Notes

A straightforward Relation to its Constrain Groundwater Models Making use of Surface Deformation.
Hyperactive mevalonate (MVA) metabolic activity is often observed in cancer cells, and blockade of this pathway inhibits tumor cell lipid synthesis and cell growth and enhances tumor immunogenicity. How tumor cell MVA metabolic blockade promotes antitumor immune responses, however, remains unclear. Here we show that inhibition of the MVA metabolic pathway in tumor cells elicits type 1 classical dendritic cells (cDC1)-mediated tumor recognition and antigen cross-presentation for antitumor immunity. Mechanistically, MVA blockade disrupted prenylation of the small GTPase Rac1 and induced cancer cell actin filament exposure, which was recognized by CLEC9A, a C-lectin receptor specifically expressed on cDC1s, in turn activating antitumor T cells. MVA pathway blockade or Rac1 knockdown in tumor cells induced CD8+ T-cell-mediated antitumor immunity in immunocompetent mice but not in Batf3 -/- mice lacking CLEC9A+ dendritic cells. These findings demonstrate tumor MVA metabolic blockade stimulates a cDC1 response through CLEC9A-mediated immune recognition of tumor cell cytoskeleton, illustrating a new immune surveillance mechanism by which dendritic cells monitor tumor metabolic dysregulation and providing insight into how MVA pathway inhibition may potentiate anticancer immunity. SIGNIFICANCE These findings suggest that mevalonate blockade in cancer cells disrupts Rac1 prenylation to increase recognition and cross-presentation by conventional dendritic cells, suggesting this axis as a potential target for cancer immunotherapy.The hypothesis that the physiological response to psychological stress influences the initiation of cancer is highly controversial. The link between initiating stressors, the psychological stress response, and disease is plausible considering that the stress response is associated with defined physiological outcomes and molecular mechanisms. In light of this, we review the clinical relevance of psychological stress on the risk of cancer, and we propose potential molecular pathways that may link the stress response to early stages of malignant cell transformation.Cutaneous human papillomavirus (cuHPV) infections may be novel targets for skin cancer prevention and treatment, but critical information regarding the development of virus-positive skin cancers following cuHPV infection has been lacking. In this study, baseline cuHPV infection was measured by serology and viral DNA detection in eyebrow hairs (EBH) and forearm skin swabs (SSW) among 1,008 individuals undergoing routine skin cancer screening exams and followed for incidence of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (cuSCC). Baseline β-HPV detection, particularly in SSW, significantly predicted cuSCC (HR = 4.32; 95% confidence interval, 1.00-18.66), whereas serologic evidence of past β-HPV infection was not associated with cuSCC. Less than 5% of baseline β-HPV types detected in SSW were present in subsequent cuSCC tumors, and cuHPV detected in SSW with higher mean fluorescence intensity values were more likely to be present in cuSCC compared with those with lower levels (P less then 0.001). β-HPV-positive cuSCC occurred more often in areas of highly sun-damaged skin than did β-HPV-negative cuSCC. Overall, no clear patterns were observed between baseline β-HPV detection and subsequent development of BCC, or between baseline γ-HPV detection and either cuSCC or BCC. Collectively, these results demonstrate that β-HPV detection in SSW is a significant predictor of cuSCC risk, although evidence suggests only a small subset of cuSCC is etiologically linked to β-HPV infection. SIGNIFICANCE β-HPV positivity may be a useful biomarker for identifying individuals who could benefit from increased screening or novel cutaneous squamous cell carcinoma prevention strategies.We used stable isotope-labeled glucose and palmitate tracer infusions, a hyperinsulinemic-euglycemic clamp, positron-emission tomography of muscles and adipose tissue after [18F]fluorodeoxyglucose and [15O]water injections, and subcutaneous adipose tissue (SAT) biopsy to test the hypotheses that i) increased glucose uptake in SAT is responsible for high insulin-stimulated whole-body glucose uptake in people with obesity who are insulin-sensitive, and ii) putative SAT factors thought to cause insulin resistance are present in people with obesity who are insulin-resistant but not in those who are insulin-sensitive. We found high insulin-stimulated whole-body glucose uptake in insulin-sensitive participants with obesity was not due to channeling of glucose into SAT, but was due to high insulin-stimulated muscle glucose uptake. Furthermore, insulin-stimulated muscle glucose uptake was not different between insulin-sensitive obese and lean participants even though adipocytes were larger, SAT perfusion and oxygenation were lower, and markers of SAT inflammation, fatty acid appearance in plasma in relation to fat-free mass, and plasma fatty acid concentration were higher in the insulin-sensitive obese than lean participants. VX11e In addition, we observed only marginal or no differences in adipocyte size, SAT perfusion and oxygenation, and markers of SAT inflammation between insulin-resistant and insulin-sensitive obese participants. Plasma fatty acid concentration was also not different between insulin-sensitive and insulin-resistant obese participants even though SAT was resistant to the inhibitory effect of insulin on lipolysis in the insulin-resistant obese group. These data suggest several putative SAT factors that are commonly implicated in causing insulin resistance are normal consequences of SAT expansion unrelated to insulin resistance.The administration of preventative therapy for chemotherapy-induced nausea and vomiting (CINV) is an essential component of the treatment plan for many patients with cancer. In May 2021, the FDA issued a draft guidance for industry to facilitate the clinical development of drugs for the prevention of CINV in adults. FDA guidance has a vital role in the regulatory dialogue between the Agency and external stakeholders. Sharing the FDA's current recommended approach can expedite drug development and ultimately the availability of safe and effective therapies to patients in need. In addition, guidance documents may be leveraged to facilitate communication between regulatory agencies, the academic community, patient advocacy groups, and the pharmaceutical industry. link2 The draft guidance for industry Chemotherapy-Induced Nausea and Vomiting Developing Drugs for Prevention (May 2021) outlines the FDA's current recommendations regarding clinical development programs for drugs for the prevention of CINV and the required attributes of patients for enrollment, aspects of trial design, and efficacy assessments. This article provides an overview of the recommendations contained in the draft guidance.
This phase I study evaluated safety, tolerability, pharmacokinetics, and preliminary activity of the PI3K/mTORC1/2 dual inhibitor gedatolisib combined with carboplatin and paclitaxel.

