tbuckley/cabot-search huggingface dataset:
HuR Small-Molecule Inhibitor Elicits Differential Effects in Adenomatosis Polyposis and Colorectal Carcinogenesis
Authors: Michaela Lang, David Berry, Katharina Passecker, Ildiko Mesteri, Sabin Bhuju, Florian Ebner, Vitaly Sedlyarov, Rayko Evstatiev, Kyle Dammann, Alexander Loy, Orest Kuzyk, Pavel Kovarik, Vineeta Khare, Martin Beibel, Guglielmo Roma, Nicole Meisner-Kober, Christoph Gasche
Journal: Cancer Research (2017)

Abstract HuR is an RNA-binding protein implicated in immune homeostasis and various cancers, including colorectal cancer. HuR binding to AU-rich elements within the 3′ untranslated region of mRNAs encoding oncogenes, growth factors, and various cytokines leads message stability and translation. In this study, we evaluated HuR as a small-molecule target for preventing colorectal cancer in high-risk groups such as those with familial adenomatosis polyposis (FAP) or inflammatory bowel disease (IBD). In human specimens, levels of cytoplasmic HuR were increased in colonic epithelial cells from patients with IBD, IBD-cancer, FAP-adenoma, and colorectal cancer, but not in patients with IBD-dysplasia. Intraperitoneal injection of the HuR small-molecule inhibitor MS-444 in AOM/DSS mice, a model of IBD and inflammatory colon cancer, augmented DSS-induced weight loss and increased tumor multiplicity, size, and invasiveness. MS-444 treatment also abrogated tumor cell apoptosis and depleted tumor-associated eosinophils, accompanied by a decrease in IL18 and eotaxin-1. In contrast, HuR inhibition in APCMin mice, a model of FAP and colon cancer, diminished the number of small intestinal tumors generated. In this setting, fecal microbiota, evaluated by 16S rRNA gene amplicon sequencing, shifted to a state of reduced bacterial diversity, with an increased representation of Prevotella, Akkermansia, and Lachnospiraceae. Taken together, our results indicate that HuR activation is an early event in FAP-adenoma but is not present in IBD-dysplasia. Furthermore, our results offer a preclinical proof of concept for HuR inhibition as an effective means of FAP chemoprevention, with caution advised in the setting of IBD. Cancer Res; 77(9); 2424–38. ©2017 AACR.
Efficiency, sufficiency, and consistency for sustainable healthy food
Authors: Adrian Muller, Christian Schader
Journal: The Lancet Planetary Health (2017)

Achievement of sustainable food systems is one of the most important global challenges and the need for a combined discussion of sustainability and health aspects is increasingly acknowledged. Climate change plays a dominant role in this issue. Notably in this regard, ruminant meat and milk production contributes roughly 40% to the total direct agricultural greenhouse gas emissions via enteric fermentation in ruminants' intestinal tracts. Another 40% stems from soil borne nitrous oxide emissions from mineral and organic nitrogen fertilisers applied to crops.
Antidepressants in pregnancy are not associated with autism risk, new study finds
Authors: Ingrid Torjesen
Journal: BMJ (2017)

Other factors may explain a proposed increased risk of autism in children of depressed mothers treated with antidepressants during pregnancy, show the findings of two large population based studies published in JAMA .1

Previous studies have suggested a higher risk of childhood autism spectrum disorder associated with antidepressant exposure during pregnancy. But researchers at the Women’s College Hospital in Toronto, Canada, evaluated the association between serotonergic antidepressant exposure (a selective serotonin reuptake inhibitor or selective norepinephrine reuptake inhibitor) during pregnancy and childhood autism, using a variety of methods to tackle the potential confounding factors.

The study included 35 906 births at an average gestational …
Engagement, Research, and Evidence
Authors: Adrian F. Hernandez, Henry P. Cruz
Journal: Circulation (2017)

