tbuckley/cabot-search huggingface dataset:
Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy
Authors: Yuqin Yao, Zhuowei Liu, Manyu Zhao, Zhengxia Chen, Peng Li, Yang Zhang, Yuxi Wang, Chengjian Zhao, Chaofeng Long, Xiaoxin Chen, Jinliang Yang
Journal: Acta Pharmaceutica Sinica B (2020)

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.
Stemming the Escalating Costs of Prescription Drugs
Authors: Paul Katz
Journal: Annals of Internal Medicine (2020)

Letters21 April 2020Stemming the Escalating Costs of Prescription DrugsPaul KatzPaul KatzMilken Institute School of Public Health, George Washington University, Washington, DC (P.K.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/L20-0110 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:The recent American College of Physicians position paper on stemming the escalating costs of prescription drugs (1) does an admirable job of highlighting issues facing the U.S. prescription drug market and of offering policy recommendations specifically for pharmacy benefit managers (PBMs). However, these recommendations largely ignore systemic components of the market that could be used to disrupt the unsustainable path that many would agree is our current trajectory. This position paper offers valid points about the structure and role of PBMs and cites the need for transparency in efforts to lower prescription drug costs but falls short ...References1. Daniel H, Bornstein SS; Health and Public Policy Committee of the American College of Physicians. Policy recommendations for pharmacy benefit managers to stem the escalating costs of prescription drugs. A position paper from the American College of Physicians. Ann Intern Med. 2019;171:823-4. [PMID: 31711103] LinkGoogle Scholar2. Congressional Budget Office. Incorporating the effects of the proposed rule on safe harbors for pharmaceutical rebates in CBO's budget projections—supplemental material for updated budget projections: 2019 to 2029. May 2019. Accessed at www.cbo.gov/system/files/2019-05/55151-SupplementalMaterial.pdf on 11 December 2019. Google Scholar3. HHS suggests getting rid of safe harbors for part D drug rebates. Modern Healthcare. Updated 31 January 2019. Accessed at www.modernhealthcare.com/article/20190131/NEWS/190139972/hhs-suggests-getting-rid-of-safe-harbors-for-part-d-drug-rebates on 11 December 2019. Google Scholar Author, Article, and Disclosure InformationAffiliations: Milken Institute School of Public Health, George Washington University, Washington, DC (P.K.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=L20-0110. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoPolicy Recommendations for Pharmacy Benefit Managers to Stem the Escalating Costs of Prescription Drugs: A Position Paper From the American College of Physicians Hilary Daniel , Sue S. Bornstein , and Stemming the Escalating Costs of Prescription Drugs Sue S. Bornstein and Thomas G. Cooney Metrics 21 April 2020Volume 172, Issue 8Page: 573-574KeywordsConflicts of interestDisclosureDrug policyDrugsFallsFear ePublished: 21 April 2020 Issue Published: 21 April 2020 Copyright & PermissionsCopyright © 2020 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Protected Health Information filter (Philter): accurately and securely de-identifying free-text clinical notes
Authors: Beau Norgeot, Kathleen Muenzen, Thomas A. Peterson, Xuancheng Fan, Benjamin S. Glicksberg, Gundolf Schenk, Eugenia Rutenberg, Boris Oskotsky, Marina Sirota, Jinoos Yazdany, Gabriela Schmajuk, Dana Ludwig, Theodore Goldstein, Atul J. Butte
Journal: npj Digital Medicine (2020)

There is a great and growing need to ascertain what exactly is the state of a patient, in terms of disease progression, actual care practices, pathology, adverse events, and much more, beyond the paucity of data available in structured medical record data. Ascertaining these harder-to-reach data elements is now critical for the accurate phenotyping of complex traits, detection of adverse outcomes, efficacy of off-label drug use, and longitudinal patient surveillance. Clinical notes often contain the most detailed and relevant digital information about individual patients, the nuances of their diseases, the treatment strategies selected by physicians, and the resulting outcomes. However, notes remain largely unused for research because they contain Protected Health Information (PHI), which is synonymous with individually identifying data. Previous clinical note de-identification approaches have been rigid and still too inaccurate to see any substantial real-world use, primarily because they have been trained with too small medical text corpora. To build a new de-identification tool, we created the largest manually annotated clinical note corpus for PHI and develop a customizable open-source de-identification software called Philter ("Protected Health Information filter"). Here we describe the design and evaluation of Philter, and show how it offers substantial real-world improvements over prior methods.
Metabolic Factors, Lifestyle Habits, and Possible Polyneuropathy in Early Type 2 Diabetes: A Nationwide Study of 5,249 Patients in the Danish Centre for Strategic Research in Type 2 Diabetes (DD2) Cohort
Authors: Diana H. Christensen, Søren T. Knudsen, Sandra S. Gylfadottir, Lotte B. Christensen, Jens S. Nielsen, Henning Beck-Nielsen, Henrik T. Sørensen, Henning Andersen, Brian C. Callaghan, Eva L. Feldman, Nanna B. Finnerup, Troels S. Jensen, Reimar W. Thomsen
Journal: Diabetes Care (2020)

