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Apheresis apply designs in the United States of America: Evaluation of the industry statements repository.
Although human adipose derived stem cells (hADSCs) hold great promises for regenerative medicine, their key biological properties remain poorly understood. In particular, proliferation defects resulted from deep quiescence (dormancy) and senescence represent a major hurdle in hADSC production and clinical application. We have developed a model system for mechanistic dissection of hADSC quiescence and senescence. p57Kip2, a major CDK inhibitor, was highly expressed in quiescent and senescent hADSCs but its level quickly declined upon stem cell activation. p57Kip2 overexpression induced quiescence in spite of proliferative signals and its knockdown promoted cell cycle reentry even with induction of quiescence presumably through modulating the CDK2-CyclinE1 complex. Given its key role in quiescence and senescence, p57Kip2 may be exploited for innovative strategies to amplify hADSCs of high quality for clinics. V.INTRODUCTION Immune-mediated toxicities are potentially fatal and can affect virtually any organ system. The prevalence of immune-mediated toxicity in patients being treated with immune checkpoint inhibitors (ICIs) is well described. However, the reasons for presentation and the prevalence of immune-mediated toxicity in acutely unwell patients being treated with ICIs is less well described. MATERIALS AND METHODS A prospective analysis of all emergency presentations in patients being treated with ICIs was performed at a specialist oncology hospital in England from 20th May 2018 to 19th May 2019. The primary outcome measure was whether the emergency presentation related to an immune-mediated toxicity. Secondary outcome measures were length of stay associated with immune-mediated toxicities and 7- and 30-day mortalities related to these presentations. RESULTS During the study period, 300 patients on ICIs presented. The most common primary presenting complaints were dyspnoea 59 (19.7%), diarrhoea 47 (15.7%) and fever 37 (12.3%). Ninety-eight (32.7%) patients were diagnosed with an immune-mediated toxicity of which colitis 38 (38.8%), hepatitis 19 (19.4%) and pneumonitis 14 (14.3%) were the most common. The mean length of inpatient stay for those diagnosed with an immune-mediated presentation was 7.1 (0-45) days compared with 6.2 (0-44) days in those without. Seven patients died within 7 days of the emergency presentation, of whom 2 died from immune-mediated toxicity. CONCLUSIONS One-third of cancer patients treated with ICIs admitted as an emergence had an immune-mediated toxicity and 2% died because of this. Acute care clinicians managing these patients need to be aware that immune-mediated toxicity is common in this patient population, but it can be challenging to differentiate these from other causes for emergency presentation. PURPOSE This is a first-in-human phase I study investigating the safety and efficacy of toripalimab, a humanized monoclonal antibody against the programmed cell death-1 (PD-1) receptor, in Chinese patients with advanced or recurrent malignant tumor refractory to standard treatment. PATIENTS AND METHODS During dose escalation, patients received a single-dose intravenous infusion of toripalimab for 56 days followed by multidose infusions every two weeks. The planned dosing groups were 1, 3 and 10 mg/kg. During dose expansion, patients received toripalimab every two weeks. Clinical response was evaluated by investigators every 6 weeks. RESULTS Thirty-three patients were enrolled, including 12 patients with alveolar soft part sarcoma (ASPS), seven with non-small-cell lung cancer and 11 with lymphoma. Patients were heavily pretreated with a median of 3 prior lines of systemic treatments. Toripalimab was well tolerated without dose-limiting toxicity. All patients experienced treatment-related adverse events. Grade 3 and above treatment-related adverse events occurred in six (18.2%) patients. Among 22 solid tumors, the objective response rate (ORR) was 22.7% per RECIST v1.1. The ORR was 90.9% in 11 lymphoma patients per IWG 2007. The median duration of response was 21.5 months. The median progression-free survival was 5.7 months for solid tumors and 8.3 months for lymphomas. The median OS was not reached for all patients and the lymphoma subgroups. The median OS was 34.7 months for patients with ASPS. CONCLUSION Toripalimab was well tolerated up to 10 mg/kg Q2W without dose-limiting toxicity and showed promising and durable antitumour activities in patients with ASPS and lymphoma, who were heavily pretreated. CLINICAL TRIAL INFORMATION ClinicalTrials.gov Identifier NCT02836834. BACKGROUND Children with cancer are in urgent need of new therapies, as approximately 25% of patients experience a relapse and 20% succumb to their disease. Moreover, the majority of survivors suffer from clinically relevant health problems. Repurposing of targeted agents developed for adult indications could provide novel therapeutic options for paediatric cancer patients. To prioritise targeted drugs for paediatric clinical development, we applied a systematic review methodology to develop a Target Actionability Review (TAR) strategy. These TARs assess the strength and completeness of published preclinical proof-of-concept (PoC) data by structured critical appraisal of and summarising the available scientific literature for a specific target (pathway) and the associated drugs in paediatric tumours. read more METHODS A sensitive literature search in PubMed was performed and relevant papers were identified. For each paper, the individual experimental findings were extracted, marked for paediatric tumour type and categorised into nine separate PoC data modules. Each experimental finding was scored for experimental outcome and quality independently by two reviewers; discrepancies were assessed by a third reviewer and resolved by adjudication. Scores corresponding to one PoC module were merged for each tumour type and visualised in a heat map matrix in the publicly available R2 data portal [r2.amc.nl]. RESULTS AND CONCLUSIONS To test our TAR methodology, we conducted a pilot study on MDM2 and TP53. The heat map generated from analysis of 161 publications provides a rationale to support drug development in specific paediatric solid and brain tumour types. Furthermore, our review highlights tumour types where preclinical data are incomplete or lacking and for which additional preclinical testing is advisable.
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