tbuckley/cabot-search huggingface dataset:
A Randomized Trial Evaluating the Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec With or Without Metformin, in Adults With Type 2 Diabetes (ONSET 9)
Authors: Wendy S. Lane, Elena Favaro, Naveen Rathor, Hak C. Jang, Maiken I.S. Kjærsgaard, Alejandra Oviedo, Ludger Rose, Peter Senior, Giorgio Sesti, Alfonso Soto Gonzalez, Edward Franek
Journal: Diabetes Care (2020)

OBJECTIVE To evaluate the efficacy and safety of fast-acting insulin aspart (faster aspart) compared with insulin aspart (IAsp), both with insulin degludec with or without metformin, in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen. RESEARCH DESIGN AND METHODS This multicenter, double-blind, treat-to-target trial randomized participants to faster aspart (n = 546) or IAsp (n = 545). All available information, regardless of treatment discontinuation or use of ancillary treatment, was used for evaluation of effect. RESULTS Noninferiority for the change from baseline in HbA1c 16 weeks after randomization (primary end point) was confirmed for faster aspart versus IAsp (estimated treatment difference [ETD] −0.04% [95% CI −0.11; 0.03]; −0.39 mmol/mol [−1.15; 0.37]; P &amp;lt; 0.001). Faster aspart was superior to IAsp for change from baseline in 1-h postprandial glucose (PPG) increment using a meal test (ETD −0.40 mmol/L [−0.66; −0.14]; −7.23 mg/dL [−11.92; −2.55]; P = 0.001 for superiority). Change from baseline in self-measured 1-h PPG increment for the mean over all meals favored faster aspart (ETD −0.25 mmol/L [−0.42; −0.09]); −4.58 mg/dL [−7.59; −1.57]; P = 0.003). The overall rate of treatment-emergent severe or blood glucose (BG)–confirmed hypoglycemia was statistically significantly lower for faster aspart versus IAsp (estimated treatment ratio 0.81 [95% CI 0.68; 0.97]). CONCLUSIONS In combination with insulin degludec, faster aspart provided effective overall glycemic control, superior PPG control, and a lower rate of severe or BG-confirmed hypoglycemia versus IAsp in adults with type 2 diabetes not optimally controlled with a basal-bolus regimen.
Cold-Inducible RNA-Binding Protein Prevents an Excessive Heart Rate Response to Stress by Targeting Phosphodiesterase
Authors: Duanyang Xie, Li Geng, Ke Xiong, Tingting Zhao, Shuo Wang, Jinfeng Xue, Cheng Wang, Guanghua Wang, Zhiqiang Feng, Huixing Zhou, Yini Li, Li Li, Yi Liu, Zhigang Xue, Jian Yang, Honghui Ma, Dandan Liang, Yi-Han Chen
Journal: Circulation Research (2020)

Rationale: The stress response of heart rate, which is determined by the plasticity of the sinoatrial node (SAN), is essential for cardiac function and survival in mammals. As an RNA-binding protein, CIRP (cold-inducible RNA-binding protein) can act as a stress regulator. Previously, we have documented that CIRP regulates cardiac electrophysiology at posttranscriptional level, suggesting its role in SAN plasticity, especially upon stress conditions. Objective: Our aim was to clarify the role of CIRP in SAN plasticity and heart rate regulation under stress conditions. Methods and Results: Telemetric ECG monitoring demonstrated an excessive acceleration of heart rate under isoprenaline stimulation in conscious CIRP-KO (knockout) rats. Patch-clamp analysis and confocal microscopic Ca 2+ imaging of isolated SAN cells demonstrated that isoprenaline stimulation induced a faster spontaneous firing rate in CIRP-KO SAN cells than that in WT (wild type) SAN cells. A higher concentration of cAMP—the key mediator of pacemaker activity—was detected in CIRP-KO SAN tissues than in WT SAN tissues. RNA sequencing and quantitative real-time polymerase chain reaction analyses of single cells revealed that the 4B and 4D subtypes of PDE (phosphodiesterase), which controls cAMP degradation, were significantly decreased in CIRP-KO SAN cells. A PDE4 inhibitor (rolipram) abolished the difference in beating rate resulting from CIRP deficiency. The mechanistic study showed that CIRP stabilized the mRNA of Pde4b and Pde4d by direct mRNA binding, thereby regulating the protein expression of PDE4B and PDE4D at posttranscriptional level. Conclusions: CIRP acts as an mRNA stabilizer of specific PDEs to control the cAMP concentration in SAN, maintaining the appropriate heart rate stress response.
Abstract P1-03-05: Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer
Authors: Chun I Yu, Te-Chia Wu, Kyung In Kim, Francesca Menghi, Vanessa Oliveira, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka
Journal: Cancer Research (2020)

