Fossstokholm7072

© 2020 John Wiley & Sons Australia, Ltd.AIM To evaluate predictive factors which associated with oncological outcomes to first-line axitinib for metastatic renal cell carcinoma (mRCC). METHODS A retrospective chart review was conducted patients who had been treated with axitinib as first-line therapy for the treatment of mRCC from September 2013 to February 2018. Axitinib was given by single daily oral administration at a dose of 10 mg, which was reduced according to adverse events (AEs). We investigated progression-free survival (PFS), overall survival (OS), objective response rate (ORR) and AEs. RESULTS Thirty-eight mRCC patients were enrolled. The median follow-up duration of axitinib treatment was 11.3 months (range = 1.0-56.9). ORR was 28.9%. Median PFS and OS was 12.8, and 17.9 months, respectively. In univariate analysis, baseline lactate dehydrogenase (LDH), neutrophil, corrected calcium (Ca), platelets (Plt) and time from diagnosis were selected as potential predictive factors. Multivariate Cox's proportional hazards model analysis showed that the number of risk factors were associated with PFS (P = 0.03) and OS (P = 0.02). CONCLUSION Baseline LDH, neutrophil, Ca, Plt and time from diagnosis are predictive factors for both PFS and OS in first-line treatment with axitinib for metastatic renal cell carcinoma. © 2020 John Wiley & Sons Australia, Ltd.Cholesterol homeostasis is critical for cell function and human health. Cholesterol is heterogeneously distributed among cellular membranes, with the redistribution of endocytosed dietary cholesterol playing a pivotal role in the regulation of cholesterol homeostasis. While gaps remain in our understanding of intracellular dietary cholesterol transport, a highly complex network of pathways is starting to emerge, often involving inter-dependent vesicular and non-vesicular transport mechanisms. The last decade has seen a surge in interest in non-vesicular transport and inter-organellar communication at membrane contact sites. By providing platforms for protein interactions, signalling events, lipid exchange and calcium flux, membrane contact sites are now appreciated as controlling the fate of large amounts of lipid and play central roles in the regulation and co-ordination of endocytic trafficking. Here, we review the role of membrane contact sites in multiple pathways for cholesterol export from the endocytic pathway and highlight the intriguing interplay between vesicular and non-vesicular transport mechanisms and relationship with neurodegenerative disease. AY-22989 cost This article is protected by copyright. All rights reserved. link2 This article is protected by copyright. All rights reserved.Streptococcus mutans is a colonizer of the human dentition, and under conditions of dysbiosis is the primary causative agent of dental caries. The pathogenic potential of S. mutans depends, in part, on its ability to regulate the transport of metal ions across the plasma membrane to maintain intracellular metal ion homeostasis. Research in our laboratory has focused on the Mn2+ -specific SloC lipoprotein importer and its regulator encoded by the S. mutans sloR gene. Herein, we used a bioinformatics approach to identify a gene on the S. mutans UA159 chromosome, SMU_1176, as a metal ion efflux transporter that contributes to S. mutans manganese ion homeostasis. Metal ion sensitivity assays performed with the wild-type S. mutans UA159 strain and an isogenic SMU_1176 insertion-deletion mutant, called GMS3000, revealed significantly heightened sensitivity of GMS3000 to MnSO4 challenge. 54 Mn uptake experiments support the accumulation of 54 Mn in GMS3000 cell pellets when compared to 54 Mn concentrations in UA159 or in a complemented strain of GMS3000, called GMS3001. Inductively-coupled plasma mass spectrometry (ICP-MS) studies were performed in parallel to quantify intracellular manganese concentrations in these strains, the results of which corroborate the 54 Mn uptake studies, and support the SMU_1176 gene product as a Mn2+ efflux protein. Expression profiling experiments revealed de-repression of SMU_1176 gene transcription in the SloR-deficient GMS584 strain of S. mutans, especially under high manganese conditions. link3 In conclusion, the S. mutans SMU_1176 gene, which we renamed mntE, is a manganese efflux transporter that contributes to essential metal ion homeostasis as part of the SloR regulon. This article is protected by copyright. All rights reserved.Anoikis (detachment-induced cell death) is a specific type of programmed cell death which occurs in response to the loss of the correct extracellular matrix (ECM) connections. Anoikis resistance is an important mechanism in cancer invasiveness and metastatic behavior. Autophagy, on the other hand, involves the degradation of damaged organelles and the recycling of misfolded proteins and intracellular components. However, the intersection of these two cellular responses in lung cancer cells has not been extensively studied. Here, we identified that upon matrix deprivation, the lymphocyte lineagespecific Ets transcription factor SPIB was activated and directly enhanced SNAP47 transcription in certain lung cancer cells. Loss of attachment-induced autophagy significantly increased anoikis resistance by SPIB activation. Consistent with this function, SPIB depletion by shRNA abrogated SNAP47 transcriptional activation upon matrix deprivation. Therefore, these data delineate an important role of SPIB in autophagy-mediated anoikis resistance in lung cancer cells. Accordingly, these findings suggest that manipulating SPIB-regulated pathways in vivo and evaluating the impact of anoikis resistance warrants further investigation. This article is