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Analysis of RISC-bound miRNAs in tumors from patients with ovarian cancer revealed that the ratio between miRNAs with toxic versus nontoxic seeds was predictive of treatment outcome. Application of the 6mer seed toxicity concept to cancer relevant miRNAs provides a new framework for understanding and predicting cancer therapy responses. SIGNIFICANCE These findings demonstrate that the balance of miRNAs that carry toxic and nontoxic 6mer seeds contributes to platinum resistance in ovarian cancer.In breast cancer, humoral immune responses may contribute to clinical outcomes, especially in more immunogenic subtypes. Here, we investigated B lymphocyte subsets, immunoglobulin expression, and clonal features in breast tumors, focusing on aggressive triple-negative breast cancers (TNBC). In samples from patients with TNBC and healthy volunteers, circulating and tumor-infiltrating B lymphocytes (TIL-B) were evaluated. CD20+CD27+IgD- isotype-switched B lymphocytes were increased in tumors, compared with matched blood. TIL-B frequently formed stromal clusters with T lymphocytes and engaged in bidirectional functional cross-talk, consistent with gene signatures associated with lymphoid assembly, costimulation, cytokine-cytokine receptor interactions, cytotoxic T-cell activation, and T-cell-dependent B-cell activation. TIL-B-upregulated B-cell receptor (BCR) pathway molecules FOS and JUN, germinal center chemokine regulator RGS1, activation marker CD69, and TNFα signal transduction via NFκB, suggesting BCR-immu Clonally expanded, IgG isotype-biased humoral immunity associates with favorable prognosis primarily in triple-negative breast cancers.Beyond anti-PD-1 therapy as a mainstay, additional strategies are being developed for HPV-associated cancers. Emerging data from two ongoing trials have shown some early efficacy with vaccines directed at HPV16-specific E6 and E7 viral oncoproteins, as well as with other therapies targeting different facets of antitumor immunity.A liquid biopsy may select patients with metastatic colorectal cancer who are good candidates for additional anti-EGFR therapy after developing resistance to it earlier in their treatment regimen. In a phase II trial, patients who received panitumumab based on an absence of resistance mutations in circulating tumor DNA had a 30% response rate to the anti-EGFR agent.Although the 14-3-3σ gene was initially identified as a p53 target gene in colorectal cancer cells, its potential role in intestinal tumorigenesis has remained unknown. Here we determined that 14-3-3σ expression is significantly downregulated in primary human colorectal cancer when compared with adjacent normal colonic tissue in patient samples. Downregulation of 14-3-3σ in primary colorectal cancers was significantly associated with p53 mutation, increasing tumor stage, distant metastasis, and poor patient survival. Poor survival was more significantly associated with decreased 14-3-3σ expression in p53 wild-type than in p53-mutant colorectal cancers. 14-3-3σ expression was detected in enterocytes of the transit amplifying zone and gradually increased towards the apical villi in the small intestinal epithelium. In small and large intestinal epithelia and adenomas, 14-3-3σ expression was upregulated in differentiated areas. Deletion of 14-3-3σ in ApcMin mice increased the number and size of adenomas in the small intestine and colon, shortening the median survival by 64 days. 14-3-3σ-deficient adenomas displayed increased proliferation and decreased apoptosis, as well as increased dysplasia. In adenomas, loss of 14-3-3σ promoted acquisition of a mesenchymal-like gene expression signature, which was also found in colorectal cancers from patients with poor relapse-free survival. The transcriptional programs controlled by the 14-3-3σ-interacting factors SNAIL, c-JUN, YAP1, and FOXO1 were activated by deletion of 14-3-3σ, potentially contributing to the enhanced tumor formation and growth. Taken together, these results provide genetic evidence of a tumor-suppressor function of 14-3-3σ in the intestine. SIGNIFICANCE Downregulation of 14-3-3σ in colorectal cancer is associated with metastasis and poor survival of patients, and its inactivation in a murine tumor model drives intestinal tumor formation and epithelial-mesenchymal transition.Inhibition of mTORC1 signaling has been shown to diminish growth of meningiomas and schwannomas in preclinical studies, and clinical data suggest that everolimus, an orally administered mTORC1 inhibitor, may slow tumor progression in a subset of patients with neurofibromatosis type 2 (NF2) with vestibular schwannoma. To assess the pharmacokinetics, pharmacodynamics, and potential mechanisms of treatment resistance, we performed a presurgical (phase 0) clinical trial of everolimus in patients undergoing elective surgery for vestibular schwannoma or meningiomas. Eligible patients with meningioma or vestibular schwannoma requiring tumor resection enrolled on study received everolimus 10 mg daily for 10 days immediately prior to surgery. Everolimus blood levels were determined immediately before and after surgery. Tumor samples were collected intraoperatively. https://www.selleckchem.com/products/u18666a.html Ten patients completed protocol therapy. Median pre- and postoperative blood levels of everolimus were found to be in a high therapeutic range (17.4 ng/mL and 9.4 ng/mL, respectively). Median tumor tissue drug concentration determined by mass spectrometry was 24.3 pg/mg (range, 9.2-169.2). We observed only partial inhibition of phospho-S6 in the treated tumors, indicating incomplete target inhibition compared with control tissues from untreated patients (P = 0.025). Everolimus led to incomplete inhibition of mTORC1 and downstream signaling. These data may explain the limited antitumor effect of everolimus observed in clinical studies for patients with NF2 and will inform the design of future preclinical and clinical studies targeting mTORC1 in meningiomas and schwannomas.BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAF V600E-driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of β-catenin in BrafV600E -driven thyroid cancer in a transgenic mouse model. In Braf V600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of β-catenin was observed in thyroid tumors. In Braf V600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFβ pathways and loss of epithelial-mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors.
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