The programmed death-1 (PD-1) and its ligand PD-L1 (B7-H1) signaling pathway has been the focus of much enthusiasm in the fields of tumor immunology and oncology with recent FDA approval of the ...anti-PD-1 antibodies pembrolizumab and nivolumab and the anti-PD-L1 antibodies durvalumab, atezolimuab, and avelumab. These therapies, referred to here as PD-L1/PD-1 checkpoint blockade therapies, are designed to block the interaction between PD-L1, expressed by tumor cells, and PD-1, expressed by tumor-infiltrating CD8
T cells, leading to enhanced antitumor CD8
T cell responses and tumor regression. The influence of PD-L1 expressed by tumor cells on antitumor CD8
T cell responses is well characterized, but the impact of PD-L1 expressed by immune cells has not been well defined for antitumor CD8
T cell responses. Although PD-L1 expression by tumor cells has been used as a biomarker in selection of patients for PD-L1/PD-1 checkpoint blockade therapies, patients whose tumor cells lack PD-L1 expression often respond positively to PD-L1/PD-1 checkpoint blockade therapies. This suggests that PD-L1 expressed by non-malignant cells may also contribute to antitumor immunity. Here, we review the functions of PD-L1 expressed by immune cells in the context of CD8
T cell priming, contraction, and differentiation into memory populations, as well as the role of PD-L1 expressed by tumor cells in regulating antitumor CD8
T cell responses.
Film festivals play an important role in the construction and circulation of not only individual films but entire taxonomies of cinema, from their “discovery of new waves” (Elsaesser 2005: 99) to ...their production of “hegemonic …canons” (Vallejo, 2020: 158). The effects of this taxonomical power are felt across filmmaking, criticism, and scholarship, foregrounded in renewed calls to decolonize film festivals and film culture more broadly (Dovey and Sendra 2022forthcoming, Shambu 2019). This article mobilizes and adapts “New Lacanian” theories of ideology critique to propose a methodology for studying the ways in which film festivals construct meaning for films and, cumulatively, entire canons. Outlining concepts such as the festival apparatus, the festival paratext, and the cinematic Real, I trace the coordinates of a three-tier critical procedure that brings into dialogue festivals’ operational and material contexts, their representation of themselves and their films, and the unruly, aesthetic qualities of the films that festivals exhibit. I demonstrate the application of this approach to a recent cause célèbre of Italian migration cinema, Fire at Sea, its awarding and representation at the 2016 edition of the Berlin International Film Festival instantiating the enduring legacy of Neorealism and a “brutal humanist” stance directed towards refugees in the new millennium (Schoonover 2012). Moving between theoretical discussions and the application of this method of ideology critique, I demonstrate how we might interrogate structures of meaning implicit within film festivals’ rhetorical operation, offering a ground from which to better understand film festivals and, if desired, advocate for change.
Over the decade between 2003 and 2012, the UK has seen major changes in how organ donation and transplantation is delivered. The number of deceased organ donors has increased from 709 (12.0 per ...million population pmp) to 1,164 (18.3 pmp); this increase has been predominantly a result of an increase in donors after circulatory death (DCD) (from 1.1 pmp to 7.9 pmp) while the numbers of donors after brain death (DBD) has remained broadly stable (around 10.5 pmp). The donor population has become older (from 14% 60 years or over to 35%) and heavier (from 14% with body mass index >=30 kg/m2 to 23%). Despite these changes in demographic factors, the number of organs retrieved from DBD donors has risen from a mean of 3.6 to 4.0 per donor and for DCD donors from 2.2 to 2.6. The number of transplants in adults in 2012 was 2,709 (967 DBD, 708 DCD, and 1,034 living) for kidney alone, 246 pancreas (including 172 kidney and pancreas), 792 (611 DBD, 142 DCD, 36 living, and 3 domino) for liver, 136 for heart only, and 179 (145 DBD and 34 DCD) for lung only. Median waiting times to transplant for adult patients were 1,167, 339, 141, 293, and 311 days, respectively. The proportion of adult non-urgent registrants in 2009 (2007 for kidneys) who were removed from the waiting list or died awaiting a graft within 1 year was 3% for kidneys, 6% for pancreas, 19% for liver, 27% for heart, and 24% for lung. Outcomes after solid organ transplants are improving; for adult patients grafted between 2003 and 2005, 5-year graft survival for kidney is 84% (DBD), 87% (DCD), and 92% (living donor), for simultaneous kidney and pancreas 72%, and for pancreas alone 50% (DBD). Five-year patient survival for liver is 77% (DBD) and 68% (DCD), heart 67%, and lung 52% (DBD). Although rates of organ donation and transplantation have increased in the UK, this has been almost solely because of a rise in DCD donation. Although donor age and weight is increasing, graft survival has generally improved. Despite a recent fall in the number of patients on the transplant waiting list, there remains a significant gap between the need for transplantation and the number of organs available from deceased and living donors. The implementation of a new strategy following the recommendations of the Organ Donation Task Force in 2008 has had a major impact in bringing together clinicians involved in both organ donation and transplantation, and these changes and clinical enthusiasm have been instrumental in achieving success. With an emphasis on the need to increase the family consent rate for organ donation, which has failed to show any improvement over the last 5 years, a new UK strategy for organ donation and transplantation, introduced in 2013, will further increase organ transplantation in the UK.
