tbuckley/cabot-search huggingface dataset:
Response to Yang, Shi, Wang et al.
Authors: Mok Oh, Ali McBride, Seongseok Yun, Sandipan Bhattacharjee, Marion Slack, Jennifer R Martin, Joanne Jeter, Ivo Abraham
Journal: JNCI Journal of the National Cancer Institute (2019)

An underrecognized issue in meta-analysis is how to address heterogeneity, not of endpoints or outcomes across studies, but of study designs.Our meta-analysis on BRCA1 and BRCA2 in colorectal cancer (CRC) certainly faced the challenge of integrating findings from (clusters of) studies that differed in elements of design such as defining BRCA mutations, CRC patients, comparison groups, and mutation carriers, which we acknowledged in our paper but also benefitted from additional perspectives by Katona et al. (1) and now also Yang et al.On the issue of including colon (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 153) but not rectal cancer (ICD-9-CM: 154) in the studies by Ford et al. (2), Van Asperen et al. (3), and the Breast Cancer Linkage Consortium (4), we chose to err on the conservative side and included only pathologically diagnosed CRC in our analysis (3).This was based on a thoughtful observation by Evan et al. (5) that two of the four CRC cases in the Phelan et al. ( 6) study were cell carcinoma of the anus, which is likely attributable to human papillomavirus.The three papers cited above used the ICD-9-CM: 154 code for rectal cancer, which includes the five subcodes of 154.0, 154.1, 154.2, 154.3, and 154.8.Of these, only 154.0 and 154.1 are codes for neoplasm of the rectum, whereas the other 154 codes include neoplasm of the anus.Therefore, we used only the colon cancer portion reported in these three papers.Type of comparison group is another issue of heterogeneity in designs, and studies varied in this regard.Yang and colleagues refer to Risch et al. ( 7), who used relatives of BRCA1/2mutation carriers as the case group, which is different from the case group in other studies.However, although the Risch et al. study was included in our systematic review, it was one of the four (out of 18) studies not retained for the meta-analysis.It did not meet inclusion criteria because of the different control group used and was labeled a cohort study involving kindred.We share the correspondents' desire for additional subgroup analyses by type of control group.However, our systematic review demonstrates the limited granularity of the studies with regard to case group stratification, as well as the limited statistical power.Continued systematic synthesis of extant and future evidence will enhance the understanding of BRCA-mutation status and the risk of CRC.In the interim, our findings provide the level of synthesis afforded by the studies performed to date.With due caution, our study points to a 1.49-fold greater risk of CRC in BRCA1-mutation carriers relative to the risk in comparator populations, but not in BRCA2-mutation carriers.
Development of adaptive immune effector therapies in solid tumors
Authors: P. Comoli, C. Chabannon, U. Koehl, F. Lanza, A. Urbano-Ispizua, M. Hudecek, A. Ruggeri, S. Secondino, C. Bonini, P. Pedrazzoli
Journal: Annals of Oncology (2019)

State-of-the-art treatment strategies have drastically ameliorated the outcome of patients affected by cancer. However, resistant and recurrent solid tumors are generally nonresponsive to conventional therapies. A central factor in the sequence of events that lead to cancer is an alteration in antitumor immune surveillance, which results in failure to recognize and eliminate the transformed tumor cell. A greater understanding of the dysregulation and evasion of the immune system in the evolution and progression of cancer provides the basis for improved therapies. Targeted strategies, such as T-cell therapy, not only generally spare normal tissues, but also use alternative antineoplastic mechanisms that synergize with other therapeutics. Despite encouraging success in hematologic malignancies, adaptive cellular therapies for solid tumors face unique challenges because of the immunosuppressive tumor microenvironment, and the hurdle of T-cell trafficking within scarcely accessible tumor sites. This review provides a brief overview of current cellular therapeutic strategies for solid tumors, research carried out to increase efficacy and safety, and results from ongoing clinical trials.
Overexpression of p53 due to excess protein O-GlcNAcylation is associated with coronary microvascular disease in type 2 diabetes
Authors: Rui Si, Qian Zhang, Atsumi Tsuji-Hosokawa, Makiko Watanabe, Conor Willson, Ning Lai, Jian Wang, Anzhi Dai, Brian T Scott, Wolfgang H Dillmann, Jason X -J Yuan, Ayako Makino
Journal: Cardiovascular Research (2019)

