tbuckley/cabot-search huggingface dataset:
Covid-19: medical students should not work outside their competency, says BMA
Authors: Anna Harvey
Journal: BMJ (2020)

Objective. To assess white matter (WM) and functional connectivity alterations in patients with posterior cortical atrophy (PCA) compared to a population of healthy controls. Background. PCA is an atypical variant of Alzheimer’s disease characterized by an early age of onset, visuospatial impairment and occipital and posterior temporal-parietal atrophy. Up to date, the functional connectivity in these patients has been poorly investigated. Methods. Seven probable PCA patients (age-at-onset: 56±5 years; age-at-MRI: 61±5 years; disease duration: 4±2 years) and 21 healthy controls underwent T1-weighted, diffusion tensor (DT) and resting state functional (RS-fMRI) MRI. We assessed WM microstructure using a voxel-wise method and RS-fMRI data using a model free approach accounting for gray matter. Results. Compared with controls, PCA patients showed a distributed and symmetrical pattern of WM microstructural alterations in the corpus callosum, parahippocampal tracts, anterior and posterior cingulum, superior and inferior longitudinal fasciculi, and inferior fronto-occipital fasciculus. Compared with controls, PCA patients showed also decreased functional connectivity of: the bilateral calcarine gyrus, left cuneus and left middle and inferior occipital gyri within the visual-network; the right calcarine gyrus and precuneus, left superior and middle temporal gyri, left cuneus and lingual gyrus within the default-mode-network; the bilateral medial-superior frontal gyrus and right anterior cingulum within the fronto-striatal network; the left thalamus and hippocampus within the attentional-network; and the left superior temporal gyrus, supramarginal gyrus and paracentral lobule within the salience-network. Conclusions. This study shows that PCA is characterized by a pattern of WM damage which is more widely distributed than expected on the basis of cortical atrophy, and altered functional connectivity which extends beyond the visual and default-mode networks. Structural and functional abnormalities in the frontal and temporal circuits of PCA patients may suggest a progression of the disease from the posterior to the most anterior brain regions. <b>Disclosure:</b> Dr. imperiale has nothing to disclose. Dr. Agosta has received personal compensation for activities with Biogen Idec and EXCEMED– Excellence in Medical Education. Dr. Canu has nothing to disclose. Dr. Mandic-Stojmenovic has nothing to disclose. Dr. Stojkovic has nothing to disclose. Dr. Stefanova has nothing to disclose. Dr. Kostic has received personal compensation for activities with Novartis, Boehringer Ingelheim Pharmaceuticals, Merck &amp; Co., Inc., Lundbeck Research USA, Inc., GlaxoSmithKline, Hoffman-La Roche, Alkaloid, and &#xD; AbbVie as a speaker. Dr. Filippi has received personal compensation for activities for consulting services and/or speaking activities from Biogen Idec, Excemed, Novartis, and Teva Pharmaceutical Industries.
OPTIMAL P2Y12 INHIBITOR IN PATIENTS WITH ST SEGMENT ELEVATION MYOCARDIAL INFARCTION UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION: A NETWORK META-ANALYSIS
Authors: Asim Rafique, Piyush Nayyar, Usman Baber, Tracy Wang, Jonathan Tobis, Jesse Currier, Ravi Dave, Timothy Henry
Journal: Journal of the American College of Cardiology (2016)
Patenting Foundational Technologies: Recent Developments in the CRISPR Patent Struggle
Authors: Julian Cockbain, Sigrid Sterckx
Journal: The American Journal of Bioethics (2020)

In a target article (Feeney et al. 2018) in this Journal in 2018, for which we were two of the coauthors, we discussed the problematic nature of the patenting of foundational (bio)technological pro...
Clinical Profiles and Health Services Patterns of Medicaid-Enrolled Youths Who Died by Suicide
Authors: Cynthia A. Fontanella, Lynn A. Warner, Danielle Steelesmith, Jeffrey A. Bridge, Helen Anne Sweeney, John V. Campo
Journal: JAMA Pediatrics (2020)

