Communications medicine最新文献

Background: Ovarian cancer is a major female reproductive health issue with heterogeneous biological features on its subtypes, which may require different therapeutic strategies. Glucagon-like peptide-1 receptor (GLP-1R) agonists were reported to be beneficial for ovarian cancer, but the causal effects and mechanisms on its heterogeneous subtypes remain unclear.

Methods: We used genetic variants robustly associated with gene expression, protein level, splicing event, and DNA methylation of GLP-1R in six endocrine-related tissues (N ≤ 35,431) as genetic instruments to proxy the effect of GLP-1R agonism. To increase power, we conducted a meta-analysis of genome-wide association studies of ovarian cancer (29,066 cases, 461,542 controls), and identified 12 genome-wide associated variants, including two previously unreported variants: rs77247401 (MIR1208) and rs56159231 (PLEKHM1).

Results: Here we show that gene expression of GLP-1R in pancreas is associated with a reduced risk of overall ovarian cancer risk odds ratio ([OR] = 0.94, 95% confidence interval [CI] 0.89-1.00) and endometrioid ovarian cancer (ENOC; OR = 0.83, 95% CI = 0.72-0.95), which the finding is validated using splicing event of GLP-1R in pancreas (OR = 0.13, 95% CI = 0.02-0.86). However, null association is found for GLP-1R expression in pancreas with other ovarian cancer subtypes. The phenome-wide MR followed by mediation MR identifies six body composition and metabolic factors as mediators, including 18:2 linoleic acid.

Conclusions: The protective effect of GLP-1R agonists on ovarian cancer, especially ENOC, needs further validation in large-scale and well-conducted clinical trials.

Background: The long-term health consequences of childhood body size and whether it can be mitigated by a healthy adult lifestyle remains unclear. This study aims to explore the associations between childhood body size and the risk of mortality and major non-communicable diseases (NCDs), and the role of a lifestyle in adulthood in these associations.

Methods: This study included 358,990 UK Biobank participants (mean age 56.3 years, 53.2% female). Childhood body size at age 10 was self-reported as thinner, average, or plumper. Adult lifestyle factors included physical activity, diet, sleep duration, smoking, and alcohol consumption. Outcomes included risk of mortality and 47 NCDs. Cox regression models were used to estimate associations between childhood body size and outcomes. Mediation and interaction analyses assessed the role of adult lifestyle in these associations.

Results: Here we show that, individuals with plumper body size have a higher risk of mortality and 26 NCDs, compared to those with average childhood body size, where 1.07% to 28.54% of these risks are mediated by adult lifestyle. Thinner body size is associated with increased risk of 24 NCDs, with 2.12% to 32.59% of the risks mediated by adult lifestyle. Significant interactions are observed between plumper childhood body size and adult lifestyle for all-cause mortality and 6 NCDs, including hypertension, alcohol problems, constipation, diverticular disease, chronic obstructive pulmonary disease, and chronic kidney disease.

Conclusions: Both plumper and thinner body sizes during childhood are associated with an increased risk of developing NCDs later in life. However, adherence to a healthier lifestyle in adulthood may partially mitigate these long-term health risks, especially for individuals with larger childhood body size.

Background: Chronological age does not capture individual health or resilience. Advances in metabolomics have enabled development of molecular aging biomarkers that capture deviations between biological and chronological age, highlighting how genetics, environment, and lifestyle shape biological aging. Despite their promise, metabolomic biomarkers face challenges such as interpretability, non-linearity, and reproducibility.

Methods: We have developed a metabolomic predictor of biological age based on untargeted metabolomic profiling of individuals aged 45-85 years from the Canadian Longitudinal Study on Aging. To enhance interpretability, we first identified metabolites related to health based on variance heterogeneity. For metabolites with identifiable optimal levels, or "sweet spots", we modeled non-linearity using deviations from these values. A penalized regression model was trained on the Frailty Index using sweet spot deviations as predictors.