deluge of information and new approaches spanning the continuum from discovery to implementation and policy promises to fundamentally alter our understanding of cardiovascular health and healthcare.Although the existing system for cardiovascular research has yielded impressive results, it remains fractured, slow, costly, and hindered by systematic gaps.Further, even when it delivers answers, they are often accompanied by uncertainty about how to interpret or apply that knowledge across different populations.If cardiovascular medicine is to maintain its traditional excellence in innovation and evidence generation, then our current research paradigms must evolve.At the same time, external forces are affecting healthcare, including the imperatives to improve the value of care by increasing quality and reducing costs, grapple with disparities in care and outcomes, and achieve meaningful integration with other technologies using electronic health data and sophisticated analytics.Also medical practice needs to be reoriented toward considering the needs, preferences, and values of individual patients and consumers instead of focusing narrowly on providing products and services.This approach is especially poignant for US healthcare, whose decades-old reimbursement model is transforming into a more patient-centered system.These challenges present a daunting prospect.But what if the move toward integrated, patient-centered, accountable healthcare could be harnessed to simultaneously drive improvements in our clinical research enterprise?What if building systems for electronic health data can also provide robust scaffolding for efficient evidence generation while breaking down silos that impede the flow of information and knowledge among all stakeholders, including patients?Throughout the current US medical care system, many decisions are made without the benefit of high-quality evidence. 1By creating a system that generates evidence as a routine component of care, we can transform the clinical enterprise to better inform decisions about health, the use of therapeutic and diagnostic technologies, and the provision of healthcare services while enabling more efficient implementation of effective, high-quality healthcare.Remaining gaps in knowledge or practice can then be swiftly addressed as we leverage a perfect storm of rapidly evolving health information technologies, electronic health records, and consumer-oriented mobile applications for research and quality-improvement purposes-all against a background of consolidation in practices, hospitals, health systems, and even payers.Ultimately, this integrated approach to healthcare can improve quality and outcomes while speeding cycles of discovery, development, and implementation.
The Impact of Postoperative Conformal Radiotherapy after Radical Surgery on Survival and Recurrence in Pathologic T3N0M0 Esophageal Carcinoma: A Propensity Score-Matched Analysis
Authors: Jinsong Yang, Wencheng Zhang, Zefen Xiao, Qifeng Wang, Zongmei Zhou, Hongxing Zhang, Dongfu Chen, Qingfu Feng, Jie He, Shugeng Gao, Kelin Sun, Xiangyang Liu, Dekang Fang, Juwei Mu, Dali Wang, Yexiong Li
Journal: Journal of Thoracic Oncology (2017)
A Zebrafish Model Discovers a Novel Mechanism of Stromal Fibroblast-Mediated Cancer Metastasis
Authors: Caifeng Liu, Yunjian Zhang, Sharon Lim, Kayoko Hosaka, Yunlong Yang, Tatiana Pavlova, Twana Alkasalias, Johan Hartman, Lasse Jensen, Xiaoming Xing, Xinsheng Wang, Yongtian Lu, Guohui Nie, Yihai Cao
Journal: Clinical Cancer Research (2017)

Purpose: Cancer metastasis can occur at the early stage of tumor development when a primary tumor is at the microscopic size. In particular, the interaction of malignant cells with other cell types including cancer-associated fibroblasts (CAF) in promoting metastasis at the early stage of tumor development remains largely unknown. Here, we investigated the role of CAFs in facilitating the initial events of cancer metastasis when primary tumors were at microscopic sizes.Experimental Design: Multicolor-coded cancer cells and CAFs were coimplanted into the transparent zebrafish body and metastasis at a single-cell level was monitored in living animals. Healthy fibroblasts, tumor factor-educated fibroblasts, and CAFs isolated from various tumors were tested for their ability to facilitate metastasis.Results: We showed that CAFs promoted cancer cell metastasis at the very early stage during primary tumor development. When a primary tumor was at the microscopic size consisting of a few hundred cells, CAFs were able to hijack cancer cells for dissemination from the primary site. Surprisingly, a majority of metastatic cancer cells remained in tight association with CAFs in the circulation. Furthermore, stimulation of non-metastasis-promoting normal fibroblasts with TGF-B, FGF-2, HGF, and PDGF-BB led to acquisition of their metastatic capacity.Conclusions: Cancer metastasis occurs at the very early stage of tumor formation consisting of only a few hundred cells. CAFs are the key cellular determinant for metastasis. Our findings provide novel mechanistic insights on CAFs in promoting cancer metastasis and targeting CAFs for cancer therapy should be aimed at the early stage during cancer development. Clin Cancer Res; 23(16); 4769-79. ©2017 AACR.
An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
Authors: Helen L. Young, Emily J. Rowling, Mattia Bugatti, Emanuele Giurisato, Nadia Luheshi, Imanol Arozarena, Juan-Carlos Acosta, Jivko Kamarashev, Dennie T. Frederick, Zachary A. Cooper, Alexandre Reuben, Jesus Gil, Keith T. Flaherty, Jennifer A. Wargo, William Vermi, Michael P. Smith, Claudia Wellbrock, Adam Hurlstone
Journal: The Journal of Experimental Medicine (2017)