Youth suicide is a major public health problem, and health care settings play a critical role in suicide prevention efforts, but limited data are available to date on health and mental health service use patterns before suicide.
Right Ventricle–to–Left Ventricle Diameter Ratio Measurement Seems to Have No Role in Low-Risk Patients with Pulmonary Embolism Treated at Home Triaged by Hestia Criteria
Authors: Stephan V. Hendriks, Frederikus A. Klok, Paul L. den Exter, Michiel Eijsvogel, Laura M. Faber, Herman M. A. Hofstee, Antonio Iglesias del Sol, Lucia J. M. Kroft, Albert T. A. Mairuhu, Menno V. Huisman
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
Safety and diagnostic efficacy of cone beam computed tomography-guided transbronchial cryobiopsy for interstitial lung disease: a cohort study
Authors: Guowu Zhou, Yanhong Ren, Jun Li, Ting Yang, Nan Su, Ling Zhao, Dan Wang, Ying Li, Zheng Tian, Ruihong Liu, Huaping Dai, Chen Wang
Journal: European Respiratory Journal (2020)

<b>Cone beam CT (CBCT) can provide 3-dimensional images enabling accurate positioning of cryoprobe. CBCT-guided transbronchial cryobiopsy had a favourable safety profile with low risks of pneumothorax and significant bleeding, with excellent diagnostic yield.</b>https://bit.ly/2WF0SPF
Cost-effectiveness of positive airway pressure modalities in obesity hypoventilation syndrome with severe obstructive sleep apnoea
Authors: Juan F Masa, Babak Mokhlesi, Iván Benítez, Francisco Javier Gómez de Terreros Caro, M-Ángeles Sánchez-Quiroga, Auxiliadora Romero, Candela Caballero, Maria Luz Alonso-Álvarez, Estrella Ordax-Carbajo, Teresa Gómez-García, Mónica González, Soledad López-Martín, Jose M Marin, Sergi Martí, Trinidad Díaz-Cambriles, Eusebi Chiner, Carlos Egea, Javier Barca, Francisco-José Vázquez-Polo, Miguel Angel Negrín, María Martel-Escobar, Ferran Barbé, Jaime Corral-Peñafiel
Journal: Thorax (2020)

Background Obesity hypoventilation syndrome (OHS) is treated with either non-invasive ventilation (NIV) or CPAP, but there are no long-term cost-effectiveness studies comparing the two treatment modalities. Objectives We performed a large, multicentre, randomised, open-label controlled study to determine the comparative long-term cost and effectiveness of NIV versus CPAP in patients with OHS with severe obstructive sleep apnoea (OSA) using hospitalisation days as the primary outcome measure. Methods Hospital resource utilisation and within trial costs were evaluated against the difference in effectiveness based on the primary outcome (hospitalisation days/year, transformed and non-transformed in monetary term). Costs and effectiveness were estimated from a log-normal distribution using a Bayesian approach. A secondary analysis by adherence subgroups was performed. Results In total, 363 patients were selected, 215 were randomised and 202 were available for the analysis. The median (IQR) follow-up was 3.01 (2.91–3.14) years for NIV group and 3.00 (2.92–3.17) years for CPAP. The mean (SD) Bayesian estimated hospital days was 2.13 (0.73) for CPAP and 1.89 (0.78) for NIV. The mean (SD) Bayesian estimated cost per patient/year in the NIV arm, excluding hospitalisation costs, was €2075.98 (91.6), which was higher than the cost in the CPAP arm of €1219.06 (52.3); mean difference €857.6 (105.5). CPAP was more cost-effective than NIV (99.5% probability) because longer hospital stay in the CPAP arm was compensated for by its lower costs. Similar findings were observed in the high and low adherence subgroups. Conclusion CPAP is more cost-effective than NIV; therefore, CPAP should be the preferred treatment for patients with OHS with severe OSA. Trial registration number NCT01405976
Paediatric to adult transition care for patients with sickle cell disease: a global perspective
Authors: Baba Psalm Duniya Inusa, Claire Elizabeth Stewart, Shamarah Mathurin-Charles, Jerlym Porter, Lewis Li-yen Hsu, Wale Atoyebi, Mariane De Montalembert, Ijeoma Diaku-Akinwumi, Norah O Akinola, Biree Andemariam, Miguel Raul Abboud, Marsha Treadwell
Journal: The Lancet Haematology (2020)
Cabazitaxel in Metastatic Prostate Cancer
Authors: Ronald de Wit, Johann de Bono, Daniel Castellano
Journal: New England Journal of Medicine (2020)