Results: Here we show that the Sweet Spot Clock built on 178 health-related metabolites is strongly associated with all-cause mortality (HR = 1.08, p = 5.8×10^-12, C-index=0.841) and age-related diseases. The biomarker outperforms models trained on chronological age and those using raw metabolite levels, underscoring the importance of modeling non-linearity. It remains predictive after adjusting for age, sex, lifestyle and socioeconomic factors, though its added value over standard health and demographic measures is modest. The model generalizes to an independent cohort of individuals aged 85 years and older.

Conclusions: The Sweet Spot Clock provides a reproducible and interpretable measure of biological age. By modeling deviations from optimal metabolite levels and training on health status rather than age, it offers a tool for understanding aging heterogeneity and identifying individuals at risk of health decline.

Background: Systematic profiling of plasma proteins in population studies offers a complementary approach to discovery of novel risk factors and may provide new insights into the causes of coronary heart disease.

Methods: To explore relationships between the circulating proteome and coronary heart disease (CHD), we evaluated associations of 4780 plasma proteins with incident CHD in the Cardiovascular Health Study (CHS, N=2856, 575 CHD events) and replicated significant associations in the Atherosclerosis Risk in Communities Study (ARIC, N = 10456; 1375 events).

Results: We find that 11 proteins significantly associate with incident CHD after adjusting for risk factors; and eight significantly replicated in ARIC. Several proteins correlate with carotid intimal medial thickness and CHD associations are attenuated in participants without subclinical atherosclerosis. Macrophage metalloelastase (MMP12) is the strongest observed association (Hazard Ratio, 1.31; 95% Confidence Interval, 1.19-1.44). Mendelian randomization (MR) identifies a causal relationship between higher MMP12 and lower CHD (Odds Ratio, OR 0.94) and ischemic stroke (OR 0.90) risk, while reverse MR found that genetic propensity to CHD increased MMP12. Taken together, multivariable MR confirms a direct protective effect of higher plasma MMP12 on CHD risk and a genetic effect of atherosclerosis and CHD on elevating MMP12.

Conclusions: Proteomic analyses reveal associations with incident CHD and genomic evidence suggests that therapeutic MMP12 inhibition may confer adverse cardiovascular effects.

Background: Despite rapid advances in treatment, breast cancer remains the leading cause of cancer mortality in women, with triple negative breast cancers having a particularly poor prognosis. Some tumors have (epi)genetic alterations causing homologous recombination deficiency, providing opportunities for targeted therapeutics including poly (ADP-ribose) polymerase inhibitors. However, the effects of targeted treatments are variable; therefore, functional assays are needed to predict the best personalized treatment options.

Methods: We developed a high-throughput spheroid-based assay using patient-derived breast cancer xenograft models sensitive and resistant to cisplatin. Methods were developed for automatic spheroid segmentation using deep learning to measure response of spheroids to treatment with cisplatin, olaparib and radiotherapy. We developed a method to distinguish between sensitive and resistant tumors based on predicting the percentage of responding and non-responding spheroids.

Results: Here we show that differences in treatment response between cisplatin-sensitive and resistant tumors faithfully correspond with the expected in vivo responses. The assay is able to discriminate between olaparib-sensitive and resistant tumors based on predicting the percentage of responding and non-responding spheroids.

Conclusions: We demonstrate that this assay, guided by automatic spheroid segmentation using deep learning, may report on the tumor's sensitivity to therapies with the potential to be applied to functional precision oncology for breast cancer.

Background: Epidemiological studies show associations between chronic noise exposure and disease, but the biological pathways remain poorly understood. In this explorative pilot study, we investigate the mechanisms that may link sleep disruption by environmental noise with disease, and the efficacy of a non-pharmacological intervention to mitigate these effects.

Methods: We conducted a cross-over trial (ClinicalTrials.gov: NCT05319262; 2022-03-09) where N = 12 healthy individuals slept for five consecutive nights in acoustically isolated bedrooms. Nights included one familiarisation night; one quiet baseline night; one night with road, rail and air traffic noise of levels 45-65 dB L_AS,max; one night with continuous 45 dB broadband pink noise; and one night with both traffic noise and pink noise. Sleep was measured with polysomnography. Perceived sleep quality and recouperation were measured with morning questionnaires. Daily blood samples were collected for metabolomics analysis.

