Intestinal Dysbiosis and the Developing Lung: The Role of Toll-Like Receptor 4 in the Gut-Lung Axis.

BackgroundIn extremely premature infants, postnatal growth restriction (PNGR) is common and increases the risk of developing bronchopulmonary dysplasia (BPD) and pulmonary hypertension (PH). Mechanisms by which poor nutrition impacts lung development are unknown, but alterations in the gut microbiota appear to play a role. In a rodent model, PNGR plus hyperoxia causes BPD and PH and increases intestinal Enterobacteriaceae, Gram-negative organisms that stimulate Toll-like receptor 4 (TLR4). We hypothesized that intestinal dysbiosis activates intestinal TLR4 triggering systemic inflammation which impacts lung development.MethodsRat pups were assigned to litters of 17 (PNGR) or 10 (normal growth) at birth and exposed to room air or 75% oxygen for 14 days. Half of the pups were treated with the TLR4 inhibitor TAK-242 from birth or beginning at day 3. After 14 days, pulmonary arterial pressure was evaluated by echocardiography and hearts were examined for right ventricular hypertrophy (RVH). Lungs and serum samples were analyzed by western blotting and immunohistochemistry.ResultsPostnatal growth restriction + hyperoxia increased pulmonary arterial pressure and RVH with trends toward increased plasma IL1β and decreased IκBα, the inhibitor of NFκB, in lung tissue. Treatment with the TLR4 inhibitor attenuated PH and inflammation.ConclusionPostnatal growth restriction induces an increase in intestinal Enterobacteriaceae leading to PH. Activation of the TLR4 pathway is a promising mechanism by which intestinal dysbiosis impacts the developing lung

Alcohol consumption and breast cancer-specific and all-cause mortality in women diagnosed with breast cancer at the New York site of the Breast Cancer Family Registry

Purpose Alcohol consumption is an established and important risk factor for breast cancer incidence in the general population. However, the relationship between alcohol and mortality among women with breast cancer is less clear. This study examines the effect of alcohol consumption on mortality in women affected with breast cancer at baseline from a high-risk family breast and ovarian cancer registry. Methods We studied 1116 women affected with breast cancer at baseline from the Metropolitan New York Registry. The examined reported alcohol consumption (total of beer, wine, liquor) was defined as the average number of drinks per week reported from age 12 to age at baseline. We assessed vital status of each participant using participant or family reported data and we used the National Death Index to supplement deaths reported through family updates. We used Cox proportional hazards models to estimate the association between alcohol intake and overall mortality (HRO), breast cancer-specific mortality (HRBC), and non-breast cancer mortality (HRNBC), adjusted for confounders. Results After a mean follow-up of 9.1 years, we observed 211 total deaths and 58 breast cancer deaths. Compared to non-drinkers, we found that both low and moderate to heavy levels of alcohol intake were not associated with greater overall mortality (≤3 drinks/week: HRO: 0.66, 95% CI: 0.38–1.14); > 3 drinks/week: HRO: 1.16, 95% CI: 0.85–1.58), breast cancer–specific mortality (≤ 3 drinks/week: HRBC:0.62, 95% CI: 0.19–2.03; >3 drinks/week: HR BC: 0.96, 95% CI: 0.49–1.89), or non-breast cancer-specific mortality (≤3 drinks/week: HR NBC: 0.73, 95% CI: 0.32–1.6; >3 drinks/week: HRNBC: 1.18, 95% CI: 0.75–1.86). Conclusions Alcohol intake reported from age 12 to age at baseline was not associated with overall or breast cancer-specific mortality in this cohort of affected women with a family history of breast cancer

Feasibility of aortic valve assessment with low dose prospectively triggered adaptive systolic (PTAS) cardiac computed tomography angiography

Background: Cardiac computed tomography angiography (CTA) is feasible for aortic valve evaluation, but retrospective gated protocols required high radiation doses for aortic valve assessment. A prospectively triggered adaptive systolic (PTAS) cardiac CT protocol was recently described in arrhythmia using second-generation dual-source CT. In this study, we sought to evaluate the feasibility of PTAS CTA to assess the aortic valve at a low radiation dose. Findings: A retrospective cohort of 29 consecutive patients whom underwent PTAS protocols for clinical indications other than aortic valve assessment and whom also received echocardiography within 2 months of CT, was identified. Images were reviewed for aortic valve morphology (tricuspid/bicuspid/prosthetic) and stenosis (AS) by experienced blinded readers. Accuracy versus echocardiography and radiation doses were assessed. All PTAS coronary CTAs were clinically diagnostic with 0 un-evaluable coronary segments. The accuracy of PTAS for aortic valve morphology was 92.6%, and for exclusion of severe AS was 93.1%. Two exams were un-evaluable for the aortic valve due to inadequate number of phases archived for interpretation. Total radiation dose was a median of 2.8 mSv (interquartile range 1.4–4.4 mSv). Conclusions: PTAS CTA protocols using second-generation dual-source CT for aortic valve evaluation are feasible at low doses. This protocol should be investigated further in larger cohorts

Estimating the cost of illness of acute Japanese encephalitis and sequelae care in Vietnam and Laos: a cross-sectional study

