tbuckley/cabot-search huggingface dataset:
Tyrosine phosphatase SHP2 inhibitors in tumor-targeted therapies
Authors: Zhendong Song, Meijing Wang, Yang Ge, Xue-Ping Chen, Ziyang Xu, Yang Sun, Xiao-Feng Xiong
Journal: Acta Pharmaceutica Sinica B (2020)

Src homology containing protein tyrosine phosphatase 2 (SHP2) represents a noteworthy target for various diseases, serving as a well-known oncogenic phosphatase in cancers. As a result of the low cell permeability and poor bioavailability, the traditional inhibitors targeting the protein tyrosine phosphate catalytic sites are generally suffered from unsatisfactory applied efficacy. Recently, a particularly large number of allosteric inhibitors with striking inhibitory potency on SHP2 have been identified. In particular, few clinical trials conducted have made significant progress on solid tumors by using SHP2 allosteric inhibitors. This review summarizes the development and structure–activity relationship studies of the small-molecule SHP2 inhibitors for tumor therapies, with the purpose of assisting the future development of SHP2 inhibitors with improved selectivity, higher oral bioavailability and better physicochemical properties.
Frontline<i>BRAF</i>Testing–Guided Treatment for Advanced Melanoma in the Era of Immunotherapies
Authors: Bin Wu, Lizheng Shi
Journal: JAMA Dermatology (2020)

The effectiveness of immune checkpoint inhibitors (ICIs) and BRAF and MEK inhibitors has improved advanced melanoma recovery. However, it is unknown whether these novel therapies are cost-effective for newly diagnosed advanced melanoma with unknown BRAF status.
A single early-in-life antibiotic course increases susceptibility to DSS-induced colitis
Authors: Ceren Ozkul, Victoria E. Ruiz, Thomas Battaglia, Joseph Xu, Claire Roubaud-Baudron, Ken Cadwell, Guillermo I. Perez-Perez, Martin J. Blaser
Journal: Genome Medicine (2020)

There is increasing evidence that the intestinal microbiota plays a crucial role in the maturation of the immune system and the prevention of diseases during childhood. Early-life short-course antibiotic use may affect the progression of subsequent disease conditions by changing both host microbiota and immunologic development. Epidemiologic studies provide evidence that early-life antibiotic exposures predispose to inflammatory bowel disease (IBD).By using a murine model of dextran sodium sulfate (DSS)-induced colitis, we evaluated the effect on disease outcomes of early-life pulsed antibiotic treatment (PAT) using tylosin, a macrolide and amoxicillin, a beta-lactam. We evaluated microbiota effects at the 16S rRNA gene level, and intestinal T cells by flow cytometry. Antibiotic-perturbed or control microbiota were transferred to pups that then were challenged with DSS.A single PAT course early-in-life exacerbated later DSS-induced colitis by both perturbing the microbial community and altering mucosal immune cell composition. By conventionalizing germ-free mice with either antibiotic-perturbed or control microbiota obtained 40 days after the challenge ended, we showed the transferrable and direct effect of the still-perturbed microbiota on colitis severity in the DSS model.The findings in this experimental model provide evidence that early-life microbiota perturbation may increase risk of colitis later in life.
Opto‐E‐Dura: A Soft, Stretchable ECoG Array for Multimodal, Multiscale Neuroscience
Authors: Aline F. Renz, Jihyun Lee, Klas Tybrandt, Maciej Brzezinski, Dayra A. Lorenzo, Mouna Cerra Cheraka, Jaehong Lee, Fritjof Helmchen, Janos Vörös, Christopher M. Lewis
Journal: Advanced Healthcare Materials (2020)

Soft, stretchable materials hold great promise for the fabrication of biomedical devices due to their capacity to integrate gracefully with and conform to biological tissues. Conformal devices are of particular interest in the development of brain interfaces where rigid structures can lead to tissue damage and loss of signal quality over the lifetime of the implant. Interfaces to study brain function and dysfunction increasingly require multimodal access in order to facilitate measurement of diverse physiological signals that span the disparate temporal and spatial scales of brain dynamics. Here the Opto-e-Dura, a soft, stretchable, 16-channel electrocorticography array that is optically transparent is presented. Its compatibility with diverse optical and electrical readouts is demonstrated enabling multimodal studies that bridge spatial and temporal scales. The device is chronically stable for weeks, compatible with wide-field and 2-photon calcium imaging and permits the repeated insertion of penetrating multielectrode arrays. As the variety of sensors and effectors realizable on soft, stretchable substrates expands, similar devices that provide large-scale, multimodal access to the brain will continue to improve fundamental understanding of brain function.
Abstract 345: Forecasting the Number of Out-Of-Hospital Cardiac Arrest in the Young Using Generalized Additive Model
Authors: Alyssa Vermeulen, Marina Del Rios, Teri L Campbell, Hai Nguyen, Hoang H Nguyen
Journal: Circulation (2019)

