Osteosarcoma is the most prevalent primary malignant bone tumor in children and adolescents. Despite advancements in adjuvant chemotherapy and surgical techniques, the overall survival rate of osteosarcoma patients remains suboptimal, particularly in cases of metastatic or recurrent disease. Programmed cell death (PCD), a highly regulated process that includes apoptosis, autophagy, ferroptosis, pyroptosis, and necroptosis, plays a pivotal role in determining cellular fate (survival and death). In osteosarcoma, PCD dysregulation enables malignant cells to evade cell death signals, thereby accelerating tumor development. Natural products derived from various medicinal plants and dietary components exhibit promising potential for osteosarcoma treatment by regulating PCD through different mechanisms. With advantages such as low cost, minimal side effects, and wide availability, natural products have attracted considerable attention for translational research. This review systematically synthesizes current knowledge on PCD subtypes in osteosarcoma and elucidates the molecular mechanisms by which natural products regulate PCD to inhibit the development of osteosarcoma. By integrating these insights, we aim to offer novel perspectives for developing targeted therapeutic strategies and improving clinical outcomes in osteosarcoma patients.
Renal ischemia-reperfusion injury (IRI) is a major pathological driver of acute kidney injury (AKI), for which effective therapeutic strategies remain lacking. Recently, novel forms of programmed cell death (PCD), including pyroptosis, ferroptosis, cuproptosis and necroptosis, have been identified as key mediators of tubular damage and inflammation in renal IRI. This review delineates a hierarchically organized and spatiotemporally regulated PCD network, positioning it as a central determinant of cellular fate following renal IRI. We systematically characterize the distinct molecular signatures of each death modality and critically examine their extensive crosstalk within the pathological renal microenvironment. Synthesizing current evidence, we demonstrate that this network operates in a cell type- and phase-specific manner, driving a vicious cycle of inflammation and oxidative stress. Targeting this interconnected network rather than isolated pathways represents a paradigm shift. We critically assess current therapeutic strategies and their limitations in the context of this network. Finally, we propose a forward-looking roadmap that emphasizes combination therapies guided by spatial transcriptomics, patient stratification using PCD-specific biomarkers and the development of smart nanosystems capable of dynamically modulating key network nodes. Deciphering and therapeutically intervening in this PCD network is pivotal for developing effective treatments for renal IRI.
Anlotinib, a novel multi-target tyrosine kinase inhibitor, has demonstrated promising antitumor efficacy by inhibiting angiogenesis. However, the potential therapeutic benefits and underlying mechanisms of combining anlotinib with immune checkpoint inhibitors in colorectal cancer remain unclear. Syngeneic models of colorectal cancer were established and treated with anlotinib, PD-1/PD-L1-IN-9 hydrochloride, or their combination. Tumor tissues were analyzed using immunohistochemistry, and Western blotting to assess angiogenesis-associated markers, tissue hypoxia, and key molecular markers. Flow cytometry, ELISA, and immunostaining were performed to evaluate immune cell infiltration, cytokine expression, and the tumor immune microenvironment. The combination of anlotinib and PD-1/PD-L1-IN-9 hydrochloride significantly inhibited tumor growth compared to monotherapy, associated with improved neovascularization and alleviated hypoxia. Combined therapy increased CD8+ T cell infiltration, reduced immunosuppressive cell populations, and partially modulated cytokine profiles, thereby enhancing the antitumor immune response. Anlotinib combined with PD-1/PD-L1-IN-9 hydrochloride exhibits superior antitumor efficacy in colorectal cancer compared to either agent alone, potentially by reshaping the tumor microenvironment. These findings support further exploration of combined anti-angiogenic and immune checkpoint therapy as a promising strategy for colorectal cancer treatment.
