51886 research outputs found
Sort by
Safety and efficacy of immune checkpoint therapy for the treatment of patients with cardiac metastasis: a multicenter international retrospective study
No full textBackground: Data on the safety profiles and clinical outcomes of patients with solid tumors and cardiac metastasis treated with immune checkpoint inhibitors (ICIs) are limited.
Methods: This is an international multicenter retrospective study of patients with cancer and cardiac metastasis at baseline. Patients who had received ≥1 dose of ICI were included. Treatment-related adverse events (trAEs) were graded per Common Terminology Criteria for Adverse Event V.5.0. Objective response rates (ORR) were evaluated by Response Evaluation Criteria in Solid Tumors V.1.1 when available. Overall survival (OS) and progression-free survival (PFS) were estimated by the Kaplan-Meier method.
Results: Among 110 pts, median age at ICI initiation was 65 (IQR: 59-75). Median follow-up time since ICI initiation was 36 (95% CI: 26 to 51) months. Melanoma (38%, n=42) and non-small cell lung cancer (24%, n=26) were the most common. 68 (62%) patients received ICIs as first-line, and 29 (26%) patients were treated with combination anti-programmed death-1 and anti-cytotoxic T-lymphocyte antigen 4. The most common location of cardiac metastasis was in the atria (37%, n=41) and ventricles (35%, n=39). 15 patients (13.6%) had bilateral cardiac/pericardial metastasis, 44 (40%) had left-sided, and 43 (39.8%) had right-sided. At ICI initiation, 21% (n=23) had a cardiac thrombus. Cardiology referrals and cardiac MRIs at the time of cancer diagnosis were completed on 58 (53%) and 52 (47%) patients, respectively. Cardiac events occurred in 40 (36%) patients, including arrhythmias (n=14, 13%), arterial/venous emboli (n=4, 3.6%), and cardiac tamponade (n=3, 2.7%). 53 (47%) patients developed trAEs; most common were colitis/diarrhea (n=16, 15%), dermatitis (n=13, 12%), and hepatitis (n=9, 8.2%). ICI-related major cardiac trAEs occurred in 2 (1.8%) patients. 22 patients (20%) developed grade ≥3 trAE. Patients with multiple cardiac metastases had significantly lower responses to ICI-based regimens compared with patients with single cardiac metastasis (11% vs 63%, p=0.02). For melanoma, ORR, median PFS, and median OS were 38%, 9.0 months, and 28.9 months, respectively. 83% of patients with melanoma had concordant responses in overall disease burden and cardiac disease. 91 patients discontinued ICIs, and the main reason was progression or death in 55 (49%) patients.
Conclusions: Among patients with pre-existing cardiac metastasis, ICIs demonstrated meaningful clinical efficacy with no increase in safety signals. Most patients had concordant responses in the overall disease burden and cardiac mass. Multidisciplinary teams are crucial for the appropriate management of patients with cardiac metastasis
Adiponectin pathway activation dampens inflammation and enhances alveolar macrophage fungal killing via LC3-associated phagocytosis
No full textAlthough innate immunity is critical for antifungal host defense against the human opportunistic fungal pathogen Aspergillus fumigatus, potentially damaging inflammation must be controlled. Adiponectin (APN) is an adipokine produced mainly in adipose tissue that exerts anti-inflammatory effects in adipose-distal tissues such as the lung. We observed increased mortality and increased fungal burden and inflammation in neutropenic mice with invasive aspergillosis (IA) that lack APN or the APN receptors AdipoR1 or AdipoR2. Alveolar macrophages (AMs), early immune sentinels that detect and respond to lung infection, express both receptors, and APN-deficient AMs exhibited an inflammatory phenotype that was associated with decreased fungal killing. Pharmacological stimulation of AMs with AdipoR agonist AdipoRon rescued deficient killing in APN-/- AMs and was dependent on the presence of either receptor. Finally, APN-enhanced fungal killing was associated with increased activation of the non-canonical LC3 pathway of autophagy. Thus, our study identifies a novel role for APN in LC3-mediated killing of A.fumigatus
Human herpesvirus‐associated transposable element activation in human aging brains with Alzheimer's disease
No full textIntroduction: Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown.
Methods: We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies.
Results: We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model.
Discussion: Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation.
