Miracle-dz/UniFAR-FTUs huggingface dataset:
Site-Specific and Targeted Therapy Based on Molecular Profiling by Next-Generation Sequencing for Cancer of Unknown Primary Site: A Nonrandomized Phase 2 Clinical Trial.

Importance Although profiling of gene expression and gene alterations by next-generation sequencing (NGS) to predict the primary tumor site and guide molecularly targeted therapy might be expected to improve clinical outcomes for cancer of unknown primary site (CUP), to our knowledge, no clinical trial has previously evaluated this approach. Objective To assess the clinical use of site-specific treatment, including molecularly targeted therapy based on NGS results, for patients with CUP. Design, Setting, and Participants This phase 2 clinical trial was conducted at 19 institutions in Japan and enrolled 111 previously untreated patients with the unfavorable subset of CUP between March 2015 and January 2018, with 97 patients being included in the efficacy analysis. Eligibility criteria included a diagnosis of unfavorable CUP after mandatory examinations, including pathological evaluation by immunohistochemistry, chest-abdomen-pelvis computed tomography scans, and a positron emission tomography scan. Interventions RNA and DNA sequencing for selected genes was performed simultaneously to evaluate gene expression and gene alterations, respectively. A newly established algorithm was applied to predict tumor origin based on these data. Patients received site-specific therapy, including molecularly targeted therapy, according to the predicted site and detected gene alterations. Main Outcomes And Measures The primary end point was 1-year survival probability. Secondary end points included progression-free survival (PFS), overall survival (OS), objective response rate, safety, efficacy according to predicted site, and frequency of gene alterations. Results Of 97 participants, 49 (50.5%) were women and the median (range) age was 64 (21-81) years. The cancer types most commonly predicted were lung (21 [21%]), liver (15 [15%]), kidney (15 [15%]), and colorectal (12 [12%]) cancer. The most frequent gene alterations were in TP53 (45 [46.4%]), KRAS (19 [19.6%]), and CDKN2A (18 [18.6%]). The 1-year survival probability, median OS, and median PFS were 53.1% (95% CI, 42.6%-62.5%), 13.7 months (95% CI, 9.3-19.7 months), and 5.2 months (95% CI, 3.3-7.1 months), respectively. Targetable EGFR mutations in tumor specimens were detected in 5 patients with predicted non-small-cell lung cancer (5.2%), 4 of whom were treated with afatinib; 2 of these patients achieved a durable PFS of longer than 6 months. Conclusions and Relevance This study's findings suggest that site-specific treatment, including molecularly targeted therapy based on profiling gene expression and gene alterations by NGS, can contribute to treating patients with the unfavorable subset of CUP. Trial Registration UMIN Identifier: UMIN000016794.
Genome‐wide association analysis of psoriasis patients treated with anti‐TNF drugs

While anti‐TNF therapies are effective against psoriasis, 30%–50% of patients do not show an adequate response to these drugs. Different candidate‐gene pharmacogenetics studies have identified single nucleotide polymorphisms that may predict anti‐TNF drugs response in psoriasis. Nevertheless, only one paper has undertaken a pharmacogenomic approach failing to find significant biomarkers of biological drug response along the whole genome. Furthermore, most of the pharmacogenetic candidate biomarkers identified previously have not been confirmed in a different cohort of patients. The objective of this study was to find biomarkers that could predict anti‐TNF drugs response along the whole genome and validate biomarkers identified previously. A genome‐wide association study (GWAS) was performed using the Human Omni Express‐8 v1.2 Beadchips in 243 psoriasis patients treated with anti‐TNF drugs. This study was multicentric and did not interfere with clinical practice. Associations between single nucleotide polymorphisms (SNP) and PASI75 (a 75% reduction with respect to baseline PASI) at 3 months were evaluated. Imputation was performed using SNPs with R2 > 0.7. There were two SNPs located in NPFFR2 that were close to the significant threshold of 5 × 10−8. These data suggest that NPFFR2 might be associated with anti‐TNF drug response. However, further studies involving a larger cohort of patients are needed in order to confirm these results.
Galectin-7 downregulation in lesional keratinocytes contributes to enhanced IL-17A signaling and skin pathology in psoriasis.

