Immunotherapy For Advanced Cancer Patients With Autoimmune Disease

Purpose Immunotherapy (IT) has been shown to improve cancer survival but there is limited evidence regarding use in patients with advanced cancer and pre-existing autoimmune disease (AI). We sought to address these knowledge gaps and determine IT utilization patterns and overall survival (OS) for these patients. Patients and Methods This retrospective cohort study used data from Flatiron Health’s nationwide oncology database. Patients diagnosed with advanced cancer where there was ≥ 1 FDA approved IT were included. Baseline demographics were analyzed using χ2 and t-tests. Patterns of IT use were assessed using logistic regression. OS was estimated using Kaplan-Meier and Cox proportional hazards models. Results Of the 70,964 patients included, 1,801 had AI. Controlling for demographic and clinical variables, AI was not associated with IT use in general (Odds Ratio [OR]=0.90, 95% CI 0.79-1.03), but was associated with lower odds of receiving first-line IT (OR=0.72, 95% CI 0.61-0.84). IT usage differed by cancer type. Overall, on multivariate analysis, patients with AI had better survival than those without AI. This remained true for overall IT (Hazard Ratio [HR]=0.86, 95% CI 0.81-0.91) and for first-line IT (HR=0.79, 95% CI 0.71-0.88). Interaction between IT and AI was significant, with IT having stronger association in patients with AI compared to those without (HR=0.57, 95% CI 0.50-0.64 vs HR=0.66, 95% CI 0.64-0.68). Among patients treated with IT, interaction between first-line IT and AI was not significant. Among patients with AI, receiving first-line IT had no survival benefit (HR=0.95, 95% CI 0.77-1.17). Conclusion Receipt of IT had greater survival benefit for patients with AI compared to those without AI; first-line IT did not result in further survival benefit. Patients with advanced cancer and pre-existing AI should receive IT, potentially as second or third-line treatment

CMTM2 is essential for spermiogenesis in mice

Objective: This study is to investigate whether CKLF-like MARVEL transmembrane domain-containing protein 2 (CMTM2) is involved in spermatogenesis in mice. CMTM2 is highly expressed in testis, and could possibly a potential spermagogenesis specific gene. Methods: CMTM2-deficient mouse model was generated. Northern, RT-PCR and Western blotting analysis were performed on total RNA derived from wild-type (WT, CMTM2(+/+)) and CMTM2(+/-)(heterozygote) and CMTM2(-/-)(homozygote) mice to examine the CMTM2 level. The number of litters and the number of pups were counted and pregnancy rates calculated. The motility and morphology of the sperm and the histology of testes were analyzed. Serum testosterone and FSH concentrations were also measured. Standard t-tests (Excel, Microsoft, Redmond, WA, USA) were used and standard error of means were calculated. Results: CMTM2 is highly expressed in a finely regulated pattern in the mouse testis during spermatogenesis. The body weight of adult mice with CMTM2 deficiency was not significantly different from that of wild type mice. No obvious anatomical or behavioral abnormalities were observed. The testes of CMTM2(-/-)were smaller than that of CMTM2(+/+) mice. Female CMTM2 null mice are fertile, indicating that CMTM2 is not required for female gametogenesis. The CMTM2(-/-)mice produced virtually no sperm, and CMTM2(+/-)mice sperm count showed a significant decline. The hormone levels are not significantly different. The CMTM2(-/-)male mice are sterile due to a late, complete arrest of spermiogenesis. The organized architecture of the seminiferous epithelium of the seminiferous tubules seen in CMTM2(+/+) mice was lost in CMTM2(-/-)mice. Conclusions: This study suggests CMTM2 is not required for embryonic development in the mouse but is essential for spermiogenesis.NIH [AG14875]; Specialized Research Fund for the Doctoral Program of Higher Education, China [20-120001120056]SCI(E)[email protected]

Reduction of Endothelial Nitric Oxide Increases the Adhesiveness of Constitutive Endothelial Membrane ICAM-1 through Src-Mediated Phosphorylation

Nitric oxide (NO) is a known anti-adhesive molecule that prevents platelet aggregation and leukocyte adhesion to endothelial cells (ECs). The mechanism has been attributed to its role in the regulation of adhesion molecules on leukocytes and the adhesive properties of platelets. Our previous study conducted in rat venules found that reduction of EC basal NO synthesis caused EC ICAM-1-mediated firm adhesion of leukocytes within 10–30min. This quick response occurred in the absence of alterations of adhesion molecules on leukocytes and also opposes the classical pattern of ICAM-1-mediated leukocyte adhesion that requires protein synthesis and occurs hours after stimulation. The objective of this study is to investigate the underlying mechanisms of reduced basal NO-induced EC-mediated rapid leukocyte adhesion observed in intact microvessels. The relative levels of ICAM-1 at different cell regions and their activation status were determined with cellular fractionation and western blot using cultured human umbilical vein ECs. ICAM-1 adhesiveness was determined by immunoprecipitation in non-denatured proteins to assess the changes in ICAM-1 binding to its inhibitory antibody, mAb1A29, and antibody against total ICAM-1 with and without NO reduction. The adhesion strength of EC ICAM-1 was assessed by atomic force microscopy (AFM) on live cells. Results showed that reduction of EC basal NO caused by the application of caveolin-1 scaffolding domain (AP-CAV) or NOS inhibitor, L-NMMA, for 30 min significantly increased phosphorylated ICAM-1 and its binding to mAb1A29 in the absence of altered ICAM-1 expression and its distribution at subcellular regions. The Src inhibitor, PP1, inhibited NO reduction-induced increases in ICAM-1 phosphorylation and adhesive binding. AFM detected significant increases in the binding force between AP-CAV-treated ECs and mAb1A29-coated probes. These results demonstrated that reduced EC basal NO lead to a rapid increase in ICAM-1 adhesive binding via Src-mediated phosphorylation without de novo protein synthesis and translocation. This study suggests that a NO-dependent conformational change of constitutive EC membrane ICAM-1 might be the mechanism of rapid ICAM-1 dependent leukocyte adhesion observed in vivo. This new mechanistic insight provides a better understanding of EC/leukocyte interaction-mediated vascular inflammation under many disease conditions that encounter reduced basal NO in the circulation system