Background Japanese encephalitis (JE) is a leading cause of acute encephalitis syndrome and resulting neurological disability in Asia and the Western Pacific. This study aims to estimate the cost of acute care, initial rehabilitation and sequelae care, in Vietnam and Laos. Methodology We conducted a cross-sectional retrospective study using a micro-costing approach from the health system and household perspectives. Out-of-pocket direct medical and non-medical costs, indirect costs, and family impact were reported by patients and/or caregivers. Hospitalization costs were extracted from hospital charts. Acute costs covered expenditures from pre-hospital to follow-up visits while sequelae care costs were estimated from expenditures in the last 90 days. All costs are in 2021 US dollars. Principal findings 242 patients in two major sentinel sites in the North and South of Vietnam and 65 patients in a central hospital in Vientiane, Laos, with laboratory-confirmed JE were recruited regardless of age, sex, and ethnicity. In Vietnam, the mean total cost was $3,371 per acute JE episode (median$2,071, standard error [SE] $464) while annual costs were$404 for initial sequelae care (median $0, SE$220) and $320 for long-term sequelae care (median$0, SE $108). In Laos, the mean hospitalization costs in acute stage were$2,005 (median $1,698, SE$279) and the mean annual costs were $2,317 (median$0, SE $2,233) for initial sequelae care and$89 (median $0, SE$57) for long-term sequelae care. In both countries, most patients did not seek care for their sequelae. Families perceived extreme impact from JE and 20% to 30% of households still had sustained debts years after acute JE. Conclusions JE patients and families in Vietnam and Laos suffer extreme medical, economic, and social hardship. This has policy implications for improving JE prevention in these two JE-endemic countries

Apramycin susceptibility of multidrug-resistant Gram-negative blood culture isolates in five countries in South-East Asia

Bloodstream infections (BSIs) are a leading cause of sepsis, a life-threatening condition that contributes significantly to the mortality of bacterial infections. Aminoglycoside antibiotics such as gentamicin or amikacin are essential medicines in the treatment of BSIs, but their clinical efficacy is increasingly compromised by antimicrobial resistance. The aminoglycoside apramycin has demonstrated preclinical efficacy against aminoglycoside- and multidrug-resistant (MDR) Gram-negative bacilli (GNB) and is currently in clinical development for the treatment of critical systemic infections. Here, we collected a panel of 470 MDR GNB isolates from health care facilities in Cambodia, Laos, Singapore, Thailand, and Vietnam for a multi-centre assessment of their antimicrobial susceptibility to apramycin in comparison to other aminoglycosides and colistin by broth microdilution assays. Apramycin and amikacin MICs ≤ 16 µg/mL were found for 462 (98.3%) and 408 (86.8%) GNB isolates, respectively. Susceptibility to gentamicin and tobramycin (MIC ≤ 4 µg/mL) was significantly lower at 122 (26.0%) and 101 (21.5%) susceptible isolates, respectively. Of note, all carbapenem- and third-generation cephalosporin (3GC) resistant Enterobacterales, all Acinetobacter baumannii, and all Pseudomonas aeruginosa isolates tested in this study appeared to be susceptible to apramycin. Of the 65 colistin-resistant isolates tested, only four (6.2%) had an apramycin MIC > 16 µg/mL. Apramycin demonstrated best-in-class activity against a panel of GNB isolates with resistances to other aminoglycosides, carbapenems, 3GC, and colistin, warranting continued consideration of apramycin as a drug candidate for the treatment of multidrug-resistant BSIs. Keywords: Bloodstream infection; Gram negative; aminoglycoside; antimicrobial resistance; apramycin; blood culture isolates

The role of microRNA-155/liver X receptor pathway in experimental and idiopathic pulmonary fibrosis

Background: Idiopathic Pulmonary Fibrosis (IPF) is progressive and rapidly fatal. Improved understanding of pathogenesis is required to prosper novel therapeutics. Epigenetic changes contribute to IPF therefore microRNAs may reveal novel pathogenic pathways. Objectives: To determine the regulatory role of microRNA(miR)-155 in the pro-fibrotic function of murine lung macrophages and fibroblasts, IPF lung fibroblasts and its contribution to experimental pulmonary fibrosis. Methods: Bleomycin-induced lung fibrosis in wild-type and miR-155-/- mice was analyzed by histology, collagen and pro-fibrotic gene expression. Mechanisms were identified by in silico and molecular approaches; validated in mouse lung fibroblasts and macrophages, and in IPF lung fibroblasts, using loss-and-gain of function assays, and in vivo using specific inhibitors. Results: miR-155-/- mice developed exacerbated lung fibrosis, increased collagen deposition, collagen 1 and 3 mRNA expression, TGFβ production, and activation of alternatively-activated macrophages, contributed by deregulation of the microRNA-155 target gene the liver X receptor (LXR)α in lung fibroblasts and macrophages. Inhibition of LXRα in experimental lung fibrosis and in IPF lung fibroblasts reduced the exacerbated fibrotic response. Similarly, enforced expression of miR-155 reduced the pro-fibrotic phenotype of IPF and miR-155-/- fibroblasts. Conclusion: We describe herein a molecular pathway comprising miR-155 and its epigenetic LXRα target that when deregulated enables pathogenic pulmonary fibrosis. Manipulation of the miR-155/LXR pathway may have therapeutic potential for IPF

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin