tbuckley/cabot-search huggingface dataset:
Molecular rationale for ERK and EGFR inhibition in colorectal cancer.
Authors: Timothy Joseph Yeatman, Thomas Davis, Mingli Yang, Michael J. Schell, Heiman Wang, Caio Max S. Rocha Lima, Jack Pledger
Journal: Journal of Clinical Oncology (2018)

679 Background: Mutational activation of the RAS pathway occurs in &gt;50% of human CRC tumors, and to date has been difficult to overcome. We recently identified receptor tyrosine phosphatase-S (PTPRS) as an important regulator of the RAS pathway, which is mutated in ~11% of CRC. Methods: Global gene expression and DNA sequencing data (1321 cancer genes) were integrated across 468 CRC tumors to identify PTPRS as one of the most commonly mutated genes with a high correlation to a RAS activation score. Apoptotic responses to inhibitors of ERK, EGFR and their combination were tested in isogenic wild-type and mutant RAS cell lines where PTPRS had been knocked out by CRISPR. Results: PTPRS was in the top 15 genes correlating with RAS pathway activation scores; as expected, KRAS, BRAF were the most correlated genes. In order to determine the effect of the loss of PTPRS on RAS/ERK signaling, we used CRISPR to knockout PTPRS in an isogenic pair of CRC cell lines (HCT116) with mutant or wild type KRAS. Cell lines lacking PTPRS expression had elevated phospho-ERK activity. Interestingly, cell lines with PTPRS knockout and elevated ERK phosphorylation had an increased sensitivity to ERK inhibitors. Moreover, the loss of PTPRS allowed ERK to localize to the nucleus. Apoptosis increased dramatically from 13.1% in control cells to 53.8% in PTPRS KO cells treated with both ERK and EGFR inhibitors (Table), a synergistic effect not seen in wild type KRAS cells, where only ERK inhibitors were active. Conclusions: The loss of PTPRS allows increased activation of ERK (and the RAS pathway) which is associated with ERK addiction and increased sensitivity to ERK inhibitors. Surprisingly, ERK inhibitors synergize with EGFRi in wild type KRAS cell lines absent PTPRS. These data suggest the potential for mutant PTPRS to serve as a biomarker for ERK/EGFR inhibition. [Table: see text]
Non-syndromic retinitis pigmentosa
Authors: Sanne K. Verbakel, Ramon A.C. van Huet, Camiel J.F. Boon, Anneke I. den Hollander, Rob W.J. Collin, Caroline C.W. Klaver, Carel B. Hoyng, Ronald Roepman, B. Jeroen Klevering
Journal: Progress in Retinal and Eye Research (2018)

Retinitis pigmentosa (RP) encompasses a group of inherited retinal dystrophies characterized by the primary degeneration of rod and cone photoreceptors. RP is a leading cause of visual disability, with a worldwide prevalence of 1:4000. Although the majority of RP cases are non-syndromic, 20–30% of patients with RP also have an associated non-ocular condition. RP typically manifests with night blindness in adolescence, followed by concentric visual field loss, reflecting the principal dysfunction of rod photoreceptors; central vision loss occurs later in life due to cone dysfunction. Photoreceptor function measured with an electroretinogram is markedly reduced or even absent. Optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging show a progressive loss of outer retinal layers and altered lipofuscin distribution in a characteristic pattern. Over the past three decades, a vast number of disease-causing variants in more than 80 genes have been associated with non-syndromic RP. The wide heterogeneity of RP makes it challenging to describe the clinical findings and pathogenesis. In this review, we provide a comprehensive overview of the clinical characteristics of RP specific to genetically defined patient subsets. We supply a unique atlas with color fundus photographs of most RP subtypes, and we discuss the relevant considerations with respect to differential diagnoses. In addition, we discuss the genes involved in the pathogenesis of RP, as well as the retinal processes that are affected by pathogenic mutations in these genes. Finally, we review management strategies for patients with RP, including counseling, visual rehabilitation, and current and emerging therapeutic options.
Abord endoscopique transgastrique de la cavité péritonéale (NOTES): comparaisons randomisées sur modèle porcin vivant
Authors: X Dray, G Donatelli, EJ Shin, JM Buscaglia, SA Giday, LR Assumpcao, AN Kalloo, LJ Pipitonie, RJ Wroblewski, D Mukkai Krishnamurty, SV Kantsevoy
Journal: Endoscopy (2009)

