Citations

ABSTRACT Extracellular vesicles (EVs) are membrane‐enclosed nanoparticles that mediate intercellular communication by transferring proteins, nucleic acids, and lipids. Within the hematopoietic system, EVs orchestrate critical signaling between bone marrow (BM) niche cells and hematopoietic stem and progenitor cells (HSPCs) to regulate quiescence, proliferation, and lineage commitment. During aging, senescence and telomere attrition drive a profound remodeling of EV biogenesis and cargo. Aged EVs, particularly those released from senescent mesenchymal stromal cells (MSCs) and osteoblasts, exhibit altered microRNA profiles and reduced protective antioxidants. These changes perpetuate niche dysfunction, induce senescence in recipient cells, and promote myeloid‐biased hematopoiesis. Importantly, this communication is a selective process governed by vesicle‐intrinsic surface signatures, such as tetraspanins and integrins, which interact with specific receptors on distinct hematopoietic subsets to regulate signaling fidelity. Conversely, EVs from young or pluripotent stem cells deliver rejuvenating signals that can restore aged HSPC function and attenuate inflammaging. Elucidating these mechanisms of selective targeting and stress‐responsive cargo remodeling provides vital insights for developing EV‐based diagnostic tools and rejuvenation strategies to prevent age‐related immune imbalances and hematologic malignancies.

Summary Background Clonal haematopoiesis (CH), the age-related expansion of mutated blood stem cells, is detectable in around 10% of people in their seventies, rises steeply with age, and is associated with several diseases. Its relationship with neurodegeneration remains contentious, with conflicting evidence for both protective and detrimental effects on Alzheimer’s disease (AD). Methods Here, we applied COMET, a mutation-agnostic, methylation-based predictor of clonal haematopoiesis burden that estimates predicted VAF (pVAF), to examine longitudinal associations between clonal burden and brain structure in the Lothian Birth Cohort 1936. In addition, to capture broader clonal burden, we developed CIMS, a novel methylation-based score derived from clonal haematopoiesis of indeterminate potential (CHIP) EWAS summary statistics, which reflects the epigenetic profile of both mutant and wild-type blood immune cells. Blood DNA methylation and structural MRI data were available at three timepoints spanning ages 73–79 years. The analytic dataset comprised 1,091 participants, of whom 808 (pVAF) and 836 (CIMS) contributed clonality data and 744 had brain MRI; 479–481 had complete baseline and longitudinal imaging measures with covariates. Trajectories were modelled with latent growth curve models fitted by full information maximum likelihood. Findings Longitudinal trajectories of clonality and grey matter volume were significantly associated over 6 years (Std. est. = −0.176, p adj = 0.030), revealing a progressive, left-lateralised cortical atrophy pattern affecting medial temporal and parietal regions. This pattern showed significant spatial correspondence with established AD signatures ( r = 0.357, p = 0.003), suggesting that clonality is linked to AD-related patterns of neurodegeneration. Subcortical analyses revealed nominal relative preservation of the caudate and did not detect a statistically significant association with hippocampal volume, suggesting potential divergence from the canonical AD subcortical profile. The CIMS confirmed global atrophy but revealed divergent tissue-type and regional patterns, suggesting the two measures may capture distinct aspects of CH biology. Interpretation Together, these findings suggest that CH burden may mark biological processes associated with structural brain atrophy in cognitively healthy older adults, with clonality showing a regional pattern that resembles the one reported in AD. CH burden may therefore be a candidate marker of adverse brain ageing; whether it tracks AD pathology in particular, rather than age-related neurodegeneration more broadly, remains to be tested.

Introduction Advancements in transplant care have led to an increasing number of women with solid organ transplantation (SOT) living through peri- and postmenopause. Menopause can significantly impact quality of life, and the added burden of SOT may exacerbate symptoms. Few studies have evaluated the menopausal experience in this population, and existing data rarely use validated questionnaires. Research Question This study aimed to characterize menopausal symptoms and menopausal hormone therapy (MHT) use in peri- and postmenopausal SOT recipients using validated measures. Design A cross-sectional survey study of female patients ≥18 years who underwent SOT between 2018 and 2023 was conducted at a tertiary transplant center. A reproductive and sexual health questionnaire incorporating validated instruments, including the Menopause Rating Scale (MRS), was administered. Results Among peri- and postmenopausal SOT recipients ( n = 192), 8.9% reported use of MHT. The median MRS total score was 8.0, consistent with mild-to-moderate symptom severity overall. Symptom severity differed by menopausal status for vasomotor symptoms ( P =.03), sleep disturbances ( P = .04), depressive mood ( P = .04), and anxiety ( P <.001), with perimenopausal participants generally reporting more symptoms in these domains than postmenopausal participants. Despite these differences, overall symptom severity remained mild to moderate in both groups. Conclusion Menopausal symptoms among female SOT recipients are common but generally mild to moderate, with low utilization of MHT. The lack of increased vasomotor burden compared to prior literature may reflect under-recognition or misattribution of symptoms to transplant-related factors. Incorporating menopause-specific screening into transplant care may improve symptom recognition, quality of life, and long-term health outcomes.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