Psoriasis is a chronic inflammatory skin disease characterized by inflammatory cell infiltration, as well as hyperproliferation of keratinocytes in skin lesions, and is considered a metabolic syndrome. We found that the expression of galectin-7 is reduced in the skin lesions of patients with psoriasis. IL-17A and TNF-α, two cytokines intimately involved in the development of psoriatic lesions, suppressed galectin-7 expression in human primary keratinocytes (HEKn cells) and the immortalized human keratinocyte cell line HaCaT. A galectin-7 knockdown in these cells elevated the production of IL-6 and IL-8 and enhanced ERK signaling when the cells were stimulated with IL-17A. Galectin-7 attenuated IL-17A-induced production of inflammatory mediators by keratinocytes via the miR-146a-ERK pathway. Moreover, galectin-7-deficient mice showed enhanced epidermal hyperplasia and skin inflammation in response to intradermal IL-23 injection. We identified fluvastatin as an inducer of galectin-7 expression by connectivity map (cMAP) analysis, confirmed this effect in keratinocytes, and demonstrated that fluvastatin attenuated IL-6 and IL-8 production induced by IL-17A. Thus, we validate a role of galectin-7 in the pathogenesis of psoriasis, in both epidermal hyperplasia and keratinocyte-mediated inflammatory responses, and formulated a rationale for the use of statins in the treatment of psoriasis.
Korean Familial Amyotrophic Lateral Sclerosis Family with a Novel Gly10Val Mutation in the SOD1 Gene

Background : Approximately 5 to 10% of amyotrophic lateral sclerosis (ALS) patients have recorded family history (FALS) and in most cases, the pattern of inheritance is autosomal dominant (DFALS). Twenty percent of DFALS families are linked to chromosome 21q22.1, which is associated to a mutation in the Cu/Zn superoxide dismutase (SOD1) gene. However, these cases, especially with SOD1 gene mutations have not yet been reported in Korea. We investigated the clinical features of familial ALS pedigrees and screened the SOD1 gene in search of potential mutations. Methods : The clinical histories and neurological findings of the family members were obtained. Genomic DNA was extracted from leukocytes of whole blood samples and PCR and direct sequencing analyzed the coding region of the SOD1 gene. Results : Five affected members in a three-generation family exhibited early onset and rapid progression. The family has a novel missense mutation in the SOD1 gene, which was heterozygous for point mutation GGC to GTT, causing a ubstitution of valine for glycine at codon 10 (Gly10Val) in exon 1. Conclusions : Familial ALS with a novel Gly10Val mutation in the SOD1 gene showed severe clinical features. The mutation lies in a region involved in a dimer contact in the third-dimensional structure of the SOD1 protein. This study is the first report of familial ALS cases in Korea and contributes to expand the number of ALS-associated SOD1 gene mutations.
Influence of decompensated heart failure on cardiac acoustic biomarkers: impact on early readmissions

Preventing hospitalization by detecting early evidence of heart failure (HF) decompensation in an outpatient setting can improve patient's quality of life and reduce costs of care. The purpose of this study was to assess the value of cardiac acoustic biomarkers (CABs), a combination of cardiohaemic vibrations synchronized with ECG signals, and heart rate (HR) for detecting HF decompensation during first 3 months after hospital discharge for HF.
Paclitaxel exposure and long-term mortality of patients treated with the Zilver PTX drug-eluting stent

Objectives Paclitaxel-eluting stents have demonstrated improved patency over balloon angioplasty and bare metal stenting for endovascular interventions in the femoral-popliteal segment. Recently, concerns have arisen regarding the safety of paclitaxel use and its association with mortality. This study aims to examine real-world, long-term mortality, and patency of patients treated with the Zilver PTX drug-eluting stent. Methods Patients treated with the PTX stent after FDA approval between 2013 and 2015 were identified from an institutional database. Demographic, procedural, and device information was collected and initial- and lifetime-exposure dose of paclitaxel was calculated. The primary outcome was all-cause mortality and its association with paclitaxel exposure. Long-term patency was also evaluated. Results Seventy-nine procedures involving PTX placement were performed on 64 individual patients during the study period, with 15 (23.4%) having bilateral procedures. Average age was 70 years, and 71.9% were male. Forty-five patients (70.3%) were claudicants, and 19 (29.7%) had chronic, limb-threatening ischemia. An average of 2.3 PTX stents, totaling 203 mm in length, were placed per procedure. Paclitaxel exposure was 1.87 mg/procedure initially (range 0.38–4.03 mg), and average lifetime exposure was 4.65 mg/patient (range 0.38–27.91 mg). Average follow-up was 59.6 months. Kaplan–Meier estimated survival was 96.9%, 81.2% and 71.7% at one , three, and five years. On multivariate analysis, no specific factors were associated with overall morality including initial paclitaxel dose (HR 0.99, 95% CI 0.99–1.00) and lifetime paclitaxel exposure (HR 0.98, 95% CI 0.89–1.08). Kaplan–Meier primary patency was 76.2%, 60.1%, and 29.3% at one, two, and five years, respectively. Secondary patency was 92.2%, 85.4%, and 75.2% at the same intervals. Conclusions At a mean follow-up of five years, exposure to higher doses of paclitaxel from Zilver PTX does not appear to be associated with increased mortality compared to lower doses in real-world patients. Long-term patency rates confirm the efficacy of Zilver PTX, and further investigation may be warranted before abandoning paclitaxel use altogether.
Burden of respiratory syncytial virus infection in community-dwelling older adults in Europe (RESCEU): an international prospective cohort study

