Cancer incidence is rising in low- and especially middle-income countries (MICs), driven primarily by four high-burden cancers (breast, cervix, lung, colorectal). By 2030, more than two-thirds of all ...cancer deaths will occur in MICs. Prevention and early detection are required alongside efforts to improve access to cancer treatment. Successful strategies for decreasing cancer mortality in high-income countries (HICs) are not always effective, feasible or affordable in other countries. In this review we evaluate strategies for prevention and early detection of breast, cervix, lung and colorectal cancers, focusing on modifiable risk factors and high-risk subpopulations. Tobacco taxation, HPV vaccination, cervical cancer screen-and-treat strategies, and efforts to reduce patient and health-system related delays in the early detection of breast and colorectal cancer represent the highest yield strategies for advancing cancer control in many MICs. An initial focus on high-risk populations is appropriate, with increasing population coverage as resources allow. These strategies can deliver significant cancer mortality gains, and serve as a foundation from which countries can develop comprehensive cancer control programs. Investment in national cancer surveillance infrastructure is needed; the absence of national cancer data to identify at-risk groups remains a barrier to the development of context-specific cancer control strategies.
Discusses the importance of assessing the patient-doctor encounter directly through observation, in the context of the trainee intern long case examination. Argues for the retention of the long case ...as an assessment tool for final year medical students on the basis of its high face validity and close resemblance to real life patient encounters. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Details some of the key factors that have led to the successful implementation of year-long regional and rural clinical placements for medical students in NZ. Refers to the experiences of the ...Universities of Auckland and Otago in implementing regional and rural programmes. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Background: Hepatic steatosis is increasingly encountered among organ donors. Currently, there is no consensus guideline as to the type or degree of donor steatosis considered acceptable for liver ...transplantation (LT), and little is known about local practices in this area. The aim of this survey was to evaluate current clinical practices amongst liver transplant surgeons in Australia and New Zealand (ANZ) in the evaluation and use of steatotic donor livers in LT. Methods: An anonymous online twelve-question survey was emailed to all practicing LT surgeons in ANZ (n = 23) in January 2010. Results: The response rate was 83%. Estimated prevalence of steatosis in donor livers was between 40% and 60%. In determining suitability for LT, 90% of respondents reported rejecting organs with "severe" steatosis based on visual and palpation grounds alone. A total of 68% sought further histological assessment if the donor liver looked bad and there were risk factors for steatosis. The majority of respondents performed only one biopsy of the liver (79%), using hematoxylin and eosin staining for fat assessment (53%). There was wide variation in the upper limit of steatosis considered to be acceptable for LT (40%-80% steatosis). A total of 21% of respondents still considered microvesicular steatosis a risk factor for primary graft nonfunction. Conclusion: This survey highlights the significant variation in the appraisal and use of steatotic grafts by LT surgeons in ANZ. Accurate evaluation and judicious use of mild and moderately steatotic grafts is required if we are to utilize the available donor pool best. Keywords: liver transplantation, steatosis, fatty liver, organ donors
CARMA-BCL10-MALT1 signalosomes play important roles in antigen receptor signaling and other pathways. Previous studies have suggested that as part of this complex, MALT1 functions as both a ...scaffolding protein to activate NF-κB through recruitment of ubiquitin ligases, and as a protease to cleave and inactivate downstream inhibitory signaling proteins. However, our understanding of the relative importance of these two distinct MALT1 activities has been hampered by a lack of selective MALT1 protease inhibitors with suitable pharmacologic properties. To fully investigate the role of MALT1 protease activity, we generated mice homozygous for a protease-dead mutation in MALT1. We found that some, but not all, MALT1 functions in immune cells were dependent upon its protease activity. Protease-dead mice had defects in the generation of splenic marginal zone and peritoneal B1 B cells. CD4+ and CD8+ T cells displayed decreased T cell receptor-stimulated proliferation and IL-2 production while B cell receptor-stimulated proliferation was partially dependent on protease activity. In dendritic cells, stimulation of cytokine production through the Dectin-1, Dectin-2, and Mincle C-type lectin receptors was also found to be partially dependent upon protease activity. In vivo, protease-dead mice had reduced basal immunoglobulin levels, and showed defective responses to immunization with T-dependent and T-independent antigens. Surprisingly, despite these decreased responses, MALT1 protease-dead mice, but not MALT1 null mice, developed mixed inflammatory cell infiltrates in multiple organs, suggesting MALT1 protease activity plays a role in immune homeostasis. These findings highlight the importance of MALT1 protease activity in multiple immune cell types, and in integrating immune responses in vivo.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RIP1 regulates necroptosis and inflammation and may play an important role in contributing to a variety of human pathologies, including immune-mediated inflammatory diseases. Small-molecule ...inhibitors of RIP1 kinase that are suitable for advancement into the clinic have yet to be described. Herein, we report our lead optimization of a benzoxazepinone hit from a DNA-encoded library and the discovery and profile of clinical candidate GSK2982772 (compound 5), currently in phase 2a clinical studies for psoriasis, rheumatoid arthritis, and ulcerative colitis. Compound 5 potently binds to RIP1 with exquisite kinase specificity and has excellent activity in blocking many TNF-dependent cellular responses. Highlighting its potential as a novel anti-inflammatory agent, the inhibitor was also able to reduce spontaneous production of cytokines from human ulcerative colitis explants. The highly favorable physicochemical and ADMET properties of 5, combined with high potency, led to a predicted low oral dose in humans.
Due to the ramping down of cancer surgery in early pandemic, many newly diagnosed patients received other treatments first. We aimed to quantify the pandemic-related shift in rate of surgery ...following chemotherapy. This is a retrospective population-based cohort study involving adults diagnosed with cancer between 3 January 2016 and 7 November 2020 in Ontario, Canada who received chemotherapy as first treatment within 6-months of diagnosis. Competing-risks regression models with interaction effects were used to quantify the association between COVID-19 period (receiving a cancer diagnosis before or on/after 15 March 2020) and receipt of surgical reSection 9-months after first chemotherapy. Among 51,653 patients, 8.5% (
= 19,558) of them ultimately underwent surgery 9-months after chemotherapy initiation. Receipt of surgery was higher during the pandemic than before (sHR 1.07, 95% CI 1.02-1.13). Material deprivation was independently associated with lower receipt of surgery (least vs. most deprived quintile: sHR 1.11, 95% CI 1.04-1.17), but did not change with the pandemic. The surgical rate increase was most pronounced for breast cancer (sHR 1.13, 95% CI 1.06-1.20). These pandemic-related shifts in cancer treatment requires further evaluations to understand the long-term consequences. Persistent material deprivation-related inequity in cancer surgical access needs to be addressed.
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