Suicide remains a leading cause of mortality in the United States, and substance use disorders (SUD) are strong predictors of suicide risk. Long-term trends and disparities in SUD-related suicide mortality remain insufficiently characterized. We analyzed 2001-2023 mortality data from the CDC WONDER Multiple Cause of Death database, using the most recent complete 23-year national time series. SUD-related suicide deaths were defined as deaths with suicide as the underlying cause (ICD-10 U03, X60-X84, Y87.0) and SUD listed among multiple-cause or contributing conditions (ICD-10 F10-F19). Each death was counted once. AAMRs were calculated by sex, race/ethnicity, census region, and urban-rural status, while age-specific rates were calculated by age group. Joinpoint regression estimated APC and AAPC. ARIMA and ETS models forecasted AAMRs through 2035. The overall AAMR increased from 0.45 in 2001 to 0.74 in 2023, representing a 64% rise (AAPC, 1.70, 95% CI, 1.16-2.24). Men consistently had higher mortality than women, whereas women showed steeper proportional increases. Mortality was highest among adults aged 45-54 years and lowest among those aged 15-24 years. Non-Hispanic White individuals, the Midwest, and nonmetropolitan areas had the highest burdens. ARIMA projected largely stable rates with widening prediction intervals, whereas ETS suggested a modest increase through 2035, mainly driven by the male series. SUD-related suicide mortality increased substantially and remained unevenly distributed across demographic and geographic groups. Divergent forecasts highlight uncertainty and the need for targeted prevention.
Digoxin use after the Norwood procedure has been associated with improved interstage survival in hypoplastic left heart syndrome and related conditions. Whether this benefit translates into improved longer-term outcomes through staged palliation remains unknown. We aimed to determine the association of digoxin use at Norwood discharge with transplant-free survival and Fontan completion. We conducted a retrospective cohort study using the Pediatric Heart Network (PHN) Single Ventricle Reconstruction trial public dataset, including 549 infants enrolled at 15 North American centers between 2005 and 2008. Competing risk analysis was used to evaluate Fontan completion and Cox regression to assess death or transplantation within 6 years after the Norwood procedure. Mixed-effects models compared pre-Fontan hemodynamic and echocardiographic right ventricular indices between patients treated with and without digoxin after accounting for center clustering and adjustment for sex, shunt type, heart failure medications at Norwood discharge, and census block poverty level. The 6-year cumulative incidence of Fontan completion was higher among patients discharged on digoxin than among those not receiving digoxin (82% vs 71%; p = 0.013). Competing-risk analysis accounting for death and transplant demonstrated a greater likelihood of Fontan completion among digoxin users (aHR 1.31; 95%CI 1.09-1.58; p = 0.005), without significant difference in the hazard of death or transplant (aHR 0.78; 95%CI 0.53-1.15; p = 0.208). No significant differences in pre-Fontan hemodynamic or echocardiographic indices were observed between groups. Initiation of digoxin post Stage II procedure was not associated with improved survival or likelihood to complete Fontan. Digoxin use at the time of Norwood discharge was associated with a 30% greater likelihood of Fontan completion by 6 years, without accompanying improvement in transplant-free survival. These findings extend prior observations of improved interstage outcomes associated with digoxin use and suggest that treatment may facilitate progression through staged palliation. What is new?: 1)Digoxin use during the interstage was associated with a greater likelihood of reaching Fontan completion within 6 years after Norwood discharge. However, this association was not accompanied by differences in right ventricular hemodynamic or echocardiographic indices at the time of Fontan evaluation.What are the clinical implications?: 2)These findings extend prior observations of improved interstage outcomes associated with digoxin use and provide important information for clinicians caring for patients with single-ventricle heart disease. Further studies are needed to clarify the mechanisms underlying this association and to identify patients most likely to benefit.
Cancer remains one of the leading is associated with of death globally. This study analyzed adverse drug event (ADE) signals and potential factors associated with reporting in ipilimumab and nivolumab-treated cancer data from the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) database. This study collected ADEs associated with ipilimumab, nivolumab, and their combination therapy for all cancers from the first quarter of 2004 to the fourth quarter of 2024 through the FAERS database. It investigated the basic information of all adverse reaction reports, analyzed the cumulative trends of ADE onset time across different age groups, and mined safety signals significantly associated with the three drug groups via disproportionality analysis. Additionally, the study explored potential factors associated with reporting of these adverse reactions. A total of 21,712,563 reports were included in this study as research subjects, among which there were 4,600, 36,556, and 10,862 adverse reaction reports for ipilimumab, nivolumab, and ipilimumab/nivolumab, respectively. Separate analysis of these three groups of drugs showed that the onset time of adverse reactions mostly exhibited a bimodal pattern characterized by "early concentrated outbreak + long-term persistent risk", which was related to age. These three groups of drugs showed a stronger associated with colitis, adrenal insufficiency, malignant neoplasm progression, death, and intentional product use issues. Age and weight were identified as potential factors associated with reporting of adverse reactions related to these three groups of drugs. Based on the FAERS database, this study identifies significant pharmacovigilance signals and potential reporting-associated factors for ipilimumab, nivolumab, and their combination. Importantly, these findings represent hypothesis-generating signal detections rather than definitive causal risk estimations, underscoring the absolute necessity for heightened clinical vigilance and routine endocrinological monitoring. These findings inform clinical monitoring strategies and provide a foundation for future research into the molecular potential mechanisms underlying irAEs.
