tbuckley/cabot-search huggingface dataset:
High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells
Authors: Ruochen Jia, Leon Kutzner, Anna Koren, Kathrin Runggatscher, Peter Májek, André C. Müller, Michael Schuster, Christoph Bock, Joanna I. Loizou, Stefan Kubicek, Robert Kralovics
Journal: Blood Cancer Journal (2021)

Mutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia and primary myelofibrosis. To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we searched for small molecules that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89 172 compounds using isogenic cell lines carrying CALR mutations and identified synthetic lethality with compounds targeting the ATR-CHK1 pathway. The selective inhibitory effect of these compounds was validated in a co-culture assay of CALR mutated and wild-type cells. Of the tested compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing wild-type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to ATR-CHK1 inhibition, thus suggesting specificity for the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. This was accompanied by S-phase cell cycle arrest due to incomplete DNA replication. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by oncogenic CALR, suggesting an intrinsic vulnerability to CHK1 perturbation. This study reveals the ATR-CHK1 pathway as a potential therapeutic target in CALR mutated hematopoietic cells.
Abstract 17391: Effect of Advanced Heart Failure Care on the Risk of Early Readmission
Authors: Snehalkumar A Patel, Todd M Koelling
Journal: Circulation (2011)

Introduction: Risk adjusted rates of 30-day readmission (30DR) for heart failure (HF) have been publicly reported since 2008 and are included in the Medicare Shared Savings Program for Accountable Care Organizations. Whether the risk represented by HF patients followed in Advanced Heart Failure Programs (AHFP) offering LVAD and heart transplantation (HTX) services is adequately adjusted using the CMS model is unknown. To examine this issue, we sought to compare readmission risk and comorbidity distributions in patients under evaluation for LVAD or HTX and in patients followed by the AHFP at our institution. Methods: We collected data on patients discharged from the University of Michigan Hospital with a HF DRG from July, 2008 to November, 2010. Data collection included comorbidities used in the CMS risk model and laboratory values. LVAD and HTX evaluation status and discharging service type were determined. Patients &lt; 19 years old and those expiring in the hospital were excluded from the analysis. Result: A total of 1412 patients admitted for HF were analyzed in this sample (30DR 27%). Patients under evaluation for LVAD or HTX trended to have higher 30DR compared to other patients (34.5% vs 26.4%, p=0.06). Predicted probability of readmission for the AHFP team (n=407) was higher than other services (0.230±0.002 vs 0.218±0.002, p&lt;0.001), but 30DR was similar for the two groups (27.8% vs 26.8%, p=0.70). Logistic regression analysis, controlling for variables included in the CMS risk model and laboratory values, demonstrated that patients under evaluation for LVAD or HTX were more likely to experience 30DR (OR 1.76, 95% CI 1.10-2.82, p=0.018) while patients treated on the AHFP service were less likely to experience 30DR (OR 0.74, 95% CI 0.55-0.99, p=0.047). Conclusion: HF patients treated in our AHFP have higher predicted probability of readmission compared to those admitted to general cardiology or medicine services. Patients under evaluation for LVAD or HTX have a higher risk of readmission, and when controlling for these patients, our AHFP service demonstrated a reduced risk of early readmission compared to other services. Further study is needed to determine what elements of care provided through the AHFP are responsible for this reduced readmission risk.
Magneto‐Endosomalytic Therapy for Cancer
Authors: Pengfei Zhao, Yan Han, Holly Nguyen, Eva Corey, Xiaohu Gao
Journal: Advanced Healthcare Materials (2021)