Respiratory syncytial virus (RSV) infection in older adults is recognised, but the burden in the community is still uncertain. This European study found that RSV infection is prevalent but rarely caused severe disease in community-dwelling older adults. https://bit.ly/30gsiMD Background Respiratory syncytial virus (RSV) infection in older adults is recognised as an important health issue. We aimed to assess the community burden of RSV in Europe in older adults aged ≥60 years. Methods This international, prospective, observational cohort study is part of work by the REspiratory Syncytial virus Consortium in EUrope (RESCEU). Participants were recruited through general practitioners' (GPs) offices before two independent RSV seasons. Participants reported weekly about symptoms of acute respiratory tract infection (ARTI) during one RSV season. ARTI patients were tested for RSV during home visits and completed a daily symptom diary. RSV illness included PCR-confirmed ARTI and those showing seroconversion over the season. RSV ARTI was based on PCR alone (ClinicalTrials.gov, NCT03621930). Results We recruited 1040 participants (527 in season 2017–2018 and 513 in season 2018–2019) with a median age of 75 years (range 60–100 years). Of these, 1023 (99%) lived independently at home at baseline. RSV illness incidence was 22 out of 527 (4.2%) and 37 out of 513 (7.2%) in the respective seasons. RSV illness did not affect frailty or cardiopulmonary status during the course of the study. No patients were hospitalised or died from RSV illness. In the 36 patients with PCR confirmed RSV ARTI, symptom duration averaged 19 days, while a doctor's visit took place in 11 out of 36 cases (31%). RSV ARTI could not be differentiated clinically from all other ARTIs based on symptoms. Conclusion This European study showed that RSV is prevalent in community-dwelling older adults and rarely causes severe disease. This suggests that watchful waiting, using a continuity of care approach to identify those who do need more intensive care, is often justified when RSV is suspected in family practice.
Positive Impact of Routine Testing for Enterovirus and Parechovirus on Length of Hospitalization and Antimicrobial Use among Inpatients ≤6 Months of Age

Enterovirus (EV) and parechovirus (PeV) are leading viral causes of central nervous system (CNS) infection among hospitalized neonates and young infants, yet testing for PeV is not routinely performed. The goal of our study was to determine how EV and PeV CSF RT-PCR testing impacted the duration of antibiotic use and the length of hospitalization (LOS) in children ≤6 months old with suspected CNS infection. This retrospective cohort study at Children’s Mercy Kansas City evaluated data from patients ≤6 months old for whom routine CSF EV and PeV reverse transcription-PCR (RT-PCR) testing was performed during January 2011 to December 2018. ABSTRACT Enterovirus (EV) and parechovirus (PeV) are leading viral causes of central nervous system (CNS) infection among hospitalized neonates and young infants, yet testing for PeV is not routinely performed. The goal of our study was to determine how EV and PeV CSF RT-PCR testing impacted the duration of antibiotic use and the length of hospitalization (LOS) in children ≤6 months old with suspected CNS infection. This retrospective cohort study at Children’s Mercy Kansas City evaluated data from patients ≤6 months old for whom routine CSF EV and PeV reverse transcription-PCR (RT-PCR) testing was performed during January 2011 to December 2018. Electronic data were abstracted from the electronic medical record, including demographics, systemic antimicrobial use, imaging data, herpes simplex virus (HSV) testing, and overall hospital charges. Among 1,926 patients, 345 (17.9%) were RT-PCR positive for EV and 172 (8.9%) were positive for PeV. A significantly shorter LOS was observed for patients with EV (51.6 h; P < 0.001) and PeV (66.3 h; P = 0.048) compared to patients that tested negative for both viruses (74.1 h). Discontinuation of empirical antibiotic therapy following test result availability occurred more frequently for PeV patients (57.8%; P = 0.03) and EV patients (65.4%; P < 0.001) than RT-PCR-negative patients (48.5%). Routine EV/PeV RT-PCR testing of cerebrospinal fluid (CSF) samples in children impacted care of hospitalized neonates and young infants. Rapid and prompt diagnosis has the potential to reduce antibiotic usage, length of stay, and patient charges.
Epigenetics/Epigenomics and Prevention of Early Stages of Cancer by Isothiocyanates