Patients with advanced solid tumors treated with ≤ 2 prior chemotherapies received intravenous gedatolisib on days 1, 8, 15, and 22 (95, 110, or 130 mg according to dose level); carboplatin (AUC5) on day 8 (day 1 following protocol amendment); and paclitaxel at 80 mg/m
on days 8, 15, and 22 (1, 8, and 15 after amendment), every 28 days. Patients without progressive disease after cycle 6 received maintenance gedatolisib until progression.

Seventeen patients were enrolled [11 ovarian (10 clear cell ovarian cancer, CCOC), 4 endometrial, 2 lung cancers]. Median number of prior chemotherapies was 1 (range, 0-2). Median number of administered cycles was 6 (range, 2-16). Dose-limiting toxicities occurred in 4 patients 2 (cycle 2 delay due to G2-G3 neutropenia) at 110 mg leading to a change in the treatment schedule, 2 at 130 mg (G2 mucositis causing failure to deliver ≥ 75% of gedatolisib at cycle 1). The recommended phase II dose is gedatolisib 110 mg on days 1, 8, 15, and 22 with carboplatin AUC5 on day 1 and paclitaxel 80 mg/m
on days 1, 8, and 15. The most frequent ≥G3 treatment-related adverse events were neutropenia (35%), anemia (18%), and mucositis (12%). The overall response rate was 65% (80% in CCOC). Pharmacokinetic parameters of gedatolisib were consistent with single-agent results.

Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.
Gedatolisib combined with carboplatin and paclitaxel is tolerable, and preliminary efficacy was observed especially in CCOC.
The Cancer Immune Monitoring and Analysis Centers - Cancer Immunologic Data Commons (CIMAC-CIDC) Network is supported by the NCI to identify biomarkers of response to cancer immunotherapies across clinical trials using state-of-the-art assays. A primary platform for CIMAC-CIDC studies is cytometry by time of flight (CyTOF), performed at all CIMAC laboratories. To ensure the ability to generate comparable CyTOF data across labs, a multistep cross-site harmonization effort was undertaken.

We first harmonized standard operating procedures (SOPs) across the CIMAC sites. Because of a new acquisition protocol comparing original narrow- or new wide-bore injector introduced by the vendor (Fluidigm), we also tested this protocol across sites before finalizing the harmonized SOP. We then performed cross-site assay harmonization experiments using five shared cryopreserved and one lyophilized internal control peripheral blood mononuclear cell (PBMC) with a shared lyophilized antibody cocktail consisting of 14 isotype-tagged antibodies previously validated, plus additional liquid antibodies. These reagents and samples were distributed to the CIMAC sites and the data were centrally analyzed by manual gating and automated methods (Astrolabe).

Average coefficients of variation (CV) across sites for each cell population were reported and compared with a previous multisite CyTOF study. We reached an intersite CV of under 20% for most cell subsets, very similar to a previously published study.

These results establish the ability to reproduce CyTOF data across sites in multicenter clinical trials, and also highlight the importance of quality control procedures, such as the use of spike-in control samples, for tracking variability in this assay.
These results establish the ability to reproduce CyTOF data across sites in multicenter clinical trials, and also highlight the importance of quality control procedures, such as the use of spike-in control samples, for tracking variability in this assay.Chromosome gains and losses are a frequent feature of human cancers. link3 However, how these aberrations can outweigh the detrimental effects of aneuploidy remains unclear. An initial comparison of existing chromosomal instability (CIN) mouse models suggests that aneuploidy accumulates to low levels in these animals. We therefore developed a novel mouse model that enables unprecedented levels of chromosome missegregation in the adult animal. At the earliest stages of T-cell development, cells with random chromosome gains and/or losses are selected against, but CIN eventually results in the expansion of progenitors with clonal chromosomal imbalances. Clonal selection leads to the development of T-cell lymphomas with stereotypic karyotypes in which chromosome 15, containing the Myc oncogene, is gained with high prevalence. Expressing human MYC from chromosome 6 (MYC Chr6) is sufficient to change the karyotype of these lymphomas to include universal chromosome 6 gains. Interestingly, while chromosome 15 is still gained in MYC Chr6 tumors after genetic ablation of the endogenous Myc locus, this chromosome is not efficiently gained after deletion of one copy of Rad21, suggesting a synergistic effect of both MYC and RAD21 in driving chromosome 15 gains.
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