protected by copyright. All rights reserved.Cardiotoxicities are associated with immune checkpoint inhibitor (ICI) therapy. Recent case series and retrospective studies have shown that cardiac immune-related adverse events (irAEs) are rare but potentially fatal complications of immunotherapy, with various underlying risk factors such as combinations of different ICIs. High mortality rates and overreactive inflammation have been observed with ICI-associated cardiotoxicities, highlighting the necessity of baseline and serial evaluations and the identification and management of cardiac irAEs as early as possible. The clinical presentations of irAEs range from asymptomatic cardiac biomarker elevation, myocarditis and pericardial diseases to heart failure and mild to fatal arrhythmia. Troponin measurement and electrocardiogram are sensitive initial tests, whereas cardiac magnetic resonance imaging and endomyocardial biopsy are both gold standard components of the diagnostic criteria. Close monitoring and timely consultation with a cardiologist are important for the diagnosis of ICI-related cardiotoxicities, with decisions of stopping or rechallenging ICIs and strategies to manage heart injuries. Treatment principles are made according to risk stratifications. The first-line medication is glucocorticoids of various doses, and the second-line immunosuppression includes intravenous immunoglobin, antithymocyte globulin and other immunosuppressants, which are recommended in life-threatening cases or in cases of resistance/no response to steroids. © 2020 John Wiley & Sons Australia, Ltd.BACKGROUND Immunotherapy plays an important role in advanced non-small cell lung cancer (NSCLC). However, radiological evaluation is challenging due to the potential inflammatory effects of immunotherapy, which can lead to atypical response patterns. Identifying these atypical responses is critical to making treatment decisions and prognostication. METHODS We performed a retrospective analysis of consecutive advanced NSCLC patients treated with immunotherapy (alone or in combination). We collected patients' clinical and pathological data, analyzed the proportion of patients who continued immunotherapy beyond progressive disease (PD) per RECIST 1.1, and compared the differences in response patterns between the RECIST 1.1 and iRECIST criteria. RESULTS A total of 43 patients treated at the Peking Union Medical College, China from January 2018 to April 2019 were included. Continued immunotherapy beyond PD per RECIST 1.1 was observed in 10 (33.3%, 10/30) patients, of which there were discordant assessments (30%, 3/10) between the RECIST 1.1 and iRECIST, which were evaluated as PD by RECIST 1.1 and immune unconfirmed PD by iRECIST. Among seven patients with immune confirmed PD, one (1/30, 3.3%) had pseudoprogression. Patients who continued immunotherapy beyond PD (n = 10) experienced significantly prolonged overall survival (not reached vs. 8.1 months hazard ratio, 2.8; 95% confidence interval 2.7-13.6, P = 0.03) compared with patients who did not continue immunotherapy beyond PD (n = 20). CONCLUSIONS RECIST 1.1 evaluation underestimated the benefit of immunotherapy. Further research is required to optimize iRECIST and establish some criteria for selecting patients who will benefit from continued immunotherapy beyond PD per RECIST 1.1. © 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.AIM High-altitude pulmonary oedema (HAPE) is a non-cardiogenic pulmonary oedema that can occur during rapid ascent to a high-altitude environment. Classically, HAPE has been described as a condition resulting from a combination of pulmonary vasoconstriction and hypertension. Inflammation has been described as important in HAPE, although as a side effect of pulmonary oedema rather than as a causative factor. In this study, we aim to understand the role of hypoxic response in myeloid cells and its involvement in pathogenesis of HAPE. METHODS We have generated a conditional deletion in mice of the von Hippel-Lindau factor (VHL) in myeloid cells to determine the effect of a deregulated hypoxic response in pulmonary oedema. RESULTS The deletion of VHL in pulmonary myeloid cells gave rise to pulmonary oedema, increased pulmonary vascular permeability and reduced performance during exertion. These changes were accompanied by reduced stroke volume in the left ventricle. CONCLUSION In this model, we show that a deregulated myeloid cell hypoxic response can trigger some of the most important symptoms of HAPE, and thus mice with a deletion of VHL in the myeloid lineage can function as a model of HAPE. © 2020 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.We introduce a new boron-doped cyclophane, the hexabora[16 ]cyclophane B6-F Mes, in which six tricoordinate borane moieties alternate with short conjugated p-phenylene linkers. Exocyclic 2,4,6-tris(trifluoromethyl)phenyl (F Mes) groups serve not only to further withdraw electron density but at the same time sterically shield the boron atoms, resulting in a macrocycle that is both highly electron-deficient and stable. The optical and electronic properties are compared with those of related linear oligomers and the electronic structure is further evaluated by computational methods. The studies uncover unique properties of B6-F Mes, including a low-lying and extensively delocalized LUMO and a wide HOMO-LUMO gap, which arise from the combination of a cyclic π-system, strong electronic communication between the closely spaced borons, and the attachment of electron-deficient pendent groups. The binding of small anions to the electron-deficient macrocycle and molecular model compounds is investigated and emissive exciplexes are detected in aromatic solvents.