tbuckley/cabot-search huggingface dataset:
<i>Ex Vivo</i> Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids
Authors: Russell W. Jenkins, Amir R. Aref, Patrick H. Lizotte, Elena Ivanova, Susanna Stinson, Chensheng W. Zhou, Michaela Bowden, Jiehui Deng, Hongye Liu, Diana Miao, Meng Xiao He, William Walker, Gao Zhang, Tian Tian, Chaoran Cheng, Zhi Wei, Sangeetha Palakurthi, Mark Bittinger, Hans Vitzthum, Jong Wook Kim, Ashley Merlino, Max Quinn, Chandrasekar Venkataramani, Joshua A. Kaplan, Andrew Portell, Prafulla C. Gokhale, Bart Phillips, Alicia Smart, Asaf Rotem, Robert E. Jones, Lauren Keogh, Maria Anguiano, Lance Stapleton, Zhiheng Jia, Michal Barzily-Rokni, Israel Cañadas, Tran C. Thai, Marc R. Hammond, Raven Vlahos, Eric S. Wang, Hua Zhang, Shuai Li, Glenn J. Hanna, Wei Huang, Mai P. Hoang, Adriano Piris, Jean-Pierre Eliane, Anat O. Stemmer-Rachamimov, Lisa Cameron, Mei-Ju Su, Parin Shah, Benjamin Izar, Manisha Thakuria, Nicole R. LeBoeuf, Guilherme Rabinowits, Viswanath Gunda, Sareh Parangi, James M. Cleary, Brian C. Miller, Shunsuke Kitajima, Rohit Thummalapalli, Benchun Miao, Thanh U. Barbie, Vivek Sivathanu, Joshua Wong, William G. Richards, Raphael Bueno, Charles H. Yoon, Juan Miret, Meenhard Herlyn, Levi A. Garraway, Eliezer M. Van Allen, Gordon J. Freeman, Paul T. Kirschmeier, Jochen H. Lorch, Patrick A. Ott, F. Stephen Hodi, Keith T. Flaherty, Roger D. Kamm, Genevieve M. Boland, Kwok-Kin Wong, David Dornan, Cloud Peter Paweletz, David A. Barbie
Journal: Cancer Discovery (2017)

Ex vivo systems that incorporate features of the tumor microenvironment and model the dynamic response to immune checkpoint blockade (ICB) may facilitate efforts in precision immuno-oncology and the development of effective combination therapies. Here, we demonstrate the ability to interrogate ex vivo response to ICB using murine- and patient-derived organotypic tumor spheroids (MDOTS/PDOTS). MDOTS/PDOTS isolated from mouse and human tumors retain autologous lymphoid and myeloid cell populations and respond to ICB in short-term three-dimensional microfluidic culture. Response and resistance to ICB was recapitulated using MDOTS derived from established immunocompetent mouse tumor models. MDOTS profiling demonstrated that TBK1/IKKε inhibition enhanced response to PD-1 blockade, which effectively predicted tumor response in vivo Systematic profiling of secreted cytokines in PDOTS captured key features associated with response and resistance to PD-1 blockade. Thus, MDOTS/PDOTS profiling represents a novel platform to evaluate ICB using established murine models as well as clinically relevant patient specimens.Significance: Resistance to PD-1 blockade remains a challenge for many patients, and biomarkers to guide treatment are lacking. Here, we demonstrate feasibility of ex vivo profiling of PD-1 blockade to interrogate the tumor immune microenvironment, develop therapeutic combinations, and facilitate precision immuno-oncology efforts. Cancer Discov; 8(2); 196-215. ©2017 AACR.See related commentary by Balko and Sosman, p. 143See related article by Deng et al., p. 216This article is highlighted in the In This Issue feature, p. 127.
A Death in the Family
Authors: Asif Khan
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Insertion of fully covered self-expandable metal stent during balloon-assisted ERCP in patient with surgically altered upper gastrointestinal anatomy
Authors: Benjamin Hewitt, Ivan Jovanovic, Alvaro Martínez-Alcalá, P. Kröner, Marco D’Assunçao, Klaus Mönkemüller
Journal: Endoscopy (2017)

