tbuckley/cabot-search huggingface dataset:
Effect of green-Mediterranean diet on intrahepatic fat: the DIRECT PLUS randomised controlled trial
Authors: Anat Yaskolka Meir, Ehud Rinott, Gal Tsaban, Hila Zelicha, Alon Kaplan, Philip Rosen, Ilan Shelef, Ilan Youngster, Aryeh Shalev, Matthias Blüher, Uta Ceglarek, Michael Stumvoll, Kieran Tuohy, Camilla Diotallevi, Urska Vrhovsek, Frank Hu, Meir Stampfer, Iris Shai
Journal: Gut (2021)

Objective To examine the effectiveness of green-Mediterranean (MED) diet, further restricted in red/processed meat, and enriched with green plants and polyphenols on non-alcoholic fatty liver disease (NAFLD), reflected by intrahepatic fat (IHF) loss. Design For the DIRECT-PLUS 18-month randomized clinical trial, we assigned 294 participants with abdominal obesity/dyslipidaemia into healthy dietary guidelines (HDG), MED and green-MED weight-loss diet groups, all accompanied by physical activity. Both isocaloric MED groups consumed 28 g/day walnuts (+440 mg/day polyphenols provided). The green-MED group further consumed green tea (3–4 cups/day) and Mankai (a Wolffia globosa aquatic plant strain; 100 g/day frozen cubes) green shake (+1240 mg/day total polyphenols provided). IHF% 18-month changes were quantified continuously by proton magnetic resonance spectroscopy (MRS). Results Participants (age=51 years; 88% men; body mass index=31.3 kg/m 2 ; median IHF%=6.6%; mean=10.2%; 62% with NAFLD) had 89.8% 18-month retention-rate, and 78% had eligible follow-up MRS. Overall, NAFLD prevalence declined to: 54.8% (HDG), 47.9% (MED) and 31.5% (green-MED), p=0.012 between groups. Despite similar moderate weight-loss in both MED groups, green-MED group achieved almost double IHF% loss (−38.9% proportionally), as compared with MED (−19.6% proportionally; p=0.035 weight loss adjusted) and HDG (−12.2% proportionally; p&lt;0.001). After 18 months, both MED groups had significantly higher total plasma polyphenol levels versus HDG, with higher detection of Naringenin and 2-5-dihydroxybenzoic-acid in green-MED. Greater IHF% loss was independently associated with increased Mankai and walnuts intake, decreased red/processed meat consumption, improved serum folate and adipokines/lipids biomarkers, changes in microbiome composition (beta-diversity) and specific bacteria (p&lt;0.05 for all). Conclusion The new suggested strategy of green-Mediterranean diet, amplified with green plant-based proteins/polyphenols as Mankai, green tea, and walnuts, and restricted in red/processed meat can double IHF loss than other healthy nutritional strategies and reduce NAFLD in half. Trial registration number NCT03020186 .
Cortisol-Producing Adrenal Adenomas With Intense Activity on 68Ga-Pentixafor PET/CT
Authors: Jie Ding, Anli Tong, YuShi Zhang, Hui Zhang, Li Huo
Journal: Clinical Nuclear Medicine (2021)

Abstract CXC chemokine receptor type 4 as a G-protein–coupled receptor has been confirmed to be highly expressed in functional adrenocortical adenomas. 68 Ga-pentixafor, a CXC chemokine receptor type 4–specific ligand, has been reported as a promising tracer to evaluate functional nature of adrenal adenomas. We report intense 68 Ga-pentixafor activity of cortisol-producing adrenal adenomas in 2 patients with adrenocorticotropic hormone–independent Cushing syndrome.