Abstract A remarkably simple yet effective mode of cancer treatment is reported by repurposing clinically approved magnetic nanoparticles (MNPs). Intracellular nanoparticle self‐assembly directed by static parallel magnetic fields leads to cell death in targeted tissues while leaving other cells and organs intact. This simple concept opens a new avenue to treat cancer, capitalizing on nanosciences and the nanoparticle (NP) design principles accumulated in the past decades.
Impaired Function of Circulating CD34 + CD45 - Cells in Patients with Persistent Atrial Fibrillation is Restored by the Bepridil Hydrochloride
Authors: Yozu Gakuto, Katoh Youichi, Yuu Hiroshige, Yamase Miki, Enjohji Yoshihisa, Daida Hiroyuki, Nakazato Yuji
Journal: Circulation (2012)
Gemcitabine Plus Cisplatin Versus Fluorouracil Plus Cisplatin as First-Line Therapy for Recurrent or Metastatic Nasopharyngeal Carcinoma: Final Overall Survival Analysis of GEM20110714 Phase III Study
Authors: Shaodong Hong, Yaxiong Zhang, Gengsheng Yu, Peijian Peng, Jiewen Peng, Jun Jia, Xuan Wu, Yan Huang, Yunpeng Yang, Qing Lin, Xuping Xi, Mingjun Xu, Dongping Chen, Xiaojun Lu, Rensheng Wang, Xiaolong Cao, Xiaozhong Chen, Zhixiong Lin, Jianping Xiong, Qin Lin, Conghua Xie, Zhihua Li, Jianji Pan, Jingao Li, Shixiu Wu, Yingni Lian, Quanlie Yang, Chong Zhao, Wenfeng Fang, Li Zhang
Journal: Journal of Clinical Oncology (2021)

GEM20110714 (ClinicalTrials.gov identifier: NCT01528618), the first randomized, phase III study of systemic chemotherapy in recurrent or metastatic nasopharyngeal carcinoma (NPC), reported significant progression-free survival improvement with gemcitabine plus cisplatin (GP) versus fluorouracil plus cisplatin (FP; hazard ratio, 0.55; 95% CI, 0.44 to 0.68;
26033 Exacerbation and appearance of dermatosis during COVID-19 quarantine period in Bogotá, Colombia: A descriptive study of the psychological impairments
Authors: David A. Castillo Molina, Jesus D. Fierro Lozada, Luisa F. Camacho-Lazaro, Mariana Reyes Rey, Daniela M. Molina Dorado, Maria Daniela Polania Tovar, Paula Andrea Chacon Jaramillo, Maria Juliana Sanchez Zapata, Nelson José Alvis-Zakzuk, Diana P. Cantillo
Journal: Journal of the American Academy of Dermatology (2021)

Introduction: Quarantine established in several countries by the new coronavirus pandemic, dramatically changed our lifestyle, affecting quality of life, skin, and psyche. We described the skin diseases that initiated or were exacerbated in quarantine and assessed the impact on quality of life and the possible presence of anxiety. Materials and methods: We performed a descriptive study from April 2020 to August 2020, assessing two questionnaires: Dermatology Life Quality Index (DLQI) and Hospital Anxiety and Depression Scale (HADS-A) in a dermatologic center. Variables analyzed were age, sex, onset or exacerbation of skin disease, DLQI and HADS-A scores. We used relative and absolute frequencies to describe patients. We collected data using Microsoft Excel and analyzed with SPSS. Results: Of 124 patients, 85 (69%) were women. Acne was the most frequent dermatosis with 18,5% (n = 23), followed by contact dermatitis with 22 patients (17,7%). HADS-A results showed that 24.2% of patients had psychological distress. DLQI most frequent results had a small effect in life (29.8%; n = 37). Patients with psoriasis and eczematous diseases showed a major impact on their quality of life. Conclusions: Quarantine has been related to exacerbation of pre-existent dermatologic conditions and the onset of skin affections. Lifestyle changes influenced the occurrence of acne and contact dermatitis. DLQI and HADS results did not show an important impact in patients' quality of life. Further epidemiologic studies are needed to determine whether there is a causal relationship between quarantine and these dermatologic conditions.
Polymers in pharmaceutical additive manufacturing: A balancing act between printability and product performance
Authors: Rydvikha Govender, Eric Ofosu Kissi, Anette Larsson, Ingunn Tho
Journal: Advanced Drug Delivery Reviews (2021)

Materials and manufacturing processes share a common purpose of enabling the pharmaceutical product to perform as intended. This review on the role of polymeric materials in additive manufacturing of oral dosage forms, focuses on the interface between the polymer and key stages of the additive manufacturing process, which determine printability. By systematically clarifying and comparing polymer functional roles and properties for a variety of AM technologies, together with current and emerging techniques to characterize these properties, suggestions are provided to stimulate the use of readily available and sometimes underutilized pharmaceutical polymers in additive manufacturing. We point to emerging characterization techniques and digital tools, which can be harnessed to manage existing trade-offs between the role of polymers in printer compatibility versus product performance. In a rapidly evolving technological space, this serves to trigger the continued development of 3D printers to suit a broader variety of polymers for widespread applications of pharmaceutical additive manufacturing.
Taking BMJ investigative journalism into a new era
Authors: Rebecca Coombes
Journal: BMJ (2021)

British members of parliament fiddling with their expenses, the treatment of Windrush immigrants, and the dangers of the drug thalidomide to unborn children. All these scandals were revealed by investigative journalism, a tradition that The BMJ has followed in recent years to deliver its own scoops, including on pandemic drug Tamiflu; medical device regulation; the measles, mumps, and rubella vaccine; and infant formula milk.

