tbuckley/cabot-search huggingface dataset:
Metabolic remodeling by TIGAR overexpression is a therapeutic target in esophageal squamous-cell carcinoma
Authors: Jiahui Chu, Xiangjie Niu, Jiang Chang, Mingming Shao, Linna Peng, Yiyi Xi, Ai Lin, Chengcheng Wang, Qionghua Cui, Yingying Luo, Wenyi Fan, Yamei Chen, Yanxia Sun, Wenjia Guo, Wen Tan, Dongxin Lin, Chen Wu
Journal: Theranostics (2020)

Rationale: Whole-genome sequencing has identified many amplified genes in esophageal squamous-cell carcinoma (ESCC).This study investigated the role and clinical relevance of these genes in ESCC.Methods: We collected ESCC and non-tumor esophageal tissues from 225 individuals who underwent surgery.Clinical data were collected and survival time was measured from the date of diagnosis to the date of last follow-up or death.Patient survival was compared with immunohistochemical staining score using Kaplan-Meier methods and hazard ratios were calculated by Cox models.Cells with gene overexpression and knockout were analyzed in proliferation, migration and invasion assays.Cells were also analyzed for levels of intracellular lactate, NADPH, ATP and mRNA and protein expression patterns.Protein levels in cell line and tissue samples were measured by immunoblotting or immunohistochemistry. ESCC cell were grown as xenograft tumors in nude mice.Primary ESCC in genetically engineered mice and patient-derived xenograft mouse models were established for test of therapeutic effects.Results: We show that TP53-induced glycolysis and apoptosis regulator (TIGAR) is a major player in ESCC progression and chemoresistance.TIGAR reprograms glucose metabolism from glycolysis to the glutamine pathway through AMP-activated kinase, and its overexpression is correlated with poor disease outcomes.Tigar knockout mice have reduced ESCC tumor burden and growth rates.Treatment of TIGAR-overexpressing ESCC cell xenografts and patient-derived tumor xenografts in mice with combination of glutaminase inhibitor and chemotherapeutic agents achieves significant more efficacy than chemotherapy alone.Conclusion: These findings shed light on an important role of TIGAR in ESCC and might provide evidence for targeted treatment of TIGAR-overexpressing ESCC.
Spectrum of abnormalities and clonal transformation in germline RUNX1 familial platelet disorder and a genomic comparative analysis with somatic RUNX1 mutations in MDS/MPN overlap neoplasms
Authors: Emma C. DiFilippo, Giacomo Coltro, Ryan M. Carr, Abhishek A. Mangaonkar, Moritz Binder, Shakila P. Khan, Vilmarie Rodriguez, Naseema Gangat, Alexandra Wolanskyj, Rajiv K. Pruthi, Dong Chen, Rong He, David S. Viswanatha, Terra Lasho, Christy Finke, Ayalew Tefferi, Animesh Pardanani, Mrinal M. Patnaik
Journal: Leukemia (2020)
Call to Action: Rural Health: A Presidential Advisory From the American Heart Association and American Stroke Association
Authors: Robert A. Harrington, Robert M. Califf, Appathurai Balamurugan, Nancy Brown, Regina M. Benjamin, Wendy E. Braund, Janie Hipp, Madeleine Konig, Eduardo Sanchez, Karen E. Joynt Maddox
Journal: Circulation (2020)

Understanding and addressing the unique health needs of people residing in rural America is critical to the American Heart Association's pursuit of a world with longer, healthier lives. Improving the health of rural populations is consistent with the American Heart Association's commitment to health equity and its focus on social determinants of health to reduce and ideally to eliminate health disparities. This presidential advisory serves as a call to action for the American Heart Association and other stakeholders to make rural populations a priority in programming, research, and policy. This advisory first summarizes existing data on rural populations, communities, and health outcomes; explores 3 major groups of factors underlying urban-rural disparities in health outcomes, including individual factors, social determinants of health, and health delivery system factors; and then proposes a set of solutions spanning health system innovation, policy, and research aimed at improving rural health.
Abstract P6-05-13: Crosstalk of post-translational modifications upon ERalpha activation
Authors: Kai-Hsiung Chang, Hui-Chin Wen, Sin-Yin Tsai
Journal: Cancer Research (2020)