Tuberculosis (TB) remains a leading global cause of infectious mortality due, in part, to the limited efficacy of the Mycobacterium bovis BCG vaccine against pulmonary TB. Previous studies in mice have shown that stimulating type I interferon (IFN) signaling during BCG vaccination can bolster protection against Mycobacterium tuberculosis , yet clinically feasible delivery strategies for this approach are lacking. Adenoviral vectors, which induce potent type I IFN responses and are utilized in approved vaccine platforms, represent a promising adjuvant strategy. To evaluate the host immune response to this combination, bone marrow-derived murine macrophages were co-infected with replication-deficient adenovirus and BCG. Adenovirus-infected macrophages elicited a robust type I IFN response via the cGAS/STING pathway. Compared to BCG infection alone, co-infected macrophages exhibited additive expression of genes with known host-protective roles against M. tuberculosis . Conversely, co-infection with BCG suppressed adenovirus-induced type I IFN signaling and diminished the production of IFN-stimulated genes compared to adenovirus infection alone. Together, these findings reveal a complex regulatory interplay during adenovirus and BCG co-infection. While BCG partially restricts adenoviral IFN induction, the co-infection still drives an enhanced host-protective gene profile, suggesting that adenoviral vectors could serve as a viable platform to modulate innate immunity and improve BCG vaccine efficacy. Tuberculosis (TB) remains the leading cause of death by a single infectious organism with approximately 1.25 million deaths annually. M. bovis BCG remains the only approved vaccine for TB; however, its efficacy against the contagious and most common pulmonary form of the disease is limited. There have been numerous attempts to improve BCG efficacy, but these approaches have not resulted in any clinically approved vaccine. We propose that BCG combined with a replication-deficient adenovirus presents a way to bolster vaccine-conferred protection as the combination may elicit a robust innate immune response and drive a more protective T cell response. Moreover, BCG and replication-deficient adenoviruses have well-assessed safety profiles and decades of studies regarding their use in patients. The significance of our work is in leveraging their complementary immunology to function as a combined vaccine platform. This approach presents a novel and clinically feasible approach to improve the BCG vaccine.
Despite advancements in reperfusion strategies, patients with acute myocardial infarction (AMI) face significant risks of long-term mortality. Systemic inflammation and nutritional/immune depletion synergistically impact prognosis. This study investigated the prognostic value of the neutrophil count to prognostic nutritional index ratio (NPNR)-a novel composite index reflecting inflammatory burden and nutritional reserves-in AMI patients. This dual-cohort study included 2020 patients from the NOAFCAMI-SH registry in China and 1,433 patients from the MIMIC-IV database in the USA. The primary endpoint was all-cause mortality; the secondary endpoint was cardiovascular mortality. Associations were analyzed using Kaplan-Meier curves, Cox regression, and restricted cubic splines. During a median 2.5-year follow-up in the discovery cohort, 285 all-cause and 234 cardiovascular deaths occurred. Higher NPNR levels correlated with myocardial injury and lower LVEF. Kaplan-Meier analysis showed significantly worse survival with elevated NPNR (P < 0.001). In fully adjusted models, NPNR independently predicted all-cause (HR: 2.59, 95% CI: 1.21-5.54) and cardiovascular mortality (HR: 2.87, 95% CI: 1.34-6.15). Compared to the lowest tertile, patients in the highest NPNR tertile had a 2.19-fold higher risk of all-cause mortality (HR: 2.19, 95% CI: 1.55-3.09) and a 2.36-fold higher risk of cardiac death (HR: 2.36, 95% CI: 1.60-3.48).This was validated in the MIMIC-IV cohort (HR:1.91 for 1-year mortality). The association was particularly strong in patients aged ≥65 years. Adding NPNR to a baseline clinical model significantly improved overall discrimination (C-statistic: 0.807-0.811, P = 0.011) and risk reclassification for mortality (continuous NRI = 0.368, IDI = 0.011; both P = 0.013). NPNR is a robust, independent predictor of long-term all-cause and cardiac mortality in AMI patients, validated in the external MIMIC-IV cohort. This simple biomarker effectively aids in risk stratification.