Introduction: L'accès transgastrique à la cavité péritonéale en chirurgie endoscopique transviscérale par les orifices naturels (NOTES) doit être sûr et rapide.
Rethinking Criminalization of HIV Exposure — Lessons from California’s New Legislation
Authors: Y. Tony Yang, Kristen Underhill
Journal: New England Journal of Medicine (2018)

Rethinking Criminalization of HIV Exposure A recent California law reduces the criminal charges associated with exposing a sexual partner to HIV without disclosing one’s HIV status. The legislation represents a move away from the use of criminal law as a strategy for preventing the spread of HIV.
Glypican-3 as a novel target for an antibody-drug conjugate
Authors: Albina Nesterova, Paul Carter, Leia Smith
Journal: Cancer Research (2007)

656  A novel oncofetal antigen Glypican-3 (GPC-3) has been reported to be highly expressed in primary hepatocellular carcinoma (HCC) and melanoma. Our data using a commercial anti-GPC-3 mAb confirmed a strong signal in 70% of HCC tumors tested by immunohistochemistry. Expression profiling of 32 normal human tissues showed that expression of GPC-3 was restricted to placenta and faint cytoplasmic staining in normal kidney. We also evaluated breast, lung, uterus and ovarian cancer tissue microarrays for GPC-3 expression. Thirty-two out of 42 ovarian tumors (76%) showed elevated GPC-3 expression. We found moderate to high levels of expression of GPC-3 in HCC, colon cancer and melanoma cell lines and undetectable levels in normal renal cells by quantitative FACS. Using an anti-GPC-3 mAb conjugated to the potent cytotoxic agent monomethylauristatin F, we showed specific growth inhibition of GPC-3+ cells in vitro, thus indicating internalization of the antibody-target complex. With the restricted normal tissue expression of GPC-3 and efficient internalization of the antibody-drug conjugate (ADC), an anti-GPC-3 ADC may be useful for targeted therapy of hepatocellular carcinomas. Possible additional indications are in ovarian cancer and melanomas.
Termination of T cell priming relies on a phase of unresponsiveness promoting disengagement from APCs and T cell division
Authors: Armelle Bohineust, Zacarias Garcia, Hélène Beuneu, Fabrice Lemaître, Philippe Bousso
Journal: The Journal of Experimental Medicine (2018)

T cells are primed in secondary lymphoid organs by establishing stable interactions with antigen-presenting cells (APCs). However, the cellular mechanisms underlying the termination of T cell priming and the initiation of clonal expansion remain largely unknown. Using intravital imaging, we observed that T cells typically divide without being associated to APCs. Supporting these findings, we demonstrate that recently activated T cells have an intrinsic defect in establishing stable contacts with APCs, a feature that was reflected by a blunted capacity to stop upon T cell receptor (TCR) engagement. T cell unresponsiveness was caused, in part, by a general block in extracellular calcium entry. Forcing TCR signals in activated T cells antagonized cell division, suggesting that T cell hyporesponsiveness acts as a safeguard mechanism against signals detrimental to mitosis. We propose that transient unresponsiveness represents an essential phase of T cell priming that promotes T cell disengagement from APCs and favors effective clonal expansion.
EVALUATION OF ENDOSCOPIC ULTRASOUND-GUIDED FINE NEEDLE ASPIRATION AND BIOPSY WITH A 19-GAUGE PUNCTURE FORCEPS FOR THE DIAGNOSIS OF PANCREATIC MASSES
Authors: E Dvoinikova, R Goncharuk, K Stegniy, M Agapov
Journal: Endoscopy (2018)

Pancreatic masses include large group of surgical pancreatic diseases. A large-caliber needle such as a 19-gauge puncture forceps may help overcome the limitations of a fine needle aspiration by acquiring a larger amount of tissue sample. However, there has been no study for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endoscopic ultrasound-guided fine needle biopsy with a 19-gauge puncture forceps (EUS-FNB).
Endoscopic Sphincterotomy of the Ampulla of Vater
Authors: K. Kawai, M. Nakajima, K. Kimoto, K. Sugawara, K. Fukumoto
Journal: Endoscopy (1975)