Abstract Breast cancer risk correlates highly with sustained estrogen receptor (ER) activities. Estrogen antagonists (e.g. anti-estrogens) and estrogen synthesis blockers (e.g. aromatase inhibitors) are frontline treatment to hinder disease progression in patients with breast cancer because most malignant breast tumors exhibit ERalpha positive expression signature. ERalpha harbors several post-translational modifications such as phosphorylation, acetylation, methylation, ubiquitination, sumoylation, palmitoylation, and others. Dysregulation of such PTMs on ERalpha enables abnormal tumor cell proliferation and promote malignancy. Although individual PTM on ERalpha is extensively deciphered, it remains relatively unclear how PTMs interact with each other to coordinate and execute 1) the recruitment of co-activators and RNA polymerase machinery to chromatin and 2) promoter clearance after transcription activation. Here, we report a novel PTM crosstalk between transcription-coupled phosphorylation and an ubiquitination-like modification on ERalpha. We also reveal its potential roles in regulating ER transcriptional activation and its future application in managing ER positive breast cancer. Citation Format: Kai-Hsiung Chang, Hui-Chin Wen, Sin-Yin Tsai. Crosstalk of post-translational modifications upon ERalpha activation [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 P6-05-13.
Abstract P2-16-20: Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67
Authors: Bernardo Leon Rapoport, Jacqui Barnard-Tidy, Ronwyn van Eeden, Teresa Smit, Simon Nayler, Carol Benn
Journal: Cancer Research (2020)

Abstract Aim of study: The aim of this retrospective project is to evaluate the treatment outcomes including pathological complete response (pCR), time to progression and overall survival in patients (pts) treated with taxane, and/or anthracycline/alkylating agents based neoadjuvant chemotherapy (NAC). Background: Ki-67 immunohistochemical determination is a widely used biomarker of cell proliferation in pts undergoing endocrine treatment for breast cancer. The role of Ki-67 in triple negative breast cancer (TNBC) pts undergoing NAC for early disease remains controversial. Pathological Complete Response following NAC has been proposed as a prognostic indicator of long-term outcome. Methods: We analyzed retrospectively data on 86 pts with TNBC. Pathological complete response (pCR) was defined as the complete disappearance of the invasive cancer in the breast and absence of tumor in the axillary lymph nodes examined by axillary clearance. The purpose of this analysis was to investigate factors associated with combined pCR. Results: There were 35 pCR’s (40.7%). At 2 years 82% of pts who attained a pCR were disease free compared to 67% of pts who did not attain a pCR (log rank test p &amp;lt; 0.0117). On univariate analysis factors associated with higher combined pCR included primary tumor size (T1=84% vs T2 and T3 =50% of pts, chi2= 6.81, p&amp;lt;0.03317), Ki67 (&amp;gt;30=68% vs. eq or &amp;lt; 30%= 18% of pts, p&amp;lt;0.00020), age (&amp;lt; than 50 =71% vs. equal or &amp;gt;50 =44% of pts), tumor grade (1=88% vs. 2=60% vs. 3=44% of pts, chi2 = 6.2560 p&amp;lt;0.04381) and stage (I= 89% vs. IIA=60% vs. IIB=46% vs. III=40% of pts, p&amp;lt;0.01350). Factors not associated with a higher pCR included menopausal status, extranodal spread and lympho-vascular invasion. In a logistic regression model Ki-67 as a continuous variable (p&amp;lt;0.012577) and age &amp;lt; than 50 (p&amp;lt;0.03318) retained its significance; while tumor size, stage of disease, tumor grade loss significance. Conclusion: Ki67 and age are independent prognostic factors of pCR in pts with early TNBC undergoing NAC. Citation Format: Bernardo Leon Rapoport, Jacqui Barnard-Tidy, Ronwyn van Eeden, Teresa Smit, Simon Nayler, Carol Benn. Treatment outcomes in triple negative breast cancer patients undergoing neoadjuvant chemotherapy. The importance of Ki-67 [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 P2-16-20.
Unsuspected Accessory Ossicle in Possible Sinus Tarsi Syndrome
Authors: Dwight M. Achong
Journal: Clinical Nuclear Medicine (2020)