Liver transplantation (LT) remains the most effective treatment for patients with hepatocellular carcinoma (HCC), offering 5-y recurrence rates as low as 15%. Recent advances in organ preservation, particularly hypothermic oxygenated machine perfusion (HOPE), have demonstrated the ability to attenuate ischemia-reperfusion injury (IRI). However, whether HOPE can reduce HCC recurrence rates by mitigating IRI remains an open question. In this study, we aimed to compare oncological outcomes after LT for HCC with and without the use of HOPE. We conducted a retrospective cohort study including 137 patients who underwent LT for HCC with grafts from donation after brain death. Risk factors for HCC recurrence were analyzed using Cox regression. To assess the impact of HOPE on oncological outcomes, propensity score matching was used to adjust for baseline differences. Cox regression identified Milan Criteria status as a significant predictor of HCC recurrence. Among the 32 patients in the HOPE group, no HCC recurrence was observed over a median follow-up of 2.11 y. In contrast, within the control group of 105 patients, 8 (7.6%) experienced recurrence within 2 y posttransplantation. Although this translated into a significant difference in time-to-recurrence after propensity score matching, recurrence-free survival and overall survival did not differ significantly. Our findings suggest that HOPE treatment of donation after brain death liver grafts may reduce early HCC recurrence after LT. Although only nonsignificant trends were observed in recurrence-free survival and overall survival within the first 2 y posttransplant, these results underscore the potential of HOPE to influence oncological outcomes. Long-term follow-up, prospective randomized controlled trials, and basic research are warranted to further elucidate the role of HOPE and IRI.
Selective neuronal vulnerability is a hallmark of many neurodegenerative diseases, yet how ubiquitous genetic insults cause highly selective neuronal loss remains poorly understood. In spinal muscular atrophy (SMA), reduced SMN levels trigger degeneration of specific motor neuron pools. Although non-apoptotic, p53-mediated death pathways have been implicated, p53 is expressed in both vulnerable and resistant neurons, leaving the downstream determinants of selective vulnerability unresolved. Here, we identify a p53-ΔNp73 signaling axis as a previously unrecognized execution pathway driving motor neuron degeneration. Using differential transcriptional profiling of SMA motor neurons following pharmacological modulation of p53 activity, we uncover p73 as a critical downstream mediator of neuronal death. Notably, SMN deficiency induces cell-autonomous, p53-dependent expression of the ΔNp73 isoform selectively in vulnerable, but not resistant, motor neurons. ΔNp73 induction precisely parallels the spatial and temporal pattern of degeneration in mouse models and is also detected in motor neurons from SMA patients. Strikingly, despite its established role as a pro-survival antagonist of p53, depletion of ΔNp73 improves motor neuron survival and partially preserves neuromuscular junction integrity in SMA mice. These findings reveal a context-dependent, isoform-specific functional switch in p53 family signaling that redirects a canonical survival factor into a driver of neurodegeneration, identifying a novel molecular mechanism underlying selective neuronal vulnerability in SMA and a potential therapeutic target for neuroprotection.