Abstract Aims We previously reported that increased protein O-GlcNAcylation in diabetic mice led to vascular rarefaction in the heart. In this study, we aimed to investigate whether and how coronary endothelial cell (EC) apoptosis is enhanced by protein O-GlcNAcylation and thus induces coronary microvascular disease (CMD) and subsequent cardiac dysfunction in diabetes. We hypothesize that excessive protein O-GlcNAcylation increases p53 that leads to CMD and reduced cardiac contractility. Methods and results We conducted in vivo functional experiments in control mice, TALLYHO/Jng (TH) mice, a polygenic type 2 diabetic (T2D) model, and EC-specific O-GlcNAcase (OGA, an enzyme that catalyzes the removal of O-GlcNAc from proteins)-overexpressing TH mice, as well as in vitro experiments in isolated ECs from these mice. TH mice exhibited a significant increase in coronary EC apoptosis and reduction of coronary flow velocity reserve (CFVR), an assessment of coronary microvascular function, in comparison to wild-type mice. The decreased CFVR, due at least partially to EC apoptosis, was associated with decreased cardiac contractility in TH mice. Western blot experiments showed that p53 protein level was significantly higher in coronary ECs from TH mice and T2D patients than in control ECs. High glucose treatment also increased p53 protein level in control ECs. Furthermore, overexpression of OGA decreased protein O-GlcNAcylation and down-regulated p53 in coronary ECs, and conferred a protective effect on cardiac function in TH mice. Inhibition of p53 with pifithrin-α attenuated coronary EC apoptosis and restored CFVR and cardiac contractility in TH mice. Conclusions The data from this study indicate that inhibition of p53 or down-regulation of p53 by OGA overexpression attenuates coronary EC apoptosis and improves CFVR and cardiac function in diabetes. Lowering coronary endothelial p53 levels via OGA overexpression could be a potential therapeutic approach for CMD in diabetes.
Tumor control with palliative external beam radiation therapy (EBRT) in advanced and unresectable osteosarcoma (OS) progressing after standard treatment.
Authors: Francesco Tolomeo, Marco Gatti, Lorenzo D'Ambrosio, Monica Rampino, Antonella Boglione, Alessandra Merlini, Giulia Manessi, Sara Miano, Antonia Salatino, Gabriella Cattari, Ilaria Bertotto, Tiziana Robba, Anna Mussano, Laura Rossi, Raimondo Piana, Alessandro Comandone, Sandra Aliberti, Massimo Aglietta, Giovanni Grignani
Journal: Journal of Clinical Oncology (2019)

e22508 Background: Advanced OS still represents an unmet medical need. Chemotherapy and targeted therapies have only limited activity in this disease. Moreover, OS is considered a radioresistant tumor at doses conventionally achieved by EBRT. We retrospectively evaluated the impact of palliative EBRT in patients (pts) with advanced OS. Methods: Main inclusion criteria: confirmed histological diagnosis of OS; EBRT for advanced/metastatic disease deemed unresectable after multidisciplinary tumor board discussion; ECOG performance status ≤3, age ≥18 years at RT start; progressive disease at site of irradiation with symptoms (e.g., pain or neurological deficit) or involving critical structures (e.g., superior vena cava compression). Endpoints: progression-free survival (PFS), PFS for RT-treated lesions (RT-PFS), best response with RT, overall survival. All survival endpoints were computed from RT start. We calculated the equivalent total dose in 2 Gy fractions (EQD2). Results: 23 pts, 15 males, median age at diagnosis 33 (17-82), median age at RT start 36 (20-83) were included. All pts had grade 3-4 OS (12 osteoblastic; 6 chondroblastic; 5 other), 7 were metastatic at diagnosis. At time of RT, median metastatic sites were 2 (1-5), 15 pts were symptomatic (11 pain, 4 neurological deficit) and were mainly heavily pretreated [median previous chemotherapies 2 (1-5), median previous surgery 1 (0-2)]. Overall, 45 lesions underwent EBRT. Median EBRT dose per lesion was 33 Gy (IQR 25 - 46.5) with a median dose per fraction of 3 Gy (IQR 3-7.5). Calculated median EQD2 was 50 Gy (IQR 36 - 88). Median PFS, RT-PFS, and overall survival were 5 (95%CI 2-9), 11 (5-15), and 12 months (8-16), respectively. Compared to systemic progression, median progression delay of irradiated lesions was 6 months (95%CI 2 - 12). In 40 lesions evaluable for dimensional response, we observed tumor shrinkage &gt; 30% in 7 lesions, stability in 24, and progression in 9. Conclusions: EBRT might have a role in the treatment of advanced OS. In consideration of the limited activity of medical treatments, EBRT might help in disease control in the advanced setting, delaying progression especially at critical sites.
Factors Associated With Immune Checkpoint Inhibitor–Related Myocarditis
Authors: Yoshito Zamami, Takahiro Niimura, Naoto Okada, Toshihiro Koyama, Keijo Fukushima, Yuki Izawa-Ishizawa, Keisuke Ishizawa
Journal: JAMA Oncology (2019)

