NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Hepatocellular carcinoma (HCC) can have viral or non-viral causes(1-5). Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need(6,7). Here we report the progressive accumulation of exhausted, unconventionally activated CD8(+)PD1(+) T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8(+)PD1(+) T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH-HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8(+)PD1(+)CXCR6(+), TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8(+) T cells or TNF neutralization, suggesting that CD8(+) T cells help to induce NASH-HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8(+)PD1(+) T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH-HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment

Diagnostic yield of asymptomatic arrhythmias detected by mobile cardiac outpatient telemetry and autotrigger looping event cardiac monitors.

Asymptomatic arrhythmias can have important therapeutic implications in certain patient populations, for example, atrial fibrillation in patients with prior ischemic stroke. We sought to compare the diagnostic yield of two commercially available monitoring systems with automated arrhythmia detection algorithms. We queried a large, proprietary database containing rhythm data for patients receiving ambulatory EKG monitoring (BioTelemetry, Malvern, PA, USA). We compared all patients prescribed mobile cardiac outpatient telemetry (MCOT™, Braemar Manufacturing, LLC, Eagan, MN, USA) versus autotrigger looping event recorder (AT-LER) devices over a consecutive 8-month period. Data from both device types were analyzed for diagnostic yields in detecting asymptomatic (device-triggered) arrhythmias consisting of atrial fibrillation (of any detected duration), bradycardia (ventricular rate ≤ 40 bpm), ventricular pause (≥ 3 seconds), supraventricular tachycardia (≥ 6 consecutive supraventricular beats), and ventricular tachycardia (≥ 4 consecutive premature ventricular contractions). The mean time to first diagnosis of each arrhythmia for each device was determined. Physician-designated diagnostic codes for patients prescribed each device were also determined from the database. The MCOT™ device had significantly higher diagnostic yields of all evaluated asymptomatic arrhythmias than the AT-LER. The MCOT™ device also produced an earlier mean time to diagnosis for all evaluated asymptomatic arrhythmias. These findings were noted despite a shorter average prescription length for MCOT™ monitored patients. In patients with conventional diagnostic monitoring indications, MCOT™ had significantly higher diagnostic yields for five asymptomatic arrhythmias compared to the AT-LER.12 month embargo; published online: 22 September 2017This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Central role for dermal fibroblasts in skin model protection against Candida albicans

The fungal pathogen Candida albicans colonizes basically all human epithelial surfaces, including the skin. Under certain conditions, such as immunosuppression, invasion of the epithelia occurs. Not much is known about defense mechanisms against C. albicans in subepithelial layers such as the dermis. Using immune cell-supplemented 3D skin models we defined a new role for fibroblasts in the dermis and identified a minimal set of cell types for skin protection against C. albicans invasion. Dual RNA sequencing of individual host cell populations and C. albicans revealed that dermal invasion is directly impeded by dermal fibroblasts. They are able to integrate signals from the pathogen and CD4+ T cells and shift toward an antimicrobial phenotype with broad specificity that is dependent on Toll-like receptor 2 and interleukin 1β. These results highlight a central function of dermal fibroblasts for skin protection, opening new possibilities for treatment of infectious diseases

Neue Benzimidazol-2-yl-alkylamine und ihre Anwendung als mikrobizide Wirkstoffe

The present invention relates to novel benzimidazole-2-yl-alkylamines having antimicrobial properties, to methods for the production of said compounds, and the use thereof as microbicidal agents in pharmaceutical preparations or plant protectants. Although numerous microbicidal agents are known, the adaptability of microorganisms and thus the creation of resistance results in a continuous need for new, highly effective, but also physiologically sustainable substances with preferably new mechanisms of action and broader spectrums of activity. The described benzimidazol derivates of the following formula have a good antimicrobial effect, particularly against species of the genus candida. Toxicology tests have shown a good compatibility of the new agents. Two different methods are described for the production of the compounds. The compounds are used for the systemic and local treatment of humans, animals, and plants that are infected by harmful microorganisms, particularly fungi, bacteria, viruses, algae, protozoa, and other parasites (Formula I)

The haemodynamic status of cardiac surgical patients in the initial 2-h recovery period

BackgroundCritical care nurses caring for cardiac patients in the immediate postoperative period continually make decisions about the implications and treatment of their patients\u27 haemodynamic status.AimThe aim of this study was to describe the haemodynamic status of patients on admission to critical care and over the 2-h period following cardiac surgery.MethodsA quantitative, descriptive design was used. Data were collected using non-participant observation and an observation tool. The sample consisted of 38 patients.ResultsAnalysis of data revealed the dynamic nature of the haemodynamic status of postoperative cardiac patients. On admission, 60% of patients (n = 23) were haemodynamically unstable. The instability in these patients (n = 23) was due to hypotension (34%), bleeding (21%) and hypoxaemia (18%). During the 2-h recovery period, 55% of patients were hypotensive, 16% of patients had low cardiac output syndrome and 16% of patients had low systemic vascular resistance (SVR) syndrome. Twenty-one percent of patients experienced bleeding complications. Shivering was a clinically significant problem in terms of occurrence (23%) and duration (X = 45, S.D. = 30 min). Twenty-nine percent of patients (n = 11) had a profound deterioration in haemodynamic status, necessitating urgent interventions.ConclusionHaemodynamic parameters indicate that 95% of patients in this study were haemodynamically unstable at some time during the initial 2-h recovery period. These findings inform resourcing decisions by organisations and have implications for nurses\u27 assessment and interventional haemodynamic decision making.<br /

memo - Magazine of European Medical Oncology / Anti-angiogenic therapies in brain metastases

Brain metastases are a major challenge in modern oncology, as treatment options upon the diagnosis of symptomatic brain metastases are limited. Neo-angiogenesis was identified as a hallmark of brain metastasis development and inhibition using anti-angiogenic therapy might therefore be an experimental promising preventive as well as therapeutic approach. The current review will summarize the current available data on the efficacy of neo-angiogenic therapies in patients with brain metastases.(VLID)357543