tbuckley/cabot-search huggingface dataset:
A dual drug therapy for sunitinib resistant RCC: An in vitro analysis.
Authors: Jacob W. Greenberg, Hogyoung Kim, Ahmed A Moustafa, Pedro C. Barata, Asim Abdel-Mageed, L. Spencer Krane
Journal: Journal of Clinical Oncology (2021)

340 Background: Over the last decade, medical treatment for metastatic renal cell carcinoma has made significant advances through the development of tyrosine kinase inhibitors (TKI) like sunitinib. However, of patients initiated on TKI therapy, 70% respond well while 30% are believed to be primarily resistant to treatment. Additionally, 30% of patients who initially respond to treatment gain secondary drug resistance and present with increased tumor burden. In this study, we seek to develop a combination therapy of Tipifarnib + Sunitinib to target exosome conferred drug resistance. Methods: 786-O, 786-0 Sunitinib Resistant (SR), and 293-T cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 2mM L-glutamine, and 1% penicillin/streptomycin (P/S). Exosomes were collected from conditioned media treated with Tipifarnib and isolated using differential ultracentrifugation. Exosomes were analyzed using the qNano IZON system. Colony forming units assay and Immunoblot analysis were used to further characterize or samples. Results: Exosomes collected from 786-O, 786-0 SR, and 293-T cells treated with 0.5 uM of Tipifarnib were compared using our qNANO IZON system. Exosome concentrations of all cell lines showed a decrease after Tipifarnib treatment. However, our 293-T cells showed a 16% decrease in exosome concentration while our 786-O and 786-0 SR lines displayed a 66% and 75% decrease respectively. To assess the pathway Tipifarnib used to decrease exosome concentrations, immunoblot assay was used after treating cells with 0, 0.1, 0.25, 0.5, 1 uM of tipifarnib. 293-T cells showed a dose dependent increase in ESCRT-dependent marker Alix and no change in either ESCRT-independent marker nSMase or trafficking marker Rab27a. Conversely, our 786-O and 786-0 SR cell lines showed a decrease in all 3 markers: Alix, nSMase, and Rab27a. Furthermore, a colony forming units assay was used to assess the drug combination of tipifarnib + sunitinib ability to alter cell growth. After 48hr, 293-T cell showed no decrease in colony forming units when compared to DMSO control. Our drug combination showed a synergistic ability to decrease colony forming units in the RCC 786-O cell line. 786-O SR cells were resistant to sunitinib treatment, showing comparable CFUs to DMSO control. When treated with the combination of sunitinib and tipifarnib, CTUs of 786-0 SR cells dropped significantly when compared to unaccompanied sunitinib and tipifarnib treatments. Conclusions: Tipifarnib has the ability to attenuate both the exosome ESCRT–dependent and –independent pathways. Our study also showed that when used injunction with sunitinib, tipifarnib is effective at decreasing cell proliferation. This drug combination is also pre-clinically useful in sunitinib resistance cancer cells. We believe this drug combination to be efficacious at decreasing tumor burden through blocking exosome biogenesis and secretion.
The genetic background significantly impacts the severity of kidney cystic disease in the Pkd1RC/RC mouse model of autosomal dominant polycystic kidney disease
Authors: Jennifer Arroyo, Diana Escobar-Zarate, Harrison H. Wells, Megan M. Constans, Ka Thao, Jessica M. Smith, Cynthia J. Sieben, Madeline R. Martell, Timothy L. Kline, Maria V. Irazabal, Vicente E. Torres, Katharina Hopp, Peter C. Harris
Journal: Kidney International (2021)
Screening for HIV Among Patients at Tuberculosis Clinics — Results from Population-Based HIV Impact Assessment Surveys, Malawi, Zambia, and Zimbabwe, 2015–2016
Authors: Nikhil Kothegal, Alice Wang, Sasi Jonnalagadda, Adam MacNeil, Elizabeth Radin, Kristin Brown, Owen Mugurungi, Regis Choto, Shirish Balachandra, John H. Rogers, Godfrey Musuka, Thokozani Kalua, Michael Odo, Andrew Auld, Laurence Gunde, Evelyn Kim, Danielle Payne, Patrick Lungu, Lloyd Mulenga, Ahmed Saadani Hassani, Tepa Nkumbula, Hetal Patel, Bharat Parekh, Andrew C. Voetsch
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

