High sense of purpose in life, a fundamental domain of eudaimonic well-being, has been consistently associated with lower risk for various obesity-related chronic diseases. Although this psychological feature correlates with some health behaviors as potential mediators, its association with healthy eating remains less explored. In addition, studies of these psycho-behavioral and health relationships in the South American population are lacking. This research sought to assess: (1) the cross-sectional association between self-reported purpose in life and overall healthy eating patterns, and (2) healthy food intake as a potential mediator of the inverse relationship between purpose in life and waist circumference. Data collected of 2060 US adults from the MIDUS study (5 ± 12 years, 55% women, mostly white people, and 42.5% obese) and 223 Chilean adults from the CHILEMED study (46.6 ± 9 years, 58.3% women, and 71.3% obese) were used. Anthropometric and sociodemographic variables were collected. Sense of purpose was assessed using the purpose in life subscale of the Ryff’s psychological well-being questionnaire. Diet quality was evaluated using healthy eating or low-fat diet indexes, according to extant food intake data in each cohort. The relationship between these variables was estimated by bivariate and multivariate linear regressions with appropriate adjustments. To establish whether a better diet quality could mediate a link of purpose in life and improved nutritional status (assessed by waist circumference), the association between these three variables was tested by bootstrapping-based mediation analysis. Our results show significant associations of sense of purpose with healthy eating and low-fat dietary patterns in both US and Chilean cohorts, respectively, even after adjusting for sociodemographic variables. According to the mediation analysis, the relationship between sense of purpose and waist circumference, as an indicator of abdominal obesity, appears to be partially mediated by healthier food intake in both samples. In conclusion, our findings suggest a plausible mechanism underlying the favorable impact of this well-being dimension on physical health. Given its protective effects, interventions aimed at increasing purpose in life may facilitate adherence to better dietary patterns, which, in turn, will reduce the risk for obesity-related chronic diseases.

Background: The aim of this study was to identify the blood lipidomic profile associated with a healthy eating pattern in a middle-aged US population sample and to determine its relationship with metabolic disorders and cardiovascular risk (CVR). Methodology: Self-reported information about diet and blood samples were obtained from 2114 adult participants in the Midlife in the United States study (MIDUS). Food intake data were used to design a Healthy Diet Index (MIDUS-HEI) and to evaluate the predictive value by examining its association with health variables. The associated lipid signature (HEI-LS) was constructed using Lasso regression, from lipidomic data (LC/MS). Associations between HEI-LS, cardiometabolic biomarkers, and estimated CVR were assessed using multiple linear regression. Results: MIDUS-HEI score was a robust indicator of dietary quality and inversely associated with body mass index (p < 0.001) and metabolic syndrome (p = 0.012). A lipidomic signature comprising 57 distinct lipid species was highly correlated with the MIDUS-HEI score (r = 0.39, p < 10⁻¹⁶). It was characterized by lower levels of saturated fatty acid and adrenic acid (n-6) and higher levels of docosahexaenoic acid (n-3). Healthier HEI-LS scores were strongly associated with better cardiometabolic indicators and lower estimated CVR (OR 0.89 CI 95% 0.87–0.91). Conclusions: The MIDUS-HEI effectively assessed dietary quality, confirming the link between poor diet quality and metabolic disorders in American population. Lipidomic profiling offered an objective assessment of dietary patterns and provided insights into the relationship between diet quality, metabolic responses, and CVR. This approach supports precision nutrition strategies for at-risk populations.

Background/Objectives: We performed a systematic review of the current clinical and preclinical literature on the use of particle therapy, DDRi, and/or immunotherapy, specifically for pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, carbon) either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICI), or X-ray radiotherapy (XRT) in combination with DDRi/ICI. Results: In total, 133 studies met the inclusion criteria, including 62 clinical studies. Clinically, particle therapies show excellent local control and normal tissue sparing, with manageable toxicity profiles. Trials with any form of radiation and DDRi are few, potentially owing to toxicity concerns. ICI combinations showed promising efficacy with XRT, with no randomized trials comparing them to particle radiation. Conclusions: Particle radiation and/or DDRi have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increase response rates to immunotherapy (presented in the companion manuscript). Despite strong preclinical evidence and rationale, clinical trials including all three modalities are scarce. Existing evidence suggests a potential benefit based on extrapolation from photon-based studies and supports prospective evaluation with careful attention to treatment-related toxicity, which remains a concern.