This analysis investigates risk factors for immune checkpoint inhibitor–related myocarditis using a large pool of data gathered from the US Food and Drug Administration Adverse Event Reporting System database.
Effectiveness of pneumococcal conjugate vaccine against hospital admissions for pneumonia in Australian children: a retrospective, population-based, record-linked cohort study
Authors: Parveen Fathima, Heather F Gidding, Peter B McIntyre, Thomas L Snelling, Lisa McCallum, Nicholas de Klerk, Christopher C Blyth, Bette Liu, Hannah C Moore
Journal: The Lancet Child & Adolescent Health (2019)
Circular RNA circNHSL1 promotes gastric cancer progression through the miR-1306-3p/SIX1/vimentin axis
Authors: Zhonglin Zhu, Zeyin Rong, Zai Luo, Zhilong Yu, Jing Zhang, Zhengjun Qiu, Chen Huang
Journal: Molecular Cancer (2019)

Mounting evidences indicate that circular RNAs (circRNAs) play vital roles in the development and progression of various cancers. However, the detail functions and underlying mechanisms of circRNAs in gastric cancer remain largely unknown.The expression profile of metastasis-related circRNAs was screened by RNA-seq analysis. qRT-PCR was used to determine the level and prognostic values of circNHSL1 in gastric cancer tissues. In vitro cell wound healing and transwell (migration and invasion) and in vivo tumorigenesis and metastasis assays were performed to evaluate the functions of circNHSL1. Luciferase reporter, RNA immunoprecipitation (RIP) and rescued assays were employed to confirm the interactions between circNHSL1, miR-1306-3p and SIX1. It's widely accepted that as a mesenchymal marker, Vimentin promotes invasion and metastasis in various cancers. Luciferase reporter assay was used to determine the regulation of SIX1 on Vimentin. In addition, In situ hybridization (ISH) was performed to detect the level and prognostic values of miR-1306-3p.We found that the level of circNHSL1 was significantly up-regulated in gastric cancer, and positively correlated with clinicopathological features and poor prognosis of patients with gastric cancer. Functionally, circNHSL1 promoted cell mobility and invasion, as well as in vivo tumorgenesis and metastasis. Mechanistically, circNHSL1 acted as a miR-1306-3p sponge to relieve the repressive effect of miR-1306-3p on its target SIX1. Moreover, SIX1 enhanced Vimentin expression in the transcriptional level through directly binding to the promoter domain of Vimentin, thereby promoting cell migration and invasion. In addition, miR-1306-3p was down-regulated and negatively correlated with pathological features and poor prognosis in gastric cancer.CircNHSL1 promotes gastric cancer progression through miR-1306-3p/SIX1/Vimentin axis, and may serve as a novel diagnostic marker and target for treatment of gastric cancer patients.
Antiemetic Prophylaxis with Granisetron and Fosaprepitant during Moderate and High Emetogenic Chemotherapy in Pediatric Patients
Authors: Michaela Döring, Karin Melanie Cabanillas Stanchi, Manon Queudeville, Ulrike Hartmann, Michael Ost, Marie-Sarah Koch, Carmen Malaval, Markus Mezger, Sarah Schober, Simone Weber, Veit Lange, Rupert Handgretinger, Martin Ebinger
Journal: Blood (2017)
Pleural Plaques and the Risk of Lung Cancer in Asbestos-exposed Subjects
Authors: Fraser J. H. Brims, Karen Kong, Ed J. A. Harris, Nita Sodhi-Berry, Alison Reid, Conor P. Murray, Peter J. Franklin, A. Bill Musk, Nicholas H. de Klerk
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Asbestos exposure is associated with a dose-dependent risk of lung cancer. The association between lung cancer and the presence of pleural plaques remains controversial.Objectives: To define the relationship between pleural plaques and lung cancer risk.Methods: Subjects were from two cohorts: 1) crocidolite mine and mill workers and Wittenoom Township residents and 2) a mixed-asbestos-fiber, mixed-occupation group. All subjects underwent annual review since 1990, chest X-ray or low-dose computed tomography scan, and outcome linkage to national cancer and mortality registry data. Cox regression, with adjustment for age (as the underlying matching time variable), was used to estimate hazard ratios (HRs) for lung cancer incidence by sex, tobacco smoking, asbestos exposure, presence of asbestosis, and pleural plaques.Measurements and Main Results: For all 4,240 subjects, mean age at follow up was 65.4 years, 3,486 (82.0%) were male, 1,315 (31.0%) had pleural plaques, and 1,353 (32.0%) had radiographic asbestosis. Overall, 3,042 (71.7%) were ever-smokers with mean tobacco exposure of 33 pack-years. In total, 200 lung cancers were recorded. Risk of lung cancer increased with cumulative exposure to cigarettes, asbestos, and presence of asbestosis. Pleural plaques did not confer any additional lung cancer risk in either cohort (cohort 1: HR, 1.03; 95% confidence interval, 0.64-1.67; P = 0.89; cohort 2: HR, 0.75; 95% confidence interval, 0.45-1.25; P = 0.28).Conclusions: The presence of pleural plaques on radiologic imaging does not confer additional increase in the risk of lung cancer. This result is consistent across two cohorts with differing asbestos fiber exposures and intensity.
Time-Series Analysis of Health Care–Associated Infections in a New Hospital With All Private Rooms
Authors: Emily G. McDonald, Nandini Dendukuri, Charles Frenette, Todd C. Lee
Journal: JAMA Internal Medicine (2019)

