Lipogenesis mediated by OGR1 regulates metabolic adaptation to acid stress in cancer cells via autophagy

Malignant tumors exhibit altered metabolism resulting in a highly acidic extracellular microenvironment. Here, we show that cytoplasmic lipid droplet (LD) accumulation, indicative of a lipogenic phenotype, is a cellular adaption to extracellular acidity. LD marker PLIN2 is strongly associated with poor overall survival in breast cancer patients. Acid-induced LD accumulation is triggered by activation of the acid-sensing G-protein-coupled receptor (GPCR) OGR1, which is expressed highly in breast tumors. OGR1 depletion inhibits acid-induced lipid accumulation, while activation by a synthetic agonist triggers LD formation. Inhibition of OGR1 downstream signaling abrogates the lipogenic phenotype, which can be rescued with OGR1 ectopic expression. OGR1-depleted cells show growth inhibition under acidic growth conditions in vitro and tumor formation in vivo. Isotope tracing shows that the source of lipid precursors is primarily autophagy-derived ketogenic amino acids. OGR1-depleted cells are defective in endoplasmic reticulum stress response and autophagy and hence fail to accumulate LDs affecting survival under acidic stress

A rare case of an aldosterone secreting metastatic adrenocortical carcinoma and papillary thyroid carcinoma in a 31-year-old male

We report a rare synchronous presentation of adrenocortical carcinoma (ACC) and papillary thyroid carcinoma (PTC). A 31-year-old male first presented with a large left adrenal mass that was identified during the workup for refractory hypertension due to hyperaldosteronism. The mass was removed surgically with pathology showing ACC. The patient was then treated with adjuvant radiation therapy and mitotane chemotherapy. Four months post ACC resection, metastatic ACC to the right upper lung and PTC in the left lobe of the thyroid were found in surveillance imaging. He subsequently developed pulmonary, contralateral adrenal and brain metastases from his ACC. Li Fraumeni syndrome and Multiple Endocrine Neoplasia Type I (MEN I) were considered, but testing of both P53 and menin genes showed no mutation. We also performed a review of the literature and found three similar cases, however gene mutation analysis was not performed.

Precision cluster mass determination from weak lensing

Weak gravitational lensing has been used extensively in the past decade to constrain the masses of galaxy clusters, and is the most promising observational technique for providing the mass calibration necessary for precision cosmology with clusters. There are several challenges in estimating cluster masses, particularly (a) the sensitivity to astrophysical effects and observational systematics that modify the signal relative to the theoretical expectations, and (b) biases that can arise due to assumptions in the mass estimation method, such as the assumed radial profile of the cluster. All of these challenges are more problematic in the inner regions of the cluster, suggesting that their influence would ideally be suppressed for the purpose of mass estimation. However, at any given radius the differential surface density measured by lensing is sensitive to all mass within that radius, and the corrupted signal from the inner parts is spread out to all scales. We develop a new statistic that is ideal for estimation of cluster masses because it completely eliminates mass contributions below a chosen scale (which we suggest should be about 20 per cent of the virial radius), and thus reduces sensitivity to systematic and astrophysical effects. We use simulated and analytical profiles to quantify systematic biases on the estimated masses for several standard methods of mass estimation, finding that these can lead to significant mass biases that range from ten to over fifty per cent. The mass uncertainties when using our new statistic are reduced by up to a factor of ten relative to the standard methods, while only moderately increasing the statistical errors. This new method of mass estimation will enable a higher level of precision in future science work with weak lensing mass estimates for galaxy clusters.Comment: 27 pages, 7 figures, submitted to MNRAS; v2 has expanded explanation for clarity, no change in results or conclusion

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure : Pooled Analysis of 4 Clinical Studies

Background This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). Methods Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. Results Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. Conclusion Based on integrated data from 4 clinical studies, including long-term follow-up forPeer reviewe

Punica granatum (Pomegranate) juice provides an HIV-1 entry inhibitor and candidate topical microbicide

BACKGROUND: For ≈ 24 years the AIDS pandemic has claimed ≈ 30 million lives, causing ≈ 14,000 new HIV-1 infections daily worldwide in 2003. About 80% of infections occur by heterosexual transmission. In the absence of vaccines, topical microbicides, expected to block virus transmission, offer hope for controlling the pandemic. Antiretroviral chemotherapeutics have decreased AIDS mortality in industrialized countries, but only minimally in developing countries. To prevent an analogous dichotomy, microbicides should be: acceptable; accessible; affordable; and accelerative in transition from development to marketing. Already marketed pharmaceutical excipients or foods, with established safety records and adequate anti-HIV-1 activity, may provide this option. METHODS: Fruit juices were screened for inhibitory activity against HIV-1 IIIB using CD4 and CXCR4 as cell receptors. The best juice was tested for inhibition of: (1) infection by HIV-1 BaL, utilizing CCR5 as the cellular coreceptor; and (2) binding of gp120 IIIB and gp120 BaL, respectively, to CXCR4 and CCR5. To remove most colored juice components, the adsorption of the effective ingredient(s) to dispersible excipients and other foods was investigated. A selected complex was assayed for inhibition of infection by primary HIV-1 isolates. RESULTS: HIV-1 entry inhibitors from pomegranate juice adsorb onto corn starch. The resulting complex blocks virus binding to CD4 and CXCR4/CCR5 and inhibits infection by primary virus clades A to G and group O. CONCLUSION: These results suggest the possibility of producing an anti-HIV-1 microbicide from inexpensive, widely available sources, whose safety has been established throughout centuries, provided that its quality is adequately standardized and monitored