Over the past 10 years, BMJ investigations have revealed research fraud and misconduct, led to changes in clinical practice guidelines, triggered parliamentary inquiries in Europe, led a major drug company to divest a consumer product, and led a prominent professional society to divest from …
COVID-19 Vaccine Safety in Adolescents Aged 12–17 Years — United States, December 14, 2020–July 16, 2021
Authors: Anne M. Hause, Julianne Gee, James Baggs, Winston E. Abara, Paige Marquez, Deborah Thompson, John R. Su, Charles Licata, Hannah G. Rosenblum, Tanya R. Myers, Tom T. Shimabukuro, David K. Shay
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

As of July 30, 2021, among the three COVID-19 vaccines authorized for use in the United States, only the Pfizer-BioNTech BNT162b2 mRNA COVID-19 vaccine is authorized for adolescents aged 12-17 years. The Food and Drug Administration (FDA) issued an Emergency Use Authorization (EUA) for Pfizer-BioNTech vaccine for use in persons aged ≥16 years on December 11, 2020 (1); the EUA was expanded to include adolescents aged 12-15 years on May 10, 2021 (2), based on results from a Phase 3 clinical trial (3). Beginning in June 2021, cases of myocarditis and myopericarditis (hereafter, myocarditis) after receipt of Pfizer-BioNTech vaccine began to be reported, primarily among young males after receipt of the second dose (4,5). On June 23, 2021, CDC's Advisory Committee on Immunization Practices (ACIP) reviewed available data and concluded that the benefits of COVID-19 vaccination to individual persons and the population outweigh the risks for myocarditis and recommended continued use of the vaccine in persons aged ≥12 years (6). To further characterize safety of the vaccine, adverse events after receipt of Pfizer-BioNTech vaccine reported to the Vaccine Adverse Event Reporting System (VAERS) and adverse events and health impact assessments reported in v-safe (a smartphone-based safety surveillance system) were reviewed for U.S. adolescents aged 12-17 years during December 14, 2020-July 16, 2021. As of July 16, 2021, approximately 8.9 million U.S. adolescents aged 12-17 years had received Pfizer-BioNTech vaccine.* VAERS received 9,246 reports after Pfizer-BioNTech vaccination in this age group; 90.7% of these were for nonserious adverse events and 9.3% were for serious adverse events, including myocarditis (4.3%). Approximately 129,000 U.S. adolescents aged 12-17 years enrolled in v-safe after Pfizer-BioNTech vaccination; they reported local (63.4%) and systemic (48.9%) reactions with a frequency similar to that reported in preauthorization clinical trials. Systemic reactions were more common after dose 2. CDC and FDA continue to monitor vaccine safety and provide data to ACIP to guide COVID-19 vaccine recommendations.
Long‐term risk of cancer development among <scp>anti‐Th</scp>/To antibody–positive systemic sclerosis patients: comment on the article by Mecoli et al
Authors: Yuta Yamashita, Yoshinao Muro, Haruka Koizumi, Takuya Takeichi, Yasuhiko Yamano, Yasuhiro Kondoh, Masashi Akiyama
Journal: Arthritis & Rheumatology (2021)

We read the report by Mecoli et al on the relationship between cancer and anti-Th/To antibodies (AThAs) in patients with systemic sclerosis (SSc) (1). It is interesting that the presence of AThAs was reported to confer a protective effect against cancer development in those patients. However, cancer development in AThA-positive patients was significantly suppressed only within the first 3 years after SSc onset, and there was no significant difference in the number of deceased between the AThA-positive and AThA-negative patients.
Second-Line Therapy for Type 2 Diabetes Management: The Treatment/Benefit Paradox of Cardiovascular and Kidney Comorbidities
Authors: Rozalina G. McCoy, Holly K. Van Houten, Pinar Karaca-Mandic, Joseph S. Ross, Victor M. Montori, Nilay D. Shah
Journal: Diabetes Care (2021)