The World Health Organization and national guidelines recommend HIV testing and counseling at tuberculosis (TB) clinics for all patients, regardless of TB diagnosis (1). Population-based HIV Impact Assessment (PHIA) survey data for 2015-2016 in Malawi, Zambia, and Zimbabwe were analyzed to assess HIV screening at TB clinics among persons who had positive HIV test results in the survey. The analysis was stratified by history of TB diagnosis* (presumptive versus confirmed†), awareness§ of HIV-positive status, antiretroviral therapy (ART)¶ status, and viral load suppression among HIV-positive adults, by history of TB clinic visit. The percentage of adults who reported having ever visited a TB clinic ranged from 4.7% to 9.7%. Among all TB clinic attendees, the percentage who reported that they had received HIV testing during a TB clinic visit ranged from 48.0% to 62.1% across the three countries. Among adults who received a positive HIV test result during PHIA and who did not receive a test for HIV at a previous TB clinic visit, 29.4% (Malawi), 21.9% (Zambia), and 16.2% (Zimbabwe) reported that they did not know their HIV status at the time of the TB clinic visit. These findings represent missed opportunities for HIV screening and linkage to HIV care. In all three countries, viral load suppression rates were significantly higher among those who reported ever visiting a TB clinic than among those who had not (p<0.001). National programs could strengthen HIV screening at TB clinics and leverage them as entry points into the HIV diagnosis and treatment cascade (i.e., testing, initiation of treatment, and viral load suppression).
Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial
Authors: Sara Costi, Laurel S. Morris, Katherine A. Kirkwood, Megan Hoch, Morgan Corniquel, Brittany Vo-Le, Tabish Iqbal, Nisha Chadha, Diego A. Pizzagalli, Alexis Whitton, Laura Bevilacqua, Manish K. Jha, Stefan Ursu, Alan C. Swann, Katherine A. Collins, Ramiro Salas, Emilia Bagiella, Michael K. Parides, Emily R. Stern, Dan V. Iosifescu, Ming-Hu Han, Sanjay J. Mathew, James W. Murrough
Journal: American Journal of Psychiatry (2021)

Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression.Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively.The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred.The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.
Development of digital measures for nighttime scratch and sleep using wrist-worn wearable devices
Authors: Nikhil Mahadevan, Yiorgos Christakis, Junrui Di, Jonathan Bruno, Yao Zhang, E. Ray Dorsey, Wilfred R. Pigeon, Lisa A. Beck, Kevin Thomas, Yaqi Liu, Madisen Wicker, Chris Brooks, Nina Shaafi Kabiri, Jaspreet Bhangu, Carrie Northcott, Shyamal Patel
Journal: npj Digital Medicine (2021)

Abstract Patients with atopic dermatitis experience increased nocturnal pruritus which leads to scratching and sleep disturbances that significantly contribute to poor quality of life. Objective measurements of nighttime scratching and sleep quantity can help assess the efficacy of an intervention. Wearable sensors can provide novel, objective measures of nighttime scratching and sleep; however, many current approaches were not designed for passive, unsupervised monitoring during daily life. In this work, we present the development and analytical validation of a method that sequentially processes epochs of sample-level accelerometer data from a wrist-worn device to provide continuous digital measures of nighttime scratching and sleep quantity. This approach uses heuristic and machine learning algorithms in a hierarchical paradigm by first determining when the patient intends to sleep, then detecting sleep–wake states along with scratching episodes, and lastly deriving objective measures of both sleep and scratch. Leveraging reference data collected in a sleep laboratory (NCT ID: NCT03490877), results show that sensor-derived measures of total sleep opportunity (TSO; time when patient intends to sleep) and total sleep time (TST) correlate well with reference polysomnography data (TSO: r = 0.72, p &lt; 0.001; TST: r = 0.76, p &lt; 0.001; N = 32). Log transformed sensor derived measures of total scratching duration achieve strong agreement with reference annotated video recordings ( r = 0.82, p &lt; 0.001; N = 25). These results support the use of wearable sensors for objective, continuous measurement of nighttime scratching and sleep during daily life.
Abstract 16016: Identification of Optimal Timing for Pulmonary Valve Replacement in Asymptomatic Repaired Tetralogy of Fallot Using Feature Tracking
Authors: Akio Inage, Kanako Kishiki, Ryusuke Suzuki, Naokazu Mizuno
Journal: Circulation (2019)