Model comparisons for estimating carbon emissions from North American wildland fire

Research activities focused on estimating the direct emissions of carbon from wildland fires across North America are reviewed as part of the North American Carbon Program disturbance synthesis. A comparison of methods to estimate the loss of carbon from the terrestrial biosphere to the atmosphere from wildland fires is presented. Published studies on emissions from recent and historic time periods and five specific cases are summarized, and new emissions estimates are made using contemporary methods for a set of specific fire events. Results from as many as six terrestrial models are compared. We find that methods generally produce similar results within each case, but estimates vary based on site location, vegetation (fuel) type, and fire weather. Area normalized emissions range from 0.23 kg C m−2 for shrubland sites in southern California/NW Mexico to as high as 6.0 kg C m−2 in northern conifer forests. Total emissions range from 0.23 to 1.6 Tg C for a set of 2003 fires in chaparral-dominated landscapes of California to 3.9 to 6.2 Tg C in the dense conifer forests of western Oregon. While the results from models do not always agree, variations can be attributed to differences in model assumptions and methods, including the treatment of canopy consumption and methods to account for changes in fuel moisture, one of the main drivers of variability in fire emissions. From our review and synthesis, we identify key uncertainties and areas of improvement for understanding the magnitude and spatial-temporal patterns of pyrogenic carbon emissions across North America

Asian outflow and trans-Pacific transport of carbon monoxide and ozone pollution: An integrated satellite, aircraft, and model perspective

Satellite observations of carbon monoxide (CO) from the Measurements of Pollution in the Troposphere (MOPITT) instrument are combined with measurements from the Transport and Chemical Evolution Over the Pacific (TRACE-P) aircraft mission over the northwest Pacific and with a global three-dimensional chemical transport model (GEOS-CHEM) to quantify Asian pollution outflow and its trans-Pacific transport during spring 2001. Global CO column distributions in MOPITT and GEOS-CHEM are highly correlated (R2 = 0.87), with no significant model bias. The largest regional bias is over Southeast Asia, where the model is 18% too high. A 60% decrease of regional biomass burning emissions in the model (to 39 Tg yr−1) would correct the discrepancy; this result is consistent with TRACE-P observations. MOPITT and TRACE-P also give consistent constraints on the Chinese source of CO from fuel combustion (181 Tg CO yr−1). Four major events of trans-Pacific transport of Asian pollution in spring 2001 were seen by MOPITT, in situ platforms, and GEOS-CHEM. One of them was sampled by TRACE-P (26–27 February) as a succession of pollution layers over the northeast Pacific. These layers all originated from one single event of Asian outflow that split into northern and southern plumes over the central Pacific. The northern plume (sampled at 6–8 km off California) had no ozone enhancement. The southern subsiding plume (sampled at 2–4 km west of Hawaii) contained a 8–17 ppbv ozone enhancement, driven by decomposition of peroxyacetylnitrate (PAN) to nitrogen oxides (NOx). This result suggests that PAN decomposition in trans-Pacific pollution plumes subsiding over the United States could lead to significant enhancements of surface ozone

The META tool optimizes metagenomic analyses across sequencing platforms and classifiers

A major challenge in the field of metagenomics is the selection of the correct combination of sequencing platform and downstream metagenomic analysis algorithm, or “classifier”. Here, we present the Metagenomic Evaluation Tool Analyzer (META), which produces simulated data and facilitates platform and algorithm selection for any given metagenomic use case. META-generated in silico read data are modular, scalable, and reflect user-defined community profiles, while the downstream analysis is done using a variety of metagenomic classifiers. Reported results include information on resource utilization, time-to-answer, and performance. Real-world data can also be analyzed using selected classifiers and results benchmarked against simulations. To test the utility of the META software, simulated data was compared to real-world viral and bacterial metagenomic samples run on four different sequencers and analyzed using 12 metagenomic classifiers. Lastly, we introduce “META Score”: a unified, quantitative value which rates an analytic classifier’s ability to both identify and count taxa in a representative sample