A 44-year-old woman was admitted with severe epigastric pain and jaundice seven months after cholecystectomy. Retrograde cholangiography revealed a solitary floating stone in the common bile duct. Endoscopic electrosurgical papillotomy was successfully performed and the stone was extracted with a basket-tipped catheter. During a total of 11 papillotomies no complications were noted. Of these cases stones were completely removed in 7. Follow-up observations were negative in regard to stenosis, secondary inflammation of the bile ducts or reflux pancreatitis.
ASSESSMENT OF COLONOSCOPY QUALITY IN CLINICAL PRACTICE IN SWEDEN
Authors: E Toth, A Agrawal, P Amaro, L Brink, W Fischbach, M Hünger, R Jover, U Kinnunen, A Koulaouzidis, A Ono, Á Patai, L Petruzziello, C Spada, B Amlani, JF Riemann
Journal: Endoscopy (2018)

Population-based CRC screening is planned in Sweden and its success will depend upon the quality of colonoscopy. Our aim was to assess quality of colonoscopy in current clinical practice in Sweden, through the use of online questionnaires developed by the European Colonoscopy Quality Investigation (ECQI) Group, compared with recently published European Society of Gastrointestinal Endoscopy (ESGE) performance measures.
A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome
Authors: Jian Li, Xu‐Fei Huang, Qian‐Qian Cai, Chen Wang, Hao Cai, Hao Zhao, Lu Zhang, Xin‐Xin Cao, Robert Peter Gale, Dao‐bin Zhou
Journal: American Journal of Hematology (2018)

Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty-one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21-70 years). Twenty-one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534-14 328 pg/mL) to 832 pg/mL (95-6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment-related deaths occurred and no patients suffered from lenalidomide-related grade 3 or above adverse events. After a median follow-up of 34 months, median overall survival (OS) and progression-free survival (PFS) were not reached, with an estimated 3-year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620.
SINGLE VERSUS MULTIPLE PANCREATIC STENTS IN CHRONIC PANCREATITIS: A RETROSPECTIVE COMPARATIVE STUDY
Authors: C Musala, M Arvanitakis, M Delhaye, J Deviere
Journal: Endoscopy (2018)

Stent insertion has been shown to be effective regarding pain resolution in patients with chronic pancreatitis (CP) and ductal strictures. It is not known if there is a benefit from inserting more than one stents, parallel one to the other. The aim of this study was to evaluate the outcome of pain in patients with painful PC who underwent insertion of a single versus multiple stents.
USEFULNESS OF FULLY COVERED SELF-EXPANDABLE METAL STENTS AS TREATMENT OF POST-ERCP BLEEDING
Authors: A Conthe Alonso, C Martinez Flores, S Garcia Mulas, L Rayon Moreno, O Nogales Rincon, B Merino Rodriguez, J Garcia Lledo, L Perez Carazo, M Lopez Ibañez, R Bañares Cañizares
Journal: Endoscopy (2018)

In patients undergoing ERCP, post-procedure bleeding is a frequent complication with a high morbidity and mortality. The placement of a fully covered self-expandable metal stent (FCSMES) has been documented as a useful procedure for treatment of refractory bleeding. Our objective is to evaluate our experience in using FCSMS for treatment of inmmediate and delayed post-ERCP bleeding.
Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract
Authors: Ayush Sharma, Naoki Oishi, Rebecca L. Boddicker, Guangzhen Hu, Hailey K. Benson, Rhett P. Ketterling, Patricia T. Greipp, Darlene L. Knutson, Sara M. Kloft-Nelson, Rong He, Bruce W. Eckloff, Jin Jen, Asha A. Nair, Jaime I. Davila, Surendra Dasari, Konstantinos N. Lazaridis, N. Nora Bennani, Tsung-Teh Wu, Grzegorz S. Nowakowski, Joseph A. Murray, Andrew L. Feldman
Journal: Blood (2018)
Exérèse endoscopique d'une tumeur endocrine duodénale
Authors: P Bulois, V Maunoury, J Boitard, L Arnalsteen
Journal: Endoscopy (2009)

