tbuckley/cabot-search huggingface dataset:
Safe and effective digestive endoscopic resection in patients with cirrhosis: a single-center experience
Authors: Clothilde Miaglia, Olivier Guillaud, Jérôme Rivory, Vincent Lépilliez, Christine Chambon-Augoyard, Valérie Hervieu, Thierry Ponchon, Jérôme Dumortier, Mathieu Pioche
Journal: Endoscopy (2020)

Abstract Background Endoscopic resection has developed over the years. The main complications are perforation and bleeding. This study aimed to evaluate safety and effectiveness of digestive endoscopic resection in patients with cirrhosis. Methods This retrospective, open-label, single-center study included all consecutive patients with cirrhosis who were admitted for endoscopic resection between 2009 and 2016. Safety, efficacy, and risk factors for delayed bleeding were analyzed. Results 126 patients undergoing 164 procedures were included: 65 endoscopic resections (49 patients) in the upper gastrointestinal tract (esophagus 34, stomach 20, duodenum 11) and 99 in the lower gastrointestinal tract (77 patients). Mean Model for End-Stage Liver Disease score was 9.9 (standard deviation 4.5). Esophageal varices were present in 50 patients, and 21 patients had decompensated cirrhosis. The overall curative rate of endoscopic resection was 84.0 %. No patients died during 30-day follow-up. Immediate overall morbidity was 6.1 %, with two postoperative fevers and eight bleeds. Risk factors for delayed bleeding were duodenal location (P &lt; 0.01), antiplatelet medication (P = 0.02), and lower glomerular filtration rate (GFR) (P = 0.01) in univariate analysis. Duodenal location and lower GFR remained statistically significant in multivariate analysis, with respective odds ratios for bleeding of 52.12 and 1.04. No liver decompensation occurred after endoscopic resection. Conclusions Endoscopic resection was safe and effective in patients with mild (Child – Pugh class A/B) cirrhosis, and should be proposed as a first option for treatment of superficial neoplasia. Additional data in patients with severe cirrhosis are needed to confirm the safety in this population.
99mTc Tamoxifen for Imaging Estrogen Receptor Expression in Metastatic Breast Cancer Patient
Authors: Anupriya Chhabra, Jaya Shukla, Rajender Kumar, Ishita Laroiya, Rakhee Vatsa, Amanjit Bal, Gurpreet Singh, Bhagwant Rai Mittal
Journal: Clinical Nuclear Medicine (2019)

Abstract Estrogen receptor–expressing breast cancer exhibits better prognosis due to responsiveness to antiestrogen treatment. Therefore, knowledge of the estrogen receptor status of a tumor is an important prognostic and predictive indicator in breast cancer. We present noninvasive imaging of estrogen receptors with 99m Tc tamoxifen that can identify the active tumor and approachable sites for biopsy. It may help in selection of patients for hormone replacement therapy and in assessment of receptor status in recurrent disease and also in response evaluation.
Our Conflict with Transposable Elements and Its Implications for Human Disease
Authors: Kathleen H. Burns
Journal: Annual Review of Pathology Mechanisms of Disease (2020)

Our genome is a historic record of successive invasions of mobile genetic elements. Like other eukaryotes, we have evolved mechanisms to limit their propagation and minimize the functional impact of new insertions. Although these mechanisms are vitally important, they are imperfect, and a handful of retroelement families remain active in modern humans. This review introduces the intrinsic functions of transposons, the tactics employed in their restraint, and the relevance of this conflict to human pathology. The most straightforward examples of disease-causing transposable elements are germline insertions that disrupt a gene and result in a monogenic disease allele. More enigmatic are the abnormal patterns of transposable element expression in disease states. Changes in transposon regulation and cellular responses to their expression have implicated these sequences in diseases as diverse as cancer, autoimmunity, and neurodegeneration. Distinguishing their epiphenomenal from their pathogenic effects may provide wholly new perspectives on our understanding of disease.
Subtype switching in breast cancer brain metastases: a multicenter analysis
Authors: Alexander F C Hulsbergen, An Claes, Vasileios K Kavouridis, Ali Ansaripour, Claudine Nogarede, Melissa E Hughes, Timothy R Smith, Priscilla K Brastianos, Joost J C Verhoeff, Nancy U Lin, Marike L D Broekman
Journal: Neuro-Oncology (2020)