The presence of complex, surgically altered gastrointestinal (GI) anatomy poses a diagnostic and therapeutic challenge to the endoscopist treating patients with pancreaticobiliary disorders. Placing fully covered metal stents into the bile duct during endoscopic retrograde cholangiopancreatography (ERCP) through standard forward-viewing scopes, such as double- and single-balloon enteroscopes and colonoscopes, is impossible as the working channel is too small, even with the new-generation short double-balloon enteroscopes [1] [2]. Herein, we present a novel technique to insert fully covered metal stents into the bile duct using balloon-assisted ERCP, whereby the overtube is used as a giant working channel.
Harmful and Beneficial Effects of Anticoagulants in Patients With Cirrhosis and Portal Vein Thrombosis
Authors: Vincenzo La Mura, Simon Braham, Giulia Tosetti, Federica Branchi, Niccolò Bitto, Marco Moia, Anna Ludovica Fracanzani, Massimo Colombo, Armando Tripodi, Massimo Primignani
Journal: Clinical Gastroenterology and Hepatology (2017)
Falling NHS staff numbers and high turnover threaten patient care, says report
Authors: Matthew Limb
Journal: BMJ (2017)

NHS workforce planning in England is “not fit for purpose,” with high staff turnover in many trusts threatening the continuity of care of patients, an analysis has found.1

Falling numbers of GPs and nurses contradict the government’s rhetoric about increasing staff in “priority” areas of the NHS such as primary care and mental health, said the damning report from the think tank the Health Foundation. The government has pledged to increase the number of GPs by 5000 by 2020, but evidence indicates that numbers are “moving further away” from the target, said the report. It showed that GP numbers fell by 0.7% between December 2016 and the end of June 2017 and nurse numbers by 0.2% in the year to April 2017. …
TCT-371 Acute and short term performance of MAGMARIS Bioresorbable Scaffold implantation using the PSP-technique: a multicenter experience
Authors: Enrico Cerrato, Salvatore Geraci, Dario Buccheri, Cristina Rolfo, Giorgio Quadri, Fabio Mariani, Francesco Tomassini, Fabio Ferrari, Ferdinando Varbella
Journal: Journal of the American College of Cardiology (2017)
Loss of SMAD3 Promotes Vascular Remodeling in Pulmonary Arterial Hypertension via MRTF Disinhibition
Authors: Diana Zabini, Elise Granton, Yijie Hu, Maria Zena Miranda, Ulrike Weichelt, Sandra Breuils Bonnet, Sébastien Bonnet, Nicholas W. Morrell, Kim A. Connelly, Steeve Provencher, Bahil Ghanim, Walter Klepetko, Andrea Olschewski, Andras Kapus, Wolfgang M. Kuebler
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Vascular remodeling in pulmonary arterial hypertension (PAH) results from smooth muscle cell hypertrophy and proliferation of vascular cells. Loss of BMPR-II (bone morphogenetic protein receptor 2) signaling and increased signaling via TGF-β (transforming growth factor β) and its downstream mediators SMAD (small body size [a C. elegans protein] mothers against decapentaplegic [a Drosophila protein family])-2/3 has been proposed to drive lung vascular remodeling; yet, proteomic analyses indicate a loss of SMAD3 in PAH.We proposed that SMAD3 may be dysregulated in PAH and that loss of SMAD3 may present a pathophysiological master switch by disinhibiting its interaction partner, MRTF (myocardin-related transcription factor), which drives muscle protein expression.SMAD3 levels were measured in lungs from PAH patients, rats treated either with Sugen/hypoxia or monocrotaline (MCT), and in mice carrying a BMPR2 mutation. In vitro, effects of SMAD3 or BMPR2 silencing or SMAD3 overexpression on cell proliferation or smooth muscle hypertrophy were assessed. In vivo, the therapeutic and prophylactic potential of CCG1423, an inhibitor of MRTF, was investigated in Sugen/hypoxia rats.SMAD3 was downregulated in lungs of patients with PAH and in pulmonary arteries of three independent PAH animal models. TGF-β treatment replicated the loss of SMAD3 in human pulmonary artery smooth muscle cells (huPASMCs) and human pulmonary artery endothelial cells. SMAD3 silencing increased proliferation and migration in huPASMCs and human pulmonary artery endothelial cells. Coimmunoprecipitation revealed reduced interaction of MRTF with SMAD3 in TGF-β-treated huPASMCs and pulmonary arteries of PAH animal models. In huPASMCs, loss of SMAD3 or BMPR-II increased smooth muscle actin expression, which was attenuated by MRTF inhibition. Conversely, SMAD3 overexpression prevented TGF-β-induced activation of an MRTF reporter and reduced actin stress fibers in BMPR2-silenced huPASMCs. MRTF inhibition attenuated PAH and lung vascular remodeling in Sugen/hypoxia rats.Loss of SMAD3 presents a novel pathomechanism in PAH that promotes vascular cell proliferation and-via MRTF disinhibition-hypertrophy of huPASMCs, thereby reconciling the parallel induction of a synthetic and contractile huPASMC phenotype.
Running causes knee osteoarthritis: myth or misunderstanding
Authors: William O Roberts
Journal: British Journal of Sports Medicine (2017)