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All eleven (11) analyzed to date PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among 11 PDX tumors tested, five did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastasis (lung and liver). Transcriptional profiling with RNAseq revealed significant differences in the immune landscape of primary and metastatic tumors. In particular, liver metastases were enriched in myeloid and plasma cell transcripts. Further analysis is ongoing to uncover specific pathways involved. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis. Citation Format: Chun I Yu, Te-Chia Wu, Kyung In Kim, Francesca Menghi, Vanessa Oliveira, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-05.
Future Research Suggestions for Multigene Testing in Unselected Populations—Reply
Authors: Ranjit Manchanda, Diana S. M. Buist, D. Gareth R. Evans
Journal: JAMA Oncology (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Generation of Genetically Engineered Mouse Lung Organoid Models for Squamous Cell Lung Cancers Allows for the Study of Combinatorial Immunotherapy
Authors: Josephine Hai, Hua Zhang, Jin Zhou, Zhong Wu, Ting Chen, Eleni Papadopoulos, Catríona M. Dowling, Val Pyon, Yuanwang Pan, Jie Bin Liu, Roderick T. Bronson, Heather Silver, Patrick H. Lizotte, Jiehui Deng, Joshua D. Campbell, Lynette M. Sholl, Christine Ng, Ming-Sound Tsao, Cassandra Thakurdin, Adam J. Bass, Kwok-Kin Wong
Journal: Clinical Cancer Research (2020)

Abstract Purpose: Lung squamous cell carcinoma (LSCC) is a deadly disease for which only a subset of patients responds to immune checkpoint blockade (ICB) therapy. Therefore, preclinical mouse models that recapitulate the complex genetic profile found in patients are urgently needed. Experimental Design: We used CRISPR genome editing to delete multiple tumor suppressors in lung organoids derived from Cre-dependent SOX2 knock-in mice. We investigated both the therapeutic efficacy and immunologic effects accompanying combination PD-1 blockade and WEE1 inhibition in both mouse models and LSCC patient-derived cell lines. Results: We show that multiplex gene editing of mouse lung organoids using the CRISPR–Cas9 system allows for efficient and rapid means to generate LSCCs that closely mimic the human disease at the genomic and phenotypic level. Using this genetically defined mouse model and three-dimensional tumoroid culture system, we show that WEE1 inhibition induces DNA damage that primes the endogenous type I IFN and antigen presentation system in primary LSCC tumor cells. These events promote cytotoxic T-cell–mediated clearance of tumor cells and reduce the accumulation of tumor-infiltrating neutrophils. Beneficial immunologic features of WEE1 inhibition are further enhanced by the addition of anti–PD-1 therapy. Conclusions: We developed a mouse model system to investigate a novel combinatory approach that illuminates a clinical path hypothesis for combining ICB with DNA damage–inducing therapies in the treatment of LSCC.
Do PCSK9 inhibitors do anything more than reduce LDL cholesterol?
Authors: Andrew N Bamji
Journal: BMJ (2020)

Byrne and colleagues point out the lack of reliable evidence on cardiovascular risk with inclisiran, and the omens are not good.1

Inclisiran undoubtedly has a marked lowering effect on low density lipoprotein (LDL) cholesterol, which was first reported in 2017. But does a 30-50% reduction in LDL cholesterol translate to a 30-50% reduction in cardiovascular risk? Almost certainly not. 

The inclisiran results include an “exploratory cardiovascular endpoint” (a secondary …
Abstract 15926: Impact of Extent of Coronary Revascularization on Mortality After Transcatheter Aortic Valve Replacement: A Systematic Review and Meta-Analysis
Authors: Muhammad Junaid Ahsan, Noman Lateef, Saad Ullah Malik, Muhammad Fazeel Anwar, Hafiz Muhammad Z Zubair, Azka Latif, Mohsin M Mirza, Mark J Holmberg
Journal: Circulation (2019)

Background: The concurrent incidence of aortic stenosis (AS) and coronary artery disease is estimated to be 50 - 60%. Coronary intervention in patients with severe CAD leads to improved outcomes, h...
Epigenetic Therapeutics for Cardiovascular Disease
Authors: Jorge Plutzky
Journal: JAMA (2020)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract P3-02-06: Tracing glucose catabolism in human triple negative breast cancer tumors
Authors: Jonathan Michael Ghergurovich, Joyce O’Shaughnessy, Maren K Levin, Aaron Killian, William Hendricks, Virginia Espina, Joshua D Rabinowitz
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) is an aggressive tumor type for which few targeted treatments exist. Altered tumor metabolism may provide novel diagnostic and therapeutic opportunities. Recent genetic analyses in TNBC demonstrate augmented expression of pathways related to glucose metabolism, including glycolysis, the pentose phosphate (PPP), and serine biosynthetic pathways. No studies, however, have directly probed how glucose is utilized by TNBCs in vivo. Here, we trace these metabolic fates by infusing TNBC patients with isotopically labeled 1,2-13C-glucose, a tracer that can determine which of these pathways predominate. Upon achieving stable tracer enrichment in serum, patient primary TNBC biopsies were collected and flash frozen. Subsequent analysis by liquid chromatography mass spectroscopy (LC-MS) revealed most TNBC tumors locally ferment glucose to lactate, with limited exchange of pyruvate/lactate with the systemic circulation. This contrasts with lung cancer, where pyruvate/lactate exchange is extensive. In addition, isotopic labeling patterns indicate that glycolysis dominates the PPP in terms of total flux. Nevertheless, ribose-phosphate for nucleotide synthesis consistently arises from the oxidative branch of the PPP. Furthermore, a subset of patients demonstrated high levels of de novo serine production. To better understand these observations, next generation sequencing (NGS) and reverse phase protein array (RPPA) analyses on adjacent biopsies from these patients are underway. Together, these findings provide the first comprehensive in vivo characterization of glucose metabolism in TNBC and raise the potential to use tracing to guide development of metabolic therapeutics. Citation Format: Jonathan Michael Ghergurovich, Joyce O’Shaughnessy, Maren K Levin, Aaron Killian, William Hendricks, Virginia Espina, Joshua D Rabinowitz. Tracing glucose catabolism in human triple negative breast cancer tumors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-02-06.
Discontinuation of nucleos(t)ide analogues is not associated with a higher risk of HBsAg seroreversion after antiviral-induced HBsAg seroclearance: a nationwide multicentre study
Authors: Minseok Albert Kim, Seung Up Kim, Dong Hyun Sinn, Jeong Won Jang, Young-Suk Lim, Sang Hoon Ahn, Jae-Jun Shim, Yeon Seok Seo, Yang Hyun Baek, Sang Gyune Kim, Young Seok Kim, Ji Hoon Kim, Won Hyeok Choe, Hyung Joon Yim, Hyun Woong Lee, Jung Hyun Kwon, Sung Won Lee, Jae Young Jang, Hwi Young Kim, Yewan Park, Gi-Ae Kim, Hyun Yang, Han Ah Lee, Myeongseok Koh, Young-Sun Lee, Minkoo Kim, Young Chang, Yoon Jun Kim, Jung-Hwan Yoon, Fabien Zoulim, Jeong-Hoon Lee
Journal: Gut (2020)