Introduction: Accurate forecasting could help in resource planning and evaluation of intervention efforts to reduce out-of-hospital cardiac arrest. Hypothesis: Generalized additive model can rapidly and accurately forecast the number of OHCA in the young (1-35 years old) when compared to other auto regressive moving average (ARIMA) based models. Methods: Data were obtained from CARES in Chicago from May 2013 to December 2017. Monthly forecasts of the number of OHCA were performed using a generative additive model framework using the open source software Prophet and R. The first 50 months served as training and the last 6 months served as testing. Results: Figure 1 shows the distribution of the number of cases over the 3-year study period showing yearly seasonality and upward trend. Figure 2 shows the forecast of the number of arrest (middle line) along with the actual number of arrest (dots). The shaded band represents the 95% confidence interval of the prediction. Figure 3 show the comparison of the 6-month forecast and actual data. This model has low root mean square error score when compared with other ARIMA based models (2 vs. 4). Conclusion: Accurate time series forecasting of the number of OHCA arrests could be achieved. Time series analysis and forecasting are essential tools in evaluating the effectiveness of intervention efforts to reduce OHCA as they allow for causality hypothesis testing.
Insufficient evidence for benefits/harms of cognitive impairment screening in asymptomatic older adults
Authors: KoKo Aung, Thwe Htay
Journal: Annals of Internal Medicine (2020)

Source Citation US Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for cognitive impairment in older adults: US Preventive Services Task Force recommendation statement. JAMA. 2020;323:757-63. 32096858
Abstract 15676: The Prevalence and Prognostic Impact of Right Ventricular Abnormalities on Cardiovascular Magnetic Resonance Imaging in Patients With Sarcoidosis
Authors: Pratik Velangi, Ko-hsuan A Chen, Felipe Kazmirczak, Osama Okasha, Lisa Von Wald, Henri Roukoz, Jeremy Markowitz, Prabhjot S Nijjar, Maneesh Bhargava, David Perlman, Mehmet Akcakaya, Chetan Shenoy
Journal: Circulation (2019)

Introduction: In patients with sarcoidosis, right ventricular (RV) abnormalities have been described on many imaging modalities. RV abnormalities that have been described on cardiovascular magnetic...
Cell-Type Specificity of Genomic Imprinting in Cerebral Cortex
Authors: Susanne Laukoter, Florian M. Pauler, Robert Beattie, Nicole Amberg, Andi H. Hansen, Carmen Streicher, Thomas Penz, Christoph Bock, Simon Hippenmeyer
Journal: Neuron (2020)