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.
TCTAP C-179 Coronary Computed Tomographic Angiography Improved the Strategy of Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy with Mid-ventricular and Outflow Obstruction
Authors: Takahiro Sawada, Yu Takahashi, Tomofumi Takaya, Yoshinori Yasaka
Journal: Journal of the American College of Cardiology (2017)
TCTAP A-063 Medium-term Clinical Outcomes of the Everolimus-eluting Bioresorbable Vascular Scaffold in Real-world Practice
Authors: Takashi Kajiya, Michael Mao-Chen Liang, Perryn Ng, Ronald Chi-Hang Lee, Mark Chan, Edgar Lik-Wui Tay, Koo Hui Chan, Joshua P. Loh, Poay-Huan Loh, Huay Cheem Tan, Adrian Low
Journal: Journal of the American College of Cardiology (2017)
Mobilization of allogeneic peripheral blood stem cell donors with intravenous plerixafor mobilizes a unique graft
Authors: Mark A. Schroeder, Michael P. Rettig, Sandra Lopez, Stephanie Christ, Mark Fiala, William Eades, Fazia A. Mir, Jin Shao, Kyle McFarland, Kathryn Trinkaus, William Shannon, Elena Deych, Jinsheng Yu, Ravi Vij, Keith Stockerl-Goldstein, Amanda F. Cashen, Geoffrey L. Uy, Camille N. Abboud, Peter Westervelt, John F. DiPersio
Journal: Blood (2017)
Longitudinal peripheral blood transcriptional analysis of a patient with severe Ebola virus disease
Authors: John C. Kash, Kathie-Anne Walters, Jason Kindrachuk, David Baxter, Kelsey Scherler, Krisztina B. Janosko, Rick D. Adams, Andrew S. Herbert, Rebekah M. James, Spencer W. Stonier, Matthew J. Memoli, John M. Dye, Richard T. Davey, Daniel S. Chertow, Jeffery K. Taubenberger
Journal: Science Translational Medicine (2017)

Transcriptomic analysis of leukocytes from a severe Ebola virus disease patient revealed transitions driven by viral clearance, coagulopathy, and multiorgan dysfunction.
A randomized phase II/III study of cabazitaxel versus vinflunine in metastatic or locally advanced transitional cell carcinoma of the urothelium (SECAVIN)
Authors: J. Bellmunt, J.M. Kerst, F. Vázquez, R. Morales-Barrera, E. Grande, A. Medina, M.B. González Graguera, G. Rubio, U. Anido, O. Fernández Calvo, E. González-Billalabeitia, A.J.M. Van den Eertwegh, E. Pujol, J.L. Perez-Gracia, J.L. González Larriba, R. Collado, M. Los, S. Maciá, R. De Wit
Journal: Annals of Oncology (2017)
Effect of intracoronary administration of AAV1/SERCA2a on ventricular remodelling in patients with advanced systolic heart failure: results from the AGENT-HF randomized phase 2 trial
Authors: Jean‐Sébastien Hulot, Joe‐Elie Salem, Alban Redheuil, Jean‐Philippe Collet, Shaida Varnous, Patrick Jourdain, Damien Logeart, Estelle Gandjbakhch, Claude Bernard, Stéphane N. Hatem, Richard Isnard, Philippe Cluzel, Claude Le Feuvre, Pascal Leprince, Nadjib Hammoudi, François M. Lemoine, David Klatzmann, Eric Vicaut, Michel Komajda, Gilles Montalescot, Anne‐Marie Lompré, Roger J. Hajjar
Journal: European Journal of Heart Failure (2017)
Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis
Authors: Sarah Tomkovich, Ye Yang, Kathryn Winglee, Josee Gauthier, Marcus Mühlbauer, Xiaolun Sun, Mansour Mohamadzadeh, Xiuli Liu, Patricia Martin, Gary P. Wang, Eric Oswald, Anthony A. Fodor, Christian Jobin
Journal: Cancer Research (2017)

Abstract Inflammation and microbiota are critical components of intestinal tumorigenesis. To dissect how the microbiota contributes to tumor distribution, we generated germ-free (GF) ApcMin/+and ApcMin/+;Il10−/− mice and exposed them to specific-pathogen-free (SPF) or colorectal cancer-associated bacteria. We found that colon tumorigenesis significantly correlated with inflammation in SPF-housed ApcMin/+;Il10−/−, but not in ApcMin/+mice. In contrast, small intestinal neoplasia development significantly correlated with age in both ApcMin/+;Il10−/− and ApcMin/+ mice. GF ApcMin/+;Il10−/− mice conventionalized by an SPF microbiota had significantly more colon tumors compared with GF mice. Gnotobiotic studies revealed that while Fusobacterium nucleatum clinical isolates with FadA and Fap2 adhesins failed to induce inflammation and tumorigenesis, pks+Escherichia coli promoted tumorigenesis in the ApcMin/+;Il10−/− model in a colibactin-dependent manner, suggesting colibactin is a driver of carcinogenesis. Our results suggest a distinct etiology of cancers in different locations of the gut, where colon cancer is primarily driven by inflammation and the microbiome, while age is a driving force for small intestine cancer. Cancer Res; 77(10); 2620–32. ©2017 AACR.
CD19 Epitope Escape after 4SCAR19 T Cell Therapy Resulted in Re-Establishment of Chemo-Sensitivity in Adult B-Cell Acute Lymphocytic Leukemia Patients
Authors: Xun Lai, Jian-Qiong Liu, Lujia Dong, Hong-Mei Ou-Yang, Zi-Jin Dian, Jian-Xin Song, Ya-Xian Jiang, Xiang-Mei Yao, Xue-Zhong Gu, Xiao-Li Gao, Ya-Yun Wu, Lung-Ji Chang
Journal: Blood (2016)
Endoscopic ultrasound-guided creation of a transgastric fistula for the management of hepatobiliary disease in patients with Roux-en-Y gastric bypass
Authors: Saowanee Ngamruengphong, Jose Nieto, Rastislav Kunda, Vivek Kumbhari, Yen-I Chen, Majidah Bukhari, Mohamad El Zein, Renata Bueno, Gulara Hajiyeva, Amr Ismail, Yamile Chavez, Mouen Khashab
Journal: Endoscopy (2017)

Abstract Background and aims Endoscopic retrograde cholangiopancreatography (ERCP) in patients who have undergone Roux-en-Y gastric bypass (RYGB) is technically challenging. We describe our multicenter experience using lumen-apposing metal stents (LAMSs) to create an endoscopic ultrasound-guided transgastric fistula (EUS-TG) to facilitate peroral ERCP in these patients. Patients and methods Thirteen patients with RYGB who underwent EUS-TG at three tertiary centers were included. EUS was used to guide puncture of the excluded stomach from the gastric pouch or jejunum; a LAMS was placed across the transgastric fistula. ERCP was performed via a duodenoscope passed through the LAMS. Results The technical success of EUS-TG was 100 % (13/13). ERCP through the LAMS was successful and clinical success was achieved in all patients. LAMS dislodgement during ERCP occurred in two patients and the stent was successfully repositioned without sequelae. After removal of the LAMS, the fistula was closed in 92 % of patients, either by endoscopic closure devices or argon plasma coagulation. None of the patients experienced procedure-related adverse events. Conclusion EUS-TG is an effective and safe method of accessing the excluded stomach and performing ERCP in patients with RYGB.
Spontaneous pneumothorax: stop chest tube as first-line therapy
Authors: Jean-Marie Tschopp, Charles-Hugo Marquette
Journal: European Respiratory Journal (2017)

Spontaneous pneumothorax is traditionally divided between primary spontaneous pneumothorax (PSP) and secondary spontaneous pneumothorax (SSP) when there is some underlying lung disease. For decades management of spontaneous pneumothorax has remained highly debatable despite different published guidelines [1–3], many of which contradict each other. Our task force, comprising a multidisciplinary panel of pulmonologists, thoracic surgeons and epidemiologists, recently published a consensus statement [4] on PSP to highlight new findings on the clinical approach, pathophysiology and management strategies of this disease. Pneumothorax remains an under-researched area. The epidemiology of PSP is still poorly documented regarding risk factors or rates of recurrence of PSP. Although smoking remains the principal and well-established risk factor [5], advice for quitting smoking [6] should be routinely given. This disease affects young patients in good health. They are therefore an ideal target population for receiving preventive advice. The pathophysiology of PSP is better understood because of many recent findings. The old concept [7] of PSP because of a localised rupture of a bleb or a bulla is obsolete and has been questioned by many recent studies. We now have robust evidence that the occurrence of PSP is mainly the result of a diffuse histopathological change of the lung parenchyma under the visceral pleura known as emphysema-like changes [8, 9]. There is also a diffuse decrease in the lung density measured by computed tomography (CT) [10] and diffuse increased porosity [11] at the periphery of both lungs. These recent findings explain why a localised surgical approach is less effective than a diffuse pleurodesis, whatever the method of pleurodesis used [12, 13, 14]. Most patients with PSP have no or minimal symptoms, and the entire panel of this European task force [4] agreed that the clinical evaluation of patients with PSP should be more symptom driven and not based only on the measurement of the size of pneumothorax on plain chest radiography or CT, which have little clinical value [15, 16]. Tension pneumothorax is very rare [17]. Most patients with spontaneous pneumothorax commonly experience minimal or no symptoms. In this issue of the ERJ , a randomised study shows that simple aspiration can be very successful in both PSP and SSP <http://ow.ly/8h7u309Wmji>
Risk Stratification for Surgical Site Infections in Colon Cancer
Authors: Ramzi Amri, Anne M. Dinaux, Hiroko Kunitake, Liliana G. Bordeianou, David L. Berger
Journal: JAMA Surgery (2017)

