Discoveries made in the past 5 years indicate that the composition of the intestinal microbiota has a major influence on the effectiveness of anticancer immunosurveillance and thereby contributes to ...the therapeutic activity of immune-checkpoint inhibitors that target cytotoxic T lymphocyte protein 4 (CTLA-4) or the programmed cell death protein 1 (PD-1)-programmed cell death 1 ligand 1 (PD-L1) axis, as well as the activity of immunogenic chemotherapies. Herein, we highlight some of the bacteria, such as Akkermansia muciniphila, Bacteroides fragilis, Bifidobacterium spp. and Faecalibacterium spp., that have been associated with favourable anticancer immune responses in both preclinical tumour models and patients with cancer. Importantly, these bacteria also seem to have a positive influence on general health, thus reducing the incidence of metabolic disorders and a wide range of chronic inflammatory pathologies. We surmise that a diverse and propitious microbial ecosystem favours organismal homeostasis, particularly at the level of the cancer-immune dialogue.
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NUK, OILJ, SBMB, UL, UM, UPUK
Sudden cardiac death (SCD) is a tragic incident accountable for up to 50% of deaths from cardiovascular disease. Sports-related SCD (SrSCD) is a phenomenon which has previously been associated with ...both competitive and recreational sport activities. SrSCD has been found to occur 5-33-fold less frequently in women than in men, and the sex difference persists despite a rapid increase in female participation in sports. Establishing the reasons behind this difference could pinpoint targets for improved prevention of SrSCD. Therefore, this review summarizes existing knowledge on epidemiology, characteristics, and causes of SrSCD in females, and elaborates on proposed mechanisms behind the sex differences. Although literature concerning the aetiology of SrSCD in females is limited, proposed mechanisms include sex-specific variations in hormones, blood pressure, autonomic tone, and the presentation of acute coronary syndromes. Consequently, these biological differences impact the degree of cardiac hypertrophy, dilation, right ventricular remodelling, myocardial fibrosis, and coronary atherosclerosis, and thereby the occurrence of ventricular arrhythmias in male and female athletes associated with short- and long-term exercise. Finally, cardiac examinations such as electrocardiograms and echocardiography are useful tools allowing easy differentiation between physiological and pathological cardiac adaptations following exercise in women. However, as a significant proportion of SrSCD causes in women are non-structural or unexplained after autopsy, channelopathies may play an important role, encouraging attention to prodromal symptoms and family history. These findings will aid in the identification of females at high risk of SrSCD and development of targeted prevention for female sport participants.
Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating ...pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K
channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.
Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and ...insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy.
Use of adeno-associated virus (AAV) to transduce genes into skeletal muscles can be associated with T-cell responses to viral capsid and/or to transgenic protein. Intramuscular mononuclear cell ...infiltrates primarily consisting of CD8+ T cells and also containing FOXP3+ regulatory T cells were present in rhesus macaque skeletal muscle treated with rAAVrh74.MCK.GALGT2 by vascular delivery. Administration of oral prednisone prior to AAV gene delivery and throughout the study reduced such infiltrates by 60% at 24 weeks post AAV delivery compared with AAV-treated animals not receiving prednisone, regardless of the presence of pre-existing AAV serum antibodies at the time of treatment. The majority of CD8+ T cells in AAV-treated muscles expressed activated caspase 3 and programmed cell death protein 1 (PD1), suggesting ongoing programmed cell death. AAV-transduced skeletal muscles also had elevated expression of programmed death ligand 2 (PDL2) on skeletal myofibers, and this increase in expression extended to muscles where transgene was not overexpressed. These data demonstrate that prednisone can reduce the extent of intramuscular T-cell infiltrates in AAV-treated muscles, which may aid in achieving long-term transgene expression, as may the induction of PDL2 expression on skeletal myofibers to promote PD1-mediated programmed T-cell death.
Cardiac arrhythmias are a primary contributor to sudden cardiac death, a major unmet medical need. Because right ventricular (RV) dysfunction increases the risk for sudden cardiac death, we examined ...responses to RV stress in mice. Among immune cells accumulated in the RV after pressure overload-induced by pulmonary artery banding, interfering with macrophages caused sudden death from severe arrhythmias. We show that cardiac macrophages crucially maintain cardiac impulse conduction by facilitating myocardial intercellular communication through gap junctions. Amphiregulin (AREG) produced by cardiac macrophages is a key mediator that controls connexin 43 phosphorylation and translocation in cardiomyocytes. Deletion of Areg from macrophages led to disorganization of gap junctions and, in turn, lethal arrhythmias during acute stresses, including RV pressure overload and β-adrenergic receptor stimulation. These results suggest that AREG from cardiac resident macrophages is a critical regulator of cardiac impulse conduction and may be a useful therapeutic target for the prevention of sudden death.