BACKGROUND:Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing ...obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries.
METHODS AND RESULTS:For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareaseffects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity.
CONCLUSIONS:Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target.
The use of kidneys from controlled donation after circulatory death (DCD) donors has the potential to markedly increase kidney transplants performed. However, this potential is not being realized ...because of concerns that DCD kidneys are inferior to those from donation after brain-death (DBD) donors. The United Kingdom has developed a large and successful controlled DCD kidney transplant program that has allowed for a substantial increase in kidney transplant numbers. Here we describe recent trends in DCD kidney donor activity in the United Kingdom, outline aspects of the donation process, and describe donor selection and allocation of DCD kidneys. Previous UK Transplant Registry analyses have shown that while DCD kidneys are more susceptible to cold ischemic injury and have a higher incidence of delayed graft function, short- and medium-term transplant outcomes are similar in recipients of kidneys from DCD and DBD donors. We present an updated, extended UK registry analysis showing that longer-term transplant outcomes in DCD donor kidneys are also similar to those for DBD donor kidneys, and that transplant outcomes for kidneys from expanded-criteria DCD donors are no less favorable than for expanded-criteria DBD donors. Accordingly, the selection criteria for use of kidneys from DCD donors should be the same as those used for DBD donors. The UK experience suggests that wider international development of DCD kidney transplantation programs will help address the global shortage of deceased donor kidneys for transplantation.
In 2013, the American Heart Association and American College of Cardiology published the “Guideline on Lifestyle Management to Reduce Cardiovascular Risk,” which was based on a systematic review ...originally initiated by the National Heart, Lung, and Blood Institute. The guideline supports the American Heart Association’s 2020 Strategic Impact Goals for cardiovascular health promotion and disease reduction by providing more specific details for adopting evidence-based diet and lifestyle behaviors to achieve those goals. In addition, the 2015–2020 Dietary Guidelines for Americans issued updated evidence relevant to reducing cardiovascular risk and provided additional recommendations for adopting healthy diet and lifestyle approaches. This scientific statement, intended for healthcare providers, summarizes relevant scientific and translational evidence and offers practical tips, tools, and dietary approaches to help patients/clients adapt these guidelines according to their sociocultural, economic, and taste preferences.
Amide N-methylation is important for the activity and permeability of bioactive compounds but can be challenging to perform selectively. The broad-spectrum antimicrobial natural products thiolutin ...and holomycin differ only by an N-methyl group at the endocyclic amide of thiolutin, but only thiolutin exhibits antifungal activity. The enzyme responsible for amide N-methylation in thiolutin biosynthesis has remained elusive. Here, we identified and characterized the amide N-methyltransferase DtpM that is encoded >400 kb outside of the thiolutin gene cluster. DtpM catalyzes efficient conversion of holomycin to thiolutin, exhibits broad substrate scope toward dithiolopyrrolones, and has high thermal stability. In addition, sequence similarity network analysis suggests DtpM is more closely related to phenol O-methyltransferases than some amide methyltransferases. This study expands the limited examples of amide N-methyltransferases and may facilitate chemoenzymatic synthesis of diverse dithiolopyrrolone compounds as potential therapeutics.
Summary Background Use of kidneys donated after controlled circulatory death has increased the number of transplants undertaken in the UK but there remains reluctance to use kidneys from older ...circulatory-death donors and concern that kidneys from circulatory-death donors are particularly susceptible to cold ischaemic injury. We aimed to compare the effect of donor age and cold ischaemic time on transplant outcome in kidneys donated after circulatory death versus brain death. Methods We used the UK transplant registry to select a cohort of first-time recipients (aged ≥18 years) of deceased-donor kidneys for transplantations done between Jan 1, 2005, and Nov 1, 2010. We did univariate comparisons of transplants from brain-death donors versus circulatory-death donors with χ2 tests for categorical data and Wilcoxon tests for non-parametric continuous data. We used Kaplan-Meier curves to show graft survival. We used Cox proportional hazards regression to adjust for donor and recipient factors associated with graft-survival with tests for interaction effects to establish the relative effect of donor age and cold ischaemia on kidneys from circulatory-death and brain-death donors. Findings 6490 deceased-donor kidney transplants were done at 23 centres. 3 year graft survival showed no difference between circulatory-death (n=1768) and brain-death (n=4127) groups (HR 1·14, 95% CI 0·95–1·36, p=0·16). Donor age older than 60 years (compared with <40 years) was associated with an increased risk of graft loss for all deceased-donor kidneys (2·35, 1·85–3·00, p<0·0001) but there was no increased risk of graft loss for circulatory-death donors older than 60 years compared with brain-death donors in the same age group (p=0·30). Prolonged cold ischaemic time (>24 h vs <12 h) was not associated with decreased graft survival for all deceased-donor kidneys but was associated with poorer graft survival for kidneys from circulatory-death donors than for those from brain-death donors (2·36, 1·39–4·02, p for interaction=0·004). Interpretation Kidneys from older circulatory-death donors have equivalent graft survival to kidneys from brain-death donors in the same age group, and are acceptable for transplantation. However, circulatory-death donor kidneys tolerate cold storage less well than do brain-death donor kidneys and this finding should be considered when developing organ allocation policy. Funding UK National Health Service Blood and Transplant; Cambridge National Institute for Health Research Biomedical Research Centre.
PDF