To investigate the association of metabolic and lifestyle factors with possible diabetic polyneuropathy (DPN) and neuropathic pain in patients with early type 2 diabetes.We thoroughly characterized 6,726 patients with recently diagnosed diabetes. After a median of 2.8 years, we sent a detailed questionnaire on neuropathy, including the Michigan Neuropathy Screening Instrument questionnaire (MNSIq), to identify possible DPN (score ≥4) and the Douleur Neuropathique en 4 Questions (DN4) questionnaire for possible associated neuropathic pain (MNSIq ≥4 + pain in both feet + DN4 score ≥3).Among 5,249 patients with data on both DPN and pain, 17.9% (n = 938) had possible DPN, including 7.4% (n = 386) with possible neuropathic pain. In regression analyses, central obesity (waist circumference, waist-to-hip ratio, and waist-to-height ratio) was markedly associated with DPN. Other important metabolic factors associated with DPN included hypertriglyceridemia ≥1.7 mmol/L, adjusted prevalence ratio (aPR) 1.36 (95% CI 1.17; 1.59); decreased HDL cholesterol <1.0/1.2 mmol/L (male/female), aPR 1.35 (95% CI 1.12; 1.62); hs-CRP ≥3.0 mg/L, aPR 1.66 (95% CI 1.42; 1.94); C-peptide ≥1,550 pmol/L, aPR 1.72 (95% CI 1.43; 2.07); HbA1c ≥78 mmol/mol, aPR 1.42 (95% CI 1.06; 1.88); and antihypertensive drug use, aPR 1.34 (95% CI 1.16; 1.55). Smoking, aPR 1.50 (95% CI 1.24; 1.81), and lack of physical activity (0 vs. ≥3 days/week), aPR 1.61 (95% CI 1.39; 1.85), were also associated with DPN. Smoking, high alcohol intake, and failure to increase activity after diabetes diagnosis associated with neuropathic pain.Possible DPN was associated with metabolic syndrome factors, insulin resistance, inflammation, and modifiable lifestyle habits in early type 2 diabetes.
Effect of Medicaid expansion status on risk of late or no prenatal care in black and white US mothers: analysis of US natality data, 2010–17
Authors: Etinosa S Oghogho, Consuelo Beck-Sagué
Journal: The Lancet Global Health (2020)