Elevated lipoprotein(a) (Lp[a]) is an independent, causal, genetic risk factor for atherosclerotic cardiovascular disease (ASCVD). Data show that a substantial economic burden is imposed by ASCVD; however, there is a paucity of studies evaluating the economic burden of ASCVD events associated with elevated Lp(a). This study estimated the indirect economic burden of elevated Lp(a) in the primary prevention setting. A Markov model simulated ASCVD events (myocardial infarction, stroke, and cardiovascular death) and associated indirect costs (patient and caregiver) across Lp(a) groups (<60 nmol/L, ≥60-<105 nmol/L, ≥105-<150 nmol/L, ≥150-<190 nmol/L, and ≥190 nmol/L) over 5 years. Compared with the Lp(a) <60 nmol/L group, the Lp(a) ≥150 nmol/L group in the model had an estimated 42.4% higher indirect costs, representing an estimated incremental indirect cost of $253 million over 5 years or $506 per person per year. The model, based on predicted ASCVD events, suggested that the majority (68.8%) of incremental indirect costs were patient-related, comprising productivity loss from premature cardiovascular death (37.9%), disability/early retirement (17.3%), acute/post-event productivity loss (9.6%), and foregone leisure time (3.9%). Caregiver costs accounted for 31.2% of estimated incremental indirect costs in the model: unpaid caregiving time (17.3%), caregiver income loss (11.7%), and paid caregiving services (2.2%). This simulation model-based study projected that increasing Lp(a) levels were associated with more ASCVD events and higher indirect costs, primarily driven by patient productivity loss and caregiver burden. These findings suggest that the broader societal impact of elevated Lp(a) extends beyond the healthcare system.
Cardiomyopathy and channelopathy (CC) gene variants have been linked to sudden cardiac arrest (SCA) or death (SCD) in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP). However, the utility of clinical whole exome sequencing (WES) panels as a risk stratification tool in unselected MVP samples is unknown. The goal of the study was to test the utility of clinical WES panels with CC variant screening for arrhythmic risk stratification in MVP. We performed research-based WES in 203 consecutive MVPs without other arrhythmic substrate. Variants were filtered for rare (<0.1%) and protein altering variants in 157 CC genes within an existing clinical panel and annotated with a clinical significance predictor. Overall frequency of CC variants was compared to a sample of general population exomes from gnomad v4.1.0. We assessed a composite severe arrhythmic outcome of SCD or frequent ectopy/ventricular tachycardia or ventricular fibrillation/SCA requiring catheter ablation or defibrillator implantation, respectively. CC variants were more common in MVPs compared to the general population (RR: 4.3, p < 0.01). Pathogenic/Likely Pathogenic (P/LP) variants were identified in 18 MVPs (9%; 8 CC variants among 12 genes). P/LP variants were independently associated with the composite arrhythmic outcome after adjustment for traditional imaging parameters of risk including mitral annular disjunction and bileaflet involvement (OR: 1.23 [95% CI: 1.03 - 1.47], p = 0.01). P/LP variant carriers were at greater arrhythmic risk in time-to-event analyses starting at birth (HR: 2.87 [95% CI: 1.24 - 6.62], p = 0.01). A subset of MVPs with P/LP variants in CC genes are at higher arrhythmic risk. A clinical WES panel inclusive of CC variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters. What Is Known: Cardiomyopathy/channelopathy gene variants have been linked to sudden cardiac arrest or death in small, selected pedigree or post-mortem studies of arrhythmic mitral valve prolapse (MVP).Imaging studies have highlighted a diffuse myopathic process in patients with arrhythmic MVP and their family members.What The Study Adds: In consecutive MVP patients, cardiomyopathy/channelopathy genetic mutations are linked to a subclinical myopathy by strain echocardiography and a greater risk for severe ventricular arrhythmias independently of bileaflet involvement and mitral annular disjunctionA clinical whole exome sequencing panel inclusive of cardiomyopathy/channelopathy genetic variants may represent a valuable arrhythmic risk stratification tool in MVP beyond traditional imaging parameters.
Sepsis, a life-threatening dysregulated host response to infection that causes organ dysfunction, remains a major source of preventable health loss worldwide. However, its burden in China has not been fully characterized. We therefore estimated sepsis incidence and mortality in China from 1990 to 2021 within the framework of the Global Burden of Disease (GBD) 2021 study. Using China-specific GBD 2021 anchor values together with publicly available GBD outputs, we reconstructed annual all-age sepsis incidence and mortality from 1990 to 2021 with piecewise log-linear interpolation between published anchor years. Broad cause-group burden was allocated using annual shares from the China GBD outputs. Because direct Chinese age-standardized anchor values were unavailable, age-standardized incidence and mortality were treated as sensitivity analyses. Piecewise linear and monotonic cubic Hermite (PCHIP) interpolation were also examined in sensitivity analyses. In 2021, China had an estimated 6,773,717 incident sepsis cases (95% uncertainty interval [UI] 4,828,778-9,275,569) and 2,480,000 sepsis-related deaths (2,080,000-2,950,000). From 1990 to 2021, absolute numbers of incident cases increased, sepsis-related deaths declined modestly, and age-standardized incidence and mortality fell substantially. Infection-attributed sepsis remained the largest contributor to mortality, while the burden was disproportionately concentrated in males and older adults. Sepsis remains a major source of health loss in China. Despite declining age-standardized rates, the absolute burden remains large, with infection-attributed sepsis continuing to drive the greatest share of mortality and with older adults, males, and people with chronic diseases bearing disproportionate risk.