CRISPR/Cas9-Mediated Gene Editing Corrects Disease-Causing Mutation in Crigler-Najjar Syndrome Mice
Authors: Giulia Bortolussi, Edoardo Schneider, Fabiola Porro, Filippo Ferrucci, Alessandra Iaconcig, Luka Bockor, Claudia Galletta, Cristian Munoz, Alessia De Caneva, Luca Braga, Lorena Zentilin, Mauro Giacca, Andres F. Muro
Journal: Molecular Therapy (2020)
BET proteins are associated with the induction of small airway fibrosis in COPD
Authors: Razia Zakarya, Yik L Chan, Sandra Rutting, Karosham Reddy, Jack Bozier, Roy R Woldhuis, Dikaia Xenaki, David Van Ly, Hui Chen, Corry-Anke Brandsma, Ian M Adcock, Brian G Oliver
Journal: Thorax (2021)

In COPD, small airway fibrosis occurs due to increased extracellular matrix (ECM) deposition in and around the airway smooth muscle (ASM) layer. Studies of immune cells and peripheral lung tissue have shown that epigenetic changes occur in COPD but it is unknown whether airway mesenchymal cells are reprogrammed.Determine if COPD ASM cells have a unique epigenetic response to profibrotic cytokine transforming growth factor β1 (TGF-β1).Primary human ASM cells from COPD and non-COPD smoking patients were stimulated with TGF-β1. Gene array analysis performed to identify differences in ECM expression. Airway accumulation of collagen 15α1 and tenascin-C proteins was assessed. Aforementioned ASM cells were stimulated with TGF-β1 ± epigenetic inhibitors with qPCR quantification of COL15A1 and TNC. Global histone acetyltransferase (HAT) and histone deacetylase (HDAC) activity were assessed. chromatin immunoprecipitation (ChIP)-qPCR for histone H3 and H4 acetylation at COL15A1 and TNC promoters was carried out. Effects of bromoterminal and extraterminal domain (BET) inhibitor JQ1(+) on expression and acetylation of ECM target genes were assessed.COPD ASM show significantly higher COL15A1 and TNC expression in vitro and the same trend for higher levels of collagen 15α1 and tenascin-c deposited in COPD airways in vivo. Epigenetic screening indicated differential response to HDAC inhibition. ChIP-qPCR revealed histone H4 acetylation at COL15A1 and TNC promoters in COPD ASM only. ChIP-qPCR found JQ1(+) pretreatment significantly abrogated TGF-β1 induced histone H4 acetylation at COL15A1 and TNC.BET protein binding to acetylated histones is important in TGF-β1 induced expression of COL15A1 and TNC and maintenance of TGF-β1 induced histone H4 acetylation in cell progeny.
Phase I study of BI 754091 plus BI 754111 in Asian patients with gastric/gastroesophageal junction or esophageal cancer.
Authors: Kensei Yamaguchi, Yoon-Koo Kang, Do-Youn Oh, Shunsuke Kondo, Sun Young Rha, Yasutoshi Kuboki, Manabu Morimoto, Hiroki Hara, Chia-Chi Lin, Yoshifumi Tachibana, Jianrui Hou, Mabrouk M. Elgadi, Shigehisa Kitano
Journal: Journal of Clinical Oncology (2021)

212 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, has been proposed to restore T-cell function and thus enhance antitumor responses. This Phase I trial evaluated BI 754091 (anti-PD-1) with BI 754111 (anti-LAG-3) antibodies in Asian pts with advanced solid tumors (NCT03433898). Here, we present results from pts with anti-PD-(L)1 inhibitor-naïve gastric/gastroesophageal junction or esophageal cancer (Cohorts A and B). Methods: In Parts 1 and 2 (dose escalation), the recommended dose for the combination was determined as BI 754091 240 mg + BI 754111 600 mg IV Q3W. In Part 3, the combination was assessed in expansion cohorts including pts with gastric/gastroesophageal junction cancer (Cohort A) and esophageal cancer (Cohort B). Eligible pts had received ≥1 line of prior systemic therapy but no prior anti-PD-(L)1 therapy. The primary endpoint in Part 3 was objective response (OR; confirmed complete response or partial response [PR]) per RECIST 1.1. Results: In Cohort A/B, 36/37 pts were treated:26/31 (72/84%) male, median age 60/63 years. Patients were enrolled in Taiwan (1/7 pts, 3/19%), Japan (12/27 pts, 33/73%) or Korea (23/3 pts, 64/8%). The median number of regimens of prior systemic therapy was 2/2 (Cohorts A/B, range: 16/14). All