BackgroundPrenatal care is essential for a good pregnancy outcome for mothers and infants. Many women in the USA receive late (starting in third trimester) or no prenatal care (PNC), resulting in avoidable adverse health outcomes. Black women have been more likely to receive late or no PNC for decades. The Affordable Care Act provided for the option of Medicaid expansion that would improve access to health care, including prenatal health services, for many US women. However, not all states accepted Medicaid expansion, thus allowing us to make a comparison of rates of late or no PNC by Medicaid expansion status, before and after expansion was implemented.MethodsWe extracted data from the Births Files, CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) to calculate the proportion of women who received late or no PNC for the periods 2010–13 (baseline) and 2014–17 (after implementation of Medicaid expansion). We compared the numbers and proportions of births in women who received late or no PNC by whether states had accepted or decided against Medicaid expansion at baseline and also after implementation, by maternal race (black women and white women). Risk ratios [RR] and 95% CIs were calculated for each race at baseline and after Medicaid expansion implementation.FindingsBy 2014, 26 of 50 US states had accepted Medicaid expansion, and 24 had decided against. At baseline, the risk of late or no PNC in black women was 7·24% in states that went on to implement Medicaid expansion and 7·69% in states that decided against Medicaid expansion (RR=0·94, 95% CI=0·93–0·95). In 2014–17, the risk of late or no PNC in black women rose in all states, but the protective effect associated with being in a state that implemented Medicaid expansion increased: in non-Medicaid-expansion states, risk of late or no PNC rose to 9·39%, whereas in Medicaid expansion states, it rose to only 8·53% (RR=0·90, 0·90–0·92), with a 9·17% difference in the protective effect of being in a Medicaid expansion state between baseline and 2014–17. In white women, however, overall risk of late or no PNC rose modestly from 4·26% at baseline to 5·02% in 2014–17 (from 3·30% to 4·20% in Medicaid expansion states and from 5·26% to 5·71% in non-Medicaid-expansion states; the protective effect of being in an ME state declined from 37·0% to 26·4%).InterpretationIt is unclear why the risk of receiving late or no PNC rose in women of both races, or why the protective effect of living in an Medicaid expansion state declined for white women after implementation and what aspects of Medicaid expansion were associated with its protective effect in black women. However, Medicaid expansion introduction was associated with a modest but significant mitigation of the rise in the risk of late or no PNC in black women, in whom late or no PNC is a much greater problem.FundingNone
Depletion of Vascular Endothelial Progenitor Cells Inhibits Inflammation
Authors: Olaf Penack, Erik Henke, David Suh, Christopher King, Marsinay O Smith, Il-Kang Na, Amanda Holland, Arnab Ghosh, Sydney X Lu, Robert Jenq, Chen Liu, George F Murphy, Theresa Lu, Chad May, David A. Scheinberg, Ding Cheng Gao, Vivek Mittal, Robert Benezra, Marcel Van Den Brink
Journal: Blood (2008)
Neuroimaging of hypothalamic mechanisms related to glucose metabolism in anorexia nervosa and obesity
Authors: Joe J. Simon, Marion A. Stopyra, Esther Mönning, Sebastian Sailer, Nora Lavandier, Lars P. Kihm, Martin Bendszus, Hubert Preissl, Wolfgang Herzog, Hans-Christoph Friederich
Journal: Journal of Clinical Investigation (2020)

BACKGROUND. Given the heightened tolerance to self-starvation in anorexia nervosa (AN), a hypothalamic dysregulation of energy and glucose homeostasis has been hypothesized. Therefore, we investigated whether hypothalamic reactivity to glucose metabolism is impaired in AN.
MLL-Aberrations, Associated to T-AML, Are Induced by Chemotherapy In Vivo.
Authors: Jorg Basecke, Edda Seiffert, Kamran Karim, Martina Podleschny, Annegret Becker, Detlef Haase, Bertram Glass, Lorenz Trumper, Frank Griesinger
Journal: Blood (2005)
The effect of exacerbation history on outcomes in the IMPACT trial
Authors: David M.G. Halpin, Mark T. Dransfield, MeiLan K. Han, C. Elaine Jones, Sally Kilbride, Peter Lange, David A. Lipson, David A. Lomas, Fernando J. Martinez, Steve Pascoe, Dave Singh, Robert Wise, Gerard J. Criner
Journal: European Respiratory Journal (2020)

IMPACT, a 52-week, randomised, double-blind trial, assessed the efficacy and safety of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy
Effect of Helicobacter pylori eradication on ulcer recurrence after simple closure of perforated duodenal ulcer.
Authors: Ayman El-Nakeeb, Amir Fikry, Tito M Abd El-Hamed, El Yamani Fouda, Saleh El Awady, Tamer Youssef, Doaa Sherief, Mohamed Farid
Journal: International Journal of Surgery (2009)
Human lipopolysaccharide models provide mechanistic and therapeutic insights into systemic and pulmonary inflammation
Authors: Daniel Brooks, Laura C. Barr, Sarah Wiscombe, Daniel F. McAuley, A. John Simpson, Anthony J. Rostron
Journal: European Respiratory Journal (2020)