Results: Here we show that discrete traffic noise events induced acute elevations of the odds ratio product, indicating acute sleep fragmentation, even while total sleep time and overall sleep macrostructure were preserved. Traffic noise is further associated with significant elevations in concentrations of leucine, lactic acid, and acetone relative to quiet control. Sleep and metabolic disturbances by traffic noise are attenuated when pink noise is played continuously throughout the night.

Conclusions: Noise-induced sleep fragmentation is followed by changes in metabolic processes that in the long-term may be precursors for cardiometabolic disorders. Masking of traffic noise by continuous, neutral sound may mitigate acute physiological sleep disturbance and downstream metabolic effects. These results should be interpreted cautiously, given the limited sample size and subject homogeneity.

Background: Chronic pain may involve both nociceptive pain driven by peripheral tissue damage and nociplastic pain reflecting central nervous system dysregulation, as in fibromyalgia. Electroacupuncture has been shown to modulate these pathways, but the underlying brain mechanisms remain unclear. This study investigated how electroacupuncture influences nociceptive-initiated and centrally maintained pain via changes in brain activation and functional connectivity.

Methods: In this randomized controlled trial (NCT02064296), female adults with fibromyalgia received either electroacupuncture (n = 19) or sham treatment with inactive laser stimulation (n = 25) over four weeks. Changes in brain activation and connectivity during evoked pressure-pain stimulation were assessed using functional magnetic resonance imaging before and after treatment. Here, we present a secondary analysis of data from the trial. Clinical outcomes assessed include pressure-pain tolerance and widespread pain, and analyses tested whether brain measures mediated treatment-related effects.

Results: Here we show that in the electroacupuncture group, reductions in widespread pain are associated with increases in pressure-pain tolerance. This relationship is mediated by greater activation of the primary somatosensory cortex and stronger connectivity between somatosensory and insular regions, consistent with a bottom-up mechanism linking peripheral nociceptive-initiated input to central nociplastic pain modulation. In contrast, the sham group shows reductions in widespread pain linked to decreased precuneus activity and precuneus-insula connectivity, consistent with a top-down process.

Conclusions: Electroacupuncture and sham treatments engage distinct neural pathways to influence pain perception. These findings highlight that electroacupuncture modulates nociceptive-initiated and nociplastic pain through a bottom-up sensory pathway, whereas sham treatment engages top-down control. This mechanistic dissociation may inform patient selection and optimization of acupuncture-based therapies for chronic pain.

Background: Paraneoplastic autoimmunity develops as consequences of immune reactions to cancer and exhibits a wide range of clinical manifestations. The autoimmune signs are often visible before the underlying malignancy is diagnosed, and a prompt diagnosis of paraneoplasia is crucial to enable early tumor detection. We characterized the immune responses underlying the severe mucocutaneous blistering disease paraneoplastic pemphigus.

Methods: We used a two-step approach to proteome-wide autoantibody repertoire analysis and independent validation in patients with paraneoplastic pemphigus (n = 84) and non-paraneoplastic autoimmune blistering diseases (n = 103).

Results: Our findings reveal that paraneoplastic pemphigus features a broad repertoire of disease-specific autoantibodies that mainly target tissue-specific proteins in the skin and mucous membranes. Importantly, we identify SERPINB3 as a major autoantibody target with an expression pattern and clinical association suggesting a role in bronchiolitis obliterans. Autoantibody profiles are similar across neoplasias, except in thymoma patients, who additionally express multiple cytokine autoantibodies.

Conclusions: Our findings reveal a disease-defining autoantibody repertoire in paraneoplastic pemphigus that corresponds with clinical manifestations and holds high potential for early cancer detection in patients with blistering disease.