Jill is a 35-year-old woman who has just nursed her 60-year-old mother through a total knee replacement. She ran 800–5000 m competitively in high school and has continued to run for fitness. She has no knee pain and no history of knee injury. What can we tell her regarding her knee osteoarthritis (OA) risk if she continues to run?

Among the lay public, running is often considered a cause of knee OA, and many people use this as an excuse not to run for fitness, even though knee OA may be more common in sedentary individuals.1 While there is a vast literature addressing knee OA, there is no common conclusion regarding the risk of knee OA from running.

One cross-sectional study and two systematic reviews have recently addressed this question.

The retrospective study included 2637 men and women aged 45–79 (mean 64 years, body mass index of 29) who had either knee-specific pain or knee …
Increased frequencies of Th17 cells and IL17a-producing regulatory T-cells preceding the immunodiscordant response to antiretroviral treatment
Authors: Isaac Rosado-Sánchez, Inés Herrero-Fernández, Laura Tarancon-Diez, Santiago Moreno, Jose Antonio Iribarren, David Dalmau, Francisco Vera-Méndez, Manuel Leal, Yolanda María Pacheco
Journal: Journal of Infection (2017)
TCT-430 Nine-Month Angiographic and 1-Year Clinical Outcomes of the RECOVERY Study: A Randomized Trial Evaluating the Safety and Efficacy of the Combo Bio-Engineered Sirolimus-Eluting Stent Versus the Nano Polymer-Free Sirolimus-Eluting Stent in Patients with Coronary Artery Disease
Authors: Ling tao, Zhanquan LI, Zhiyong Yin, Wenhua Lin, Yin Liu, Hui Li, Bo Yu, Wei Li, None helen lau, Bo Xu
Journal: Journal of the American College of Cardiology (2017)
TCT-109 Ten-year clinical outcome in patients with Coronary Chronic Total Occlusions not revascularized by Percutaneous Coronary Intervention
Authors: Cosmo Godino, Luca Baldetti, Alessia Giannattasio, Andrea Munafò, Carlo Andrea Pivato, Andrea Scotti, Alessandro Beneduce, Giulia Perfetti, Alberto Cappelletti, Valeria Magni, Mauro Carlino, Alberto Margonato, Antonio Colombo
Journal: Journal of the American College of Cardiology (2017)
A Containerized Software System for Generation, Management, and Exploration of Features from Whole Slide Tissue Images
Authors: Joel Saltz, Ashish Sharma, Ganesh Iyer, Erich Bremer, Feiqiao Wang, Alina Jasniewski, Tammy DiPrima, Jonas S. Almeida, Yi Gao, Tianhao Zhao, Mary Saltz, Tahsin Kurc
Journal: Cancer Research (2017)

