Citations

This study demonstrates that circulating extracellular vesicles (cEVs) isolated from young mice reverse the transcriptional alterations of the aged mouse pulmonary vasculature, leading to a more youthful endothelial transcriptional phenotype. As a result of this vascular phenotype, aged mice are protected from bleomycin-induced pulmonary fibrosis. These findings highlight the therapeutic potential of targeting vascular aging to alleviate pulmonary fibrosis.

Abstract Cutaneous T-cell lymphoma (CTCL) is a rare malignancy of skin-resident T cells characterized by an aberrant cytokine profile, notably elevated Interleukin-17A (IL-17A) levels. However, the functional importance of IL-17A dysregulation in the CTCL pathogenesis remains poorly understood. Our analysis revealed increased IL-17A receptor (IL-17RA) expression in CTCL patient samples, supporting the importance of IL-17A signaling in CTCL progression. Proteomic and metabolomic profiling of IL-17A-treated malignant T cells revealed mitochondrial electron transport chain (ETC) complex I as a key downstream target of IL-17A signaling. Furthermore, we confirmed the elevated expression of ETC complex I in CTCL patient samples compared to healthy control T cells, hence highlighting the clinical relevance of the IL-17A signaling-ETC complex 1 axis. Altogether, our data unveil the function of IL-17A signaling in the metabolic axis in CTCL progression, which could be useful for developing advanced therapeutic strategies. Significance statement: We uncover an IL-17A-induced electron transport chain (ETC) complex I pro-tumorigenic circuit and provide proof of concept evidence that ETC complex I can be targeted to combat the challenges posed by Cutaneous T-cell Lymphoma aggressiveness.

Abstract Background Pediatric cancer rehabilitation is a growing field, and pediatric rehabilitation medicine physicians play an important role in the care continuum for children and adolescents with cancer. However, the current practice patterns and experiences of pediatric physiatrists in cancer rehabilitation are not well known. Objective To evaluate the status of pediatric cancer rehabilitation care by board‐certified pediatric physiatrists in the United States, including their practice pattern, experience, and comfort level in cancer‐related conditions. Design An online 37‐question Research Electronic Data Capture survey was developed by members of a pediatric cancer rehabilitation committee of a national physiatry organization. Descriptive data analysis was performed. Setting Survey invitations were sent via email to potential participants and posted on social media sites, including an online physiatry community forum and a pediatric physiatrist private group. Patients (or Participants) Targeted participants were board‐certified pediatric physiatrists who treat pediatric patients with cancer diagnoses. Interventions Not applicable. Main Outcome Measure(s) Survey questions pertained to respondents' practice setting and patient population, type of cancer rehabilitation provided, presence of a cancer rehabilitation program at their institution, and their learning experience in pediatric cancer rehabilitation. Results A total of 107 board‐certified pediatric physiatrists completed the survey, representing 57 institutions in the United States, the majority of which were academic centers ( n = 95; 88.8%). Ninety‐seven (90.7%) reported their practice consisted of >75% pediatric patients, and 95 (88.8%) indicated <25% pediatric patients in the practice have cancer diagnoses. Forty respondents representing 19 institutions (33.3%) reported an established cancer rehabilitation program at their institution, though of these, 23 (57.5%) indicated that more improvement to their program was needed. Sixty‐three respondents (58.9%) gained experience in cancer rehabilitation from fellowship, 51 (47.7%) from residency, and 47 (43.9%) from mentorship; majority ( n = 102; 95.3%) also learned from self‐study or on the job. Participants' comfort level on cancer‐related conditions varied. Conclusions This survey, aimed at board‐certified pediatric physiatrists who practice pediatric cancer rehabilitation, highlights the variety in training experiences and practice exposure among respondents. Concomitant with this was a variance in reported comfort levels in treating the different cancer‐related diagnoses. This raises for discussion what training opportunities might be strengthened as the subspeciality continues to grow.

Abstract The Alzheimer's disease (AD) scientific field continues to make significant advances in early detection and treatments, which importantly rest on advances in our fundamental understanding of AD pathobiology and its contribution to cognitive decline. Clinical readouts of monoclonal antibodies against various forms of the amyloid beta (Aβ) protein indicate that the impact of these treatments may extend beyond reduction in amyloid plaques. The Alzheimer's Association Research Roundtable meeting held on May 17 and 18, 2022, reviewed our understanding to date of the impact of treatments targeting various species of Aβ; its impact on other related pathophysiology including tau; and ultimately, its effects on neurodegeneration and clinical decline, driven by the latest available data. Participants discussed the current evidence for a causal relationship among amyloid accumulation, tau alteration, and cognitive decline; the effect of anti‐amyloid therapies on clinical and biomarker endpoints; and how we can accelerate the pathway to therapeutic approval and what should guide us for the near future. Highlights The Alzheimer's Association Research Roundtable convened leaders from industry and academia, as well as patients, clinicians, and government and regulatory agency scientists to discuss the topic “Current Understanding of AD Pathophysiology & Impact of Amyloid‐beta Targeted Treatments on Biomarkers and Clinical Endpoints.” The totality of scientific evidence (clinical trials, animal data, modeling, and observational studies) on the relationship between amyloid beta (Aβ), amyloid, tau, and cognitive impairment is helping our understanding of the downstream effects and overall importance of lowering amyloid plaque load. Based on data from multiple phase 2 and 3 clinical trials of anti‐amyloid monoclonal antibodies, there is strong evidence to support that a sufficiently large reduction in amyloid plaque load to near‐normal levels is associated with positive changes in tau biomarkers and clinical endpoints. Reduction of Aβ plaque, measured easily by plasma amyloid biomarkers, is reasonably likely to predict benefit in clinical outcome measures.