Abstract Background Breast cancer (BC) brain metastases (BM) can have discordant hormonal or human epidermal growth factor receptor 2 (HER2) expression compared with corresponding primary tumors. This study aimed to describe incidence, predictors, and survival outcomes of discordant receptors and associated subtype switching in BM. Methods BCBM patients seen at 4 tertiary institutions who had undergone BM resection or biopsy were included. Surgical pathology reports were retrospectively assessed to determine discordance between the primary tumor and the BCBM. In discordant cases, expression in extracranial metastases was also assessed. Results In BM from 219 patients, prevalence of any discordance was 36.3%; receptor-specific discordance was 16.7% for estrogen, 25.2% for progesterone, and 10.4% for HER2. Because estrogen and progesterone were considered together for hormonal status, 50 (22.8%) patients switched subtype as a result; 20 of these switches were HER2 based. Baseline subtype predicted switching, which occurred in up to 37.5% of primary HR+ patients. Moreover, 14.8% of initially HER2-negative patients gained HER2 in the BM. Most (63.6%) discordant patients with extracranial metastases also had discordance between BM and extracranial subtype. Loss of receptor expression was generally associated with worse survival, which appeared to be driven by estrogen loss (hazard ratio = 1.80, P = 0.03). Patients gaining HER2 status (n = 8) showed a nonsignificant tendency toward improved survival (hazard ratio = 0.64, P = 0.17). Conclusions In this multicenter study, we report incidence and predictors of subtype switching, the risk of which varies considerably by baseline subtype. Switches can have clinical implications for prognosis and treatment choice.
Unraveling Disease Pathophysiology with Mathematical Modeling
Authors: Brody H. Foy, Bronner P. Gonçalves, John M. Higgins
Journal: Annual Review of Pathology Mechanisms of Disease (2020)

Modeling has enabled fundamental advances in our understanding of the mechanisms of health and disease for centuries, since at least the time of William Harvey almost 500 years ago. Recent technological advances in molecular methods, computation, and imaging generate optimism that mathematical modeling will enable the biomedical research community to accelerate its efforts in unraveling the molecular, cellular, tissue-, and organ-level processes that maintain health, predispose to disease, and determine response to treatment. In this review, we discuss some of the roles of mathematical modeling in the study of human physiology and pathophysiology and some challenges and opportunities in general and in two specific areas: in vivo modeling of pulmonary function and in vitro modeling of blood cell populations.
Arthur Graham Blyth
Authors: Nicky Cooke, Fiona Blyth, Alison Blyth, Elspeth Inman, Bruce Blyth
Journal: BMJ (2020)

After a house job at Guy’s Hospital and three and a half years in the Royal Air Force, mostly as a family doctor in Malta, Arthur Graham Blyth was house surgeon in obstetrics at Winchester Hospital, before joining a practice in …
Structure-inherent near-infrared bilayer nanovesicles for use as photoacoustic image-guided chemo-thermotherapy
Authors: Ilkoo Noh, MunSik Kim, Jeesu Kim, DaeYong Lee, Donghyeon Oh, Juhwan Kim, Chulhong Kim, Sangyong Jon, Yeu-Chun Kim
Journal: Journal of Controlled Release (2020)
IA07 Plasma Proteomic, Glycomic, and Autoantibody Biomarkers for Lung Cancer Early Detection
Authors: K.L. Lastwika, Y. Zhang, M. Shipley, P.E. Kinahan, S. Pipovath, V. Wu, P.P. Massion, A.M. Houghton, P.D. Lampe
Journal: Journal of Thoracic Oncology (2020)
Questioning the benefit of lung metastasectomy in colorectal cancer
Authors: Tom Treasure
Journal: BMJ (2020)