In mammalian genomes, a subset of genes is regulated by genomic imprinting, resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development, but prevalence and functional impact in individual cells is unclear. Here, we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental chromosome disomy (UPD) containing two copies of either the maternal or the paternal chromosome; hence, imprinted genes will be 2-fold overexpressed or not expressed. By genetic labeling of UPD, we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single-cell resolution. We discovered an unexpected degree of cell-type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally, our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell-type diversity.
FRI0143 Comparison of organ damage in systemic lupus erythematosus patients with and without antiphospholipid syndrome
Authors: M Inanç, S Öncü, A Gül, S Kamali, A Çefle, M Sayarlioglu, L Öcal, O Aral, M Koniçe
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Organ damage in systemic lupus erythematosus (SLE) may result from SLE itself or other comorbid conditions. Several items (subitems) of the SLICC/ACR damage index were previously reported as clinical manifestations associated with antiphospholipid syndrome (APS) or antiphospholipid antibodies. The contribution of APS to organ damage in SLE remains to be determined. <h3>Objectives</h3> To determine and compare end organ damage in patients with SLE with and without APS. <h3>Methods</h3> A preliminary analysis was performed by using the data of an ongoing study on organ damage in patients with SLE. Permanent organ damage was determined by using SLICC/ACR damage index in 106 consecutively assessed patients that were stratified according to the presence of APS. All patients fulfilled the ACR criteria for the classification of SLE. Student’s t, Fisher’s exact and Mann Whitney U tests were used for comparisons. <h3>Results</h3> Twenty-one patients (19.8%) were classified as secondary APS (sAPS) according to the published criteria. The mean age was 35 ± 11.5 vs. 36.6 ± 11.7 years, the mean disease duration was 98 ± 66 vs. 102 ± 76 months and the mean duration of follow-up was 82 ± 72 vs. 70 ± 64 months in the sAPS and non-sAPS groups respectively (p &gt; 0.05). The mean number of ACR criteria fulfilled by the patients was similar (6 ± 1.4 vs. 6 ± 1.2) in both groups. Disease activity parameters (SLEDAI, patient and doctor visual analogue scales) were not significantly different between the groups at the time of the assessment. Total and weighted organ damage scores were significantly higher in the sAPS group (1.81 ± 1.21 vs. 0.94 ± 1.21, p = 0.004; 6.10 ± 4.46 vs. 2.76 ± 3.96, p = 0.001). The comparison of the individual items showed increased scores from ocular, neuropsychiatric and peripheral vascular damage. <h3>Conclusion</h3> In this study we found that SLE patients with sAPS have higher organ damage scores than SLE patients without sAPS. Ocular, neuropsychiatric and peripheral vascular damage were found to be increased in patients with sAPS compared to the non-sAPS group. The presence of APS may significantly contribute to the organ damage in patients with SLE and specific measures are needed to avoid them.
Low-Dose Hsp90 Inhibitor Selectively Radiosensitizes HNSCC and Pancreatic Xenografts
Authors: Ranjit K. Mehta, Sanjima Pal, Koushik Kondapi, Merna Sitto, Cuyler Dewar, Theresa Devasia, Matthew J. Schipper, Dafydd G. Thomas, Venkatesha Basrur, Manjunath P. Pai, Yoshihiro Morishima, Yoichi Osawa, William B. Pratt, Theodore S. Lawrence, Mukesh K. Nyati
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Treatment approaches using Hsp90 inhibitors at their maximum tolerated doses (MTDs) have not produced selective tumor toxicity. Inhibition of Hsp90 activity causes degradation of client proteins including those involved in recognizing and repairing DNA lesions. We hypothesized that if DNA repair proteins were degraded by concentrations of an Hsp90 inhibitor below those required to cause nonspecific cytotoxicity, significant tumor-selective radiosensitization might be achieved. Experimental Design: Tandem mass tagged-mass spectrometry was performed to determine the effect of a subcytotoxic concentration of the Hsp90 inhibitor, AT13387 (onalespib), on global protein abundance. The effect of AT13387 on in vitro radiosensitization was assessed using a clonogenic assay. Pharmacokinetics profiling was performed in mice bearing xenografts. Finally, the effect of low-dose AT13387 on the radiosensitization of three tumor models was assessed. Results: A subcytotoxic concentration of AT13387 reduced levels of DNA repair proteins, without affecting the majority of Hsp90 clients. The pharmacokinetics study using one-third of the MTD showed 40-fold higher levels of AT13387 in tumors compared with plasma. This low dose enhanced Hsp70 expression in peripheral blood mononuclear cells (PBMCs), which is a biomarker of Hsp90 inhibition. Low dose monotherapy was ineffective, but when combined with radiotherapy, produced significant tumor growth inhibition. Conclusions: This study shows that a significant therapeutic ratio can be achieved by a low dose of Hsp90 inhibitor in combination with radiotherapy. Hsp90 inhibition, even at a low dose, can be monitored by measuring Hsp70 expression in PBMCs in human studies.
Targeting phosphatidylserine for Cancer therapy: prospects and challenges
Authors: Wenguang Chang, Hongge Fa, Dandan Xiao, Jianxun Wang
Journal: Theranostics (2020)