BACKGROUND
The efficacy and safety of cabazitaxel, as compared with an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients with metastatic castrationresistant prostate cancer who were previously treated with docetaxel and had progression within 12 months while receiving the alternative inhibitor (abiraterone or
enzalutamide) are unclear.
METHODS
We randomly assigned, in a 1:1 ratio, patients who had previously received docetaxel and an androgen-signaling–targeted inhibitor (abiraterone or enzalutamide) to
receive cabazitaxel (at a dose of 25 mg per square meter of body-surface area intravenously every 3 weeks, plus prednisone daily and granulocyte colony-stimulating factor) or the other androgen-signaling–targeted inhibitor (either 1000 mg of
abiraterone plus prednisone daily or 160 mg of enzalutamide daily). The primary end
point was imaging-based progression-free survival. Secondary end points of survival,
response, and safety were assessed.
RESULTS
A total of 255 patients underwent randomization. After a median follow-up of 9.2
months, imaging-based progression or death was reported in 95 of 129 patients
(73.6%) in the cabazitaxel group, as compared with 101 of 126 patients (80.2%) in
the group that received an androgen-signaling–targeted inhibitor (hazard ratio,
0.54; 95% confidence interval [CI], 0.40 to 0.73; P<0.001). The median imagingbased progression-free survival was 8.0 months with cabazitaxel and 3.7 months
with the androgen-signaling–targeted inhibitor. The median overall survival was
13.6 months with cabazitaxel and 11.0 months with the androgen-signaling–targeted inhibitor (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.89; P=0.008). The
median progression-free survival was 4.4 months with cabazitaxel and 2.7 months
with an androgen-signaling–targeted inhibitor (hazard ratio for progression or death,
0.52; 95% CI, 0.40 to 0.68; P<0.001), a prostate-specific antigen response occurred in
35.7% and 13.5% of the patients, respectively (P<0.001), and tumor response was
noted in 36.5% and 11.5% (P=0.004). Adverse events of grade 3 or higher occurred in
56.3% of patients receiving cabazitaxel and in 52.4% of those receiving an androgensignaling–targeted inhibitor. No new safety signals were observed.
CONCLUSIONS
Cabazitaxel significantly improved a number of clinical outcomes, as compared with
the androgen-signaling–targeted inhibitor (abiraterone or enzalutamide), in patients
with metastatic castration-resistant prostate cancer who had been previously treated
with docetaxel and the alternative androgen-signaling–targeted agent (abiraterone or
enzalutamide). (Funded by Sanofi; CARD ClinicalTrials.gov number, NCT02485691.)
Abstract OT3-02-03: Radiomics multi-parametric MRI of before and after neoadjuvant chemotherapy associated with axillary lymph node metastasis and prognostic in patients with breast cancer: A multicenter RBC-002 study
Authors: Herui Yao, ChenChen Li, Yunfang Yu, Chuanmiao Xie, Jie Ouyang, Yujie Tan, Nian Lu, Ying Wang, Jianli Zhao, Kai Chen, Jiafan Ma
Journal: Cancer Research (2020)

