Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.     

Evaluating <Emphasis Type="Italic">Metarhizium brunneum</Emphasis> F52 microsclerotia in hydromulch formulations using different tackifiers under forest and orchard conditions

Microsclerotia of the entomopathogenic fungus (Metarhizium brunneum Petch strain F52; Hypocreales: Clavicipitaceae) were sprayed in a hydromulch formulation onto wood samples to test persistence and biological control efficacy when exposed on forest and orchard trees. The density of viable conidia and retention of hydromulch were not significantly affected by the tackifier in the formulation (psyllium, xanthan, or a mixture of both). Forest samples had a maximum conidial density and more viable conidia (7.2 × 10⁵ conidia cm^?2) than orchard samples (1.4 × 10⁵ conidia cm^?2). Increased rainfall, temperature and the time that samples were outdoors were critical factors for conidial density. Asian longhorned beetles [Anoplophora glabripennis (Motschulsky); Coleoptera: Cerambycidae] exposed to orchard samples in laboratory bioassays did not have significantly less mortality compared to forest samples, indicating that hydromulch may be feasible in open sunny conditions, if sufficient moisture is present.     

Seminal plasma biochemistry and spermatozoa characteristics of Atlantic cod (Gadus morhua L.) of wild and cultivated origin

Our objectives were to compare spermatozoa activity, morphology, and seminal plasma (SP) biochemistry between wild and cultivated Atlantic cod (Gadus morhua). Swimming velocities of wild cod spermatozoa were significantly faster than those of cultivated males. Wild males had a significantly larger spermatozoa head area, perimeter, and length, while cultivated males had more circular heads. Total monounsaturated fatty acids and the ratio of n-3/n-6 were significantly higher in sperm from wild males, while total n-6 from cultivated males was significantly higher than the wild males. Significantly higher concentrations of the fatty acids C14:0, C16:1n-7, C18:4n-3, C20:1n-11, C20:1n-9, C20:4n-3, C22:1n-11, and C22:6n-3 were observed in wild males, while significantly higher concentrations of C18:2n-6, C20:2n-6, and C22:5n-3 occurred in cultivated males. Osmolality, protein concentration, lactate dehydrogenase and superoxide dismutase activity of SP of wild males were significantly higher than the cultivated males. Antioxidant capacity of SP was significantly higher in cultivated males, while pH and anti-trypsin did not differ between fish origins. Four bands of anti-trypsin activity and nine protein bands were detected in SP. Performing a discriminant function analysis, on morphology and fatty acid data showed significant discrimination between wild and cultivated fish. Results are relevant to breeding programs and aquaculture development.     

Signet-ring cell lymphoma. Report of a case diagnosed by fine needle aspiration cytology

A case of signet-ring cell lymphoma initially diagnosed by fine needle aspiration (FNA) cytology is described. Immediate evaluation of air-dried smears showed a mixture of large and small lymphoid cells, including some signet-ring forms. Immunocytochemical studies of Cytospin preparations of the remaining aspirate yielded a diagnosis of a large-cell-type B-cell signet-ring lymphoma. Subsequent bone marrow biopsies confirmed the diagnosis of a low-grade lymphoma. The advantages of on-site evaluation in aspiration cytology are discussed.     

Particulate matter and bacteria characteristics of the Middle East Dust (MED) storms over Ahvaz,Iran

The Middle East Dust storms have greatly affected the south and west parts of Iran during the last decade. The main purpose of this study was to examine and compare culturable airborne bacteria concentration in particulate matter (PM) during normal, semi-dust, and dust event days in different places and seasons in Ahvaz from November 2011 to May 2012. Sampling was performed every 6 days and on dust event days at different sampling stations. The overall mean concentrations of PM₁₀, PM_2.5, and PM₁ for the entire study period were 598.92, 114.8, and 34.5 μg/m³, respectively. The PM concentrations during the dust event days were much higher than normal and semi-dust event days. The highest mean PM concentrations were observed in March 2011. The low PM_2.5/PM₁₀ ratios indicate that these PM are mostly originating from natural sources such as dust storms. The overall mean concentration of total bacteria during the study period was 620.6 CFU/m³. The greatest bacterial concentrations were observed during dust event days and at areas with high traffic and more human activities compared with normal days and greener areas. The percentage of gram-positive bacteria was significantly higher than that during the study period (89 vs 11 %). During this study, 26 genera of culturable bacteria were identified from all the sampling stations. The most dominant genera in all sampling stations were Streptomyces, Bacillus, Kocuria, Corynebacterium, and Paenibacillus. The results also showed that there were positive correlations between PM and bacterial concentrations during the study period (p < 0.05).     

The Role of Paraoxonase 1 (PON1) Gene Polymorphisms in Coronary Artery Disease: A Systematic Review and Meta-Analysis

Although many studies have investigated the association of paraoxonase 1 (PON1) polymorphisms with coronary artery disease (CAD). However, the outcomes were not consistent and remain uncertain. Therefore, it is the need of the hour to analyze the available literature and evaluate the association of PON1 polymorphisms with the CAD. All the relevant studies published in the English language from January 1, 2000, up to September 20, 2020, were identified by searching through various electronic databases. The two researchers independently extracted the information. The data were analyzed by using the MetaGenyo program. The pooled odds ratio was used to find the associations between CAD and PON1 polymorphisms. In the final analysis, we include 10 studies regarding the association of PON1 polymorphisms (rs662 and rs854560) with CAD. Overall, the Q192R polymorphism increased the risk of CAD in the tested genetic models including the homozygote model: OR 1.35, CI 1.02–1.79; allelic model: OR 1.16, CI 1.00–1.33; dominant model: OR 1.25, CI 1.03–1.52. The L55M polymorphism does not significantly associated with CAD in all the tested genetic models including the homozygote model: OR 1.00 CI, 0.64–1.56; allelic model: OR 1.02, 95% CI 0.84–1.23; dominant model: OR 1.08, CI 0.89–1.31. Further analysis showed no publication bias exists in meta-analysis. Our findings suggested that rs662 in the coding region was significantly associated with the CAD however, rs854560 has no significant association with the disease. Nevertheless, in future, there is a need for more studies with a larger sample size which may provide a more definite conclusion.

Study Registration: PROSPERO registration number CRD42020202278