Well-curated sets of pathology image features will be critical to clinical studies that aim to evaluate and predict treatment responses. Researchers require information synthesized across multiple biological scales, from the patient to the molecular scale, to more effectively study cancer. This article describes a suite of services and web applications that allow users to select regions of interest in whole slide tissue images, run a segmentation pipeline on the selected regions to extract nuclei and compute shape, size, intensity, and texture features, store and index images and analysis results, and visualize and explore images and computed features. All the services are deployed as containers and the user-facing interfaces as web-based applications. The set of containers and web applications presented in this article is used in cancer research studies of morphologic characteristics of tumor tissues. The software is free and open source. Cancer Res; 77(21); e79-82. ©2017 AACR.
Human plasma C3 is essential for the development of memory B, but not T, lymphocytes
Authors: Anaïs Jiménez-Reinoso, Ana V. Marin, Marta Subias, Alberto López-Lera, Elena Román-Ortiz, Kathryn Payne, Cindy S. Ma, Giuseppina Arbore, Martin Kolev, Simon J. Freeley, Claudia Kemper, Stuart G. Tangye, Edgar Fernández-Malavé, Santiago Rodríguez de Córdoba, Margarita López-Trascasa, José R. Regueiro
Journal: Journal of Allergy and Clinical Immunology (2017)
Three-Dimensional Microbiome and Metabolome Cartography of a Diseased Human Lung
Authors: Neha Garg, Mingxun Wang, Embriette Hyde, Ricardo R. da Silva, Alexey V. Melnik, Ivan Protsyuk, Amina Bouslimani, Yan Wei Lim, Richard Wong, Greg Humphrey, Gail Ackermann, Timothy Spivey, Sharon S. Brouha, Nuno Bandeira, Grace Y. Lin, Forest Rohwer, Douglas J. Conrad, Theodore Alexandrov, Rob Knight, Pieter C. Dorrestein
Journal: Cell Host & Microbe (2017)
Taking responsibility for the unrealistic expectations about frailty
Authors: Simon Kenwright
Journal: BMJ (2017)

Oliver points out that many of us will have been with relatives who have failed to grasp that the death of a frail elderly patient has been in the offing for months or is even overdue.1 As Prince Charles said about the death of his grandmother, “Somehow, I never expected it would come.” In some way, the more it is overdue the more people come to …
Affinity maturation shapes the function of agonistic antibodies to peptidylarginine deiminase type 4 in rheumatoid arthritis
Authors: Jing Shi, Erika Darrah, Gary P Sims, Tomas Mustelin, Kevon Sampson, Maximilian F Konig, Clifton O Bingham, Antony Rosen, Felipe Andrade
Journal: Annals of the Rheumatic Diseases (2017)

The citrullinating enzyme peptidylarginine deiminase type 4 (PAD4) is the target of a polyclonal group of autoantibodies in patients with rheumatoid arthritis (RA). A subgroup of such antibodies, initially identified by cross-reactivity with peptidylarginine deiminase type 3 (PAD3), is strongly associated with progression of radiographic joint damage and interstitial lung disease and has the unique ability to activate PAD4. The features of these antibodies in terms of their T cell-dependent origin, genetic characteristics and effect of individual antibody specificities on PAD4 function remain to be defined.We used PAD4 tagged with the monomeric fluorescent protein mWasabi to isolate PAD4-specific memory B cells from anti-PAD4 positive patients with RA and applied single cell cloning technologies to obtain monoclonal antibodies.Among 44 single B cells, we cloned five antibodies with PAD4-activating properties. Sequence analysis, germline reversion experiments and antigen specificity assays suggested that autoantibodies to PAD4 are not polyreactive and arise from PAD4-reactive precursors. Somatic mutations increase the agonistic activity of these antibodies at low calcium concentrations by facilitating their interaction with structural epitopes that modulate calcium-binding site 5 in PAD4.PAD4-activating antibodies directly amplify a key process in disease pathogenesis, making them unique among other autoantibodies in RA. Understanding the molecular basis for their functionality may inform the design of future PAD4 inhibitors.
Margaret McCartney: We must be smarter about recruitment and retention
Authors: Margaret McCartney
Journal: BMJ (2017)