Mesothelioma is a rare cancer that originates from the mesothelial surfaces of certain sites within the body. Pleural mesothelioma is the most common type and represents approximately 85% of mesotheliomas. The NCCN Guidelines for Mesothelioma: Pleural provide recommendations for evaluation and treatment in patients with pleural mesothelioma. The NCCN Guidelines will continue to be updated annually based on available clinical evidence and panel consensus.

Abstract Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.

Objective Designation of a Medical Power of Attorney (MPOA) is a key component of advance care planning (ACP) that ensures patient preferences are honored when decision-making capacity is not present. This study aimed to quantify MPOA documentation rates and identify demographic and clinical factors associated with documentation presence. Methods We conducted a retrospective observational study using electronic health record data from 979 610 adult hospitalization encounters representing 459 365 unique patients within a large U.S. healthcare system from January 1, 2020, through December 31, 2021. All hospitalized patients aged ≥18 years were included. The primary outcome was MPOA documentation. Demographic and clinical variables were analyzed using multivariable logistic regression. Statistical significance was defined as P < .05. Results Among 979 610 encounters, 260 752 encounters (26.6%) had documented MPOA. Male sex, White race, older age (67.0 vs 54.3 years), and unmarried status were associated with a higher MPOA documentation rate (all, P < .001). In multivariable analyses, male sex (adjusted odds ratio [AOR], 1.07; 95% CI, 1.06-1.08) and unmarried status (AOR range, 1.41-1.75) were associated with higher odds of MPOA documentation. Dementia (AOR, 1.90; 95% CI, 1.86-1.93) and malignancy (AOR, 2.22; 95% CI, 2.19-2.25) were associated with higher odds, while discharge against medical advice was associated with lower odds (AOR, 0.91; 95% CI, 0.88-0.94) of MPOA documentation. Conclusions MPOA documentation rates were low, highlighting missed opportunities to identify alternate decision makers when a patient lacks capacity. Targeted interventions to promote surrogate decision-maker designation and documentation are needed, especially in inpatient care settings.

Abstract Background The potential risks and benefits of moderate‐intensity exercise in the management of fetal growth restriction (FGR) are controversial. Objective We sought to evaluate fetal responses to a 30‐min bout of moderate‐intensity exercise in pregnancies complicated by FGR. Study design This prospective study included 28 participants at a single academic institution. Pregnant individuals between 28w0d and 36w6d gestation with a diagnosis of FGR with normal Dopplers were enrolled. FGR was defined as total estimated fetal weight less than 10th percentile for estimated gestational age or abdominal circumference less than 10th percentile. Participants were excluded for body mass index (BMI) > 40, tobacco or substance use, hypertension on medications, or other contraindications to exercise. Participants exercised on a treadmill at a moderate intensity monitored using rate of perceived exertion (Borg scale) for 30 min. Fetal umbilical artery (UA), middle cerebral artery (MCA), aortic Dopplers, and maternal uterine artery Dopplers were sampled immediately before and after exercise. Biophysical profile and non‐stress tests were also performed. Maternal vital signs and rate of perceived exertion were monitored throughout exercise. Cerebro‐placental ratios (CPRs) were calculated after sampling. We hypothesized that there is no significant difference in fetal well‐being or Doppler flow in fetuses with FGR immediately after a 30‐min bout of moderate‐intensity maternal exercise compared to pre‐exercise. Results Biophysical profiles and non‐stress tests were reassuring before and after exercise. The primary outcome of UA Doppler values did not differ from pre‐ to post‐exercise. There was no difference in MCA, aortic Dopplers, or CPR. There was an increase in fetal heart rate ( p < 0.05) post‐exercise, which returned to baseline within several minutes. There was a decrease in uterine artery Dopplers ( p < 0.05) post‐exercise, which was driven by a non‐significant decrease in systolic flow and an increase in diastolic flow. Conclusions In this cohort, there were no acute adverse changes in fetal status after a single bout of moderate‐intensity maternal exercise with fetuses with FGR. These findings add to the limited available data in pregnancies complicated by FGR with normal Dopplers. Additional studies are needed to investigate the fetal and maternal effects of vigorous‐intensity and chronic exercise in this population or in populations with more evidence of placental dysfunction. Clinical trial registration NCT06039319.