Health care-associated infections are often caused by multidrug-resistant organisms and substantially factor into hospital costs and avoidable iatrogenic harm. Although it is recommended that new facilities be built with single-room, low-acuity beds, this process is costly and evidence of reductions in health care-associated infections is weak.To examine whether single-patient rooms are associated with decreased rates of common multidrug-resistant organism transmissions and health care-associated infections.A time-series analysis comparing institution-level rates of new multidrug-resistant organism colonization and health care-associated infections before (January 1, 2013-March 31, 2015) and after (April 1, 2015-March 31, 2018) the move to the hospital with 100% single-patient rooms. In the largest hospital move in Canadian history, inpatients in an older, tertiary care, 417-bed hospital in Montréal, Canada, that consisted of mainly mixed 3- and 4-person ward-type rooms were moved to a new 350-bed facility with all private rooms.A synchronized move of all patients on April 26, 2015, to a new hospital with 100% single-patient rooms equipped with individual toilets and showers and easy access to sinks for hand washing.Rates of nosocomial vancomycin-resistant Enterococcus (VRE) and methicillin-resistant Staphylococcus aureus (MRSA) colonization, VRE and MRSA infection, and Clostridioides difficile (formerly known as Clostridium difficile) infection (CDI) per 10 000 patient-days.Compared with the 27 months before, during the 36 months after the hospital move, an immediate and sustained reduction in nosocomial VRE colonization (from 766 to 209 colonizations; incidence rate ratio [IRR], 0.25; 95% CI, 0.19-0.34) and MRSA colonization (from 129 to 112 colonizations; IRR, 0.57; 95% CI, 0.33-0.96) was noted, as well as VRE infection (from 55 to 14 infections; IRR, 0.30, 95% CI, 0.12-0.75). Rates of CDI (from 236 to 223 infections; IRR, 0.95; 95% CI, 0.51-1.76) and MRSA infection (from 27 to 37 infections; IRR, 0.89, 95% CI, 0.34-2.29) did not decrease.The move to a new hospital with exclusively single-patient rooms appeared to be associated with a sustained decrease in the rates of new MRSA and VRE colonization and VRE infection; however, the move was not associated with a reduction in CDI or MRSA infection. These findings may have important implications for the role of hospital construction in facilitating infection control.
Binimetinib in heavily pretreated patients with <i> <scp>NRAS</scp> </i> ‐mutant melanoma with brain metastases
Authors: S.M. Goldinger, A. Valeska Matter, U. Urner‐Bloch, J. Narainsing, S. Micaletto, I. Blume, J. Mangana, R. Dummer
Journal: British Journal of Dermatology (2019)
Hematopoietic stem cell response to acute thrombocytopenia requires signaling through distinct receptor tyrosine kinases
Authors: Beáta Ramasz, Anja Krüger, Julia Reinhardt, Anupam Sinha, Michael Gerlach, Alexander Gerbaulet, Susanne Reinhardt, Andreas Dahl, Triantafyllos Chavakis, Ben Wielockx, Tatyana Grinenko
Journal: Blood (2019)
UTX/KDM6A Deletion Promotes Recovery of Spinal Cord Injury by Epigenetically Regulating Vascular Regeneration
Authors: Shuangfei Ni, Zixiang Luo, Liyuan Jiang, Zhu Guo, Ping Li, Xiang Xu, Yong Cao, Chunyue Duan, Tianding Wu, Chengjun Li, Hongbin Lu, Jianzhong Hu
Journal: Molecular Therapy (2019)