A hundred million pounds is a lot of money. NHS England has pledged to spend as much as this on recruitment agency fees to bring in GPs from abroad. The aim is for 5000 extra GPs. Overseas recruitment will make up a large portion of this new wave of doctors.

In the 1960s, general practice in the NHS was saved by Indian and Pakistani doctors, at a time when a third to a half of UK medical graduates were emigrating themselves.1 But these doctors were not always well cared for. They often found themselves in the most deprived parts of the country, frequently without much support, discriminated against, and in the least competitive posts (but often the hardest).2 …
Abstract #1278: Impact of AhR knockdown on cell cycle progression in human keratinocytes (HaCaT)
Authors: Michaela Kalmes, Brunhilde Blömeke
Journal: Cancer Research (2009)

While the activation of the arylhydrocarbon receptor (AhR) by exogenous ligands is well investigated, the physiological activation of this receptor is less understood. By extending research in AhR biology, evidence appeared that the AhR interacts with endogenous ligands and generally plays an important role in cell physiology. In skin, up to now little is known about the endogenous functions of the AhR. We could recently show that an AhR knockdown variant of the human keratinocyte cell line HaCaT (siAhR HaCaT) exhibited changes in cell cycle state distribution in comparison to wildtype HaCaT cells in the absence of exogenous ligands. Significantly more cells were detected in the G0/G1 phase of the cell cycle in siAhR HaCaT cells than in wildtype HaCaT cells. In order to expand this knowledge and to reveal the underlying molecular mechanisms in the absence of exogenous ligands, we now compared DNA synthesis rate of both cell lines and determined protein levels of cell cycle regulatory polypeptides involved in the transition from G0/G1 to S phase in both, wildtype HaCaT and siAhR HaCaT cells. Compared to wildtype HaCaT cells, DNA synthesis rate of siAhR HaCaT cells was significantly decreased, whereas the protein level of the cyclin dependent kinase inhibitor (CKI) p27KIP1 was increased and the protein level of the retinoblastoma protein (pRB) was reduced. A decreased protein level of the cyclin dependent kinase (CDK)2 was detected in siAhR HaCaT and protein levels of CDK4 and CDK6 remained unchanged compared to wildtype HaCaT cells. In conclusion, we could show that in the absence of exogenous ligands the AhR promotes cell cycle progression in HaCaT cells and one can speculate that this is one of the physiological functions of the receptor in this cell line.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1278.
A convenient 96-well cell adhesion assay for cell binding studies to galectins
Authors: Lothar Goretzki, Jue Wang, Mo Saedi
Journal: Cancer Research (2005)