pts in Cohort B had squamous cell carcinoma. At the time of analysis, pts in Cohort A/B had undergone a median of 84/73 days on treatment (range: 31346/8325), from the start of treatment until the date of snapshot, death or discontinuation. Confirmed OR (PR) was observed in 4/7 pts in Cohorts A/B; overall response rate (ORR) was 11% and 19%. Stable disease (SD) was observed in 10/8 (28/22%) pts in Cohorts A/B and overall disease control rate was 39/41%. In Cohorts A/B, adverse events (AEs) and treatment-related AEs were experienced by 30/34 (83/92%) and 12/22 (33/59%) pts, respectively. The most commonly reported AEs were pyrexia (25/19%), decreased appetite (17/19%), increased aspartate aminotransferase (11/14%), anemia (11/11%) and nausea (6/14%). In Cohort A/B, 9/15 (25/41%) pts experienced immune-related AEs, most commonly rash in Cohort A (4 pts; 11%) and hyperthyroidism in Cohort B (4 pts; 11%). In Cohorts A/B, 2/6 (6/16%) patients experienced AEs leading to discontinuation of treatment. Conclusions: Treatment was well tolerated and preliminary antitumor activity was seen. Addition of LAG3 did not improve ORR beyond that expected for an anti-PD-1 monotherapy in gastric and esophageal cancer without patient selection. Clinical trial information: NCT03433898. [Table: see text]
THU0219 Retrospective evaluation of 180 patients who were diagnosed as undifferentiated connective tissue disease
Authors: E Doganavsargil, F Oksel, G Keser, V Inal, K Aksu
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To review the outcome and diagnosis of patients whose initial clinical and laboratory findings were suggestive of a well established and undifferentiated connective tissue disease (uCTD), without fulfilling the diagnostic criteria of any connective tissue disease. <h3>Methods</h3> Medical records of patients being followed up by Ege University rheumatology department between 1990 and 1999 were retrospectively screened. The data of 478 patients, constituting 18% of the total, whose initial diagnosis was uCTD, were further investigated. Patients with missing data were omitted and only 180 patients having reliable and complete initial clinical and laboratory data with regular controls were included. <h3>Results</h3> The mean ages of 180 patients (F/M:173/7) at the time of initial clinical symptoms and at the time of diagnosis of uCTD were 35 ± 12 years and 38 ± 12 years, respectively. The distribution of initial symptoms and clinical findings were as follows: arthralgia/arthritis 97.2%, Raynaud phenomenon (RP) 30.5%, mucocutaneous findings 68.2%, symptoms of keratoconjunktivitis sicca 14.4%. It was notable that none of the patients had presented with initial symptoms or clinical finding reflecting direct involvement of a specific organ. In the final evaluation, 46 out of 180 patients (25.5%) were found to evolve into a definite clinical diagnosis: Sjögren’s syndrome 21 (11.6%), systemic lupus erythematosus 8 (4.4%), rheumatoid arthritis 8 (4.4%), CREST syndrome 7 (3.8%), diffuse systemic sclerosis 1 and seronagative polyarthritis 1. In 5 patients a nonrheumatologic diagnosis was made, while in 11 patients fibromyalgia was diagnosed. The diagnosis of 118 (65%) patients (F/M:115/3) remained unchanged. The evaluation of initial clinical and laboratory parameters with respect to their contribution to final diagnosis revealed that, presence of Raynaud phenomenon and anti-centromeric antibodies were highly suggestive of later diagnosis of limited ScS. On the other hand, anti-dsDNA antibodies, leucopenia and thrombocytopenia, which are important parameters in well established SLE, were initially unpredictive of later SLE development in patients whose initial diagnosis was uCTD. <h3>Conclusion</h3> In most of the patients whose initial diagnosis was uCTD, the disease tends to remain undifferentiated.
Update results of paclitaxel and cisplatin in combination with anlotinib as first-line regimen for advanced esophageal squamous cell carcinoma (ESCC): A multicenter, single-arm, open-label phase Ⅱ clinical trial.
