Hegelundjuarez3520

5, p=0.0001) and insulin (-1.5±4.6 mU/L, p=0.001) were observed in submerged crews. Changes in serum lipids were positively associated with changes in body weight within crews combined. Energy intake was maintained during submerged patrols but was lower compared with non-submerged (11 139±2792 vs. 9617±2466 kJ, p=0.001; 11 062±2775 vs. 9632±2682 kJ, p=0.003). CONCLUSIONS The environment of a submerged submarine produced no adverse effects on serum biomarkers of cardiometabolic risk in crew. Conversely, modest improvements in these biomarkers were associated with a decrease in body weight. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND Spartalizumab is a humanized IgG4κ monoclonal antibody that binds programmed death-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2. This phase 1/2 study was designed to assess the safety, pharmacokinetics, and preliminary efficacy of spartalizumab in patients with advanced or metastatic solid tumors. METHODS In the phase 1 part of the study, 58 patients received spartalizumab, intravenously, at doses of 1, 3, or 10 mg/kg, administered every 2 weeks (Q2W), or 3 or 5 mg/kg every 4 weeks (Q4W). RESULTS Patients had a wide range of tumor types, most commonly sarcoma (28%) and metastatic renal cell carcinoma (10%); other tumor types were reported in ≤3 patients each. Most patients (93%) had received prior antineoplastic therapy (median three prior lines) and two-thirds of the population had tumor biopsies negative for PD-L1 expression at baseline. The maximum tolerated dose was not reached. The recommended phase 2 doses were selected as 400 mg Q4W or 300 mg Q3W. No dose-limiting toxicities werese. See rights and permissions. Published by BMJ.BACKGROUND There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib. METHODS Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8+ T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8+ T cells. RESULTS CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8+ T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells. CONCLUSIONS CKI acts on macrophages and CD8+ T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Hydrogen sulfide (H2S), a plant gasotransmitter, functions in the plant response to cadmium (Cd) stress, implying a role for cysteine desulfhydrase in producing H2S in this process. Whether D-CYSTEINE DESULFHYDRASE (DCD) acts in the plant Cd response remains to be identified, and if it does, how DCD is regulated in this process is also unknown. Here, we report that DCD-mediated H2S production enhances plant Cd tolerance in Arabidopsis (Arabidopsis thaliana). When subjected to Cd stress, a dcd mutant accumulated more Cd and reactive oxygen species (ROS) and showed increased Cd sensitivity, whereas transgenic lines overexpressing DCD had decreased Cd and ROS levels and were more tolerant to Cd stress compared with wild-type plants. ARRY382 Furthermore, the expression of DCD was stimulated by Cd stress, and this upregulation was mediated by a Cd-induced transcription factor, WRKY13, which bound to the DCD promoter. Consistently, the higher Cd sensitivity of the wrky13-3 mutant was rescued by the overexpression of DCD. Together, our results demonstrate that Cd-induced WRKY13 activates DCD expression to increase the production of H2S, leading to higher Cd tolerance in plants. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.In plants, water use efficiency is a complex trait arising from numerous physiological and developmental characteristics. Here, we investigated the involvement of circadian regulation in long-term water use efficiency in Arabidopsis under light and dark conditions. Circadian rhythms are generated by the circadian oscillator, which provides a cellular measure of the time of day. In plants, the circadian oscillator contributes to the regulation of many aspects of physiology, including stomatal opening, rate of photosynthesis, carbohydrate metabolism, and developmental processes such as the initiation of flowering. We investigated the impact of the misregulation of numerous genes encoding various components of the circadian oscillator on whole plant, long-term water use efficiency. From this analysis, we identified a role for the circadian oscillator in water use efficiency. It appears that the circadian clock contributes to the control of transpiration and biomass accumulation. We also established that the circadian oscillator within guard cells can contribute to long-term water use efficiency. Our experiments indicate that knowledge of circadian regulation will be important for developing crops with improved water use efficiency. copyright, serif 2020 American Society of Plant Biologists. All rights reserved.