AbstractINTRODUCTIONThis study investigated the role of the ubiquitin–proteasome system (UPS) in dominantly inherited Alzheimer's disease (DIAD) by examining cerebrospinal fluid (CSF) levels of UPS proteins.METHODThe SOMAscan assay was used to detect changes in UPS proteins in mutation carriers (MCs) relative to disease progression; imaging and CSF biomarkers of amyloid, tau, and neurodegeneration measures; and Clinical Dementia Rating scale.RESULTSSubtle increases in specific ubiquitin enzymes were detected in MCs up to two decades before symptom onset, with more pronounced elevations in UPS‐activating enzymes near symptom onset. Significant correlations were found between UPS proteins and Alzheimer's disease (AD) biomarkers, especially between autophagy markers and late‐stage tau biomarkers, microglia, and axonal degeneration.DISCUSSIONThe rise in UPS proteins alongside tau‐related markers suggests UPS involvement in tau neurofibrillary tangles. Elevated CSF UPS proteins in DIAD MCs may serve as indicators of disease progression, and may support the UPS as a therapeutic target in AD.Highlights This study investigates the ubiquitin‐proteasome system (UPS) in Dominantly Inherited Alzheimer's Disease (DIAD), highlighting early molecular changes linked to disease progression. Using SOMAscan proteomics, we identified significant UPS protein alterations in cerebrospinal fluid of mutation carriers, notably up to 20 years before clinical symptom onset. Correlations between UPS protein levels and Alzheimer's biomarkers, particularly tau and neurodegeneration markers, suggest a strong association between UPS dysregulation and tau pathology in DIAD. Dynamic UPS changes align with A/T biological staging: UPS proteins were shown to increase across Aβ/tau (A/T) groups, with largest increases in the A+/T+ group, reinforcing their role in late‐stage tau pathology and disease progression. These findings underscore the potential of UPS proteins as early biomarkers for Alzheimer's disease progression and as novel therapeutic targets, especially in tau‐pathology‐driven neurodegeneration. This work contributes to understanding AD pathogenesis, by emphasizing the importance of protein quality control systems and by offering avenues for future biomarker discovery and therapeutic development in Alzheimer's disease.

AbstractINTRODUCTIONWe previously demonstrated that single‐domain amnestic mild cognitive impairment (SDAm‐MCI) detected through longitudinal neuropsychological testing in our research cohort is less severe than in clinically incident symptomatic individuals. This study aims to replicate and expand this work using a National Alzheimer's Coordinating Center dataset.METHODSParticipants were classified into two groups: those enrolled with normal cognition (Normal Enrollees) and those enrolled with SDAm‐MCI (Amnestic Enrollees). Groups were compared at the time of diagnosis and on rates of cognitive decline post‐diagnosis.RESULTSAt SDAm‐MCI diagnosis, Normal Enrollees were 17% to 39% less impaired on memory tasks, after which the slope of change over time steepened compared to their pre‐symptomatic change and was steeper than in Amnestic Enrollees.DISCUSSIONIncident MCI detected through longitudinal neuropsychological testing is initially milder but may progress more steeply than in clinically established MCI. Sensitive assessment of cognitive decline is essential for capturing early changes that are more likely to be amenable to therapeutic treatment.Highlights Longitudinal cognitive evaluation detects symptomatic Alzheimer's disease earlier than mental status exams. At the time of diagnosis, converters were less impaired compared to initially symptomatic patients. Converters’ cognition declined more steeply than initially symptomatic patients. Sensitive cognitive tests are essential to capture early changes, given new disease‐modifying therapies.