Introduction: Pulmonary regurgitation is common complication of repaired tetralogy of Fallot (TOF). Subsequently, right ventricular (RV) dilationinfluences long-term ventricular mechanism in repair...
Reduction in asthma admissions during the COVID-19 pandemic: consequence of public health measures in Singapore
Authors: Liang En Wee, Edwin Philip Conceicao, Jing Yuan Tan, Jean Xiang Ying Sim, Indumathi Venkatachalam
Journal: European Respiratory Journal (2021)

<b>A sustained reduction in asthma admissions with PCR-proven respiratory viral infections coincided with the widespread adoption of public health measures, including social distancing and wearing of face coverings, during a pandemic</b>https://bit.ly/2Kug9iw
Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory <i>Parabacteroides goldsteinii</i> lipopolysaccharide
Authors: Hsin-Chih Lai, Tzu-Lung Lin, Ting-Wen Chen, Yu-Lun Kuo, Chih-Jung Chang, Tsung-Ru Wu, Ching-Chung Shu, Ying-Huang Tsai, Simon Swift, Chia-Chen Lu
Journal: Gut (2021)

Chronic obstructive pulmonary disease (COPD) is a global disease characterised by chronic obstruction of lung airflow interfering with normal breathing. Although the microbiota of respiratory tract is established to be associated with COPD, the causality of gut microbiota in COPD development is not yet established. We aimed to address the connection between gut microbiota composition and lung COPD development, and characterise bacteria and their derived active components for COPD amelioration.A murine cigarette smoking (CS)-based model of COPD and strategies evaluating causal effects of microbiota were performed. Gut microbiota structure was analysed, followed by isolation of target bacterium. Single cell RNA sequencing, together with sera metabolomics analyses were performed to identify host responsive molecules. Bacteria derived active component was isolated, followed by functional assays.Gut microbiota composition significantly affects CS-induced COPD development, and faecal microbiota transplantation restores COPD pathogenesis. A commensal bacterium Parabacteroides goldsteinii was isolated and shown to ameliorate COPD. Reduction of intestinal inflammation and enhancement of cellular mitochondrial and ribosomal activities in colon, systematic restoration of aberrant host amino acids metabolism in sera, and inhibition of lung inflammations act as the important COPD ameliorative mechanisms. Besides, the lipopolysaccharide derived from P. goldsteinii is anti-inflammatory, and significantly ameliorates COPD by acting as an antagonist of toll-like receptor 4 signalling pathway.The gut microbiota-lung COPD axis was connected. A potentially benefial bacterial strain and its functional component may be developed and used as alternative agents for COPD prevention or treatment.
Salvage, reloading, and deployment of a metal biliary stent using an improvised delivery catheter
Authors: Zain A. Sobani, Tarun Rustagi
Journal: Endoscopy (2021)