Three-phase bone scan was performed for evaluation of possible sinus tarsi syndrome in a 52-year-old man with chronic left ankle pain. MRI was initially read as unremarkable, and there was little symptomatic improvement after intra-articular anesthetic injection. The primary finding that appreciated only delayed bone SPECT/CT images was focal increased uptake associated with a well-corticated 8-mm bony fragment adjacent to the left calcaneus, thought to represent an accessory ossicle within the left sinus tarsi. The increased uptake suggested fracture or severe degenerative change of the ossicle, likely contributing to the patient's chronic pain.
Secondary Abdominal-Pelvic Malignancies Attributable to Diagnostic Radiation Exposure in Patients With Testicular Malignancies Reply
Authors: Carl van Walraven, Dean Fergusson, Craig Earle, Nancy Baxter, Shabbir Alibhai, Blair MacDonald, Alan J Forster, Ilias Cagiannos
Journal: Journal of Clinical Oncology (2012)
Four US doctors convicted of fraud in $150m scheme to swap opioids for back injections
Authors: Owen Dyer
Journal: BMJ (2020)

Four physicians from Michigan in the US have been convicted of fraud after providing 6.6 million doses of medically unnecessary opioids to patients. In return for receiving the prescriptions, the patients submitted to back injections they didn’t need that the doctors then billed to Medicare.

A federal court found Spilios Pappas, 62, Joseph Betro, 59, Tariq Omar, 62, and Mohammed Zahoor, 53, of Oakland County, Michigan, guilty of healthcare fraud. They will be sentenced this summer.

Seventeen other defendants, including eight other doctors, have already pleaded guilty in the case.

Prosecutors in the trial said that …
Annals Graphic Medicine - Progress Notes: Cancer
Authors: Michael Natter
Journal: Annals of Internal Medicine (2019)

Web Exclusives19 February 2019Annals Graphic Medicine - Progress Notes: CancerFREEMichael Natter, MDMichael Natter, MDNYU School of Medicine, New York, New York (M.N.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/G19-0002 SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Download figure Download PowerPoint Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: NYU School of Medicine, New York, New York (M.N.)Disclosures: The author has disclosed no conflicts of interest. The form can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=G19-0002.Author/Illustrator Information: Michael Natter, MD, is a current internal medicine resident at NYU School of Medicine and a graduate of Sidney Kimmel Medical College of Thomas Jefferson University in Philadelphia. His artwork is inspired by his medical training, patient encounters, and the human condition. A type 1 diabetic, Dr. Natter views himself as a patient as well as a doctor and plans to pursue a fellowship in endocrinology to help others who also share his disease. You can find more of his illustrations, stories, and comics on Instagram (www.instagram.com/mike.natter) and Twitter (@mike_natter).About Progress Notes: Progress Notes explores the everyday emotional, clinical, humorous, and ethical challenges of the medical residency training process. As implied by the title of the series, these pieces act as a visual bildungsroman, graphically dissecting the subtext of what it means to be a young doctor in today's medical world. Progress Notes appears monthly in Annals Graphic Medicine at Annals.org. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoAnnals Graphic Medicine: Introducing “Dr. Mom” and “Progress Notes” Metrics 19 February 2019Volume 170, Issue 4Page: W73-W77KeywordsConflicts of interestDisclosureEmotionsEndocrinologyFellowshipsGraduate medical educationResidency ePublished: 19 February 2019 Issue Published: 19 February 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Incidental 18F-Fluorocholine Uptake in an Esophageal Diverticulum
Authors: Mine Araz, Murat Cinel, Cigdem Soydal, Elgin Ozkan, N. Ozlem Kucuk
Journal: Clinical Nuclear Medicine (2020)

Abstract 18 F-fluorocholine has recently emerged as a very sensitive agent for seeking parathyroid adenomas. We represent a case with esophageal diverticulum incidentally detected on 18 F-fuorocholine PET/CT, which should be kept in mind as a reason of false positivity in primary hyperparathyroidism.
JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function
Authors: Susanne Adam, Nils Simon, Ulrike Steffen, Fabian T. Andes, Carina Scholtysek, Dorothea I. H. Müller, Daniela Weidner, Darja Andreev, Arnd Kleyer, Stephan Culemann, Madelaine Hahn, Georg Schett, Gerhard Krönke, Silke Frey, Axel J. Hueber
Journal: Science Translational Medicine (2020)

JAK inhibition enhances the function of bone-forming osteoblasts, increases bone mass, and induces repair of arthritic bone erosions.
Early Salvage Treatment with Second-Generation Novel Agents at Biochemical Relapse Prolongs Overall Survival: A Real-World Single Center Experience
Authors: Uros Markovic, Valerio Leotta, Alessandra Romano, Vittorio Del Fabro, Giuseppe Sapienza, Enrica Antonia Martino, Marina Parisi, Valeria Calafiore, Francesco Di Raimondo, Concetta Conticello
Journal: Blood (2019)
Abstract P2-08-16: The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017
Authors: Yue Gong, Peng Ji, Xin Hu, Zhi-Ming Shao
Journal: Cancer Research (2020)