OBJECTIVE Cervical spondylotic myelopathy (CSM) is often accompanied by neck pain, which, along with more recognized neurological deficits like motor and sensory changes, significantly impacts patients’ quality of life. The authors examined whether age influences improvements in neck disability and related quality-of-life measures after surgery for CSM. Using the Neck Disability Index (NDI) as the primary outcome, they compared long-term outcomes at 24 months among patients aged ≥ 65, ≥75, and < 65 years, exploring the effects of surgical intervention on both pain-related disability and functional recovery in older adults. METHODS Using the Quality Outcomes Database, the authors conducted a detailed propensity score–matched analysis on cohorts aged ≥ 65 and ≥ 75 years compared with a < 65-year-old cohort while controlling for baseline NDI scores, other demographic variables, health status, underlying pathology, number of levels, indication for surgery, surgical approach, and type of surgery. Differences in NDI total and subdomain scores at 24 months postoperatively were the primary measures of improvement. Age-related variability in NDI differential was assessed. EQ-5D and calculated SF-6D were secondary measures. RESULTS Of the 1141 patients in the cohort (January 2016 to December 2018), 687 patients were < 65 years, 325 were 65 to < 75 years, and 129 were ≥ 75 years of age. After propensity score matching, 197 patients each were well matched in the ≥ 65-year (mean 71.4 years) and < 65-year (mean 55.3 years) cohorts; similarly, 57 patients each were matched in the ≥ 75-year (mean 78.3 years) and < 65-year (mean 55.8 years) cohorts. Improvements in NDI scores and subdomain scores, EQ-5D, and calculated SF-6D were consistent at 3, 12, and 24 months postoperatively across all cohorts. At 24 months, patients ≥ 65 years showed NDI score improvements (−14.7 ± 22.3) similar to those < 65 years (−13.0 ± 21.3, p = 0.454), and patients ≥ 75 years demonstrated NDI improvements (−15.0 ± 19.7) comparable to those < 65 years (−17.6 ± 20.4, p = 0.499). A sensitivity analysis for linear relationship found that NDI improvement was statistically greater in older patients (7.5 points every 30 years, p < 0.0001), but this difference was below the minimal clinically important difference. Other clinical outcomes were similar between cohorts. CONCLUSIONS Surgical intervention for CSM yields substantial and similar improvements in NDI scores and other metrics among various age groups, including those aged at least 65 and 75 years. These results highlight the effectiveness of surgery across a broad patient demographic, underscoring its value in treating CSM irrespective of age.

PURPOSE Many trials ask patients to complete patient-reported outcome measures (PROMs) via the web, excluding patients unable to use/access the Internet. The PRO-TECT trial (AFT-39, ClinicalTrials.gov identifier: NCT03249090 ) also offered a telephone interface option (interactive voice response [IVR]). We compared patients choosing IVR versus web on alert rates to nurses and clinical outcomes to determine if a telephone option can close disparities in symptom management. METHODS PRO-TECT randomized 26 community oncology practices to the PROM intervention arm where concerning symptoms generated automated alerts to nurses. IVR and web patients were compared for social determinants of health (SDOH) using analysis of variance and chi-square tests. After accounting for clustering and confounders, we used generalized estimating equations to compare alert rates, mixed models for quality of life (QOL) at 3 months, and Cox regression for emergency visits and survival at 12 months. RESULTS Among 593 patients, 215 (36%) chose IVR and 378 (64%) chose web. IVR patients were older (65.2 v 60.8 years) and were more often rural residents (32% v 23%), Black (27% v 11%), and with less education (54% v 27% ≤high school; all P < .01). Patients choosing IVR had more surveys with concerning symptoms (49% v 37%) and nurses felt clinical attention was warranted more often (4.8 surveys v 3.4 surveys; all P < .001) but ultimately experienced similar benefits as web in QOL, emergency visits, and survival. CONCLUSION One third of community patients choose a telephone option over the web for reporting PROMs during cancer care. These patients are disproportionately from SDOH backgrounds at risk of poor clinical outcomes and have higher symptom management needs but ultimately experience similar clinical benefits as patients choosing the web. PROM programs should offer web alternatives to close disparities in symptom management.

Immunotherapy has significantly affected cancer treatment and survival rates, accompanied by an increase in immune-related adverse events (irAEs) requiring new management strategies. irAEs can affect various organ systems and have varying severity levels, with higher rates observed when combining immune checkpoint inhibitors. National organizations such as ASCO, the National Comprehensive Cancer Network, the Society for Immunotherapy of Cancer, and the European Society for Medical Oncology have created guidelines for managing irAEs. This chapter expands on these guidelines by discussing practical strategies to improve the multidisciplinary management in irAE care, focusing on the who, what, and how to bridge gaps in care and enhance collaboration between academic and community oncology practices. Effective irAE management involves early recognition and guideline-adherent approaches using a multidisciplinary team, including oncologists, other subspecialists, primary care clinicians, and all care team members. Institutions are developing methods to integrate irAE care into clinical workflows, such as incorporating urgent care clinics and e-consults for efficient irAE management and developing hub-and-spoke models to extend specialized care from academic centers to community hospitals for equitable care delivery. Additionally, effective patient education is critical for improving irAE recognition and health literacy. The new ASCO Community of Practice called the Alliance for Support and Prevention of Immune-Related Adverse Events consortium and patient advocacy group Standing Together to Optimize Research, Interventions, and Education in irAEs initiatives aim to advance irAE clinical care, research, and education through global collaboration, standardized data collection, and improved outreach to patients and caregivers.