Chronic obstructive pulmonary disease (COPD) remains a leading cause of premature mortality and disability worldwide. National averages in the United States often obscure heterogeneity across sex, geography, rurality, and age. We examined U.S. COPD mortality trends from 1999 to 2024 and contextualized findings using Global Burden of Disease (GBD) 2023 data. We conducted a serial cross-sectional ecological study using Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research (CDC WONDER) mortality data and investigator-generated GBD 2023 visual outputs. Age-adjusted mortality rates (AAMRs, per 100,000 population, standardized to the year 2000 U.S. standard population) were assessed by sex, age group, race and ethnicity, census region, state, and urbanization. Joinpoint regression (National Cancer Institute Joinpoint software, v5.2.0) was used to estimate annual percent changes (APCs), average annual percent changes (AAPCs), and 95% confidence intervals (CIs). GBD 2023 figures contextualized global prevalence, socio-demographic development and COPD disability-adjusted life-years (DALYs), and regional risk-factor contributions. From 1999 to 2024, COPD deaths rose from 99,550 to 132,115 (+32.71%), while the AAMR declined from 56.38 to 45.26 per 100,000 (AAPC, -0.88; 95% CI, -1.15 to -0.61). Men showed greater improvement (74.09 to 47.97; AAPC, -1.59) than women (46.03 to 43.17; AAPC, -0.31), whose rates rose until 2016 before declining. Urban-rural disparities widened: metropolitan areas improved (54.91 to 47.16; AAPC, -0.61), whereas nonmetropolitan areas worsened (62.73 to 72.41; AAPC, +0.77). In 2024, state-level AAMRs ranged from 18.51 to 85.39 per 100,000. Age gradients were steep, from 0.08 among adults aged 25-34 years to 523.69 per 100,000 among those aged ≥85 years. GBD 2023 data confirmed a non-linear pattern across socio-demographic development, with burden driven by smoking, ambient particulate pollution, occupational exposures, and household air pollution. U.S. COPD mortality has improved nationally, yet progress remains uneven. Population ageing, slower decline among women, and persistent rural and geographic inequalities sustain the burden. Public health strategies should prioritize women-centered case finding, rural access to smoking cessation and pulmonary rehabilitation, and place-based exposure reduction.
Acute necrotizing encephalopathy (ANE) is a rare, rapidly progressive, immune-mediated encephalopathy most commonly triggered by viral infections such as influenza, characterized by acute encephalopathy, seizures, and a high risk of severe neurological sequelae or death. We report a six-year-old previously healthy female who presented with several days of fever, reduced oral intake, progressive altered mental status, and new-onset seizures, requiring intensive care admission and mechanical ventilation due to worsening encephalopathy and respiratory compromise. Laboratory evaluation demonstrated systemic inflammation, and respiratory viral testing confirmed Influenza B infection. Neuroimaging revealed characteristic bilateral, symmetric lesions involving the thalami, external capsules, brainstem, and periventricular white matter with diffusion restriction, consistent with ANE. After exclusion of alternative infectious, metabolic, toxic, and autoimmune etiologies, a diagnosis of Influenza B-associated ANE was established. The patient was managed with high-dose corticosteroids, intravenous immunoglobulin, empirical antimicrobials, and comprehensive pediatric intensive care support, including antiseizure therapy and mechanical ventilation. Her course was complicated by ventilator-associated pneumonia, transient arrhythmias, and electrolyte disturbances, but she gradually improved with multidisciplinary management, achieving successful extubation and partial neurological recovery. Follow-up imaging demonstrated regression of acute lesions with residual changes. This case highlights the importance of early recognition, prompt neuroimaging, and aggressive immunomodulatory and supportive therapy in ANE, while underscoring its potential for significant morbidity despite intensive treatment.