Results from the DANISH Study (Danish Study to Assess the Efficacy of ICDs in Patients With Non-Ischemic Systolic Heat Failure on Mortality) suggest that for many patients with dilated cardiomyopathy ...(DCM), implantable cardioverter-defibrillators do not increase longevity. Accurate identification of patients who are more likely to die of an arrhythmia and less likely to die of other causes is required to ensure improvement in outcomes and wise use of resources. Until now, left ventricular ejection fraction has been used as a key criterion for selecting patients with DCM for an implantable cardioverter-defibrillator for primary prevention purposes. However, registry data suggest that many patients with DCM and an out-of-hospital cardiac arrest do not have a markedly reduced left ventricular ejection fraction. In addition, many patients with reduced left ventricular ejection fraction die of nonsudden causes of death. Methods to predict a higher or lower risk of sudden death include the detection of myocardial fibrosis (a substrate for ventricular arrhythmia), microvolt T-wave alternans (a marker of electrophysiological vulnerability), and genetic testing. Midwall fibrosis is identified by late gadolinium enhancement cardiovascular magnetic resonance imaging in ≈30% of patients and provides incremental value in addition to left ventricular ejection fraction for the prediction of sudden cardiac death events. Microvolt T-wave alternans represents another promising predictor, supported by large meta-analyses that have highlighted the negative predictive value of this test. However, neither of these strategies have been routinely adopted for risk stratification in clinical practice. More convincing data from randomized trials are required to inform the management of patients with these features. Understanding of the genetics of DCM and how specific mutations affect arrhythmic risk is also rapidly increasing. The finding of a mutation in lamin A/C, the cause of ≈6% of idiopathic DCM, commonly underpins more aggressive management because of the malignant nature of the associated phenotype. With the expansion of genetic sequencing, the identification of further high-risk mutations appears likely, leading to better-informed clinical decision making and providing insight into disease mechanisms. Over the next 5 to 10 years, we expect these techniques to be integrated into the existing algorithm to form a more sensitive, specific, and cost-effective approach to the selection of patients with DCM for implantable cardioverter-defibrillator implantation.
We previously showed that oxaliplatin induces necrotic-like cell death in hepatocarcinomas, and combination with ursodexoycholic acid (UDCA) significantly shifts the necrotic-like death to apoptosis. ...Since cell death mode is crucial on inflammatory responses and chemotherapeutic efficacy, the mechanism underlying determination of cell death mode by UDCA was investigated in this study.
Apoptosis or necrosis was determined by apoptotic body formation, caspase-8 activity, LDH release and PI inclusion. The involvement of lipid rafts and death receptors was examined by rafts fractionation, confocal microscopy and gene silencing assays.
UDCA combination enhanced recruitment of death receptors and adaptors into cholesterol-enriched lipid rafts, and induced a stronger raft clustering. Lipid raft disruption decreased the UDCA/oxaliplatin-mediated apoptosis and increased necrotic-like death.
UDCA promotes lipid raft localization of multiple death receptors, thereby contributing to a shift of cell death mode from oxaliplatin-induced necrotic death to apoptosis in HepG2 cells.
Although the US infant mortality rate reached a record low in 2020, the sudden infant death syndrome (SIDS) rate increased from 2019. To understand if the increase was related to changing death ...certification practices or the coronavirus disease 2019 (COVID-19) pandemic, we examined sudden unexpected infant death (SUID) rates as a group, by cause, and by race and ethnicity.
We estimated SUID rates during 2015 to 2020 using US period-linked birth and death data. SUID included SIDS, unknown cause, and accidental suffocation and strangulation in bed. We examined changes in rates from 2019 to 2020 and assessed linear trends during prepandemic (2015-2019) using weighted least squares regression. We also assessed race and ethnicity trends and quantified COVID-19-related SUID.
Although the SIDS rate increased significantly from 2019 to 2020 (P < .001), the overall SUID rate did not (P = .24). The increased SIDS rate followed a declining linear trend in SIDS during 2015 to 2019 (P < .001). Other SUID causes did not change significantly. Our race and ethnicity analysis showed SUID rates increased significantly for non-Hispanic Black infants from 2019 to 2020, widening the disparities between these two groups during 2017 to 2019. In 2020, <10 of the 3328 SUID had a COVID-19 code.
Diagnositic shifting likely explained the increased SIDS rate in 2020. Why the SUID rate increased for non-Hispanic Black infants is unknown, but warrants continued monitoring. Interventions are needed to address persistent racial and ethnic disparities in SUID.
Despite good long-term outcomes of kidney transplants from controlled donation after circulatory death (DCD) donors, there are few uncontrolled DCD (uDCD) programs. This longitudinal study compares ...outcomes for all uDCD (N = 774) and all donation after brain death (DBD) (N = 613) kidney transplants performed from 1996 to 2015 at our center. DBD transplants were divided into those from standard-criteria (SCD) (N = 366) and expanded-criteria (N = 247) brain-dead donors (ECD). One-, 5-, and 10-year graft survival rates were 91.7%, 85.7%, and 80.6% for SCD; 86.0%, 75.8%, and 61.4% for ECD; and 85.1%, 78.1%, and 72.2% for uDCD, respectively. Graft survival was worse in recipients of uDCD kidneys than of SCD (P = .004) but better than in transplants from ECD (P = .021). The main cause of graft loss in the uDCD transplants was primary nonfunction. Through logistic regression, donor death due to pulmonary embolism (OR 4.31, 95% CI 1.65-11.23), extrahospital CPR time ≥75 minutes (OR1.94, 95%CI 1.18-3.22), and in-hospital CPR time ≥50 minutes (OR 1.79, 95% CI 1.09-2.93) emerged as predictive factors of primary nonunction. According to the outcomes of our long-standing kidney transplantation program, uDCD could help expand the kidney donor pool.
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BFBNIB, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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