Highlights: Via analysis of bulk RNA-seq data in two large-scale human brain biobanks, ROS/MAP (n = 109 pathologically confirmed AD and n = 44 cognitively healthy controls) and MSBB (n = 284 AD and n = 150 cognitively healthy controls), we identified widespread TE activation in HHV-positive human AD brains and significantly positive associations of HHV RNA abundance with APOE4 genotype, Braak staging score, and CERAD score. We identified cell type-specific LINE1 upregulation in both microglia and astrocytes of human AD brains via long-range enhancer-promoter chromatin interactions on lncRNA nuclear enriched abundant transcript 1 (NEAT1). We determined that usage of valacyclovir and acyclovir was significantly associated with reduced incidence of AD in a large real-world patient database. Using the HEK293 tau P301S model and U2OS mt-Keima cell model, we determined that valacyclovir treatment rescued tau-associated neuropathology and alleviated activation of LINE1 with increased cellular autophagy-level mechanistically supported clinical benefits of valacyclovir in real-world patient data
Autophagy-related 7 (ATG7) regulates food intake and liver health during asparaginase exposure
No full textAmino acid starvation by the chemotherapy agent asparaginase is a potent activator of the integrated stress response (ISR) in the liver and can upregulate autophagy in some cell types. We hypothesized that autophagy-related 7 (ATG7), a protein that is essential for autophagy and an ISR target gene, was necessary during exposure to asparaginase to maintain liver health. We knocked down Atg7 systemically (Atg7Δ/Δ) or in hepatocytes only (ls-Atg7KO) in mice before exposure to pegylated asparaginase for 5 days. Intact mice injected with asparaginase lost body weight due to reduced food intake and increased energy expenditure. Systemic Atg7 ablation reduced liver protein synthesis and increased liver injury in vehicle-injected mice but did not further reduce liver protein synthesis, exacerbate steatosis or liver injury, or alter energy expenditure following 5 days of asparaginase exposure. Atg7Δ/Δ mice were unexpectantly protected from asparaginase-induced anorexia and weight loss. This protection corresponded with reduced phosphorylation of hepatic GCN2 and blunted increases in ISR gene targets including growth differentiation factor 15 (GDF15), a negative regulator of food intake. Interestingly, asparaginase elevated serum GDF15 and reduced food intake in ls-Atg7KO mice, similar to intact mice. Liver triglycerides and production of the hepatokine fibroblast growth factor 21, another ISR gene target, were suppressed in asparaginase-exposed Atg7Δ/Δ and ls-Atg7KO mice. This work identifies a bidirectional relationship between autophagy and the ISR in the liver during asparaginase, affecting food intake and liver health
Methods to address functional unblinding of raters in CNS trials
No full textTreatment-emergent adverse events (TEAEs) associated with the unique properties of a pharmaceutical product may functionally unblind clinician ratings, obscure true medication effects, and affect confidence about clinical trial results. Central nervous system studies are particularly susceptible to functional unblinding because they rely on relatively subjective symptom assessments. Two different methods were used to examine possible functional unblinding in pooled data from three recent five-week, double-blind, placebo-controlled trials of xanomeline and trospium chloride (formerly known as KarXT) in participants with schizophrenia experiencing acute psychosis. Xanomeline/trospium is an M1/M4 muscarinic receptor agonist that may produce cholinergic side effects. First, we compared the scores of remote (site-independent) raters, blinded to TEAEs, who listened to audio recorded, site-based Positive and Negative Syndrome Scale (PANSS) interviews. Second, we conducted a post hoc analysis of participant subgroups with or without reported cholinergic-related TEAEs to ascertain whether cholinergic TEAEs influenced trial outcome. Remote ratings closely replicated 575 available "paired" site-based PANSS total scores at baseline and endpoint (intraclass correlation coefficient = 0.88 and 0.93, respectively). Both site-based and remote PANSS scores yielded significant improvement favouring xanomeline/trospium over placebo (both p < 0.0001) and yielded significantly greater treatment response (≥30% improvement from baseline) than placebo (both p < 0.0001). The significant improvement of PANSS scores favouring xanomeline/trospium over placebo was comparable in magnitude for all subgroups regardless of whether participants reported cholinergic-related TEAEs, or any TEAEs at all (all p < 0.001). In sum, the two different methods used to assess functional unblinding in these studies found no impact of cholinergic TEAEs, or any TEAEs, on the trial results. These methods may have utility across all clinical trials
Comparing the long-term prognosis and renal function changes of partial nephrectomy (PN) and radical nephrectomy (RN) in T1 stage renal cell carcinoma patients
No full textBackground: Radical nephrectomy (RN) and partial nephrectomy (PN) are common surgical treatments for T1 stage renal cell carcinoma (RCC). However, the long-term impact of these surgical approaches on prognosis and renal function remains an area of ongoing investigation. This study compared the effects of these procedures on prognosis and renal function.
Methods: The data of 1,030 T1 stage RCC patients treated at Peking University Cancer Hospital & Institute between January 2014 and August 2022 were analyzed. The primary endpoints of the study were overall survival (OS) and cancer-specific survival (CSS). The secondary endpoints included the annual mean estimated glomerular filtration rate (eGFR) and the average annual eGFR change rates.