3783   Galectins are a growing family of carbohydrate binding adhesion molecules (lectins) with affinity for lactose and other β-galactosides. Mammals express at least 10 different galectins. Galectins are characterized by Ca 2+  independence and extensive sequence identity in the carbohydrate recognition domain. Cell adhesion involves protein-protein interaction (recognition of peptide motifs) as well as protein-carbohydrate interaction. Galectins can be found intracellularly and extracellularly. Extracellular galectins cross-link cell-surface and extracellular glycoproteins and may thereby modulate cell adhesion and induce intracellular signals. Galectin-1 is a monomeric or homodimeric prototype galectin that is expressed in a variety of cells. Galectin-1 is involved in multiple biological functions, including cell adhesion, apoptosis, and tumor metastasis. Galectin-1 can modulate cell-cell as well as cell-matrix interactions. Galectin-3 is expressed in normal and neoplastic cells and regulates cell growth, cell adhesion, differentiation, and cell death. There is evidence to suggest that galectin-3 plays an important role in tumor progression and metastasis. Recombinant galectin-3 was shown to bind α 1 β 1  integrin, a receptor for laminin and collagen. Galectin-3 is also a substrate for MMP-2 and MMP-9. We have developed a cell adhesion kit using recombinant galectin-1 and 3 immobilized on the plastic surface of a 96-well plate. The assay is specific and sensitive. The adhesion of cells to immobilized galectin-1 or galectin-3 could be inhibited by lactose in a dose-dependent manner. Immobilized BSA served as negative control and poly-L-lysine as positve control, respectively. For instance, A431 (epidermoid cancer) and SW480 (colon adenocarcimona) cells exhibited considerable binding to both, galectin-1 and galectin-3, whereas SK-BR-3 (breast adenocarcinoma) cells did not exhibit appreciable binding to galectin-3 but considerable binding to galectin-1. Quantification of bound cells was performed with calcein-AM, a sensitive fluorescent cell dye that only detects viable cells. In conclusion, Galectin-1 and galectin-3 interactions with galactoside-bearing ligands seem to be important in cell adhesion. Due to their strong implication in inflammation and cancer they are useful targets for development of new anti-inflammatory and anti-cancer therapies. The kit provides a simple and fast method for assessing relative cell attachment of various cell lines to galectin-1 and 3; the kit is also suitable for screening of potent inhibitors of galectin -1 and 3 interactions with cell surface receptors.
Long non-coding RNA UICLM promotes colorectal cancer liver metastasis by acting as a ceRNA for microRNA-215 to regulate ZEB2 expression
Authors: Dong-Liang Chen, Yun-Xin Lu, Jia-Xing Zhang, Xiao-Li Wei, Feng Wang, Zhao-Lei Zeng, Zhi-Zhong Pan, Yun-Fei Yuan, Feng-Hua Wang, Helene Pelicano, Paul J Chiao, Peng Huang, Dan Xie, Yu-Hong Li, Huai-Qiang Ju, Rui-Hua Xu
Journal: Theranostics (2017)

Long non-coding RNAs (lncRNAs) are involved in the pathology of various tumors, including colorectal cancer (CRC). However, the role of lncRNA in CRC liver metastasis remains unclear. Methods: a microarray was performed to identify the differentially expressed lncRNAs between CRC tissues with and without liver metastasis. Survival analysis was evaluated using the Kaplan-Meier method and assessed using the log-rank test. In vitro and in vivo assays were preformed to explore the biological effects of the differentially expressed lncRNA in CRC cells. Results: the lncRNA UICLM (up-regulated in colorectal cancer liver metastasis) was significantly up-regulated in cases of CRC with liver metastasis. Moreover, UICLM expression was higher in CRC tissues than in normal tissues, and UICLM expression was associated with poor patient survival. Knockdown of UICLM inhibited CRC cell proliferation, invasion, epithelial-mesenchymal transition (EMT) and CRC stem cell formation in vitro as well as tumor growth and liver metastasis in vivo. Ectopic expression of UICLM promoted CRC cell proliferation and invasion. Mechanistic investigations revealed that UICLM induced its biological effects by regulating ZEB2, as the oncogenesis facilitated by UICLM was inhibited by ZEB2 depletion. Further study indicated that UICLM acted as a competing endogenous RNA (ceRNA) for miR-215 to regulate ZEB2 expression. Conclusions: taken together, our findings demonstrate how UICLM induces CRC liver metastasis and may offer a novel prognostic marker and therapeutic target for this disease.