Authors: Junsheng Wang, Suxia Luo, Ning Li, Tao Wu, Yonggui Hong, Yanzhen Guo, Yufeng Cheng, Baosheng Li, Bingxu Tan
Journal: Journal of Clinical Oncology (2021)

181 Background: The prognosis of pts with advanced ESCC remains dismal clinically. Paclitaxel and cisplatin were used as the standard first-line regimen in ESCC for almost two decades. As a novel multitarget tyrosine kinase inhibitor mainly targeting antiangiogenic single pathway, anlotinib was demonstrated to be an effective second-line monotherapy for pts with advanced or recurrent ESCC in China. Consequently, the aim of this study was to investigate the efficacy and toxicity of paclitaxel and cisplatin combined with anlotinib as first-line therapy for advanced ESCC. Methods: Pts with previously untreated metastatic or unresectable, locally advanced ESCC, who had not received (neo) adjuvant therapy/radical surgery within 6 months were recruited in this study. Eligible subjects were given paclitaxel (135mg/m 2 , iv, q3w) and cisplatin (60~75mg/m 2 , iv, d1~3, q3w) plus anlotinib (10mg, po, d1~14, q3w) for 4~6 cycles during initial therapy. For those without progressive disease, maintenance treatment was administrated with anlotinib monotherapy (10mg, po, d1~14, q3w) until progression or unacceptable toxicity. The tumor response was assessed by investigator according to RECIST version 1.1 using CT scans every two cycles. And the calculated sample size of this study was 47. The primary endpoint was PFS, secondary endpoints were safety, objective response rate (ORR), disease control rate (DCR) and duration of response (DOR). Results: From Oct 2019 to Aug 2020, 27 pts were available for efficacy and safety evaluation. In best overall response assessment, there were 7.4% CR (2/27), 66.7% PR (18/27) and 25.9% SD (7/27). ORR was 74.1% (95%CI: 53.7. ~ 88.9), and DCR was 100.0% (95%CI: 87.2~100.0). The median PFS of the 27 pts was not yet available. The safety profile indicated that the most common drug-related adverse events were myelosuppression, gastrointestinal reaction, fatigue, hypertension, constipation, hypokalemia and hepatotoxicity. The common grade 3-4 treatment-related adverse events were myelosuppression (18.5%), hypertension (7.4%). Conclusions: The current results indicated that paclitaxel and cisplatin combined with anlotinib as first line therapy for advanced ESCC exhibited encouraging efficacy and manageable adverse events. The conclusion should be validated in more pts consecutively. Clinical trial information: NCT04063683. [Table: see text]
towards a taxonomy of modes of moral decision-making
Authors: elke u. weber, jessica s. ancker
Journal: Behavioral and Brain Sciences (2005)

sunstein advocates a more systematic approach to the study of moral decision-making, namely the heuristics-and-biases paradigm. we offer two concerns and suggest that a focus on decision processes can add value. recent research on decision modes suggest that it is useful to distinguish between the qualitative differences in the ways in which moral decisions can be made when they are not made by reflective, consequentialist reasoning.
Editorial Health Engineering for Combating CVD and COVID-19
Journal: IEEE Reviews in Biomedical Engineering (2021)

Health Engineering for Combating CVD and COVID-19 T HE steady increases in cardiovascular disease (CVD) and the continuing spread of coronavirus disease (COVID-19) remain unprecedented public health crises of international concerns.The multiple crises are causing catastrophic human losses and tremendous health and economic burdens worldwide [in item 1) of the Appendix].According to the most recent Global Health Estimates from 2000 to 2019 released by the World Health Organization (WHO) on 9 December 2020, CVD has remained the global leading cause of death for the last 20 years.However, it is now killing more people than ever before [in item 2) of the Appendix].Besides the CVD crisis, COVID-19 continues widely spread affecting more than 210 countries throughout the world with nearly 70 million confirmed cases and 1.6 million deaths as of 12 December 2020 [in item 3) of the Appendix].It is projected that the total global deaths from CVDs and the total cases of COVID-19 infection will all continue to rise if no timely effective and preventive measures are taken.The success of fighting against both deadly diseases will only come from a paradigm shift transforming the current reactive medicine focusing on the last stage of treatment to proactive health focusing on the early prediction, early diagnosis and prevention of diseases.Health engineering is emerging as a new interdisciplinary field for the implementation of proactive health.To call for urgent actions addressing the society's most press health challenges, the President of IEEE-EMBS Dr. Shankar Subramaniam and the President-Elect Dr. Metin Akay led the COVID-19 initiative early this year and had some extensive strategic discussions with different stakeholders including Dr.