Abstract Background: Axillary lymph node metastasis is a vital factor of prognosis in patients with invasive breast cancer. However, sensitivity and noninvasive for prediction of lymph node metastasis and survival after neoadjuvant chemotherapy is limited. This study aims to develop radiomics combining multi-parametric MRI before and after neoadjuvant chemotherapy to predict axillary lymph node metastasis and prognosis, as well as investigate the relationship between the radiomics and tumor microenvironment in invasive breast- cancer. Methods: RBC-02 is a multicenter, ambispective cohort study proposes to build a clinical predictive model to predict axillary lymph node metastasis and prognosis in invasive-breast- cancer patients who received neoadjuvant chemotherapy. Patients are recruited from Sun Yat-sen Memorial Hospital of Sun Yat-sen University (training cohort), Sun Yat-sen University Cancer Center (validation cohort), and Tungwah hospital of Sun Yat-sen University (validation cohort) in China. Invasive breast cancer patients undergo multi-parametric MRI at baseline, then undergo multi-parametric MRI after received neoadjuvant chemotherapy for at least 4 cycles as planned. After the surgery, responses to neoadjuvant chemotherapy are determined according to the histopathologically examination of the surgically resected specimens. The model is built based on breast MRI signatures extracted and analyzed via deep machine- learning algorithm methods. The correlation between radiomics features and tumor microenvironment is also planned to investigate. Decision curve analysis was performed with the combined training and validation set to estimate the clinical usefulness of the radiomics nomogram, which is built with a multivariate logistic regression model. The primary endpoint is disease-free survival. Secondary endpoints include pathological complete response, pathological axillary lymph node status, and overall survival. The trial is registered with ClinicalTrials.gov, number NCT04004559, and Chinese Clinical Trail Registry, number ChiCTR1900024113. Citation Format: Herui Yao, ChenChen Li, Yunfang Yu, Chuanmiao Xie, Jie Ouyang, Yujie Tan, Nian Lu, Ying Wang, Jianli Zhao, Kai Chen, Jiafan Ma. Radiomics multi-parametric MRI of before and after neoadjuvant chemotherapy associated with axillary lymph node metastasis and prognostic in patients with breast cancer: A multicenter RBC-002 study [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 OT3-02-03.
Vitamin D levels and nosocomial infections in HPB surgery
Authors: Estefanía Laviano, Helga Kälviäinen, María Sánchez-Rubio, Teresa González-Nicolás, Javier López-Coscojuela, Yolanda Gilaberte, Pilar Palacian, Antonio Rezusta, Alejandro Serrablo
Journal: International Journal of Surgery (2020)
Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate
Authors: Stijn JH Waaijer, Danique Giesen, Takahiro Ishiguro, Yuji Sano, Naofumi Sugaya, Carolina P Schröder, Elisabeth GE de Vries, Marjolijn N Lub-de Hooge
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 ( 89 Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging. Methods To study both the role of GPC3 and CD3 on the biodistribution of [ 89 Zr]Zr-N-suc-Df-ERY974, 89 Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [ 89 Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [ 89 Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution. Results In tumor-bearing immunodeficient mice, [ 89 Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [ 89 Zr]Zr-N-suc-Df-KLH/CD3 and [ 89 Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [ 89 Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [ 89 Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [ 89 Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes. Conclusion [89Zr] Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.
Non-coding RNA therapeutics for cardiac regeneration
Authors: Luca Braga, Hashim Ali, Ilaria Secco, Mauro Giacca
Journal: Cardiovascular Research (2020)

A growing body of evidence indicates that cardiac regeneration after myocardial infarction can be achieved by stimulating the endogenous capacity of cardiomyocytes (CMs) to replicate. This process is controlled, both positively and negatively, by a large set of non-coding RNAs (ncRNAs). Some of the microRNAs (miRNAs) that can stimulate CM proliferation is expressed in embryonic stem cells and is required to maintain pluripotency (e.g. the miR-302∼367 cluster). Others also govern the proliferation of different cell types, including cancer cells (e.g. the miR-17∼92 cluster). Additional miRNAs were discovered through systematic screenings (e.g. miR-199a-3p and miR-590-3p). Several miRNAs instead suppress CM proliferation and are involved in the withdrawal of CMs from the cell cycle after birth (e.g. the let-7 and miR-15 families). Similar regulatory roles on CM proliferation are also exerted by a few long ncRNAs. This body of information has obvious therapeutic implications, as miRNAs with activator function or short antisense oligonucleotides against inhibitory miRNAs or lncRNAs can be administered to stimulate cardiac regeneration. Expression of miRNAs can be achieved by gene therapy using adeno-associated vectors, which transduce CMs with high efficiency. More effective and safer for therapeutic purposes, small nucleic acid therapeutics can be obtained as chemically modified, synthetic molecules, which can be administered through lipofection or inclusion in lipid or polymer nanoparticles for efficient cardiac delivery. The notion that it is possible to reprogramme CMs into a regenerative state and that this property can be enhanced by ncRNA therapeutics remains exciting, however extensive experimentation in large mammals and rigorous assessment of safety are required to advance towards clinical application.
Targeting clinical epigenetic reprogramming for chemoprevention of metabolic and viral hepatocellular carcinoma
Authors: Frank Jühling, Nourdine Hamdane, Emilie Crouchet, Shen Li, Houssein El Saghire, Atish Mukherji, Naoto Fujiwara, Marine A Oudot, Christine Thumann, Antonio Saviano, Armando Andres Roca Suarez, Kaku Goto, Ricard Masia, Mozhdeh Sojoodi, Gunisha Arora, Hiroshi Aikata, Atsushi Ono, Parissa Tabrizian, Myron Schwartz, Stephen J Polyak, Irwin Davidson, Christian Schmidl, Christoph Bock, Catherine Schuster, Kazuaki Chayama, Patrick Pessaux, Kenneth K Tanabe, Yujin Hoshida, Mirjam B Zeisel, François HT Duong, Bryan C Fuchs, Thomas F Baumert
Journal: Gut (2020)