We conducted a retrospective review of adult kidney transplant recipients (KTRs) who received belatacept in addition to calcineurin inhibitors, antimetabolites, and corticosteroids for recurrent or refractory rejection or for persistent donor-specific antibodies (DSAs) unresponsive to standard therapy. Fifteen recipients were included. Kidney function remained stable on follow-up; median eGFR was 52 mL/min (R 23-91) at baseline and 54 mL/min (R 25-105) at 6 months (p = 0.15) after belatacept initiation. The DSA intensity declined significantly from a median of 4,990 mean fluorescence intensity (MFI) (R 0-23,305) at baseline to 1,644 MFI (R 0-6,903) at 3-6 months (p = 0.03). There was also a small reduction in biopsy-proven rejections from 85.7% to 63.6%. Infections occurred in most recipients (73.3%), with a majority arising more than 6 months after therapy initiation. Two patients developed post-transplant lymphoproliferative disorder (PTLD), each with either substantial prior exposure to lymphocyte-depleting agents or prolonged immunosuppression. Two deaths occurred, one related to PTLD and one to septic shock. These findings suggest that belatacept-based quadruple immunosuppression may reduce DSA and stabilize kidney function in patients with persistent alloimmunity, but without a statistically significant reduction in rejections. There is also a significant burden of infections and PTLD, highlighting the need for careful patient selection and caution before adopting this approach.
Obicetrapib is a potent, selective cholesteryl ester transfer protein (CETP) inhibitor that lowers LDL-C and raises HDL-C. Although prior studies have demonstrated efficacy and general tolerability, a comprehensive evaluation of its safety profile across later-stage clinical trials is needed. Safety outcomes were assessed in a pooled analysis of two phase III trials comparing obicetrapib 10 mg daily with placebo in adults with heterozygous familial hypercholesterolemia (HeFH) or atherosclerotic cardiovascular disease (ASCVD). Participants received treatment for 365 days. Safety endpoints included treatment-emergent adverse events (TEAEs) and prespecified events of special interest including hepatic, muscular, glycemic, renal and ocular parameters as well as overall rates of discontinuation. A total of 2,880 participants were included (mean age 64 years; 36 % female; 82 % with ASCVD; 35.8 % with diabetes). Overall TEAE rates were similar between obicetrapib and placebo (60.2 % vs 62.0 %). AEs leading to treatment discontinuation occurred in 4.1 % of obicetrapib-treated participants and 5.3 % on placebo, Risk Ratio (RR) 0.77 [0.54-1.08]. No clinically significant change in blood pressure was observed between groups and hypertension events were comparable. There was no difference between the groups in liver or muscle-related endpoints. Reduction in eGFR occurred less often with obicetrapib ( compared to placebo (6.7 % vs. 8.7 % RR 0.77 [0.59, 1.00])). Macular degeneration was reported once in the obicetrapib group (n= 1 [0.1 %]). Deaths were similar between treatment groups. No new safety signals were identified. Obicetrapib demonstrated a favorable safety profile over 12 months, with AE rates comparable to placebo. These findings extend our understanding of the safety and tolerability of obicetrapib.
Vascular calcification (VC), a prominent clinical characteristic of cardiovascular diseases, is intricately linked to chronic renal disease, diabetes, atherosclerosis, and other conditions, markedly increasing the risk of cardiovascular events. Traditionally perceived as a passive accumulation due to calcium-phosphate imbalance, recent findings now depict vascular calcification (VC) as an active mineralization process directed by vascular smooth muscle cells (VSMCs). This review seeks to elucidate the crucial role of VSMC phenotypic switching: Under the combined effects of metabolic disturbances (calcium-phosphate dysregulation, glucolipotoxicity), oxidative stress, and chronic inflammation, VSMCs shift from a contractile phenotype to an osteogenic/chondrogenic-like state. This transformation facilitates the establishment of a self-reinforcing mineralized microenvironment through matrix metalloproteinase (MMP)-mediated degradation of the extracellular matrix (ECM), release of matrix vesicles (MVs), and activation of pro-mineralization signal pathways (e.g., Wnt/β-catenin, BMP/SMAD). Additionally, endothelial-mesenchymal transition (EndoMT), macrophage polarization (M1/M2 imbalance), epigenetic regulation (histone modifications, non-coding RNAs), and regulated cell death (apoptosis, pyroptosis, ferroptosis) intensify calcification by releasing mineralization initiators and remodeling the ECM. This review emphasizes the complex interplay between metabolism-related calcification and proposes prospective treatment options, such as targeting metabolic checkpoints (e.g., PDK4, PPARγ), preventing phenotypic flipping, or influencing epigenetic reprogramming. These findings provide a theoretical foundation for the development of targeted therapies in the treatment of vascular calcification.