SAT0055 Effect of rofecoxib, celecoxib, and naproxen on blood pressure and urinary sodium excretion in elderly volunteers
Authors: JI Schwartz, MP Malice, KC Lasseter, GB Holmes, KM Gottesdiener, K Brune
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Nonsteroidal anti-inflammatory drugs (NSAIDs) can affect sodium reabsorption by decreasing the synthesis of renal prostaglandins. Since COX-2 is constitutively expressed in the kidney, it is hypothesised that the effects of COX-2 inhibitors on sodium handling would be similar to non-selective NSAIDs. It is hypothesised moreover that the effects of the two COX-2 inhibitors on sodium handling would be similar. <h3>Objectives</h3> This study evaluated the effects of two COX-2 inhibitors [rofecoxib, 25 mg QD and celecoxib, 200 mg BID], a nonselective NSAID [naproxen, 500 mg BID], and placebo on blood pressure (BP) and urinary sodium excretion during a 2-week in-house administration. <h3>Methods</h3> 67 healthy elderly (60 to 80 years) subjects participated in a double-blind, placebo-controlled, parallel-group study. Subjects received a weight-maintaining isocaloric diet (200 mEq sodium, 0.8 g/kg protein, 80 to 120 mEq potassium daily), beginning 8–13 days prior to the first dose of study drug. After attaining sodium balance [based on stable weight (within 0.5 kg) and 24-hour urinary sodium between 180 to 220 mEq on 2 consecutive days], subjects were randomised to treatment. Daily 24-hour urine collections were obtained. Daily BP measurements were taken at 8AM and 8PM, and more often (8 AM, Noon, 4 PM, and 8 PM) on Days -1, 1, 7, and 14. <h3>Results</h3> Least-Squares mean changes from baseline (SE) for average daily BP on Day 14 (prespecified primary endpoint for BP) are shown in the Table 1 below. There was no significant difference between the active treatment groups in daily average sodium excretion during the first 3 days or over 2 weeks of treatment (p &gt; 0.05). No incidence of peripheral oedema occurred during the 2 week treatment. Two subjects experienced elevated systolic BP during the course of the trial (one on each COX-2 inhibitor). <h3>Conclusion</h3> These results, obtained under well-controlled conditions for two weeks, suggest that the COX-2 selective agents, rofecoxib and celecoxib, have similar effects on BP and urinary sodium excretion; their effect is similar also to that of non-selective NSAIDs.
Physician Density by Specialty Type in Urban and Rural Counties in the US, 2010 to 2017
Authors: Sara R. Machado, Sahan Jayawardana, Elias Mossialos, Muthiah Vaduganathan
Journal: JAMA Network Open (2021)

This cross-sectional study uses data from the American Medical Association Physician Masterfile to examine physician density by specialty type across metropolitan and rural US counties from 2010 to 2017.
Efficacy and preclinical safety of ARB202, a potential first-in-class anti-CDH17/CD3 bispecific T-cell engager, for treatment of pancreatic and colorectal cancers.