OBJECTIVE To examine whether glucagon-like peptide 1 receptor agonists (GLP-1RA) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) are preferentially initiated among patients with cardiovascular disease, heart failure (HF), or nephropathy, where these drug classes have established benefit, compared with dipeptidyl peptidase 4 inhibitors (DPP-4i), for which corresponding benefits have not been demonstrated. RESEARCH DESIGN AND METHODS We retrospectively analyzed claims of adults with type 2 diabetes included in OptumLabs Data Warehouse, a deidentified database of commercially insured and Medicare Advantage beneficiaries, who first started GLP-1RA, SGLT2i, or DPP-4i therapy between 2016 and 2019. Using multinomial logistic regression, we examined the relative risk ratios (RRR) of starting GLP-1RA and SGLT2i compared with DPP-4i for those with a history of myocardial infarction (MI), cerebrovascular disease, HF, and nephropathy after adjusting for demographic and other clinical factors. RESULTS We identified 75,395 patients who started GLP-1RA, 58,234 who started SGLT2i, and 91,884 who started DPP-4i. Patients with prior MI, cerebrovascular disease, or nephropathy were less likely to start GLP-1RA rather than DPP-4i compared with patients without these conditions (RRR 0.83 [95% CI 0.78–0.88] for MI, RRR 0.77 [0.74–0.81] for cerebrovascular disease, and RRR 0.87 [0.84–0.91] for nephropathy). Patients with HF or nephropathy were less likely to start SGLT2i (RRR 0.83 [0.80–0.87] for HF and RRR 0.57 [0.55–0.60] for nephropathy). Both medication classes were less likely to be started by non-White and older patients. CONCLUSIONS Patients with cardiovascular disease, HF, and nephropathy, for whom evidence suggests a greater likelihood of benefiting from GLP-1RA and/or SGLT2i therapy, were less likely to start these drugs. Addressing this treatment/benefit paradox, which was most pronounced in non-White and older patients, may help reduce the morbidity associated with these conditions.
Trends in Total and Out-of-pocket Payments for Insulin Among Privately Insured U.S. Adults With Diabetes From 2005 to 2018
Authors: Michael Laxy, Ping Zhang, Stephen R. Benoit, Giuseppina Imperatore, Yiling J. Cheng, Edward W. Gregg, Shuang Yang, Hui Shao
Journal: Diabetes Care (2021)

More than 30 million people in the U.S. have diabetes, and approximately 7.4 million (30% of those with diabetes) regularly use one or more insulin formulations. For those who rely on it, i.e., all patients with type 1 diabetes and many patients with type 2 diabetes, insulin is a lifesaving medication. Between 2007 and 2016, the average annual total Medicare Part D payment on insulin per person increased by 358%, which resulted in an 81% increase for the out-of-pocket (OOP) payment (1). The consequences of unaffordability for insulin can be severe and costly. High OOP payments may force individuals to choose between purchasing their medication and paying for other necessities. To date, there are limited data on how total insulin payment and the corresponding OOP payment changed in the commercially insured population within the same period. The objective of this study is to delineate total and patients’ OOP payment trends for insulin among privately insured U.S. adults.

We analyzed the IBM MarketScan Commercial Claims and Encounters (CCE) database for the period 2005 to 2018. The CCE contains de-identified patient claims data across the continuum of care (e.g., inpatient, outpatient, pharmacy) from large employers and health plans in the U.S. that provide private insurance coverage for their employees, dependents, and retirees. The primary analytical unit is the insulin prescription of adult individuals with diabetes covered by fee-for-service plans. We defined …
SO-12 Updated safety, efficacy, and PK results from an open-label, multicenter, phase I/II study of avapritinib in Chinese patients with unresectable or metastatic gastrointestinal stromal tumors
Authors: J. Li, S. Cai, Y. Deng, X. Wu, Z. Zheng, Y. Zhou, Y. Zhang, J. Zhang, K. Tao, Y. Cui, H. Cao, K. Shen, J. Yu, Y. Zhou, W. Ren, W. Zhao, Y. Wang, J. Hu, J. Yang, L. Shen
Journal: Annals of Oncology (2021)
Highlights 2014: picturing health
Authors: Joanna Palmer, Zoë Mullan
Journal: The Lancet Global Health (2014)

