunohistochemical analysis revealed significantly elevated co-expression of these two proteins in clinical prostate tumor tissues. Our results suggest that LEDGF/p75 is not an inhibitor of apoptosis but rather an antagonist of oxidative stress-induced necrosis, and that its overexpression in PCa leads to ERp57 upregulation. These findings are of significance in clarifying the role of the LEDGF/p75 stress survival pathway in PCa.

Oxidative stress-modulated signaling pathways have been implicated in carcinogenesis and therapy resistance. The lens epithelium derived growth factor p75 (LEDGF/p75) is a transcription co-activator that promotes resistance to stress-induced cell death. This protein has been implicated in inflammatory and autoimmune conditions, HIV-AIDS, and cancer. Although LEDGF/p75 is emerging as a stress survival oncoprotein, there is scarce information on its expression in human tumors. The present study was performed to evaluate its expression in a comprehensive panel of human cancers. Transcript expression was examined in the Oncomine cancer gene microarray database and in a TissueScan Cancer Survey Panel quantitative polymerase chain reaction (Q-PCR) array. Protein expression was assessed by immunohistochemistry (IHC) in cancer tissue microarrays (TMAs) containing 1735 tissues representing single or replicate cores from 1220 individual cases (985 tumor and 235 normal tissues). A total of 21 major cancer types were analyzed. Analysis of LEDGF/p75 transcript expression in Oncomine datasets revealed significant upregulation (tumor vs. normal) in 15 out of 17 tumor types. The TissueScan Cancer Q-PCR array revealed significantly elevated LEDGF/p75 transcript expression in prostate, colon, thyroid, and breast cancers. IHC analysis of TMAs revealed significant increased levels of LEDGF/p75 protein in prostate, colon, thyroid, liver and uterine tumors, relative to corresponding normal tissues. Elevated transcript or protein expression of LEDGF/p75 was observed in several tumor types. These results further establish LEDGF/p75 as a cancer-related protein, and provide a rationale for ongoing studies aimed at understanding the clinical significance of its expression in specific human cancers.

Background Esophageal cancer including squamous cell carcinoma (SCC) and adenocarcinoma represents 4% of all cancers in the United States. Patients with esophageal cancer frequently present with locally advanced disease, and about 40% of patients have evidence of metastatic disease on presentation. Common sites of metastasis include liver, lung and bone. Here, we present a rare case of colonic metastasis from primary esophageal SCC. Case presentation A 60-year-old Caucasian male with a history of 20-pack-year cigarette smoking received surgery and adjuvant chemoradiotherapy for locally advanced SCC of larynx. Approximately 9 months later, he developed dysphagia, and found to have a esophageal SCC in the mid-esophagus with regional lymph node involvement. He underwent chemoradiation treatment with good response and improved symptoms but declined subsequent surgical resection for esophageal cancer. About 1 year after the diagnosis of esophageal cancer, he developed blood streaked bowel movement and severe anemia. Colonoscopy showed a 3-cm mass in the proximal ascending colon; biopsy showed metastatic SCC, consistent with metastasis from esophageal primary. He subsequently received palliative radiation to the ascending colon metastatic tumor with improvement of anemia, and remained transfusion independent for more than 3 months. Conclusions Colonic metastasis from esophageal SCC is rare, and associated with poor prognosis. There are no definite features in terms of location, histological differentiation etc. that contribute to colonic metastasis from primary esophageal SCC. The goal of treatment is palliative and data from our and other case reports support the use of chemotherapy and radiation for symptom improvement and disease control.

Increased utilization of prostate-specific antigen screening and prostate imaging has led to detection of smaller indolent tumors that traditional brachytherapy and prostectomy may be too aggressive for. New targeted techniques require greater locational accuracy of tumor detection to guide treatment. Prostate MRIs can be important for initial staging and for guiding targeted biopsies and treatments. We compared the accuracy of local staging of prostate cancer using 1.5 Tesla MRI with endorectal coil (ERC) versus 3 Tesla MRI with pelvic array coil (PAC) to the gold standard of trans-rectal US guided biopsies (TRUS). ERC is uncomfortable and has many imaging artifacts that may limit detection, so we hypothesize that 3 T MRI with PAC will have improved performance. 72 patients underwent prostate MRIs and TRUS prostate biopsies from 2008-2011 (33 were excluded due to prior radiation therapy, 24 patients underwent 1.5 T ERC and 15 underwent 3.0 T PAC.) 3.0 T PAC was trending towards greater sensitivity although we lack the statistical power for significance.

A bstract We demonstrate a new type of cancellation of contributions to the electron and neutron electric dipole moments (EDMs) that occurs in three Higgs doublet models (3HDMs) when CP violation appears in the charged Higgs sector. The cancellation becomes exact when the two physical charged Higgs bosons in the model are degenerate in mass. Depending on the model parameters, degeneracies at the 10% level are however sufficient to evade current bounds on the electron and neutron EDMs. We demonstrate that viable parameter space remains with both charged Higgs bosons lighter than 500 GeV and large CP-violating phases while also satisfying theoretical constraints from perturbativity and experimental ones from B ¯ → X s γ and direct searches.

Patients with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2−) primary breast cancer (BC) have low pathological complete response (pCR) rates with neoadjuvant chemotherapy. A subset of ER+/HER2− BC contains dense lymphocytic infiltration. We hypothesized that addition of an anti-programmed death 1 agent may increase pCR rates in this BC subtype. We conducted a randomized, multicenter, double-blind phase 3 trial to investigate the benefit of adding nivolumab to neoadjuvant chemotherapy in patients with newly diagnosed, high-risk, grade 3 or 2 (ER 1 to ≤10%) ER+/HER2− primary BC. In total, 510 patients were randomized to receive anthracycline and taxane-based chemotherapy with either intravenous nivolumab or placebo. The primary endpoint of pCR was significantly higher in the nivolumab arm compared with placebo (24.5% versus 13.8%; P  = 0.0021), with greater benefit observed in patients with programmed death ligand 1-positive tumors (VENTANA SP142 ≥1%: 44.3% versus 20.2% respectively). There were no new safety signals identified. Of the five deaths that occurred in the nivolumab arm, two were related to study drug toxicity; no deaths occurred in the placebo arm. Adding nivolumab to neoadjuvant chemotherapy significantly increased pCR rates in high-risk, early-stage ER+/HER2− BC, particularly among patients with higher stromal tumor-infiltrating lymphocyte levels or programmed death ligand 1 expression, suggesting a new treatment paradigm that emphasizes the role of immunotherapy and T cell immunosurveillance in luminal disease. Clinical trials.gov identifier: NCT04109066 In the CheckMate 7FL trial, neoadjuvant nivolumab and chemotherapy in patients with newly diagnosed, high-risk estrogen receptor-positive breast cancer led to an increased pathological complete response rate compared with neoadjuvant chemotherapy alone, and this increase was associated with immune-related biomarkers and estrogen receptor expression.