In The BMJ five years ago my colleagues and I questioned the appropriateness of a policy of early detection of colorectal metastases for surgical resection.1 We now have direct evidence from a randomised controlled trial (RCT) that any survival advantage from resection of colorectal lung metastases is, in all likelihood, very much smaller than has been assumed.2

There have been many uncontrolled reports of lung metastasectomy with five year survival of around 40%,3 a figure matched in the Pulmonary Metastasectomy in Colorectal Cancer (PulMiCC) trial (38%, 95% confidence interval 23% to 62%).2 …
CRISPR/Cas9-generated models uncover therapeutic vulnerabilities of del(11q) CLL cells to dual BCR and PARP inhibition
Authors: Miguel Quijada-Álamo, María Hernández-Sánchez, Verónica Alonso-Pérez, Ana E. Rodríguez-Vicente, Ignacio García-Tuñón, Marta Martín-Izquierdo, Jesús María Hernández-Sánchez, Ana B. Herrero, José María Bastida, Laura San Segundo, Michaela Gruber, Juan Luis García, Shanye Yin, Elisa ten Hacken, Rocío Benito, José Luis Ordóñez, Catherine J. Wu, Jesús María Hernández-Rivas
Journal: Leukemia (2020)

Abstract The deletion of 11q (del(11q)) invariably comprises ATM gene in chronic lymphocytic leukemia (CLL). Concomitant mutations in this gene in the remaining allele have been identified in 1/3 of CLL cases harboring del(11q), being the biallelic loss of ATM associated with adverse prognosis. Although the introduction of targeted BCR inhibition has significantly favored the outcomes of del(11q) patients, responses of patients harboring ATM functional loss through biallelic inactivation are unexplored, and the development of resistances to targeted therapies have been increasingly reported, urging the need to explore novel therapeutic approaches. Here, we generated isogenic CLL cell lines harboring del(11q) and ATM mutations through CRISPR/Cas9-based gene-editing. With these models, we uncovered a novel therapeutic vulnerability of del(11q)/ ATM -mutated cells to dual BCR and PARP inhibition. Ex vivo studies in the presence of stromal stimulation on 38 CLL primary samples confirmed a synergistic action of the combination of olaparib and ibrutinib in del(11q)/ ATM -mutated CLL patients. In addition, we showed that ibrutinib produced a homologous recombination repair impairment through RAD51 dysregulation, finding a synergistic link of both drugs in the DNA damage repair pathway. Our data provide a preclinical rationale for the use of this combination in CLL patients with this high-risk cytogenetic abnormality.
Astrocyte‐Encapsulated Hydrogel Microfibers Enhance Neuronal Circuit Generation
Authors: Beom Jin Kim, Ji Yu Choi, Hyunwoo Choi, Sol Han, Jeongyeon Seo, Jungnam Kim, Sunghoon Joo, Hyo Min Kim, Chungik Oh, Seungbum Hong, Pilnam Kim, Insung S. Choi
Journal: Advanced Healthcare Materials (2020)

Abstract Astrocytes, the most representative glial cells in the brain, play a multitude of crucial functions for proper neuronal development and synaptic‐network formation, including neuroprotection as well as physical and chemical support. However, little attention has been paid, in the neuroregenerative medicine and related fields, to the cytoprotective incorporation of astrocytes into neuron‐culture scaffolds and full‐fledged functional utilization of encapsulated astrocytes for controlled neuronal development. In this article, a 3D neurosupportive culture system for enhanced induction of neuronal circuit generation is reported, where astrocytes are confined in hydrogel microfibers and protected from the outside. The astrocyte‐encapsulated microfibers significantly accelerate the neurite outgrowth and guide its directionality, and enhance the synaptic formation, without any physical contact with the neurons. This astrocyte‐laden system provides a pivotal culture scaffold for advanced development of cell‐based therapeutics for neural injuries, such as spinal cord injury.
Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity
Authors: Alana E. O’Mara, James W. Johnson, Joyce D. Linderman, Robert J. Brychta, Suzanne McGehee, Laura A. Fletcher, Yael A. Fink, Devika Kapuria, Thomas M. Cassimatis, Nathan Kelsey, Cheryl Cero, Zahraa Abdul Sater, Francesca Piccinini, Alison S. Baskin, Brooks P. Leitner, Hongyi Cai, Corina M. Millo, William Dieckmann, Mary Walter, Norman B. Javitt, Yaron Rotman, Peter J. Walter, Marilyn Ader, Richard N. Bergman, Peter Herscovitch, Kong Y. Chen, Aaron M. Cypess
Journal: Journal of Clinical Investigation (2020)