A 55-year-old man with known pancreatic adenocarcinoma presented for an outpatient biliary stent change. Two previously placed plastic stents were removed. Endoscopic retrograde cholangiography showed a moderate-grade 2.5-cm biliary stricture with upstream biliary dilation.
Assessment of Use and Fit of Face Masks Among Individuals in Public During the COVID-19 Pandemic in China
Authors: Xiangbin Pan, Xi Li, Pengxu Kong, Lin Wang, Rundi Deng, Bin Wen, Luoxi Xiao, Honglin Song, Yi Sun, Hongmei Zhou, Jiang Lu, Yang Wang, Qiuzhe Guo, Lin Duo, Chengye Sun
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Face masks are recommended to prevent transmission of coronavirus disease 2019 (COVID-19); however, there is scarce evidence on their protection efficacy and ways to improve it. <h3>Objective</h3> To determine the proportion of improper face mask use, the factors associated with face mask protection efficacy, and ways to improve efficacy. <h3>Design, Setting, and Participants</h3> This population-based cross-sectional study was conducted in China from July to August 2020 in 5 kinds of public places. Participants included convenience samples of individuals wearing face masks and able to taste the check solution. <h3>Exposures</h3> Demographic and socioeconomic characteristics, including sex, age, and education level; information on face mask model and the worn duration was recorded. <h3>Main Outcomes and Measures</h3> The main outcome as airtightness, assessed by detecting face-to-face mask gaps, movement of cotton fiber placed at the face mask edges, and using a qualitative fit test with a bitter solution spray. Masks were further assessed for whether sealing the upper face mask edge with an adhesive tape strip was associated with improved face mask airtightness. <h3>Results</h3> Among 6003 face mask wearers enrolled, the mean (SD) age of participants was 31.1 (13.7) years, and 3047 participants (50.8%) were female. The first qualitative fit test found air leakage in 2754 participants (45.9%; 95% CI, 44.6%-47.1%), which was mostly attributable to gaps at the upper face mask edge. After sealing the upper face mask edge with an adhesive tape strip, 69.7% (95% CI, 68.0%-71.5%) of masks that had exhibited leakage became airtight in the second qualitative fit test, and the rate of airtightness reached 96.2% (95% CI, 95.4%-96.8%) in a third qualitative fit test after new surgical face masks with tape on the upper edge were provided to those who had not converted initially. The tape was well tolerated; overall, 6 participants (1.2%) reported a rash and 24 participants (5.8%) reported significant discomfort. <h3>Conclusions and Relevance</h3> In this study of face mask fit among participants in China, although most people used face masks in public places, compromised protection due to suboptimal airtightness was common. The simple approach of sealing the upper edge of the face mask with an adhesive tape strip was associated with substantially improved its airtightness.
Npac Is a Co-Factor of Histone H3K36me3 and Regulates Transcriptional Elongation in Mouse Embryonic Stem Cells
Authors: Sue Yu, Jia Li, Guanxu Ji, Zhen Long Ng, Jiamin Siew, Wan Ning Lo, Ying Ye, Yuan Yuan Chew, Yun Chau Long, Wensheng Zhang, Ernesto Guccione, Yuin Han Loh, Zhi-Hong Jiang, Henry Yang, Qiang Wu
Journal: Genomics Proteomics & Bioinformatics (2021)

Chromatin modification contributes to pluripotency maintenance in embryonic stem cells (ESCs). However, the related mechanisms remain obscure. Here, we show that Npac, a "reader" of histone H3 lysine 36 trimethylation (H3K36me3), is required to maintain mouse ESC (mESC) pluripotency since knockdown of Npac causes mESC differentiation. Depletion of Npac in mouse embryonic fibroblasts (MEFs) inhibits reprogramming efficiency. Furthermore, our chromatin immunoprecipitation followed by sequencing (ChIP-seq) results of Npac reveal that Npac co-localizes with histone H3K36me3 in gene bodies of actively transcribed genes in mESCs. Interestingly, we find that Npac interacts with positive transcription elongation factor b (p-TEFb), Ser2-phosphorylated RNA Pol II (RNA Pol II Ser2P), and Ser5-phosphorylated RNA Pol II (RNA Pol II Ser5P). Furthermore, depletion of Npac disrupts transcriptional elongation of the pluripotency genes Nanog and Rif1. Taken together, we propose that Npac is essential for the transcriptional elongation of pluripotency genes by recruiting p-TEFb and interacting with RNA Pol II Ser2P and Ser5P.
Abstract PO-059: Recurrence predictive models for patients with hepatocellular carcinoma after radiofrequency ablation based on machine learning algorithms
Authors: Ja-Der Liang, Ta-Wei Yang, Po-When Chen, Cheng-Fu Chou, Yao-Ming Wu
Journal: Clinical Cancer Research (2021)