Cancer is a leading cause of mortality and morbidity worldwide. Despite major improvements in current therapeutic methods, ideal therapeutic strategies for improved tumor elimination are still lacking. Recently, immunotherapy has attracted much attention, and many immune-active agents have been approved for clinical use alone or in combination with other cancer drugs. However, some patients have a poor response to these agents. New agents and strategies are needed to overcome such deficiencies. Phosphatidylserine (PS) is an essential component of bilayer cell membranes and is normally present in the inner leaflet. In the physiological state, PS exposure on the external leaflet not only acts as an engulfment signal for phagocytosis in apoptotic cells but also participates in blood coagulation, myoblast fusion and immune regulation in nonapoptotic cells. In the tumor microenvironment, PS exposure is significantly increased on the surface of tumor cells or tumor cell-derived microvesicles, which have innate immunosuppressive properties and facilitate tumor growth and metastasis. To date, agents targeting PS have been developed, some of which are under investigation in clinical trials as combination drugs for various cancers. However, controversial results are emerging in laboratory research as well as in clinical trials, and the efficiency of PS-targeting agents remains uncertain. In this review, we summarize recent progress in our understanding of the physiological and pathological roles of PS, with a focus on immune suppressive features. In addition, we discuss current drug developments that are based on PS-targeting strategies in both experimental and clinical studies. We hope to provide a future research direction for the development of new agents for cancer therapy.
Blocking of BAFF signaling pathway by BCMA-Fc attenuates autoimmune manifestations in BAFF transgenic mice and reveals its important role in maintaining peripheral B cell homeostasis.
Authors: SA Woodcock, ZY Liu, TG Cachero, X Fang, G Thill, C Ambrose, JS Thompson, N Spinello, F Mackay, JL Browning, SL Kalled, LC Wang
Journal: Blood (2000)
Institutional Review Board Quality, Private Equity, and Promoting Ethical Human Subjects Research
Authors: Holly Fernandez Lynch, Stephen Rosenfeld
Journal: Annals of Internal Medicine (2020)

Evaluating the quality and effectiveness of the institutional review boards (IRBs) responsible for overseeing research involving human participants is critically important but perpetually challenging. Seemingly common-sense measures, such as the number of proposals approved with and without major modifications and the number of unexpected adverse events occurring in approved protocols, can be misleading indicators of participant protection, and regulatory compliance may not correspond to achieving ethical goals. These measurement challenges make it difficult to assess the validity of concerns about different IRB models. A group of U.S. senators recently raised questions about the increasing use of for-profit IRBs to review research proposals (as opposed to boards typically housed at academic medical centers and health care institutions) and, more specifically, about the growing trend of private equity ownership and consolidation of for-profit IRBs. Although all IRBs face pressure to speed reviews and none are entirely free of conflicts of interest, the private equity model is particularly susceptible to approaches that could undercut the ethical mission of IRBs to protect and promote the rights and welfare of research participants. Ideally, the quality of board oversight could be measured directly, rather than relying on the heuristic of board type; this article describes several current efforts toward this goal. In the meantime, one improvement may be to pursue a new model of IRB oversight: independent nonprofit boards that stand apart from research institutions, take advantage of business approaches to research review, and minimize conflicts of interest.
Genome-scale in vivo CRISPR screen identifies RNLS as a target for beta cell protection in type 1 diabetes
Authors: Erica P. Cai, Yuki Ishikawa, Wei Zhang, Nayara C. Leite, Jian Li, Shurong Hou, Badr Kiaf, Jennifer Hollister-Lock, Nese Kurt Yilmaz, Celia A. Schiffer, Douglas A. Melton, Stephan Kissler, Peng Yi
Journal: Nature Metabolism (2020)
Effect of casein kinase 2 (CK2) inhibitors on antitumor activity of cisplatin in an isogenic pair of sensitive and resistant ovarian tumor cell lines
Authors: Tetsuji Kurokawa, Zahid Siddik
Journal: Cancer Research (2007)

