Vomocytosis: Too Much Booze, Base, or Calcium?

Macrophages are well known for their phagocytic activity and their role in innate immune responses. Macrophages eat non-self particles, via a variety of mechanisms, and typically break down internalized cargo into small macromolecules. However, some pathogenic agents have the ability to evade this endosomal degradation through a nonlytic exocytosis process termed vomocytosis. This phenomenon has been most often studied for Cryptococcus neoformans, a yeast that causes roughly 180,000 deaths per year, primarily in immunocompromised (e.g., human immunodeficiency virus [HIV]) patients. Existing dogma purports that vomocytosis involves distinctive cellular pathways and intracellular physicochemical cues in the host cell during phagosomal maturation. Moreover, it has been observed that the immunological state of the individual and macrophage phenotype affect vomocytosis outcomes. Here we compile the current knowledge on the factors (with respect to the phagocytic cell) that promote vomocytosis of C. neoformans from macrophages

Profound Perturbation of the Metabolome in Obesity Is Associated with Health Risk.

Obesity is a heterogeneous phenotype that is crudely measured by body mass index (BMI). There is a need for a more precise yet portable method of phenotyping and categorizing risk in large numbers of people with obesity to advance clinical care and drug development. Here, we used non-targeted metabolomics and whole-genome sequencing to identify metabolic and genetic signatures of obesity. We find that obesity results in profound perturbation of the metabolome; nearly a third of the assayed metabolites associated with changes in BMI. A metabolome signature identifies the healthy obese and lean individuals with abnormal metabolomes-these groups differ in health outcomes and underlying genetic risk. Specifically, an abnormal metabolome associated with a 2- to 5-fold increase in cardiovascular events when comparing individuals who were matched for BMI but had opposing metabolome signatures. Because metabolome profiling identifies clinically meaningful heterogeneity in obesity, this approach could help select patients for clinical trials

Risk of Peritoneal Carcinomatosis After Risk-Reducing Salpingo-Oophorectomy:A Systematic Review and Individual Patient Data Meta-Analysis

PURPOSEAfter risk-reducing salpingo-oophorectomy (RRSO), BRCA1/2 pathogenic variant (PV) carriers have a residual risk to develop peritoneal carcinomatosis (PC). The etiology of PC is not yet clarified, but may be related to serous tubal intraepithelial carcinoma (STIC), the postulated origin for high-grade serous cancer. In this systematic review and individual patient data meta-analysis, we investigate the risk of PC in women with and without STIC at RRSO.METHODSUnpublished data from three centers were supplemented by studies identified in a systematic review of EMBASE, MEDLINE, and the Cochrane library describing women with a BRCA-PV with and without STIC at RRSO until September 2020. Primary outcome was the hazard ratio for the risk of PC between BRCA-PV carriers with and without STIC at RRSO, and the corresponding 5- and 10-year risks. Primary analysis was based on a one-stage Cox proportional-hazards regression with a frailty term for study.RESULTSFrom 17 studies, individual patient data were available for 3,121 women, of whom 115 had a STIC at RRSO. The estimated hazard ratio to develop PC during follow-up in women with STIC was 33.9 (95% CI, 15.6 to 73.9), P <.001) compared with women without STIC. For women with STIC, the five- and ten-year risks to develop PC were 10.5% (95% CI, 6.2 to 17.2) and 27.5% (95% CI, 15.6 to 43.9), respectively, whereas the corresponding risks were 0.3% (95% CI, 0.2 to 0.6) and 0.9% (95% CI, 0.6 to 1.4) for women without STIC at RRSO.CONCLUSIONBRCA-PV carriers with STIC at RRSO have a strongly increased risk to develop PC which increases over time, although current data are limited by small numbers of events

Liquid biopsies come of age: towards implementation of circulating tumour DNA

Improvements in genomic and molecular methods are expanding the range of potential applications for circulating tumour DNA (ctDNA), both in a research setting and as a ‘liquid biopsy’ for cancer management. Proof-of-principle studies have demonstrated the translational potential of ctDNA for prognostication, molecular profiling and monitoring. The field is now in an exciting transitional period in which ctDNA analysis is beginning to be applied clinically, although there is still much to learn about the biology of cell-free DNA. This is an opportune time to appraise potential approaches to ctDNA analysis, and to consider their applications in personalized oncology and in cancer research.We would like to acknowledge the support of The University of Cambridge, Cancer Research UK (grant numbers A11906, A20240, A15601) (to N.R., J.D.B.), the European Research Council under the European Union's Seventh Framework Programme (FP/2007-2013)/ERC Grant Agreement n. 337905 (to N.R.), the Cambridge Experimental Cancer Medicine Centre, and Hutchison Whampoa Limited (to N.R.), AstraZeneca (to R.B., S.P.), the Cambridge Experimental Cancer Medicine Centre (ECMC) (to R.B., S.P.), and NIHR Biomedical Research Centre (BRC) (to R.B., S.P.). J.G.C. acknowledges clinical fellowship support from SEOM

Kinetic and perfusion modeling of hyperpolarized (13)C pyruvate and urea in cancer with arbitrary RF flip angles.

The accurate detection and characterization of cancerous tissue is still a major problem for the clinical management of individual cancer patients and for monitoring their response to therapy. MRI with hyperpolarized agents is a promising technique for cancer characterization because it can non-invasively provide a local assessment of the tissue metabolic profile. In this work, we measured the kinetics of hyperpolarized [1-(13)C] pyruvate and (13)C-urea in prostate and liver tumor models using a compressed sensing dynamic MRSI method. A kinetic model fitting method was developed that incorporated arbitrary RF flip angle excitation and measured a pyruvate to lactate conversion rate, Kpl, of 0.050 and 0.052 (1/s) in prostate and liver tumors, respectively, which was significantly higher than Kpl in healthy tissues [Kpl =0.028 (1/s), P&lt;0.001]. Kpl was highly correlated to the total lactate to total pyruvate signal ratio (correlation coefficient =0.95). We additionally characterized the total pyruvate and urea perfusion, as in cancerous tissue there is both existing vasculature and neovascularization as different kinds of lesions surpass the normal blood supply, including small circulation disturbance in some of the abnormal vessels. A significantly higher perfusion of pyruvate (accounting for conversion to lactate and alanine) relative to urea perfusion was seen in cancerous tissues (liver cancer and prostate cancer) compared to healthy tissues (P&lt;0.001), presumably due to high pyruvate uptake in tumors