Authors: Dennis A Wong, Moon Ching Luk, Tony K Wong, Donald E Staunton, John M Harlan
Journal: Journal of Clinical Oncology (2021)

405 Background: Globally, gastrointestinal (GI) cancers, which account for around 28% of all cancers, has increased constantly at a CAGR of 2% (2014-2019), while the treatment options remain limited and often ineffective. This is largely due to late diagnosis and lack of new tumor associated antigens for most of the GI malignancies. Cadherin-17, CDH17 (aka CA17), is being evaluated as a potential therapeutic target and molecular marker for GI cancers, of which aberrant expression of CDH17 was reported in 50-90% in tumor samples (including stomach, pancreas, liver/bile duct and colon) by multiple groups. The present study aims to develop a humanized CDH17-CD3 bispecific T-cell engager antibody, ARB202, to treat advanced pancreatic and metastatic colon cancers. Methods: The ARB202 bispecific was generated from anti-CDH17 monoclonal ARB102 as previously described (Lum Y et al, Mol. Pharm. 2020) by linking a CD3-binding scFv in the format of IgG4-scFv. Biophysical properties, efficacy and safety were evaluated. Efficacy was addressed in cytotoxicity assays, IL2-release assays and subcutaneous xenograft models using multiple GI tumor target lines. Preclinical safety profiles include Tissue cross-reactivity assays and GLP repeat-dose toxicity studies in NHP. Results: The ARB202 bispecific antibody was efficiently produced (yield ~1 g/L) and remained stable for at least 3 months under accelerated stress tests. Binding affinity (Kd [M]) of ARB202 to CDH17 and CD3 was at 10 -10 and 10 -9 respectively, with cellular affinities of 10 -9 and 10 -8 . In vitro cytotoxicity assays demonstrate that ARB202-mediated tumor cell killing is CDH17-dependent and requires immune synapse formation with effector T cells. By contrast, normal cells and CDH17-negative cancer cells are resistant. Pancreatic AsPC1 xenograft model revealed an ARB202 (co-inoculated with human PBMC) dose-dependent inhibition of tumor growth. Human IL-2 release in mice blood samples was consistent with functional CDH17 and CD3 engagement. ARB202 PK profile in rodents and NHP was found to be excellent relative to other bispecifics and GLP toxicity studies showed no significant findings nor adverse effects. Conclusions: ARB202 bispecific antibody promises to be a first-in-class biologic, which may tackle approximately 50% of GI cancers that which have been reported CDH17 positive. First-in-human clinical study with advanced GI cancers is scheduled to start in Q1 2021.
Cross-talks among GBA mutations, glucocerebrosidase, and α-synuclein in GBA-associated Parkinson’s disease and their targeted therapeutic approaches: a comprehensive review
Authors: Tapan Behl, Gagandeep Kaur, Ovidiu Fratila, Camelia Buhas, Claudia Teodora Judea-Pusta, Nicoleta Negrut, Cristiana Bustea, Simona Bungau
Journal: Translational Neurodegeneration (2021)

Current therapies for Parkinson's disease (PD) are palliative, of which the levodopa/carbidopa therapy remains the primary choice but is unable to modulate the progression of neurodegeneration. Due to the complication of such a multifactorial disorder and significant limitations of the therapy, numerous genetic approaches have been proved effective in finding out genes and mechanisms implicated in this disease. Following the observation of a higher frequency of PD in Gaucher's disease (GD), a lysosomal storage condition, mutations of glycosylceramidase beta (GBA) encoding glucocerebrosidase (GCase) have been shown to be involved and have been explored in the context of PD. GBA mutations are the most common genetic risk factor of PD. Various studies have revealed the relationships between PD and GBA gene mutations, facilitating a better understanding of this disorder. Various hypotheses delineate that the pathological mutations of GBA minimize the enzymatic activity of GCase, which affects the proliferation and clearance of α-synuclein; this affects the lysosomal homeostasis, exacerbating the endoplasmic reticulum stress or encouraging the mitochondrial dysfunction. Identification of the pathological mechanisms underlying the GBA-associated parkinsonism (GBA + PD) advances our understanding of PD. This review based on current literature aims to elucidate various genetic and clinical characteristics correlated with GBA mutations and to identify the numerous pathological processes underlying GBA + PD. We also delineate the therapeutic strategies to interfere with the mutant GCase function for further improvement of the related α-synuclein-GCase crosstalks. Moreover, the various therapeutic approaches such as gene therapy, chaperone proteins, and histone deacetylase inhibitors for the treatment of GBA + PD are discussed.