Hepatocellular carcinoma (HCC) is the fastest-growing cause of cancer-related mortality with chronic viral hepatitis and non-alcoholic steatohepatitis (NASH) as major aetiologies. Treatment options for HCC are unsatisfactory and chemopreventive approaches are absent. Chronic hepatitis C (CHC) results in epigenetic alterations driving HCC risk and persisting following cure. Here, we aimed to investigate epigenetic modifications as targets for liver cancer chemoprevention.Liver tissues from patients with NASH and CHC were analysed by ChIP-Seq (H3K27ac) and RNA-Seq. The liver disease-specific epigenetic and transcriptional reprogramming in patients was modelled in a liver cell culture system. Perturbation studies combined with a targeted small molecule screen followed by in vivo and ex vivo validation were used to identify chromatin modifiers and readers for HCC chemoprevention.In patients, CHC and NASH share similar epigenetic and transcriptomic modifications driving cancer risk. Using a cell-based system modelling epigenetic modifications in patients, we identified chromatin readers as targets to revert liver gene transcription driving clinical HCC risk. Proof-of-concept studies in a NASH-HCC mouse model showed that the pharmacological inhibition of chromatin reader bromodomain 4 inhibited liver disease progression and hepatocarcinogenesis by restoring transcriptional reprogramming of the genes that were epigenetically altered in patients.Our results unravel the functional relevance of metabolic and virus-induced epigenetic alterations for pathogenesis of HCC development and identify chromatin readers as targets for chemoprevention in patients with chronic liver diseases.
Abstract P6-04-08: Mismatch repair defects induce metastasis of ER+ breast cancer
Authors: Sujita Khanal, Athena Jimenez, Svasti Haricharan
Journal: Cancer Research (2020)

Abstract Estrogen receptor (ER) positive breast cancer is a leading cause of cancer-related death among women globally. Metastasis and endocrine treatment resistance are the two principal causes of death from ER+ breast cancer. There are few available targeted therapeutics for metastatic, endocrine treatment resistant disease other than CDK4/6 inhibitors. However, CDK4/6 inhibitors only work in a subset of patients and markers that can identify these patients have not yet been discovered. Considering cost and toxicity associated with chronic use of these inhibitors, it is critical to identify (a) biomarkers of response (b) combinatorial approaches to enhance efficacy. To achieve these goals, we need to understand the biology underlying endocrine treatment resistance and CDK4/6 inhibitor response. We recently identified loss of the MutL complex of mismatch repair (MLH1 and PMS2), as a cause of endocrine treatment resistance in 5-10% of women with primary (non-metastasized) ER+ breast cancer. We also demonstrated that primary ER+ breast cancer cells defective in these genes lacked ATM/Chk2 activation and were, therefore, sensitized to CDK4/6 inhibitors. Here, we present data demonstrating that MutL loss induces metastasis of ER+ breast cancer cells, which can be prevented/treated using ATM/Chk2 activators in combination with CDK4/6 inhibitors. We observed increased migration and invasion in three independent cell line models of MutL loss when treated with endocrine therapies in vitro, and increased lung colonization in vivo. We observe a similar phenotype in a PDX model of MutL defective ER+ disease. We also demonstrate significant inhibition of metastatic phenotypes upon administration of a combination of CDK4/6 inhibitors and ATM/Chk2 activators. Alternative targeted therapies that are effective against metastatic ER+ breast cancer remain elusive, and lethality associated with this diagnosis remains high. Current standard care comprises of endocrine treatment administered with CDK4/6 inhibitors. Even when effective, this combination is costly and associated with side effects as it requires chronic administration to maintain stable disease. The results of this study suggest that (a) MutL loss can be a predictor of increased risk for metastatic disease (b) MutL defective ER+ breast cancer has increased sensitivity to CDK4/6 inhibitors (c) combinatorial use of ATM/Chk2 activators with CDK4/6 inhibitors could significantly benefit ER+ breast cancer patients with defective MutL. These potential outcomes could greatly improve quality of life and decrease cancer-related death in thousands of women every year. Citation Format: Sujita Khanal, Athena Jimenez, Svasti Haricharan. Mismatch repair defects induce metastasis of ER+ 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 P6-04-08.