Inflammation is a key feature in the pathogenesis of sepsis and acute respiratory distress syndrome (ARDS). Sepsis and ARDS continue to be associated with high mortality. A key contributory factor is the rudimentary understanding of the early events in pulmonary and systemic inflammation in humans, which are difficult to study in clinical practice, as they precede the patient's presentation to medical services. Lipopolysaccharide (LPS), a constituent of the outer membrane of Gram-negative bacteria, is a trigger of inflammation and the dysregulated host response in sepsis. Human LPS models deliver a small quantity of LPS to healthy volunteers, triggering an inflammatory response and providing a window to study early inflammation in humans. This allows biological/mechanistic insights to be made and new therapeutic strategies to be tested in a controlled, reproducible environment from a defined point in time. We review the use of human LPS models, focussing on the underlying mechanistic insights that have been gained by studying the response to intravenous and pulmonary LPS challenge. We discuss variables that may influence the response to LPS before considering factors that should be considered when designing future human LPS studies.
Assessment of Therapy-Related Myeloid Neoplasms in Patients With Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy
Authors: Mohamad Bassam Sonbol, Thorvardur R. Halfdanarson, Talal Hilal
Journal: JAMA Oncology (2020)

Peptide receptor radionuclide therapy (PRRT) is a tumor-targeted treatment that uses radiation to induce tumor cell death in neuroendocrine tumors (NET) via β particle-emitting radionuclide linked to a somatostatin peptide analog. Therapy-related myeloid neoplasm (t-MN) has been reported as a potential long-term and frequently lethal adverse event after PRRT. However, the incidence, time of diagnosis, and nature of t-MN is unclear. Therefore, a systematic review is helpful to study the incidence and characteristics of t-MN after PRRT in patients with NET.To systematically evaluate the literature and report the incidence, time of diagnosis, and nature of t-MN after PRRT.MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for articles and abstracts reporting studies of different designs studying more than 1 patient (randomized clinical trials, prospective phase I or phase II, retrospective studies, and case series) were searched from database inception through April 2019. Studies of interest included patients with NET who were treated with PRRT and reported the incidence of t-MN, if any. The primary outcome was the incidence of t-MN.Twenty-eight articles were identified comprising 7334 patients who were treated with PRRT for NET. The main reason of exclusion was not reporting the t-MN incidence. The incidence of t-MN was variable between studies with mean (SD) incidence of 2.61% (4.38%). Of all 134 cases, cytogenetic abnormalities were reported in 32 patients with the most common abnormality being complex cytogenetics, consistent with myeloid neoplasms following exposure to alkylating agents or irradiation.The risk of t-MN after PRRT is small but not insignificant given the poor prognosis after t-MN diagnosis. Close monitoring is warranted to identify such patients early in the disease course when hematologic abnormalities persist.
Imatinib Mesylate Determines a High Frequency of Major Molecular Responses in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia (CML) on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML).
Authors: Ilaria Iacobucci, Nicoletta Testoni, Gianantonio Rosti, Marilina Amabile, Angela Poerio, Simona Soverini, Sabrina Colarossi, Alessandra Gnani, Emanuela Ottaviani, Fausto Castagnetti, Carolina Terragna, Matteo Renzulli, Tiziana Grafone, Daniela Cilloni, Fabrizio Pane, Giuseppe Saglio, Michele Baccarani, Giovanni Martinelli
Journal: Blood (2005)
The Life Tape Project, an existential intervention for cancer patients: A report on perceived benefits and changes in quality of life
Authors: E. H. Rosenbaum, R. W. Garlan, A. L. Siegel, S. Henderson, N. Hirschberger, L. D. Butler, D. Spiegel
Journal: Journal of Clinical Oncology (2006)