BACKGROUNDMirabegron is a β3-adrenergic receptor (β3-AR) agonist approved only for the treatment of overactive bladder. Encouraging preclinical results suggest that β3-AR agonists could also improve obesity-related metabolic disease by increasing brown adipose tissue (BAT) thermogenesis, white adipose tissue (WAT) lipolysis, and insulin sensitivity.METHODSWe treated 14 healthy women of diverse ethnicities (27.5 ± 1.1 years of age, BMI of 25.4 ± 1.2 kg/m2) with 100 mg mirabegron (Myrbetriq extended-release tablet, Astellas Pharma) for 4 weeks in an open-label study. The primary endpoint was the change in BAT metabolic activity as measured by [18F]-2-fluoro-d-2-deoxy-d-glucose (18F-FDG) PET/CT. Secondary endpoints included resting energy expenditure (REE), plasma metabolites, and glucose and insulin metabolism as assessed by a frequently sampled intravenous glucose tolerance test.RESULTSChronic mirabegron therapy increased BAT metabolic activity. Whole-body REE was higher, without changes in body weight or composition. Additionally, there were elevations in plasma levels of the beneficial lipoprotein biomarkers HDL and ApoA1, as well as total bile acids. Adiponectin, a WAT-derived hormone that has antidiabetic and antiinflammatory capabilities, increased with acute treatment and was 35% higher upon completion of the study. Finally, an intravenous glucose tolerance test revealed higher insulin sensitivity, glucose effectiveness, and insulin secretion.CONCLUSIONThese findings indicate that human BAT metabolic activity can be increased after chronic pharmacological stimulation with mirabegron and support the investigation of β3-AR agonists as a treatment for metabolic disease.TRIAL REGISTRATIONClinicaltrials.gov NCT03049462.FUNDINGThis work was supported by grants from the Intramural Research Program of the NIDDK, NIH (DK075112, DK075116, DK071013, and DK071014).
Genomic and epigenomic EBF1 alterations modulate TERT expression in gastric cancer
Authors: Manjie Xing, Wen Fong Ooi, Jing Tan, Aditi Qamra, Po-Hsien Lee, Zhimei Li, Chang Xu, Nisha Padmanabhan, Jing Quan Lim, Yu Amanda Guo, Xiaosai Yao, Mandoli Amit, Ley Moy Ng, Taotao Sheng, Jing Wang, Kie Kyon Huang, Chukwuemeka George Anene-Nzelu, Shamaine Wei Ting Ho, Mohana Ray, Lijia Ma, Gregorio Fazzi, Kevin Junliang Lim, Giovani Claresta Wijaya, Shenli Zhang, Tannistha Nandi, Tingdong Yan, Mei Mei Chang, Kakoli Das, Zul Fazreen Adam Isa, Jeanie Wu, Polly Suk Yean Poon, Yue Ning Lam, Joyce Suling Lin, Su Ting Tay, Ming Hui Lee, Angie Lay Keng Tan, Xuewen Ong, Kevin White, Steven George Rozen, Michael Beer, Roger Sik Yin Foo, Heike Irmgard Grabsch, Anders Jacobsen Skanderup, Shang Li, Bin Tean Teh, Patrick Tan
Journal: Journal of Clinical Investigation (2020)