3268  Wild-type p53 is found in about 40% of ovarian cancers that are clinically refractory to platinum-based therapy, and this is counter-intuitive based on the central apoptotic role of this tumor suppressor. We have reported that in such cancers, wild-type p53 induced by cisplatin is unable to transactivate p21, which may be the molecular mechanism responsible for the resistance phenotype. Literature reports suggest that expression of the protein kinase CK2 may downregulate p21 expression, and, therefore, the possibility was explored that inhibitors of CK2 may restore cisplatin sensitivity by facilitating p21 induction. In our studies, we used sensitive A2780 ovarian tumor cells and its isogenic cisplatin-resistant 2780CP model that demonstrated an IC50 by MTT for cisplatin of ~0.2 µM and ~10 µM, respectively. In contrast, 2780CP cells demonstrated a reduced level of cross-resistance to the CK2 inhibitors DRB (5,6-dichloro-1-β-D-ribofuranosylbenzimidazole; IC50: A2780, 3.7 µM vs. 2780CP, 9.6 µM) and emodin (2.2 vs. 3.6 µM). When A2780 cells were pre-treated with DRB at an IC10 level (1 µM), and then exposed to cisplatin 24 h later for MTT analysis following a 5-day continuous exposure, the IC50 of cisplatin surprisingly was increased at least 2-fold. A similar upward shift in IC50 of cisplatin by DRB (5 µM) or emodin (3 µM) was also observed in 2780CP cells, and this demonstrated that the increased resistance was unrelated to initial cisplatin sensitivity or cell context. In studies to examine scheduling effects, simultaneous exposure of 2780CP cells to cisplatin and emodin also increased the IC50 of cisplatin when compared to cisplatin alone (17 vs 10 μM), but if these cells were pre-exposed to an IC10 level of emodin for 24 hr and washed before exposure to cisplatin, or if exposure to emodin was delayed 24 hr after adding cisplatin to cell cultures, then the IC50 of cisplatin remained unchanged (8.7 vs 9.3 μM; 7.8 vs 8.8 μM). Thus, our results demonstrate that, contrary to expectations, CK2 inhibitors DRB and emodin increase resistance to cisplatin, and, therefore, caution needs to be exercised when combining these inhibitors with this platinum drug. The possibility raised from scheduling studies that this increased resistance is due to interference by the inhibitors of cellular cisplatin uptake is being examined. Thus, it is possible that more specific and potent inhibitors of CK2 may be required to examine the concept of a viable combination with cisplatin to overcome resistance.
Abstract 13558: The Efficacy and Safety of Pulmonary Vasodilators in Patients With Fontan Circulation: A Meta-Analysis of Randomized-Controlled Trials
Authors: Wuwan Wang, Wei Huang, Weiting Liao, Kang Hu, WH Rutahoile, Xiaofang Zeng, Yunjing Yang
Journal: Circulation (2017)

Introduction: There has been no previous meta-analysis evaluating the efficacy and safety of pulmonary vasodilators in Fontan physiology. Recent studies investigating the efficacy of pulmonary vaso...
Face coverings and mask to minimise droplet dispersion and aerosolisation: a video case study
Authors: Prateek Bahl, Shovon Bhattacharjee, Charitha de Silva, Abrar Ahmad Chughtai, Con Doolan, C Raina MacIntyre
Journal: Thorax (2020)

To evaluate the effectiveness of the Centers for Disease Control and Prevention (CDC) recommended one- and two-layer cloth face covering against a three-ply surgical mask, we challenged the cloth covering against speaking, coughing and sneezing. The one-layer covering was made using ‘quick cut T-shirt face covering (no-sew method)’ and the two-layer covering was prepared using the sew method prescribed by CDC.1 To provide visual evidence of the efficacy of face coverings we used a tailored LED lighting system (GS Vitec MultiLED PT) along with a high-speed camera (nac MEMRECAM HX-7s) to capture the light scattered by droplets and aerosols expelled during speaking, coughing and sneezing while wearing different types of masks (figure 1 and online supplementary video). The video for speaking was captured at …
Nuclear imaging approaches facilitating nanomedicine translation
Authors: Carlos Pérez-Medina, Abraham J.P. Teunissen, Ewelina Kluza, Willem J.M. Mulder, Roy van der Meel
Journal: Advanced Drug Delivery Reviews (2020)

Nanomedicine approaches can effectively modulate the biodistribution and bioavailability of therapeutic agents, improving their therapeutic index. However, despite the ever-increasing amount of literature reporting on preclinical nanomedicine, the number of nanotherapeutics receiving FDA approval remains relatively low. Several barriers exist that hamper the effective preclinical evaluation and clinical translation of nanotherapeutics. Key barriers include insufficient understanding of nanomedicines' in vivo behavior, inadequate translation from murine models to larger animals, and a lack of patient stratification strategies. Integrating quantitative non-invasive imaging techniques in nanomedicine development offers attractive possibilities to address these issues. Among the available imaging techniques, nuclear imaging by positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are highly attractive in this context owing to their quantitative nature and uncontested sensitivity. In basic and translational research, nuclear imaging techniques can provide critical quantitative information about pharmacokinetic parameters, biodistribution profiles or target site accumulation of nanocarriers and their associated payload. During clinical evaluation, nuclear imaging can be used to select patients amenable to nanomedicine treatment. Here, we review how nuclear imaging-based approaches are increasingly being integrated into nanomedicine development and discuss future developments that will accelerate their clinical translation.