Surgical site infections (SSIs) feature prominently in surgical quality improvement and pay-for-performance measures. Multiple approaches are used to prevent or reduce SSIs, prompted by the heavy toll they take on patients and health care budgets. Surgery for colon cancer is not an exception.To identify a risk stratification score based on baseline and operative characteristics.This retrospective cohort study included all patients treated surgically for colon cancer at Massachusetts General Hospital from 2004 through 2014 (n = 1481).The incidence of SSI stratified over baseline and perioperative factors was compared and compounded in a risk score.Among the 1481 participants, 90 (6.1%) had SSI. Median (IQR) age was 66.9 (55.9-78.1) years. Surgical site infection rates were significantly higher among people who smoked (7.4% vs 4.8%; P = .04), people who abused alcohol (10.6% vs 5.7%; P = .04), people with type 2 diabetics (8.8% vs 5.5%; P = .046), and obese patients (11.7% vs 4.0%; P < .001). Surgical site infection rates were also higher among patients with an operation duration longer than 140 minutes (7.5% vs 5.0%; P = .05) and in nonlaparoscopic approaches (clinically significant only, 6.7% vs 4.1%; P = .07). These risk factors were also associated with an increase in SSI rates as a compounded score (P < .001). Patients with 1 or fewer risk factors (n = 427) had an SSI rate of 2.3%, equivalent to a relative risk of 0.4 (95% CI, 0.16-0.57; P < .001); patients with 2 risk factors (n = 445) had a 5.2% SSI rate (relative risk, 0.78; 95% CI, 0.49-1.22; P = .27); patients with 3 factors (n = 384) had a 7.8% SSI rate (relative risk, 1.38; 95% CI, 0.91-2.11; P = .13); and patients with 4 or more risk factors (n = 198) had a 13.6% SSI rate (relative risk, 2.71; 95% CI, 1.77-4.12; P < .001).This SSI risk assessment factor provides a simple tool using readily available characteristics to stratify patients by SSI risk and identify patients at risk during their postoperative admission. Thereby, it can be used to potentially focus frequent monitoring and more aggressive preventive efforts on high-risk patients.
TNF superfamily receptor OX40 triggers invariant NKT cell pyroptosis and liver injury
Authors: Peixiang Lan, Yihui Fan, Yue Zhao, Xiaohua Lou, Howard P. Monsour, Xiaolong Zhang, Yongwon Choi, Yaling Dou, Naoto Ishii, Rafik M. Ghobrial, Xiang Xiao, Xian Chang Li
Journal: Journal of Clinical Investigation (2017)

Tissue-resident immune cells play a key role in local and systemic immune responses. The liver, in particular, hosts a large number of invariant natural killer T (iNKT) cells, which are involved in diverse immune responses. However, the mechanisms that regulate survival and homeostasis of liver iNKT cells are poorly defined. Here we have found that liver iNKT cells constitutively express the costimulatory TNF superfamily receptor OX40 and that OX40 stimulation results in massive pyroptotic death of iNKT cells, characterized by the release of potent proinflammatory cytokines that induce liver injury. This OX40/NKT pyroptosis pathway also plays a key role in concanavalin A–induced murine hepatitis. Mechanistically, we demonstrated that liver iNKT cells express high levels of caspase 1 and that OX40 stimulation activates caspase 1 via TNF receptor–associated factor 6–mediated recruitment of the paracaspase MALT1. We also found that activation of caspase 1 in iNKT cells results in processing of pro–IL-1β to mature IL-1β as well as cleavage of the pyroptotic protein gasdermin D, which generates a membrane pore–forming fragment to produce pyroptotic cell death. Thus, our study has identified OX40 as a death receptor for iNKT cells and uncovered a molecular mechanism of pyroptotic cell death. These findings may have important clinical implications in the development of OX40-directed therapies.
Health-care use before a first demyelinating event suggestive of a multiple sclerosis prodrome: a matched cohort study
Authors: José M A Wijnands, Elaine Kingwell, Feng Zhu, Yinshan Zhao, Tanja Högg, Karen Stadnyk, Okechukwu Ekuma, Xinya Lu, Charity Evans, John D Fisk, Ruth Ann Marrie, Helen Tremlett
Journal: The Lancet Neurology (2017)