Abstract Background: Breast cancer is a common diagnosed malignancy and the leading cause of cancer-related death worldwide. Data on burden and changing trends of breast cancer are of value for policymaking. We therefore aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017. Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study in 2017. The number of incident cases, deaths and DALYs attributable to breast cancer are reported as well as age standardized rates. Estimated annual percentage changes (EAPCs) in breast cancer age standardized rate were calculated to quantify the temporal trends. Moreover, attributable burden to breast cancer risk factors were also estimated using the comparative risk assessment framework of the GBD study. Results: There were 878,686 incident cases and 349,581 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age standardized incidence rate increased between 1990 and 2017, while the age standardized mortality rate and DALY rate decreased. The corresponding EAPCs were 0.41 (95% CI: 0.35 to 0.47), -0.62 (95% CI: -0.68 to -0.55), -0.56 (95% CI: -0.63 to -0.48), respectively. These trends were heterogeneous across regions and countries. The increase in the age standardized incidence rate was more prominent in countries with a low socio-demographic index and the decrease in the age standardized mortality rate and DALY rate was more prominent in countries with a high socio-demographic index. Percentage of breast cancer deaths due to alcohol use (12.94% to 9.64%) and tobacco (7.15% to 5.14%) was decreasing while deaths due to high body-mass index (4.03% to 6.54%) and high fasting plasma glucose (5.94% to 7.26%) was increasing. Conclusion: Breast cancer remains a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer prevention, screening and treatment should be considered. Citation Format: Yue Gong, Peng Ji, Xin Hu, Zhi-Ming Shao. The burden and trends of breast cancer from 1990 to 2017 at the global, regional, and national level: Results from the global burden of disease study 2017 [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 P2-08-16.
AMPK Complex Activation Promotes Sarcolemmal Repair in Dysferlinopathy
Authors: Hiroya Ono, Naoki Suzuki, Shin-ichiro Kanno, Genri Kawahara, Rumiko Izumi, Toshiaki Takahashi, Yasuo Kitajima, Shion Osana, Naoko Nakamura, Tetsuya Akiyama, Kensuke Ikeda, Tomomi Shijo, Shio Mitsuzawa, Ryoichi Nagatomi, Nobukazu Araki, Akira Yasui, Hitoshi Warita, Yukiko K. Hayashi, Katsuya Miyake, Masashi Aoki
Journal: Molecular Therapy (2020)

Mutations in dysferlin are responsible for a group of progressive, recessively inherited muscular dystrophies known as dysferlinopathies. Using recombinant proteins and affinity purification methods combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), we found that AMP-activated protein kinase (AMPK)γ1 was bound to a region of dysferlin located between the third and fourth C2 domains. Using ex vivo laser injury experiments, we demonstrated that the AMPK complex was vital for the sarcolemmal damage repair of skeletal muscle fibers. Injury-induced AMPK complex accumulation was dependent on the presence of Ca2+, and the rate of accumulation was regulated by dysferlin. Furthermore, it was found that the phosphorylation of AMPKα was essential for plasma membrane repair, and treatment with an AMPK activator rescued the membrane-repair impairment observed in immortalized human myotubes with reduced expression of dysferlin and dysferlin-null mouse fibers. Finally, it was determined that treatment with the AMPK activator metformin improved the muscle phenotype in zebrafish and mouse models of dysferlin deficiency. These findings indicate that the AMPK complex is essential for plasma membrane repair and is a potential therapeutic target for dysferlinopathy.
Clonal ZEB1-Driven Mesenchymal Transition Promotes Targetable Oncologic Antiangiogenic Therapy Resistance
Authors: Ankush Chandra, Arman Jahangiri, William Chen, Alan T. Nguyen, Garima Yagnik, Matheus P. Pereira, Saket Jain, Joseph H. Garcia, Sumedh S. Shah, Harsh Wadhwa, Rushikesh S. Joshi, Jacob Weiss, Kayla J. Wolf, Jung-Ming G. Lin, Sören Müller, Jonathan W. Rick, Aaron A. Diaz, Luke A. Gilbert, Sanjay Kumar, Manish K. Aghi
Journal: Cancer Research (2020)