Background: Abdominal aortic aneurysm (AAA) is a degenerative cardiovascular disorder prevalent with ageing. While accelerated biological ageing contributes to age-related diseases, its specific role in AAA risk remains unclear. This study investigates the relationships between biological ageing and risk of incident AAA and genetic predisposition to the disease.

Methods: This retrospective study used UK Biobank data from 350,483 participants without AAA at baseline. Biological age was assessed using Klemera-Doubal Method (KDMAge) and phenotypic age (PhenoAge) algorithms. Accelerated biological ageing was determined through residual analysis against chronological age, with values above 0 indicating accelerated ageing. Cox proportional hazards models evaluated the associations of biological age accelerations with AAA risk. Polygenic risk scores were calculated to evaluate genetic predisposition to AAA. We also examined the interactions between biological age accelerations and genetic predisposition on the risk of AAA.

Results: Here we show that participants with accelerated biological ageing have an elevated risk of AAA onset compared to those without, with hazard ratios (HRs) of 1.29 (95% CI 1.17-1.42) for KDMAge and 1.63 (95% CI 1.47-1.81) for PhenoAge. For joint associations, participants with accelerated biological ageing and high genetic risk have the highest risk of incident AAA (KDMAge: HR 2.15, 95% CI 1.81-2.54; PhenoAge: HR 2.72, 95% CI 2.26-3.28). There is a significant additive interaction between high genetic risk and accelerated biological ageing of PhenoAge.

Conclusions: Accelerated biological ageing is significantly associated with an increased risk of AAA incidence, suggesting its potential as a focal point for risk assessment and targeted intervention development.

Background: Frailty is often experienced by older adults, which can lead to long-term health problems. We aimed to examine associations with improvements in nutritional status, sarcopenia (age-related loss of skeletal muscle mass and strength), and frailty in four groups with different oral exercise frequencies.

Methods: We conducted a prospective, parallel multi-arm randomized controlled trial (Japan Registry of Clinical Trials (jRCT) 1062210063) to test the effects of oral exercise on frailty in older adults. Each intervention consisted of a standardized oral exercise protocol including neck exercises, lip exercises, and tongue movements, designed to improve oral function and reduce frailty. The primary outcome was the change in the number of frailty criteria from baseline to follow-up. Individuals aged ≥60 years were screened for frailty status using standardized criteria at the Department of Preventive Dentistry at Okayama University Hospital between October 2022 and December 2023. Those identified as pre-frailty or frailty were eligible and enrolled in the study. After screening 60 individuals, 58 eligible participants were randomly assigned using block randomization to one of four oral exercise frequency groups: 3 times/day & everyday, 3 times/day & 3 days/week, once/day & everyday, and once/day & 3 days/week. A two-way repeated measures analysis of variance was used to evaluate the impact of the four frequencies of oral exercise methods on frailty in older adults. Outcome assessors were blinded; participants were not.

Results: Here we show the results of the 58 participants. Group sizes are: 3 times/day & everyday (n = 14), 3 times/day & 3 days/week (n = 15), once/day & everyday (n = 14), once/day & 3 days/week (n = 15). The trial is completed as planned, and all randomized participants are analyzed. The main effect of time is significant for the number of frailty criteria (F = 14.803, p < 0.001, partial eta squared = 0.215). The mean changes from baseline to follow-up are -0.357 (95% Confidence Interval -0.787 to 0.073) in the 3 times/day & everyday group, -0.600 (95% Confidence Interval -1.255 to 0.055) in the 3 times/day & 3 days/week group, -0.571 (95% Confidence Interval -1.379 to 0.236) in the once/day & everyday group, and -0.600 (95% Confidence Interval -1.008 to -0.192) in the once/day & 3 days/week group. The main effect of time is also significant for the number of oral hypofunction criteria (F = 16.456, p < 0.001, partial eta squared = 0.234). No important adverse events or side effects related to the intervention were observed.

Conclusions: After conducting oral exercises for 3 months on older adults with pre-frailty or frailty, improvements in frailty are observed. Overall, these exercises could be a simple, low-cost way to support healthy aging in the community.