The regeneration of the blood vessel system post spinal cord injury (SCI) is essential for the repair of neurological function. As a significant means to regulate gene expression, epigenetic regulation of angiogenesis in SCI is still largely unknown. Here, we found that Ubiquitously Transcribed tetratricopeptide repeat on chromosome X (UTX), the histone H3K27 demethylase, increased significantly in endothelial cells post SCI. Knockdown of UTX can promote the migration and tube formation of endothelial cells. The specific knockout of UTX in endothelial cells enhanced angiogenesis post SCI accompanied with improved neurological function. In addition, we found regulation of UTX expression can change the level of microRNA 24 (miR-24) in vitro. The physical binding of UTX to the promotor of miR-24 was indicated by chromatin immunoprecipitation (ChIP) assay. Meanwhile, methylation sequencing of endothelial cells demonstrated that UTX could significantly decrease the level of methylation in the miR-24 promotor. Furthermore, miR-24 significantly abolished the promoting effect of UTX deletion on angiogenesis in vitro and in vivo. Finally, we predicted the potential target mRNAs of miR-24 related to angiogenesis. We indicate that UTX deletion can epigenetically promote the vascular regeneration and functional recovery post SCI by forming a regulatory network with miR-24.
Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species
Authors: Tina Binderup, Raphaël Duivenvoorden, Francois Fay, Mandy M. T. van Leent, Joost Malkus, Samantha Baxter, Seigo Ishino, Yiming Zhao, Brenda Sanchez-Gaytan, Abraham J. P. Teunissen, Yohana C. A. Frederico, Jun Tang, Giuseppe Carlucci, Serge Lyashchenko, Claudia Calcagno, Nicolas Karakatsanis, Georgios Soultanidis, Max L. Senders, Philip M. Robson, Venkatesh Mani, Sarayu Ramachandran, Mark E. Lobatto, Barbara A. Hutten, Juan F. Granada, Thomas Reiner, Filip K. Swirski, Matthias Nahrendorf, Andreas Kjaer, Edward A. Fisher, Zahi A. Fayad, Carlos Pérez-Medina, Willem J. M. Mulder
Journal: Science Translational Medicine (2019)

A nanoimmunotherapy reduces inflammation in mouse, rabbit, and pig models of atherosclerosis.
Update on lactose malabsorption and intolerance: pathogenesis, diagnosis and clinical management
Authors: Benjamin Misselwitz, Matthias Butter, Kristin Verbeke, Mark R Fox
Journal: Gut (2019)

Lactose is the main source of calories in milk, an essential nutriedigestion, patients with visceral hypersensitivity nt in infancy and a key part of the diet in populations that maintain the ability to digest this disaccharide in adulthood. Lactase deficiency (LD) is the failure to express the enzyme that hydrolyses lactose into galactose and glucose in the small intestine. The genetic mechanism of lactase persistence in adult Caucasians is mediated by a single C→T nucleotide polymorphism at the LCTbo -13'910 locus on chromosome-2. Lactose malabsorption (LM) refers to any cause of failure to digest and/or absorb lactose in the small intestine. This includes primary genetic and also secondary LD due to infection or other conditions that affect the mucosal integrity of the small bowel. Lactose intolerance (LI) is defined as the onset of abdominal symptoms such as abdominal pain, bloating and diarrhoea after lactose ingestion by an individual with LM. The likelihood of LI depends on the lactose dose, lactase expression and the intestinal microbiome. Independent of lactose digestion, patients with visceral hypersensitivity associated with anxiety or the Irritable Bowel Syndrome (IBS) are at increased risk of the condition. Diagnostic investigations available to diagnose LM and LI include genetic, endoscopic and physiological tests. The association between self-reported LI, objective findings and clinical outcome of dietary intervention is variable. Treatment of LI can include low-lactose diet, lactase supplementation and, potentially, colonic adaptation by prebiotics. The clinical outcome of these treatments is modest, because lactose is just one of a number of poorly absorbed carbohydrates which can cause symptoms by similar mechanisms.
The dichotomous role of the glycolytic metabolism pathway in cancer metastasis: Interplay with the complex tumor microenvironment and novel therapeutic strategies
Authors: Btissame El Hassouni, Carlotta Granchi, Andrea Vallés-Martí, I Gede Putu Supadmanaba, Giulia Bononi, Tiziano Tuccinardi, Niccola Funel, Connie R. Jimenez, Godefridus J. Peters, Elisa Giovannetti, Filippo Minutolo
Journal: Seminars in Cancer Biology (2019)