Transcriptional reactivation of telomerase catalytic subunit (TERT) is a frequent hallmark of cancer, occurring in 90% of human malignancies. However, specific mechanisms driving TERT reactivation remain obscure for many tumor types and in particular gastric cancer (GC), a leading cause of global cancer mortality. Here, through comprehensive genomic and epigenomic analysis of primary GCs and GC cell lines, we identified the transcription factor early B cell factor 1 (EBF1) as a TERT transcriptional repressor and inactivation of EBF1 function as a major cause of TERT upregulation. Abolishment of EBF1 function occurs through 3 distinct (epi)genomic mechanisms. First, EBF1 is epigenetically silenced via DNA methyltransferase, polycomb-repressive complex 2 (PRC2), and histone deacetylase activity in GCs. Second, recurrent, somatic, and heterozygous EBF1 DNA-binding domain mutations result in the production of dominant-negative EBF1 isoforms. Third, more rarely, genomic deletions and rearrangements proximal to the TERT promoter remobilize or abolish EBF1-binding sites, derepressing TERT and leading to high TERT expression. EBF1 is also functionally required for various malignant phenotypes in vitro and in vivo, highlighting its importance for GC development. These results indicate that multimodal genomic and epigenomic alterations underpin TERT reactivation in GC, converging on transcriptional repressors such as EBF1.
Cost-effectiveness of boceprevir or telaprevir for previously treated patients with genotype 1 chronic hepatitis C
Authors: Calogero Cammà, Salvatore Petta, Giuseppe Cabibbo, Matteo Ruggeri, Marco Enea, Raffaele Bruno, Vincenza Capursi, Antonio Gasbarrini, Alfredo Alberti, Antonio Craxì
Journal: Journal of Hepatology (2013)
Maternal six week postnatal check should assess for postnatal anxiety
Authors: Victoria Silverwood, Carolyn Chew-Graham, Tom Kingstone
Journal: BMJ (2020)

Jakes and colleagues summarise the maternal six week postnatal check. 1 This is an important and integral part of primary care and presents general practitioners with opportunities to make a huge difference to new mothers and their children.We were disappointed, however, that the article mentioned anxiety only in the context of sleep.Perinatal anxiety might affect 22% of women 2 -higher than the 14% often quoted for perinatal depression. 3Our work indicates that awareness and understanding of perinatal anxiety among healthcare professionals is limited, with care being fragmented and interprofessional communication poor. 4 article discussing what to cover in the maternal six week health check should have emphasised the important role of the GP in identifying postnatal mental health problems and the particular need to identify and manage postnatal anxiety.
Progressive growth of a cystic lesion near the pancreatic head
Authors: Chuncheng Wu, Shuanghong Luo, Bing Hu
Journal: Endoscopy (2020)

A 56-year-old man was admitted to hospital because of upper abdominal pain and mild fever for 2 weeks. One month previously, the patient had undergone resection of the body and tail of the pancreas and splenectomy for pancreatic malignant tumor, and 2 weeks ago, the patient experienced abdominal pain with mild fever. Enhanced computed tomography (CT) showed a blurred fat space in front of the pancreatic head and swelling of the intestinal wall ([Fig. 1 a]). The symptoms gradually worsened and vomiting occurred a few days before admission. Repeat CT showed a round, low-density mass (diameter 4.6 cm) near the pancreatic head ([Fig. 1 b]). Clinicians considered the diagnosis of pancreatic pseudocyst with infection. Endoscopic ultrasonography (EUS)-guided cyst aspiration was planned.
How Valid Are the New Hypoglycemia Definitions for Use in Clinical Trials?
Authors: Philip Home
Journal: Diabetes Care (2020)

The recent changes to hypoglycemia definitions, as proposed by the International Hypoglycaemia Study Group (IHSG) and widely accepted by some regulators and major diabetes associations, were poorly evidence-based, relying on pathophysiological studies and small clinical studies (1). In this issue of Diabetes Care , Heller et al. (2) attempt to remedy this, and they present some useful information on the effect of choice of level for hypoglycemia on statistical power and effect size when comparing insulins. The definitions are for use in clinical trials, as the IHSG emphasizes, and not for application to individual people with diabetes seen in clinical practice (1).

