Citations

Abstract Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Abstract Rationale Constantly exposed to the external environment and mutagens such as tobacco smoke, human lungs have one of the highest somatic mutation rates among all human organs. However, the relationship of these mutations to lung disease and function is not known. Objectives To identify the prevalence and significance of clonal somatic mutations in chronic lung diseases. Methods We analyzed the clonal somatic mutations from 1,251 samples of normal and diseased noncancerous lung tissue RNA sequencing with paired whole-genome sequencing from the Lung Tissue Research Consortium. We examined the associations of somatic mutations with lung function, disease status, and computationally deconvoluted cell types in two of the most common diseases represented in our dataset, chronic obstructive pulmonary disease (COPD; 29%) and idiopathic pulmonary fibrosis (IPF; 13%). Measurements and Main Results Clonal somatic mutational burden was associated with reduced lung function in both COPD and IPF. We identified an increased prevalence of clonal somatic mutations in individuals with IPF compared with normal control subjects and individuals with COPD independent of age and smoking status. IPF clonal somatic mutations were enriched in disease-related and airway epithelial–expressed genes such as MUC5B in IPF. Patients who were MUC5B risk variant carriers had increased odds of developing somatic mutations of MUC5B that were explained by increased expression of MUC5B. Conclusions Our identification of an increased prevalence of clonal somatic mutation in diseased lung that correlates with airway epithelial gene expression and disease severity highlights for the first time the role of somatic mutational processes in lung disease genetics.

Abstract Under the influence of standard developmental physiology on the Earth’s surface (1 gravity equivalent known as “1G”), 70% of body fluids reside below the level of the heart.Fluid shifts towards the cephalic region during microgravity have also been speculated to contribute towards spaceflight associated neuro-ocular syndrome (SANS).Although a significant barrier to spaceflight, the underlying mechanism of SANS is not well understood, partially due to the spaceflight environment and limited medical capabilities including invasive diagnostic testing. Thus, non-invasive approaches to studying real-time fluid shifts in weightlessness could serve as critical areas of research to further SANS study and effective countermeasure protocol development. For continuous fluid shift monitoring and management, the goal is to establish baseline assessments utilizing real time point of care noninvasive imaging devices (NIID). NIID will first need to be quantified and validated through ground-based analogues, with subsequent acquisition of near continuous imaging from arrival in the weightlessness of LEO and during the time of adaptation, which may be variable among crew members. The purpose of this study was to examine temperature differential alterations, superficial venous flow patterns (head, neck, upper torso), and venous flow patterns along the lymphatic ventromedial bundles of the medial calves and thighs. Imaging was obtained in three different positions using three standards of care medical NIIDs: SnapShotTM by Kent Imaging, Scout by WoundVisionTM and LymphScannerTM by Delfin. 30 volunteers were assessed for temperature and lymphatic/venous flow using three different non-invasive devices that can measure temperature, perfusion, and image the lymphatic and venous structures. The volunteers were assessed in the sitting, supine, and 6-degree head down tilt (HDT) positions, with pre/post assessments for the HDT position. Venous and lymphatic flow patterns may vary upon position changes (sitting vs. supine vs. 6-degree head down tilt), and in response to MLD performance in the treatment group. Fifteen subjects per group (N = 30) completed all visits and were used in the full analysis. The sitting and supine position data did not show statistical significance at any of the time points and with the devices used. The HDT data from SnapShot (looking at perfusion, deoxy and oxyhemoglobin) and Wound Vision Scout (thermal imaging) did not show statistical significance between the control and treatment groups at any time points. No significant difference for any of the within-group comparisons were found with the Lymphscanner. A significant reduction in left temple TDC for the treatment group was found at post-30-minutes (5.77, 95% CI: 1.24, 10.30) and post-180-minutes. A significant reduction in right subclavicular TDC for the treatment group was found at post-180-Minutes (5.09, 95% CI: 0.16, 10.03). A significant increase in the left ventromedial bundle for the treatment group was found at post-90-Minutes (5.72, 95% CI: 0.34, 11.10) and post-120-Minutes (5.85, 95% CI: 0.47, 11.23). A significant increase in the right ventromedial bundle for the treatment group was found at post-90 minutes (5.53, 95% CI: 0.21, 10.84). This is the first HDT spaceflight analogue study, to our knowledge, in which dermal fluid shifts were evaluated using point-of-care noninvasive imaging modalities including Near Infrared Spectroscopy (NIRS), thermography and a subcutaneous edema monitor, with subsequent application of manual lymphatic drainage (MLD) techniques to stimulate dermal lymphatic function as a countermeasure and mitigation therapeutic for intervention in cephalad fluid shifts. Further validating studies are indicated for NIIDs to further quantify fluid shifts in both analogues and weightlessness.