Learn2Reg: comprehensive multi-task medical image registration challenge, dataset and evaluation in the era of deep learning

Image registration is a fundamental medical image analysis task, and a wide variety of approaches have been proposed. However, only a few studies have comprehensively compared medical image registration approaches on a wide range of clinically relevant tasks. This limits the development of registration methods, the adoption of research advances into practice, and a fair benchmark across competing approaches. The Learn2Reg challenge addresses these limitations by providing a multi-task medical image registration data set for comprehensive characterisation of deformable registration algorithms. A continuous evaluation will be possible at https://learn2reg.grand-challenge.org. Learn2Reg covers a wide range of anatomies (brain, abdomen, and thorax), modalities (ultrasound, CT, MR), availability of annotations, as well as intra- and inter-patient registration evaluation. We established an easily accessible framework for training and validation of 3D registration methods, which enabled the compilation of results of over 65 individual method submissions from more than 20 unique teams. We used a complementary set of metrics, including robustness, accuracy, plausibility, and runtime, enabling unique insight into the current state-of-the-art of medical image registration. This paper describes datasets, tasks, evaluation methods and results of the challenge, as well as results of further analysis of transferability to new datasets, the importance of label supervision, and resulting bias. While no single approach worked best across all tasks, many methodological aspects could be identified that push the performance of medical image registration to new state-of-the-art performance. Furthermore, we demystified the common belief that conventional registration methods have to be much slower than deep-learning-based methods

Minimal information for studies of extracellular vesicles (MISEV2023): From basic to advanced approaches

Extracellular vesicles (EVs), through their complex cargo, can reflect the state of their cell of origin and change the functions and phenotypes of other cells. These features indicate strong biomarker and therapeutic potential and have generated broad interest, as evidenced by the steady year-on-year increase in the numbers of scientific publications about EVs. Important advances have been made in EV metrology and in understanding and applying EV biology. However, hurdles remain to realising the potential of EVs in domains ranging from basic biology to clinical applications due to challenges in EV nomenclature, separation from non-vesicular extracellular particles, characterisation and functional studies. To address the challenges and opportunities in this rapidly evolving field, the International Society for Extracellular Vesicles (ISEV) updates its 'Minimal Information for Studies of Extracellular Vesicles', which was first published in 2014 and then in 2018 as MISEV2014 and MISEV2018, respectively. The goal of the current document, MISEV2023, is to provide researchers with an updated snapshot of available approaches and their advantages and limitations for production, separation and characterisation of EVs from multiple sources, including cell culture, body fluids and solid tissues. In addition to presenting the latest state of the art in basic principles of EV research, this document also covers advanced techniques and approaches that are currently expanding the boundaries of the field. MISEV2023 also includes new sections on EV release and uptake and a brief discussion of in vivo approaches to study EVs. Compiling feedback from ISEV expert task forces and more than 1000 researchers, this document conveys the current state of EV research to facilitate robust scientific discoveries and move the field forward even more rapidly

Development of a Performance Analysis Model for Free-Piston Stirling Power Convertor in Space Nuclear Reactor Power Systems

Space nuclear reactor power system (SNRPS) is a priority technical solution to meet the future space power requirement of high-power, low-mass, and long-life. The thermoelectric conversion subsystem is the key component of SNRPS, which greatly affects the performance, quality, and volume of SNRPS. Among all kinds of proposed thermoelectric conversion technologies, the free-piston Stirling power converter (FPSPC) has become a preferred conversion technology for small-scale advanced SNPRS due to its moderate waste heat emission temperature and high conversion efficiency, mainly composed of a linear alternator and free-piston Stirling engine (FPSE). For studying the performance of FPSPC, a quasi-steady flow thermodynamic cycle analysis model considering parasitic heat losses has been developed for FPSE. And then the performance analysis model for FPSPC has been established by coupling the thermodynamic cycle analysis model with the mechanical motion model of the piston and volt-ampere characteristic model of the linear alternator. Furthermore, the analysis model was compared and validated by the GPU-3 Stirling engine’s experimental data. The performance parameters of Component Test Power Converter (CTPT) FPSPC designed by NASA for SNRPS were also analyzed. The results show that the amplitudes position of CTPC displacer and piston are 15.1 mm and 11.2 mm, respectively. The corresponding average electric power output of CTPC is 17.316 kW. The input thermal power to the CTPT heater is 66.1 kW, leading to the converter efficiency of 26.2%. The average current and voltage of the CTPC alternator are 86.38 A and 193.15 V, respectively. Among all kinds of parasitic energy losses, the regenerator heat loss accounts for the largest proportion, with an average of about 12.7 kW. The effects of cooler and heater temperature on the performance of CTPC FPSPC were also studied

Interview with Dr. Dave Langlois

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Interview with Mandeep Mann and Setayesh Yazdani

Mandeep Mann and Setayesh Yazdani are researchers in the Department of Pharmacology and Toxicology at the University of Toronto under the supervision of Dr. Matthieu Schapira, the head of research informatics at the Structural Genomics Consortium (SGC). Mandeep is a PhD candidate in the Department of Pharmacology and Toxicology, and Setayesh recently completed her MSc in the same department. Setayesh is currently a Doctor of Pharmacy student at the Leslie Dan Faculty of Pharmacy at the University of Toronto