Abstract Background: Hepatocellular carcinoma (HCC) has been one of the leading causes of cancer death. Despite accurate diagnosis and effective treatments, the recurrence rate of HCC is still high. To build a recursive model by analyzing preoperative reports is helpful for follow-up and observing recurrence of tumor. Methods: Newly diagnosed HCC patients in National Taiwan University Hospital (NTUH) who received radiofrequency ablation (RFA) as the first treatment, were enrolled. Among 334 enrolled patients, 256 patients did not have recurrent HCC one year after RFA treatment and the other 78 patients had HCC recurrences. Data was processed with workflow of feature extraction and data imputation to acquire 16 features. We use different machine-learning methods to build the recurrence prediction model of HCC. The model performance among linear regression (LR), support vector machine (SVM), random forest (RF), and deep neural network (DNN) under a variety of experimental environment, including different parameters of models, data normalizations, and methods of data up-sampling were compared. Results: DNN model has the relatively best result that is the highest accuracy (82.65%) and second balanced accuracy (BAC=66.03%) among all models. SVM with feature selection according to importance in RF has the best BAC result (66.48%) with 10% lower accuracy (72.51%) compared with DNN. LR has the worst BAC (50.00%). Conclusion: Among all prediction models, DNN achieved the best results by considering both accuracy and balanced accuracy. Establishment of prediction model could identify the risk patients with close monitoring of tumor recurrence. Citation Format: Ja-Der Liang, Ta-Wei Yang, Po-When Chen, Cheng-Fu Chou, Yao-Ming Wu. Recurrence predictive models for patients with hepatocellular carcinoma after radiofrequency ablation based on machine learning algorithms [abstract]. In: Proceedings of the AACR Virtual Special Conference on Artificial Intelligence, Diagnosis, and Imaging; 2021 Jan 13-14. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(5_Suppl):Abstract nr PO-059.
Impact and cost-effectiveness of a lethal house lure against malaria transmission in central Côte d'Ivoire: a two-arm, cluster-randomised controlled trial
Authors: Eleanore D Sternberg, Jackie Cook, Ludovic P Ahoua Alou, Serge Brice Assi, Alphonsine A Koffi, Dimi T Doudou, Carine J Aoura, Rosine Z Wolie, Welbeck A Oumbouke, Eve Worrall, Immo Kleinschmidt, Raphael N'Guessan, Matthew B Thomas
Journal: The Lancet (2021)

BackgroundNew vector control tools are required to sustain the fight against malaria. Lethal house lures, which target mosquitoes as they attempt to enter houses to blood feed, are one approach. Here we evaluated lethal house lures consisting of In2Care (Wageningen, Netherlands) Eave Tubes, which provide point-source insecticide treatments against host-seeking mosquitoes, in combination with house screening, which aims to reduce mosquito entry.MethodsWe did a two-arm, cluster-randomised controlled trial with 40 village-level clusters in central Côte d'Ivoire between Sept 26, 2016, and April 10, 2019. All households received new insecticide-treated nets at universal coverage (one bednet per two people). Suitable households within the clusters assigned to the treatment group were offered screening plus Eave Tubes, with Eave Tubes treated using a 10% wettable powder formulation of the pyrethroid β-cyfluthrin. Because of the nature of the intervention, treatment could not be masked for households and field teams, but all analyses were blinded. The primary endpoint was clinical malaria incidence recorded by active case detection over 2 years in cohorts of children aged 6 months to 10 years. This trial is registered with ISRCTN, ISRCTN18145556.Findings3022 houses received screening plus Eave Tubes, with an average coverage of 70% across the intervention clusters. 1300 eligible children were recruited for active case detection in the control group and 1260 in the intervention group. During the 2-year follow-up period, malaria case incidence was 2·29 per child-year (95% CI 1·97–2·61) in the control group and 1·43 per child-year (1·21–1·65) in the intervention group (hazard ratio 0·62, 95% CI 0·51–0·76; p<0·0001). Cost-effectiveness simulations suggested that screening plus Eave Tubes has a 74·0% chance of representing a cost-effective intervention, compared with existing healthcare activities in Côte d'Ivoire, and is similarly cost-effective to other core vector control interventions across sub-Saharan Africa. No serious adverse events associated with the intervention were reported during follow-up.InterpretationScreening plus Eave Tubes can provide protection against malaria in addition to the effects of insecticide-treated nets, offering potential for a new, cost-effective strategy to supplement existing vector control tools. Additional trials are needed to confirm these initial results and further optimise Eave Tubes and the lethal house lure concept to facilitate adoption.FundingThe Bill & Melinda Gates Foundation.