AbstractBackgroundGastroparesis (GP) is characterized by delayed gastric emptying in the absence of mechanical obstruction.ObjectiveGenetic predisposition may play a role; however, investigation at the genome‐wide level has not been performed.MethodsWe carried out a genome‐wide association study (GWAS) meta‐analysis on (i) 478 GP patients from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Clinical Research Consortium (GpCRC) compared to 9931 population‐based controls from the University of Michigan Health and Retirement Study; and (ii) 402 GP cases compared to 48,340 non‐gastroparesis controls from the Michigan Genomics Initiative. Associations for 5,811,784 high‐quality SNPs were tested on a total of 880 GP patients and 58,271 controls, using logistic mixed models adjusted for age, sex, and principal components. Gene mapping was obtained based on genomic position and expression quantitative trait loci, and a gene‐set network enrichment analysis was performed. Genetic associations with clinical data were tested in GpCRC patients. Protein expression of selected candidate genes was determined in full thickness gastric biopsies from GpCRC patients and controls.ResultsWhile no SNP associations were detected at strict significance (p ≤ 5 × 10−8), nine independent genomic loci were associated at suggestive significance (p ≤ 1 × 10−5), with the strongest signal (rs9273363, odds ratio = 1.4, p = 1 × 10−7) mapped to the human leukocyte antigen region. Computational annotation of suggestive risk loci identified 14 protein‐coding candidate genes. Gene‐set network enrichment analysis revealed pathways potentially involved in immune and motor dysregulation (pFDR ≤ 0.05). The GP risk allele rs6984536A (Peroxidasin‐Like; PXDNL) was associated with increased abdominal pain severity scores (Beta = 0.13, p = 0.03). Gastric muscularis expression of PXDNL also positively correlated with abdominal pain in GP patients (r = 0.8, p = 0.02). Dickkopf WNT Signaling Pathway Inhibitor 1 showed decreased expression in diabetic GP patients (p = 0.005 vs. controls).ConclusionWe report preliminary GWAS findings for GP, which highlight candidate genes and pathways related to immune and sensory‐motor dysregulation. Larger studies are needed to validate and expand these findings in independent datasets.

Importance Colorectal cancers (CRCs) with deficient DNA mismatch repair (dMMR) account for 15% of all CRCs. Deficient MMR is a predictive biomarker associated with responsiveness to immune checkpoint inhibitors (ICIs) in solid tumors, including CRC. The remarkable effectiveness of ICIs in metastatic CRC has led to their evaluation in the neoadjuvant and adjuvant treatment of localized disease. Observations Multiple prospective phase 2 studies in limited numbers of patients with localized dMMR CRC demonstrate high complete clinical and pathological response rates (60%-100%) to neoadjuvant ICIs, with low rates of grade 3 or higher ICI-related toxic effects. Given the median follow-up of 12 to 25 months in these studies, longer-term monitoring is needed to determine the durability of response and to ensure that oncologic outcomes are not compromised in patients undergoing nonoperative management. Neoadjuvant ICI therapy is especially attractive for patients with rectal cancer given the significant morbidity that accompanies pelvic irradiation and total mesorectal excision. Ongoing and planned prospective phase 2 trials will provide further data on important issues, including optimal neoadjuvant treatment duration, ICI monotherapy vs combination, and the need for adjuvant ICI therapy. Conclusions and Relevance While this review found that early results of neoadjuvant immunotherapy for localized dMMR CRC show high rates of major and complete pathological response, longer-term follow-up data are needed to ensure that oncologic outcomes are not compromised and are ideally improved. Neoadjuvant ICI therapy in localized dMMR CRC represents a potential paradigm shift with implications for organ preservation.

AbstractBackground and AimEarly‐onset colorectal cancer (CRC) is a growing global health concern, especially in the Asia‐Pacific region. However, comprehensive research on this topic from the region is lacking. Our study aims to investigate trends in early‐onset CRC in Asia over 10 years, filling this research gap.MethodsThis study utilized data from the Global Burden of Disease Study 2019 to assess temporal trends in early‐onset CRC in the Asia‐Pacific. The analysis included estimating annual frequencies and age‐standardized rates (ASRs) of early‐onset CRC incidence, death, and disability‐adjusted life‐years (DALYs) by gender.ResultsThe incidence of early‐onset CRC significantly increased in both regions with higher increase and in the Western Pacific region. Notable increases were observed among males in the Western Pacific and females in Southeast Asia (SEA). Mortality rates remained stable in the Western Pacific but increased by 10.6% in SEA, especially among females. DALYs due to CRC also increased significantly in SEA, with a greater rise among females. The Western Pacific had the highest CRC incidence, and in SEA, the mortality rate was higher in females than males.ConclusionsOur study reveals a substantial increase in early‐onset CRC in the Asia‐Pacific underscoring the urgency for effective interventions. Thus, a comprehensive approach comprising controlled risk reduction, health promotion to heightened disease awareness, and implementation of effective screening strategies should be executed timely to mitigate the burden of early‐onset CRC.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.