Results: Based on a median follow-up time of 57 months, the OS and CSS rates were 96.6% and 98.5% in the overall cohort, respectively. The multivariate analysis identified age [hazard ratio (HR), 2.664; 95% confidence interval (CI): 1.147-6.192; P=0.02], tumor grade (HR, 2.247; 95% CI: 1.050-4.810; P=0.04), and surgical approach (HR, 2.585; 95% CI: 1.056-6.325; P=0.04) as adverse prognostic factors for OS, and age (HR, 4.603; 95% CI: 1.035-20.471; P=0.045) and tumor grade (HR, 4.972; 95% CI: 1.752-14.111; P=0.003) as adverse prognostic factors for CSS. Throughout the follow-up period, the eGFR of the RN patients showed a gradual increase, while that of the PN patients remained stable (P<0.001). Among the patients with preoperative diabetes, the eGFR of the RN patients decreased significantly compared to that of the PN patients (P=0.03).
Conclusions: T1 stage RCC has a favorable prognosis with surgery, and PN is an oncologically safe option. A persistent eGFR difference was observed between the PN and RN groups, with RN showing a gradual upward trend. However, patients with pre-existing diabetes experienced a greater decline in renal function after RN, which highlights the advantages of PN for such patients
Exploring Emotion Regulation and Trait Mindfulness within the Relationship between Racial Discrimination and Emotional Eating among Black Women
No full textIUIObesity is more prevalent among Black adults, particularly Black women, compared to other minority groups. Emotional eating has been identified as a potential modifiable behavior that has been linked to increased rates of obesity for Black women. Stress resulting from racial discrimination, also known as race-related stress, is as a potential risk factor for emotional eating. However, research has yet to examine the mechanisms by which race-related stress may impact emotional eating among Black women, as well as factors that may moderate these relationships. Therefore, the current aim of this study was to examine whether emotional regulation strategies mediate the relationship between race-related stress and emotional eating, and whether mindfulness may moderate these mediational pathways, among Black women. Black women across the United States (n=558, Mage= 39.88, SD =13.47) completed an online survey. Results found that race-related stress was significantly associated with emotional eating (β = 0.151; p < .001). Rumination was found to be the only emotional regulation strategy to significantly mediate the relationship between race-related stress and emotional eating (β = .035; 95%CI [.018, .055]). Trait mindfulness moderated one path; at higher levels there was an inverse relationship between race-related stress and emotional suppression (β = -1.110; 95%C [ -2.101, -.119]). This extends previous literature suggesting a relationship between race-related stress and emotional eating through rumination beyond emerging adulthood. These findings serve as a foundation for future researchers to investigate the impacts of specific race-related stressors on emotional eating through rumination and avoidant emotional regulation strategies for Black women. The long-term impacts of this body of research are to reduce disparities in obesity for black women within the broader context of systemic, cultural, intervention and policy changes
Exploring Health Equity Gaps in the Administration of Regional Anesthesia for Surgical Interventions
No full textThis review aimed to identify and synthesize existing literature on racial and ethnic disparities in the administration of regional anesthesia for patients undergoing surgical procedures. A comprehensive search of PubMed, Embase, and Ovid MEDLINE, supplemented by manual reference screening, yielded 4,931 articles, of which 26 met inclusion criteria following title, abstract, and full-text review. Studies were categorized by surgical intervention type—breast, general, and orthopedic surgery—to assess disparities in regional anesthesia administration. Additionally, system- and patient-level factors influencing these differences were examined. The findings demonstrate consistent evidence of racial and ethnic disparities in the receipt of regional anesthesia. Further research is needed to understand the underlying causes and inform strategies to promote equitable anesthesia care
Diabetic Foot Ulcer Beyond Wound Closure: Clinical Practice Guideline
No full textA total of 37.3 million Americans have diabetes, and 96 million more have prediabetes. Hyperglycemia, the hallmark of diabetes, increases the risk for diabetes-related complications, including skin breakdown and cardiovascular disease. Many clinical practice guidelines exist, but there are gaps regarding the best approaches to assess physical fitness and mobility in adults with diabetes; incorporate exercise into the care plan; and reload the diabetic foot after ulcer closure has occurred to avoid ulcer reoccurrence. The purpose of this clinical practice guideline was to review and assess previously published guidelines and address gaps within the guidelines specific to the following: best screening tools/tests and interventions to prevent a future reulceration, best screening tools and interventions to assess and address mobility impairments, best tools to measure and interventions to address reduced physical fitness and activity, best approach to reloading the foot after ulceration closure and, finally, whether improvement in physical fitness will positively change quality of life and health care costs. The Guidelines Development Group performed a systematic literature search and review of the literature. A total of 701 studies were identified. Following duplicate removal and exclusion for irrelevance, 125 studies underwent full-text review, and 38 studies were included. Recommendations were developed using a software assistant created specifically for guideline recommendation development. Recommendations resulted for physical fitness and activity inclusion and measurement for adults with diabetes and with or without foot ulceration. Exercise and physical activity should be prescribed according to the physiologic response of an adult with diabetes to exercise and preferences for optimizing long-term quality of life and reduce health care costs. Reloading following diabetic foot ulcer closure should include maximal offloading, especially during the first 3 months; loading should be titrated using a footwear schedule. Further research is necessary in the areas of exercise in the wound healing process and the assessment of methods to reload a newly reepithelialized ulcer to prevent recurrence