Introduction: L'exérèse chirurgicale d'une tumeur endocrine du duodénum est toujours délicate. Lorsque la tumeur apparait superficielle et isolée au terme du bilan, après concertation multidisciplinaire et en milieu médico – chirurgical, une exérèse endoscopique peut être proposée.
SIMPLE AND PRACTICAL EX-VIVO, NON-BIOLOGIC SIMULATION MODEL FOR PLACEMENT OF SELF-EXPANDING METAL STENTS
Authors: A Martínez-Alcalá García, MA D'Assuncao, G Schwingel, AM Ahmed, G Nelson, LC Fry, K Mönkemüller
Journal: Endoscopy (2018)

Self-expanding metal stent placement is a key therapeutic intervention in gastrointestinal endoscopy. Unfortunately, there is lack of training models for SEMS. The training is further compounded by the need to “experiment” in humans during the initial stent release experiences. Whereas the presence of an expert alleviates the burden of this approach, it still remains a suboptimal approach to train the novice therapeutic endoscopist. We have 3 developed a simple, inexpensive, practical and reproducible model to train endoscopists to insert SEMS. The aim of this model is to provide the endoscopist with the essential steps and knowledge of endoscopic stenting, thus improving the manual and cognitive dexterity needed for this procedure.
Kinase-targeted cancer therapies: progress, challenges and future directions
Authors: Khushwant S. Bhullar, Naiara Orrego Lagarón, Eileen M. McGowan, Indu Parmar, Amitabh Jha, Basil P. Hubbard, H. P. Vasantha Rupasinghe
Journal: Molecular Cancer (2018)

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
Acknowledging and managing deep constraints on moral agency and the self
Authors: Laura Niemi, Jesse Graham
Journal: Behavioral and Brain Sciences (2018)

Abstract Doris proposes that the exercise of morally responsible agency unfolds as a collaborative dialogue among selves expressing their values while being subject to ever-present constraints. We assess the fit of Doris's account with recent data from psychology and neuroscience related to how people make judgments about moral agency (responsibility, blame), and how they understand the self after traumatic events.
HIV Preexposure Prophylaxis
Authors: James Riddell, K. Rivet Amico, Kenneth H. Mayer
Journal: JAMA (2018)

<h3>Importance</h3> About 40 000 Americans and 2 million people worldwide are newly infected with HIV each year. The combination antiretroviral regimen, tenofovir disoproxil fumarate (TDF)/emtricitabine, taken as a single pill once daily, has been shown to prevent HIV transmission but is used by fewer than 20% of people who could benefit in the United States. <h3>Observations</h3> PubMed was searched on February 15, 2018, using the search terms<i>pre-exposure</i>,<i>prophylaxis</i>,<i>HIV</i>, and<i>PrEP</i>to identify English-language articles published between 2010 and 2018. Four placebo-controlled randomized clinical trials have demonstrated that preexposure prophylaxis (PrEP) with daily dosing of TDF/emtricitabine significantly reduces HIV acquisition in men who have sex with men, high-risk heterosexuals, and injection drug users who share injection equipment. The efficacy of daily TDF/emtricitabine exceeds 90% but is highly correlated with degree of adherence. TDF/emtricitabine is safe and well-tolerated. Only 2% of people discontinue PrEP because of adverse effects. Sexually transmitted infections are common among those using PrEP. Resistance to TDF/emtricitabine when used for PrEP is rare (&lt;0.1%) and usually occurs when PrEP is inadvertently prescribed to individuals with undiagnosed acute HIV infection who have false-negative findings on HIV antibody/antigen testing due to HIV infection acquired within 7 to 10 days of testing. Effective methods are needed to identify individuals at high risk for acquiring HIV, ensure their access to PrEP, and maximize medication adherence. <h3>Conclusions and Relevance</h3> TDF/emtricitabine is an effective and safe therapy for preventing HIV transmission. Increasing prescription of TDF/emtricitabine for patients at risk of acquiring HIV has the potential to reduce new HIV infections.
Time-to-Treatment-Failure and Related Outcomes Among 1000+ Advanced Non–Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients (Alliance A151711)
Authors: Ajeet Gajra, Tyler J. Zemla, Aminah Jatoi, Josephine L. Feliciano, Melisa L. Wong, Hongbin Chen, Ronald Maggiore, Ryan P. McMurray, Arti Hurria, Hyman B. Muss, Harvey J. Cohen, Jacqueline Lafky, Martin J. Edelman, Rogerio Lilenbaum, Jennifer G. Le-Rademacher
Journal: Journal of Thoracic Oncology (2018)
INTRADUCTAL CHOLANGIOSCOPY AND PANCREATOSCOPY INDICATIONS AND RESULTS
Authors: A Taha, R Garces Duran, T Moreels, R Yeung, T Aouattah, M Komuta, H Piessevaux, PH Deprez
Journal: Endoscopy (2018)