Once again we invite readers to submit their photographs to The Lancet's annual Highlights competition. We are looking for striking images on any topic in medicine, from global health to clinical medicine, from the individual person to populations. You might want to highlight a beautiful image that captures an aspect of your research, or one that conveys a powerful truth about global health. We are interested in photographs from any country; among the winning photographs last year were the hopeful faces of children in Rwanda, a vibrant hospital mural in Haiti, a gram stain of sputum from a patient with cystic fibrosis in Australia, and records to measure child health in Zambia. We invite readers to submit photographs to Highlights 2014 that capture any health issue in a compelling way. As last year, The Lancet and The Lancet Global Health will run the competition together. Winning photographs will be published in The Lancet's final issue of 2014 and might also be selected for the front cover of The Lancet Global Health. Each entry should be submitted with 300 accompanying words that put the image in context. Submissions should not have been previously published in print or online. If a person or patient is featured then you must obtain and keep written consent from the individual or, where this is not an option, their next of kin. Please complete the patient consent section of the author statements form while retaining copies of the signed forms. We also encourage you to submit any additional media to support your submission online, such as video or audio features. All photographs—colour or black and white—should be submitted through our online editorial submission system, along with the required text and any supporting material for online publication. Please select Lancet Photograph as the article type. If a digital camera is used please set it to the highest possible quality setting and submit images as JPEG files. If you are using a film camera please submit an 8 × 11 inch glossy print to The Lancet in the post. The entries will be judged by Lancet editors and there will be a £300 prize for winning entries. The deadline for entries is Nov 14, 2014. So share your photos with The Lancet and The Lancet Global Health.
Abstract 17781: Relationship Between Epicardial Adipose Tissue and Coronary Arterial Remodeling as Assessed by Intravascular Ultrasound in Patients with Coronary Artery Disease
Authors: Riyo Ogura, Yoshikazu Hiasa, Takefumi Takahashi, Shinobu Hosokawa, Koichi Kishi, Ryuji Ohtani
Journal: Circulation (2011)

Background: Recently, the interest in epicardial adipose tissue (EAT) is rapidly growing. Several study suggest that EAT induces inflammation of the artery wall by secretion of pro-inflammatory proteins and plays a role in the pathogenesis of coronary artery disease. However, there is no information regarding the impact of EAT on coronary arterial remodeling and plaque vulnerability. Objectives: The aim of this study was to evaluate the relationship between EAT and intravascular ultrasound (IVUS) findings, mainly remodeling, in patients with coronary artery disease. Methods: One hundred and eight consecutive patients with de novo lesions located in native coronary artery were studied. The EAT thickness on the right ventricle was measured using transthoracic echocardiography, and arterial remodeling of culprit lesion was assessed by preinterventional IVUS. The remodeling index (RI) was calculated as lesion divided by the reference external elastic membrane cross-sectional area, Positive remodeling (PR) was defined as RI&gt;1.05, intermediate remodeling (IR) as between 0.95 and 1.05, and negative remodeling (NR) as &lt;0.95. IVUS findings included plaque characteristics-lipid rich, mixed and calcified plaque and plaque eccentricity. Results: There was significant relationship between EAT thickness and RI(r= 0.36, p=0.0001). Higher EAT thickness (≥10mm, n=55) were associated with higher BMI(25.2±3.6 kg/m 2 vs. 23.9±2.8 kg/m 2 , p=0.04), plasma triglyceride level (189.1±103.8 mg/dl vs. 146.1±80.9 mg/dl, p=0.02), and plasma urinary acid level(6.8±1.5mg/dl vs. 5.9±1.5 mg/dl, p=0.02). PR and more lipid rich and mixed plaque were observed in patients with higher EAT thickness than lower EAT thickness (PR ;43.6% vs. 18.9%,p=0.02. lipid rich and mixed plaque; 89% vs.66%,p=0.004). Multivariate analysis showed high EAT thickness was independent factor affecting coronary positive remodeling (OR3.05,p=0.02).There was no significant association EAT thickness and plaque eccentricity. Conclusion; High EAT thickness was significantly correlated with the coronary positive remodeling and non calcified plaque characteristics.