Atherosclerosis is a vascular disease characterized by lipid deposition, chronic inflammation, and cell death. Necroptosis, a form of programmed necrosis, plays a critical role in atherosclerosis progression. This study investigates the expression of the deubiquitinating enzyme OTUD7B in atherosclerosis and its mechanism in regulating vascular injury via the RIPK1-mediated necroptosis pathway. An atherosclerosis model was established in mice fed a high-fat diet combined with partial carotid ligation. OTUD7B and necroptosis-related proteins RIPK1, RIPK3, and phosphorylated MLKL (p-MLKL) were detected in arterial tissues. In vitro, a necroptosis model was induced in human aortic smooth muscle cells (HA-SMCs) using the TSZ protocol. OTUD7B was knocked down to assess cell viability, inflammatory cytokine levels, and necroptosis. OTUD7B knockdown and RIPK1 co-overexpression were employed to validate its protective effects and dependency in vivo. OTUD7B was significantly upregulated in plaques of atherosclerosis mice, concomitant with increased expression and phosphorylation of RIPK1 and RIPK3, as well as elevated p-MLKL levels. TUNEL staining and ELISA confirmed elevated necroptosis and inflammation. In vitro, OTUD7B knockdown markedly alleviated HA-SMC injury, suppressed the expression and phosphorylation of necroptosis markers, and reduced IL-1β/TNF-α release. In vivo OTUD7B knockdown attenuated plaque formation, lipid deposition, necroptosis, and inflammation. Mechanistically, RIPK1 overexpression significantly reversed the protective effects of OTUD7B knockdown, restoring RIPK1/RIPK3 phosphorylation and downstream signaling, indicating its functional dependency on the RIPK1 pathway. Co-immunoprecipitation further confirmed a direct OTUD7B-RIPK1 interaction, facilitating downstream signaling activation. OTUD7B exacerbates necroptosis and inflammation in vascular smooth muscle cells by activating the RIPK1-RIPK3-MLKL axis, thereby playing a detrimental role in AS. This study identifies OTUD7B as a potential therapeutic target for atherosclerosis intervention.
Emerging and young adult caregivers (EYACs, aged 18-35) of a parent with cancer are an understudied, under-resourced, and growing caregiving population. Little is known about their experiences coping with and managing distressing uncertainty about their parent's prognosis, which is even more distressing when their parent is living with advanced cancer. It is critical to better understand what impacts EYACs' prognosis uncertainty as their parent's disease continues to progress to better support their psychosocial needs and promote adaptive coping and adjustment. We conducted interviews with recently bereaved EYACs (N = 33) of a parent with advanced cancer who died within 12 months after diagnosis using the Retrospective Interview Technique (RIT). Participants identify any events that caused a change in their prognostic uncertainty (i.e., turning points) between their parent's diagnosis and death by plotting them on a graph. Participants' graphs were used to guide their interview, which also captured the context and meaning of each turning point (TP). RIT graphs and interview transcripts were thematically analyzed, and a typology of 5 TP types emerged: medical events, observable condition changes, online research, clinical communication, and family communication. EYACs also characterized how the TP timing mattered: TPs that occurred early in the cancer trajectory that influenced EYACs' beliefs about their parent's prognosis in turn informed their positive or negative interpretation of future TPs. Findings highlight the significant role communication plays in EYACs' prognostic uncertainty and provide key insights for future psychosocial interventions to better support this underrepresented, unsupported population of caregivers.