Abstract Glioblastoma (GBM) responses to bevacizumab are invariably transient with acquired resistance. We profiled paired patient specimens and bevacizumab-resistant xenograft models pre- and post-resistance toward the primary goal of identifying regulators whose targeting could prolong the therapeutic window, and the secondary goal of identifying biomarkers of therapeutic window closure. Bevacizumab-resistant patient specimens and xenografts exhibited decreased vessel density and increased hypoxia versus pre-resistance, suggesting that resistance occurs despite effective therapeutic devascularization. Microarray analysis revealed upregulated mesenchymal genes in resistant tumors correlating with bevacizumab treatment duration and causing three changes enabling resistant tumor growth in hypoxia. First, perivascular invasiveness along remaining blood vessels, which co-opts vessels in a VEGF-independent and neoangiogenesis-independent manner, was upregulated in novel biomimetic 3D bioengineered platforms modeling the bevacizumab-resistant microenvironment. Second, tumor-initiating stem cells housed in the perivascular niche close to remaining blood vessels were enriched. Third, metabolic reprogramming assessed through real-time bioenergetic measurement and metabolomics upregulated glycolysis and suppressed oxidative phosphorylation. Single-cell sequencing of bevacizumab-resistant patient GBMs confirmed upregulated mesenchymal genes, particularly glycoprotein YKL-40 and transcription factor ZEB1, in later clones, implicating these changes as treatment-induced. Serum YKL-40 was elevated in bevacizumab-resistant versus bevacizumab-naïve patients. CRISPR and pharmacologic targeting of ZEB1 with honokiol reversed the mesenchymal gene expression and associated stem cell, invasion, and metabolic changes defining resistance. Honokiol caused greater cell death in bevacizumab-resistant than bevacizumab-responsive tumor cells, with surviving cells losing mesenchymal morphology. Employing YKL-40 as a resistance biomarker and ZEB1 as a target to prevent resistance could fulfill the promise of antiangiogenic therapy. Significance: Bevacizumab resistance in GBM is associated with mesenchymal/glycolytic shifts involving YKL-40 and ZEB1. Targeting ZEB1 reduces bevacizumab-resistant GBM phenotypes.
Health secretary is threatened with legal action over treatment of people with learning disabilities and autism
Authors: Abi Rimmer
Journal: BMJ (2020)

The Equality and Human Rights Commission has launched a legal challenge against England’s health and social care secretary, Matt Hancock, over a repeated failure to move people with learning disabilities and autism into appropriate accommodation.

The commission is a statutory non-departmental public body that safeguards and enforces the laws protecting people’s rights to fairness, dignity, and respect. It said that it had longstanding concerns about the rights of more than 2000 people with learning disabilities and autism who were being detained …
Purifying selection of long dsRNA is the first line of defense against false activation of innate immunity
Authors: Michal Barak, Hagit T. Porath, Gilad Finkelstein, Binyamin A. Knisbacher, Ilana Buchumenski, Shalom Hillel Roth, Erez Y. Levanon, Eli Eisenberg
Journal: Genome biology (2020)

Mobile elements comprise a large fraction of metazoan genomes. Accumulation of mobile elements is bound to produce multiple putative double-stranded RNA (dsRNA) structures within the transcriptome. These endogenous dsRNA structures resemble viral RNA and may trigger false activation of the innate immune response, leading to severe damage to the host cell. Adenosine to inosine (A-to-I) RNA editing is a common post-transcriptional modification, abundant within repetitive elements of all metazoans. It was recently shown that a key function of A-to-I RNA editing by ADAR1 is to suppress the immunogenic response by endogenous dsRNAs.Here, we analyze the transcriptomes of dozens of species across the Metazoa and identify a strong genomic selection against endogenous dsRNAs, resulting in their purification from the canonical transcriptome. This purifying selection is especially strong for long and nearly perfect dsRNAs. These are almost absent from mRNAs, but not pre-mRNAs, supporting the notion of selection due to cytoplasmic processes. The few long and nearly perfect structures found in human transcripts are weakly expressed and often heavily edited.Purifying selection of long dsRNA is an important defense mechanism against false activation of innate immunity. This newly identified principle governs the integration of mobile elements into the genome, a major driving force of genome evolution. Furthermore, we find that most ADAR1 activity is not required to prevent an immune response to endogenous dsRNAs. The critical targets of ADAR1 editing are, likely, to be found mostly in non-canonical transcripts.