Background: Cerebellar atrophy is a known feature of ataxia-telangiectasia (A-T). However, basal ganglia dysfunction contributing to extrapyramidal movement disorders in A-T remains understudied. Objectives: To characterize basal ganglia abnormalities in A-T using a normative self-supervised deep autoencoder trained on MRI-based diffusion and perfusion features from healthy children. Methods: Mean values of apparent diffusion coefficient and cerebral blood flow perfusion maps were extracted from seven regions-of-interest: caudate, hippocampus, pallidum, putamen, thalamus, cerebellar gray matter and cerebellar white matter. A normative deep autoencoder that reconstructs these features was trained on healthy subjects. Reconstruction errors for healthy and A-T participants were computed. We used Shapley Additive Explanations (SHAP) to identify the most influential features contributing to the features’ reconstruction predictions. Correlations between reconstruction errors and clinical scores in A-T patients were evaluated. Results: Features were correctly reconstructed in controls but not A-T participants, who showed significantly higher reconstruction errors. Hippocampus, caudate and putamen diffusion, and caudate and putamen perfusion were overestimated, and cerebellar diffusion and pallidum perfusion underestimated, in participants with A-T. SHAP scores revealed that caudate, putamen, and hippocampus perfusion had the greatest influence on the reconstruction of perfusion features. In contrast, cerebellar diffusion and caudate perfusion had the greatest influence on the reconstruction of diffusion features. Exploratory analysis showed that extrapyramidal movement sub-scores from A-T participants correlated with perfusion and diffusion reconstruction errors from cerebellar and subcortical structures. Conclusion: Our findings suggest that pallidum, caudate, and cerebellar gray matter are potential targets for novel treatment approaches for A-T. The approach enables identification of subtle tissue anomalies at an individual level, allowing tailored approaches.

Background/Objectives: We performed a systematic review of preclinical literature on the use of high-LET particle therapy, DDRi, and/or immunotherapy specifically in pMMR colorectal cancer. Methods: A systematic review of the literature published between 2014 and 2025 was conducted across major databases. Studies were included if they examined particle radiotherapy (e.g., proton, alpha, and carbon) or X-ray radiation either alone or in combination with DDRi and/or immune checkpoint inhibitors (ICIs) in pMMR colorectal cancer models. Results: In total, 131 studies met the inclusion criteria, including 70 preclinical studies. These studies consistently demonstrate that high-LET radiation amplifies immunogenic cell death, increases cGAS-STING pathway activation, and enhances tumor antigen presentation, thereby fostering greater immune infiltration and systemic antitumor responses. Concurrent irradiation with DDRi enhances persistent DNA damage and cytosolic DNA accumulation. In murine models, high-LET therapies show excellent local control, with manageable toxicity profiles. Combination regimens with ICIs exhibit improved local control and elicit systemic antitumor immune responses. Conclusions: High-LET particle radiation and/or the use of concurrent DDRi with ICI have significant preclinical evidence of immunostimulatory effects in pMMR rectal adenocarcinoma and increased response rates to immunotherapy. The clinical evidence will be reviewed in the companion manuscript.

A urosymphyseal fistula is an abnormal connection between the lower urinary tract (typically bladder or proximal urethra) and pubic symphysis. This is an uncommon late complication of prostate cancer treatment, often occurring after pelvic radiation and urethral instrumentation. We report a 79-year-old man who, after external radiotherapy, salvage brachytherapy, and transurethral bladder neck incision, developed a urosymphyseal fistula with urinary tracking into the anterior thigh compartment. Given comorbidities, he was managed conservatively with urinary diversion, percutaneous drainage, and antibiotic therapy. Serial imaging demonstrated nonoperative resolution. This case highlights an unusual clinical presentation and suggests selected patients may avoid extirpative surgery.