8604 Background: Facing cancer, most patients struggle with mortality and threats to their emotional equilibrium and that of their families. Families may become closer, but often communication difficulties and isolation increase. The Life Tape Project (LTP) is an intervention—involving a two hour video-taped genealogy and life story in the presence of family—designed to help patients and families confront this existential crisis. An important aspect is the cultivation of Symbolic Immortality—that some important part of the person continues to exist symbolically, even after death—helping patients identify with things greater and more enduring than themselves, and providing a sense of what will remain with the family after they are gone. Observation and pilot data suggested patients receive substantial benefits from the LTP. Results from an ongoing study designed to quantify and extend these observations are reported. Method: Adults with any cancer diagnosis are recruited from the general population. Patients complete baseline questionnaires before the LT interview and follow-up packets two and ten weeks after. Measures include the FACT-G for Quality of Life (QOL) and a Perceived Benefits Questionnaire covering eight themes suggested by previous research. A final semi-structured interview probes for unwanted effects. Results: At first follow-up (N = 23 as of 1/8/06) repeated measure t-tests revealed significant increases in FACT-G Functional and QOL (Total) scales; and a majority of patients reported substantial benefits (endorsing “very” or “extremely true for me”) in at least one theme. Final interviews revealed no unwanted effects. Conclusions: The LTP is a powerful, safe, and accessible intervention that can improve family communication and connectedness, promote personal growth, and reduce existential anxiety through the creation of symbolic immortality. Requiring minimal equipment and time, it would make an excellent addition to any supportive care program. [Table: see text] No significant financial relationships to disclose.
Potent Cytotoxicity Against Multiple Myeloma and Acute Myeloid Leukemia Cells by a New Histone Deacetylase Inhibitor ITF2357.
Authors: Alessandro Rambaldi, Caterina Micò, Lucia Cuppini, Marcello Domenghini, Gian Maria Borleri, Anna Maria Barbui, Flavio Leoni, Paolo Mascagni, Anna Salvi, Josee Golay, Martino Introna
Journal: Blood (2005)
Integrated scRNA-Seq Identifies Human Postnatal Thymus Seeding Progenitors and Regulatory Dynamics of Differentiating Immature Thymocytes
Authors: Marieke Lavaert, Kai Ling Liang, Niels Vandamme, Jong-Eun Park, Juliette Roels, Monica S. Kowalczyk, Bo Li, Orr Ashenberg, Marcin Tabaka, Danielle Dionne, Timothy L. Tickle, Michal Slyper, Orit Rozenblatt-Rosen, Bart Vandekerckhove, Georges Leclercq, Aviv Regev, Pieter Van Vlierberghe, Martin Guilliams, Sarah A. Teichmann, Yvan Saeys, Tom Taghon
Journal: Immunity (2020)
Recalibrating the risk of hamstring strain injury (HSI): A 2020 systematic review and meta-analysis of risk factors for index and recurrent hamstring strain injury in sport
Authors: Brady Green, Matthew N Bourne, Nicol van Dyk, Tania Pizzari
Journal: British Journal of Sports Medicine (2020)

Objective To systematically review risk factors for hamstring strain injury (HSI). Design Systematic review update. Data sources Database searches: (1) inception to 2011 (original), and (2) 2011 to December 2018 (update). Citation tracking, manual reference and ahead of press searches. Eligibility criteria for selecting studies Studies presenting prospective data evaluating factors associated with the risk of index and/or recurrent HSI. Method Search result screening and risk of bias assessment. A best evidence synthesis for each factor and meta-analysis, where possible, to determine the association with risk of HSI. Results The 78 studies captured 8,319 total HSIs, including 967 recurrences, in 71,324 athletes. Older age (standardised mean difference=1.6, p=0.002), any history of HSI (risk ratio (RR)=2.7, p&lt;0.001), a recent HSI (RR=4.8, p&lt;0.001), previous anterior cruciate ligament (ACL) injury (RR=1.7, p=0.002) and previous calf strain injury (RR=1.5, p&lt;0.001) were significant risk factors for HSI. From the best evidence synthesis, factors relating to sports performance and match play, running and hamstring strength were most consistently associated with HSI risk. The risk of recurrent HSI is best evaluated using clinical data and not the MRI characteristics of the index injury. Summary/conclusion Older age and a history of HSI are the strongest risk factors for HSI. Future research may be directed towards exploring the interaction of risk factors and how these relationships fluctuate over time given the occurrence of index and recurrent HSI in sport is multifactorial.
Social isolation and loneliness as risk factors for hospital admissions for respiratory disease among older adults
Authors: Feifei Bu, Keir Philip, Daisy Fancourt
Journal: Thorax (2020)

Rising hospital admissions due to respiratory disease (RD) are a major challenge to hospitals. This study explored modifiable social risk factors among 4478 older adults from the English Longitudinal Study of Ageing. Data were linked with administrative hospital records and mortality registry data (follow-up 9.6 years) and analysed using survival analysis accounting for competing risks. Living alone and social disengagement but not social contact or loneliness were associated with an increased risk of RD admissions, independent of socio-demographic, health and behaviour factors. Providing support for disengaged adults living alone who are at risk of RD admissions should be explored.