HIF-α Effects on c-Myc Distinguish Two Subtypes of Sporadic VHL-Deficient Clear Cell Renal Carcinoma

VHL tumor suppressor loss results in hypoxia inducible factor-alpha (HIF-α) stabilization, and occurs in 70% of sporadic clear cell renal carcinomas (ccRCCs). To determine whether opposing influences of HIF-1α and HIF-2α on c-Myc activity regulate human ccRCC progression, we analyzed VHL genotype and HIF-α expression in 160 primary tumors, which segregated into three groups with distinct molecular characteristics. Interestingly, ccRCCs with intact VHL, as well as pVHL-deficient, HIF-1α/HIF-2α expressing ccRCCs, exhibited enhanced Akt/mTOR and ERK/MAPK signaling. In contrast, pVHL-deficient ccRCCs expressing only HIF-2α displayed elevated c-Myc activity, resulting in enhanced proliferation and resistance to replication stress. These reproducible distinctions in ccRCC behavior delineate HIF-α effects on c-Myc in vivo and suggest molecular criteria for selecting targeted therapies

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Expanding ethics justice across borders : the role of global philosophy

Our energy systems are truly international, and yet even now, our energy policies tend to be grounded at the national level and in many instances, remain ill-equipped to tackle transboundary energy issues. Our energy policy systems are also largely detached from the concerns of ethics or justice. It follows that we must find new and innovative ways of not conceptualising these normative issues, but of operationalising response to them. This book stems from the emergent gap: the need for comparative approaches to energy justice, and for those that consider non-Western ethical traditions. Opening the edited volume, this chapter begins by giving context to the concept of “energy justice” itself and outlines our comparative philosophical approach to it, focusing specifically on “global philosophy” for its role in dialectically engaging with philosophies from around the world. We then show how the different chapters of the volume contribute to this purpose in four parts: setting the scene, practice, applying theory to practice and theoretical approaches. The final section of this chapter concludes with reflections on the contribution of global philosophy approaches to energy justice as with a set of future research recommendations. Through these recommendations, and all of those within, we position the book as one that contributes to energy justice scholarship across borders of nations, borders of ways of thinking and borders of disciplines

Screening of traditionally used Tanzanian medicinal plants for antifungal activity

Kisangau DP, Hosea KM, Lyaruu HVM, et al. Screening of traditionally used Tanzanian medicinal plants for antifungal activity. PHARMACEUTICAL BIOLOGY. 2009;47(8):708-716.Fungal infections represent a significant cause of morbidity and mortality especially in immunocompromised patients in the world today. Dichloromethane (DM) and aqueous (W) extracts of nine plants used traditionally for the treatment of fungal infections in Bukoba rural district in Tanzania were screened for antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus niger using agar well and disk diffusion methods. Dichloromethane extracts of Capparis erythrocorpos [CE] Isert (Capparaceae), Cussonia arborea [CA] Hochst. Ex A. Rich (Araliaceae), Drocaena steudneri [DS] Engl. (Dracaenaceae), Lannea schimperi [LS] (A. Rich) Engl. (Anacardiaceae), Rouvolfia vomitoria [RV] Afz (Apocynaceae), and Sapium ellipticum [SE] (Krauss) Pax (Euphorbiaceae) showed activity against all three fungi. Extracts of Rumex usambarensis [RU] (Dammer) Dammer (Polygonaceae) and Zehneria scabro [ZS] (L.f.) Sond. (Cucurbitaceae) had an activity limited to only one or two of the test organisms. Rhoicissus tridentata [RT] (L.Q Wild & Drum (Vitaceae) was the only plant without activity. Fractions of the active extracts CE, CA, DS, LS, and SE exhibited higher antifungal activity against one or more of the three fungi. Four compounds isolated from S. ellipticum also exhibited antifungal activity against one or more of the three fungi. The minimum inhibitory concentrations (MICs) and minimum fungicidal concentrations (MFCs), determined using the microplate assay method, ranged between 0.4 and 50.0 mu g/mL for crude extracts, 1.6 and 50.0 mu g/mL for semi-purified fractions, and 0.12 and 1.0 mu g/mL for pure compounds, as compared to 0.016-1.5 mu g/mL for fluconazole. We confirm the potential of traditionally used plants as a source of new drugs for treatment of fungal infections