The SpyGlass Direct Visualization System is a single-operator intraductal device used in diagnostic procedures as evaluation of indeterminate biliary strictures, intraductal papillary mucinous neoplasms of the pancreas, and therapeutic purposes as intraductal lithotripsy for difficult biliary or pancreatic duct stones.
WHAT ARE THE RESULTS OF RECTAL ESD IN FRANCE: A LARGE RETROSPECTIVE MULTICENTRE STUDY IN EXPERTS CENTERS
Authors: J Albouys, MA Guillaumin, V Lepilliez, S Chaussade, M Pioche, S Leblanc, M Barret, R Legros, F Prat, J Rivory, D Sautereau, T Ponchon, J Jacques
Journal: Endoscopy (2018)

ESD has become the standard of care for large superficial rectal precancerous and cancerous lesions. First French results were far from those reported by Japanese teams: En bloc resection: 64%; R0 resection: 53%. Since these first results, experts teams have trained with animal models and in japanese centers. We report here the largest european retrospective multicenter study of four French leading teams in rectal ESD.
FEASIBILITY AND EFFICACY OF DOUBLE OVER-THE-SCOPE CLIPPING FOR COLONIC IATROGENIC PERFORATION
Authors: P Soriani, VG Mirante, C Barbera, T Gabbani, L Miglioli, M Manno
Journal: Endoscopy (2018)

Colo-rectal iatrogenic perforation is a rare complication in diagnostic colonoscopy, occurring in a range of 0.03%-0.8%. Risk factors comprehend endoscopist inexperience, female gender, peri-colic adhesions, inflammatory colonic diseases, diverticular disease, greater age due to weakened colonic wall tissues. Over-the-scope clipping device (OTSC, Ovesco Endoscopy GmbH, Tübingen, Germany) is a useful tool, recommended as first-line endoscopic treatment for endoscopic iatrogenic perforation, which can avoid emergency surgical repair. The deployment of over-the-scope clipping device may be in some cases challenging, due to the size, the position of the hole, the presence of other endoscopic devices to completely close the defect. To the best of our knowledge, there's not described the deployment of two adjacent over-the-scope clipping devices.
Single and sequential biodegradable stent placement for refractory benign esophageal strictures: a prospective follow-up study
Authors: M. Hirdes, P. Siersema, P. van Boeckel, F. Vleggaar
Journal: Endoscopy (2012)

<b>Background and study aim:</b> Although biodegradable stents do not require removal, a single biodegradable stent may only temporarily relieve dysphagia in patients with refractory benign esophageal stricture (RBES). The aim of this study was to evaluate the safety and long term efficacy of single and sequential biodegradable stent placement in patients with RBES. <b>Patients and methods:</b> All patients who underwent biodegradable stent placement for RBES between August 2008 and March 2011 were prospectively followed to evaluate recurrent dysphagia and complication rates. <b>Results:</b> In total, 59 stents were placed in 28 patients. Patients had previously been treated with multiple dilations (n = 20) or multiple dilations and non-biodegradable esophageal stenting (n = 8). A total of 13 patients underwent sequential biodegradable stent placement (median 3, range 2 – 8) during the study period. After initial stent placement, the median dysphagia-free period was 90 days (range 14 – 618 days). Clinical success (absence of dysphagia ≥ 6 months after stent placement) was achieved in seven patients (25 %) and major complications occurred in eight patients (29 %). After placement of a second biodegradable stent, the median dysphagia-free period was 55 days (range 25 – 700 days) and clinical success was achieved in 15 % of patients. After placement of a third stent, the median dysphagia-free period was 106 days (range 90 – 150 days), but none of the patients was clinically dysphagia-free. <b>Conclusion:</b> Placement of a single biodegradable stent is only temporarily effective in the vast majority of patients with RBES treated in a tertiary referral center. Sequential stenting may however be an option to avoid serial dilations.