Objective Direct comparison of the clinical outcomes between nucleos(t)ide analogue (NA) discontinuation versus NA continuation has not been performed in patients with chronic hepatitis B who achieved HBsAg-seroclearance. Whether NA discontinuation was as safe as NA continuation after NA-induced surface antigen of HBV (HBsAg) seroclearance was investigated in the present study. Designs This multicentre study included 276 patients from 16 hospitals in Korea who achieved NA-induced HBsAg seroclearance: 131 (47.5%) discontinued NA treatment within 6 months after HBsAg seroclearance (NA discontinuation group) and 145 (52.5%) continued NA treatment (NA continuation group). Primary endpoint was HBsAg reversion and secondary endpoints included serum HBV DNA redetection and development of hepatocellular carcinoma (HCC). Results During follow-up (median=26.9 months, IQR=12.2–49.2 months), 10 patients (3.6%) experienced HBsAg reversion, 6 (2.2%) showed HBV DNA redetection and 8 (2.9%) developed HCC. Compared with NA continuation, NA discontinuation was not associated with HBsAg reversion in both univariable (HR=0.45, 95% CI=0.12 to 1.76, log-rank p=0.24) and multivariable analyses (adjusted HR=0.65, 95% CI=0.16 to 2.59, p=0.54). The cumulative probabilities of HBsAg reversion at 1, 3 and 5 years were 0.8%, 2.3% and 5.0% in the NA discontinuation group, and 1.5%, 6.3% and 8.4% in the NA continuation group, respectively. NA discontinuation was not associated with higher risk of either HBV redetection (HR=0.83, 95% CI=0.16 to 4.16, log-rank p=0.82) or HCC development (HR=0.53, 95% CI=0.12 to 2.23, log-rank p=0.38). Conclusion The discontinuation of NA was not associated with a higher risk of either HBsAg reversion, serum HBV DNA redetection or HCC development compared with NA continuation among patients who achieved HBsAg seroclearance with NA.
Abstract TS2-1: CTC Clusters, Cancer Stemness, and New Treatment Strategies
Authors: H Liu
Journal: Cancer Research (2020)

Abstract Circulating tumor cells (CTCs) seed metastases which eventually kill most of the breast cancer patients; however, CTCs have not been effectively targeted partially due to the unclear cellular and molecular mechanisms. Emerging evidence and our studies demonstrate that CTCs are detectable as singles as well as multicellular clusters in cancer patients; and presence of the latter is associated with unfavorable progression-free survival (PFS) and poor overall survival (OS). Compared to single CTCs, CTC clusters show enriched stemness properties, including enhanced tumorigenic potential and polyclonal metastases, more efficient mammosphere formation, and upregulated expression of CD44 and stemness-related signaling pathways. Using intravital multiphoton microscopic imaging of patient-derived-xenograft (PDX) models and mouse tumor models, we found that clustered tumor cells in migration and circulation resulted from aggregation of individual tumor cells rather than collective migration and cohesive shedding. Molecularly, the intercellular CD44-CD44 homophilic interactions are essential for the multicellular CTC aggregation, recruitment of downstream PAK2, and activation of the FAK signaling. Depletion of CD44 or antibody-mediated blockade of CD44 interactions effectively prevent tumor cell aggregation and abolish polyclonal metastases. In addition to CD44, we have identified other surface receptors and adhesion molecules which also contribute to CTC cluster formation. Our studies highlight that CTC clusters, whose presence is correlated with a poor prognosis of breast cancer patients, can serve as a liquid biopsy-based biomarker as well as novel therapeutic targets of polyclonal metastasis. Citation Format: H Liu. CTC Clusters, Cancer Stemness, and New Treatment Strategies [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr TS2-1.
Moving Forward in Cervical Cancer: Enhancing Susceptibility to DNA Repair Inhibition and Damage, an NCI Clinical Trials Planning Meeting Report
Authors: Matthew M Harkenrider, Merry Jennifer Markham, Don S Dizon, Anuja Jhingran, Ritu Salani, Ramy K Serour, Jean Lynn, Elise C Kohn
Journal: JNCI Journal of the National Cancer Institute (2020)