Cancer is a complex disease and cancer development takes 10–50 years involving epigenetics. Evidence suggests that approximately 80% of human cancers are linked to environmental factors impinging upon genetics/epigenetics. Because advanced metastasized cancers are resistant to radiotherapy/chemotherapeutic drugs, cancer prevention by relatively nontoxic chemopreventive “epigenetic modifiers” involving epigenetics/epigenomics is logical. Isothiocyanates are relatively nontoxic at low nutritional and even higher pharmacologic doses, with good oral bioavailability, potent antioxidative stress/antiinflammatory activities, possess epigenetic-modifying properties, great anticancer efficacy in many in vitro cell culture and in vivo animal models. This review summarizes the latest advances on the role of epigenetics/epigenomics by isothiocyanates in prevention of skin, colon, lung, breast, and prostate cancers. The exact molecular mechanism how isothiocyanates modify the epigenetic/epigenomic machinery is unclear. We postulate “redox” processes would play important roles. In addition, isothiocyanates sulforaphane and phenethyl isothiocyanate, possess multifaceted molecular mechanisms would be considered as “general” cancer preventive agents not unlike chemotherapeutic agents like platinum-based or taxane-based drugs. Analogous to chemotherapeutic agents, the isothiocyanates would need to be used in combination with other nontoxic chemopreventive phytochemicals or drugs such as NSAIDs, 5-α-reductase/aromatase inhibitors targeting different signaling pathways would be logical for the prevention of progression of tumors to late advanced metastatic states.
Evaluation of a Cognitive-Behavioral Game Design-Based Mobile Game on Alcohol Use for Adolescents.

Objective: Determine the effectiveness of a cognitive behavioral game design (CBGD) based mobile game as an alcohol use intervention. Materials and Methods: Experimental design with 140 participants randomly assigned to either play a mobile game (n = 69) or watch a video documentary (n = 71). Results: Both groups displayed a decrease in intent to use and an increase in knowledge. The video intervention was superior in affecting actual use. Conclusion: Mobile game affects intent to use and is superior to the video in affecting knowledge.
Longitudinal Evaluation of Lung Function in Gulf War I Veterans Exposed to Depleted Uranium.

OBJECTIVE Gulf War I (GWI) Veterans exposed to depleted uranium (DU) have undergone biennial surveillance to assess for DU-related health effects. No DU-specific respiratory effects have been observed cross-sectionally, but longitudinal lung function decline has not been assessed. METHODS A dynamic cohort of 71 Veterans underwent spirometry testing between 1999 and 2019. Longitudinal rates of decline of spirometry values were compared among Veterans with high vs low uranium levels using a linear mixed model. RESULTS There was no significant difference in rate of decline of spirometry values between Veterans with high vs low uranium levels. The overall rate of decline was similar to that of the general population. CONCLUSIONS In twenty years of follow-up, there does not appear to be an accelerated rate of decline of lung function among veterans exposed to depleted uranium.
Synergistic effect of UVA irradiation and phlorotannin extracts of Laminaria japonica on properties of grass carp myofibrillar protein gel.