Broadly, using data from the SWITCH 1 (type 1 diabetes [T1D]) and SWITCH 2 (type 2 diabetes [T2D]) studies of insulin degludec versus insulin glargine 100 units/mL (3,4), the difference in event rates declines below the earlier American Diabetes Association (ADA) threshold of <3.9 mmol/L (<70 mg/dL), increasing in inverse proportion to the absolute decline in event rates, at least down to 2.8–2.9 mmol/L (50–52 mg/dL) where the number of events leads to uncertainty. This is best espoused in the authors' Fig. 2 A , where for SWITCH 2 the central estimate for difference in rate of confirmed symptomatic events between insulins falls with each 0.1 mmol/L drop in threshold from 3.9 to 3.0 mmol/L (70 to 54 mg/dL). More importantly, the upper confidence limit also falls despite the overall confidence interval (CI) widening, meaning higher certainty that the difference is real. Below 3.0 mmol/L, the lower event rate leads to increasing uncertainty, with loss of statistical difference by 2.7 mmol/L (49 mg/dL).

The T1D study, where the majority of hypoglycemia events will be influenced by mealtime and not basal insulin but in which the event rate is much higher, appears confirmatory of the T2D …
Comel‐Netherton syndrome: A local skin barrier defect in the absence of an underlying systemic immunodeficiency
Authors: Kira Stuvel, Jorn J. Heeringa, Virgil A. S. H. Dalm, Ruud W. J. Meijers, Els van Hoffen, Susan A. M. Gerritsen, Menno C. van Zelm, Suzanne G. M. A. Pasmans
Journal: Allergy (2020)

Comel-Netherton syndrome (NS) is a rare autosomal disease, characterized by severe skin disease, hair shaft defects, atopic diathesis, and increased susceptibility for skin infections. Since patients with NS suffer from recurrent infections, it has been hypothesized that an underlying immunodeficiency attributes to this. Here, we studied clinical and immunological characteristics of the cohort of NS patients in the Netherlands in order to identify whether potential immunodeficiencies result in the increased risk of infectious complications.Phenotypes were scored for severity of skin condition, specific hair shaft defects, atopy, and recurrent infections. Patients' blood samples were collected for quantification of serum immunoglobulin (Ig) levels, specific antibodies against Streptococcus pneumoniae, and allergen-specific IgE, as well as detailed immunophenotyping of blood leukocyte and lymphocyte subsets by flow cytometry.A total of 14 patients were included with age range 3-46 years and varying degrees of skin involvement. All patients presented with atopic symptoms (food allergy, n = 13; hay fever, n = 10; asthma, n = 7). Recurrent skin infections were common, particularly in childhood (n = 12). Low levels of specific antibodies against S pneumoniae were found in 10 of 11 evaluated patients. Detailed immunological analysis was performed on 9 adult patients. Absolute numbers of lymphocyte subsets and serum immunoglobulin levels were all within normal ranges.Multidisciplinary evaluation of our national cohort showed no evidence for a severe, clinically relevant systemic immunodeficiency. Therefore, we conclude that in Dutch NS patients the increased risk of infections most likely results from the skin barrier disruption and that increased allergen penetration predisposes to allergic sensitization.
Author correction to ‘Up-regulation of glycolipid transfer protein by bicyclol causes spontaneous restriction of hepatitis C virus replication’ [Acta Pharmaceutica Sinica B 9 (2019) 769–781]
Authors: Meng-Hao Huang, Hu Li, Rong Xue, Jianrui Li, Lihua Wang, Junjun Cheng, Zhouyi Wu, Wenjing Li, Jinhua Chen, Xiaoqin Lv, Qiang Li, Pei Lan, Limin Zhao, Yongfeng Yang, Zonggen Peng, Jiandong Jiang
Journal: Acta Pharmaceutica Sinica B (2020)

[This corrects the article DOI: 10.1016/j.apsb.2019.01.013.].