Abstract Cervical cancer is the fourth most common cancer in women worldwide, and prognosis is poor for those who experience recurrence or develop metastatic disease, in part due to the lack of active therapeutic directions. The National Cancer Institute convened a Cervical Cancer Clinical Trials Planning Meeting in October 2018 to facilitate the design of hypothesis-driven clinical trials focusing on locally advanced, metastatic, and recurrent cervical cancer around the theme of enhancing susceptibility to DNA repair inhibition and DNA damage. Before the meeting, a group of experts in the field summarized available preclinical and clinical data to identify potentially active inducers and inhibitors of DNA. The goals of the Clinical Trials Planning Meeting focused on identification of novel experimental strategies capitalizing on DNA damage and repair (DDR) regulators and cell cycle aberrations, optimization of radiotherapy as a DDR agent, and design of clinical trials incorporating DDR regulation into the primary and recurrent or metastatic therapies for cervical carcinoma. Meeting deliverables were novel clinical trial concepts to move into the National Clinical Trials Network. This report provides an overview for the rationale of this meeting and the state of the science related to DDR regulation in cervical cancer.
Randomized Phase II Trial of Gemcitabine Plus S-1 Combination Therapy Versus S-1 in Advanced Biliary Tract Cancer: Results of the Japan Clinical Oncology Group Study (JCOG0805)
Authors: M. Ikeda, T. Okusaka, J. Mizusawa, A. Takashima, C. Morizane, M. Ueno, Y. Hamamoto, H. Ishii, H. Hara, A. Fukutomi, M. Furukawa, M. Nagase, T. Yamaguchi, N. Boku, J. Furuse
Journal: Annals of Oncology (2012)
Management of IBD during the COVID-19 outbreak: resetting clinical priorities
Authors: Silvio Danese, Maurizio Cecconi, Antonino Spinelli
Journal: Nature Reviews Gastroenterology & Hepatology (2020)

The coronavirus disease (COVID-19) worldwide outbreak has led to a dramatic challenge for all healthcare systems, including inflammatory bowel disease (IBD) centres. Here, we describe the fast changes and clinical issues that IBD specialists could face during this SARS-CoV-2 infection pandemic, highlighting the potential rearrangements of care and resetting of clinical priorities.
Peak Systolic Blood Pressure in Exercise Testing is Associated With Scintigraphic Severity of Myocardial Ischemia in Patients With Exercise-Induced ST-Segment Depression
Authors: Akihiko Uehara, Chinori Kurata, Toshihiko Sugi, Tadashi Mikami, Keisuke Yamazaki, Hiroshi Satoh, Hiroshi Watanabe, Hajime Terada
Journal: Circulation (2000)

Some electrocardiographic variables, including the degree of maximal ST-segment depression (STD), may not necessarily indicate the severity of exercise-induced myocardial ischemia. The present study examined whether maximal STD correlates with the severity and extent of exercise-induced myocardial ischemia, as assessed by thallium-201 (201Tl) imaging, and which parameter of exercise testing reflects scintigraphic severity and extent in 270 patients who had a 1 mm or greater horizontal or down-sloping STD on exercise 201Tl imaging. The scintigraphic severity and extent of exercise-induced ischemia was assessed and correlated with maximal STD, number of positive leads, workload, peak heart rate, peak systolic blood pressure (SBP), rate-pressure product, chest pain and the Duke treadmill score. Most of the scintigraphic markers of the severity and extent of ischemia had significant but weak correlation with all of those parameters. Multivariate analysis demonstrated that peak SBP and the Duke treadmill score (chest pain in only simple variables model) correlated independently with scintigraphic severity and extent of ischemia. Furthermore, most of the patients with a peak SBP of 200 mmHg or more had milder and less extensive ischemia. In patients with exercise-induced STD, the scintigraphic severity and extent of ischemia may be estimated by peak SBP and the Duke treadmill score.