BACKGROUND Oxidized phlorotannin could be used as protein cross-linking agents to produce high-quality fish gel products. Phlorotannin can be easily induced to form quinone compounds in an oxidizing environment, while o-quinone has been proven to be a reactive, electrophilic intermediate that easily reacts with proteins to form rigid molecular crosslinking network. The objective of this study was to investigate the synergistic effects of ultraviolet A (UVA) irradiation (1 h, 15 W/m2 ) and different concentrations of Laminaria japonica (L. japonica) phlorotannin extracts (PTE) on the gel properties of grass carp myofibrillar protein (MP). RESULTS UVA treatment and PTE could synergistically improve the MP gel properties more than PTE alone (P<0.05). At 625 mmol kg-1 MP PTE alone, the gel strength and cooking yield reached 3.10±0.16 g·cm and 47.45±0.35 %, respectively, while with the same level of PTE plus UVA, they became 4.26±0.19 g·cm and 53.89±1.54 %, respectively. The three-dimensional network structure of the gel (with PTE+UVA) showed higher connectivity and tightness than that of the control group (no treatment). CONCLUSION The synergistic effects of PTE and UVA could effectively induce crosslinking of grass carp MP, which could lead to an improvement of the MP gel quality. These findings would provide a new technical approach to produce high quality protein gel products in fish processing industry. This article is protected by copyright. All rights reserved.
How does management legacy, nitrogen addition and nitrification inhibition impact soil organic matter priming and nitrous oxide production?

Long-term management of croplands influences the fluxes and sources of nitrous oxide (N2 O). We examined this premise in a greenhouse study by using soils collected from a 38-year-old field experiment. The sampled treatments were continuous barley (CB), continuous fescue (CF), and two phases of an 8-year rotation: faba bean (FB) and alfalfa-bromegrass hay. Barley was grown as a test crop in the greenhouse in each soil. The ranking of N2 O emissions was hay> FB> CB> CF (P<0.001). We quantified the 15 N-site preference to assess the N2 O-producing processes. Denitrification was the predominant source, contributing with 77.4% of the N2 O production. We also evaluated nitrogen additions: urea alone or urea with a nitrification inhibitor (nitrapyrin or DMPSA). Compared with urea alone, nitrapyrin and DMPSA reduced N2 O emissions by 16% and 25%, respectively. We used urea labeled with 15 N to trace N to N2 O emissions, aboveground plant N uptake, and N retention by soils. Total 15 N-recovery (N2 O+plant+soil) was highest under FB (86%) and lowest under CB (29%). We further separated the N2 O derived from urea versus N2 O from soil organic matter (SOM). The inhibitor DMPSA reduced the N2 O derived specifically from added urea-N by more than half (P<0.001). With the addition of urea, N2 O production from mineralization of SOM-N accelerated over the control (without urea), termed the priming effect. This priming of SOM-N contributed with 13% of the total N2 O production when averaged across the four management legacies. The CB soil had the highest proportion of priming-derived N2 O, with 24%. Management legacies clearly differed in soil carbon and N, which governed N2 O production from denitrification and SOM priming. This article is protected by copyright. All rights reserved.
The selective PGI2 receptor agonist selexipag ameliorates Sugen 5416/hypoxia-induced pulmonary arterial hypertension in rats

Pulmonary arterial hypertension (PAH) is a lethal disease characterized by a progressive increase in pulmonary artery pressure due to an increase in vessel tone and occlusion of vessels. The endogenous vasodilator prostacyclin and its analogs are used as therapeutic agents for PAH. However, their pharmacological effects on occlusive vascular remodeling have not been elucidated yet. Selexipag is a recently approved, orally available and selective prostacyclin receptor agonist with a non-prostanoid structure. In this study, we investigated the pharmacological effects of selexipag on the pathology of chronic severe PAH in Sprague-Dawley and Fischer rat models in which PAH was induced by a combination of injection with the vascular endothelial growth factor receptor antagonist Sugen 5416 and exposure to hypoxia (SuHx). Oral administration of selexipag for three weeks significantly improved right ventricular systolic pressure and right ventricular (RV) hypertrophy in Sprague-Dawley SuHx rats. Selexipag attenuated the proportion of lung vessels with occlusive lesions and the medial wall thickness of lung arteries, corresponding to decreased numbers of Ki-67-positive cells and a reduced expression of collagen type 1 in remodeled vessels. Administration of selexipag to Fischer rats with SuHx-induced PAH reduced RV hypertrophy and mortality caused by RV failure. These effects were probably based on the potent prostacyclin receptor agonistic effect of selexipag on pulmonary vessels. Selexipag has been approved and is used in the clinical treatment of PAH worldwide. It is thought that these beneficial effects of prostacyclin receptor agonists on multiple aspects of PAH pathology contribute to the clinical outcomes in patients with PAH.