tbuckley/cabot-search huggingface dataset:
Insulin‐Resistant Pathways Are Associated With Disease Activity in Rheumatoid Arthritis and Are Subject to Disease Modification Through Metabolic Reprogramming: A Potential Novel Therapeutic Approach
Authors: Lorna Gallagher, Sian Cregan, Monika Biniecka, Clare Cunningham, Douglas J. Veale, David J. Kane, Ursula Fearon, Ronan H. Mullan
Journal: Arthritis & Rheumatology (2019)

To investigate a role for insulin-resistant pathways in inflammation and therapeutic targeting for disease modification in rheumatoid arthritis (RA).RA disease activity and cardiovascular risk factors, including insulin resistance and body mass index (BMI), were assessed in an Irish RA cohort. Glucose transporter 1 (GLUT-1) and GLUT-4 activity in RA and osteoarthritis (OA) synovial tissue was examined using immunohistochemistry. Spontaneous release of proinflammatory mediators from ex vivo RA synovial explants and primary synovial fibroblast (SF) cell culture supernatants was quantified by enzyme-linked immunosorbent assay. Phosphorylated AMP-activated protein kinase (p-AMPK) and GLUT-1 protein expression was analyzed by Western blotting. Cellular glycolytic and oxidative phosphorylation was assessed using extracellular flux analysis.Insulin resistance was independently associated with both BMI (unstandardized coefficient B 0.113 [95% confidence interval (95% CI) 0.059-0.167]; P < 0.001) (n = 61) and swollen joint count in 28 joints (SJC28) (B 0.114 [95% CI 0.032-0.197]; P = 0.008) (n = 61). Increased GLUT-1 expression in RA synovium (n = 26) versus OA synovium (n = 16) was demonstrated (P = 0.0003), with increased expression in the lining, sublining, and vascular regions. In contrast, decreased GLUT-4 expression in the RA lining layer (n = 21) versus the OA lining layer (n = 8) was observed (P = 0.0358). Decreased GLUT-1 protein expression was observed in parallel with increased p-AMPK protein expression in SFs in the presence of metformin (n = 4). Metformin increased glycolytic activity and decreased oxidative phosphorylation in RASFs (n = 7) (P < 0.05 for both). Metformin or aminoimidazole carboxamide ribonucleotide presence decreased spontaneous production of interleukin-6 (IL-6), IL-8, and monocyte chemotactic protein 1 in RA synovial explants and SFs (n = 5-7).Insulin resistance is significantly associated with BMI and synovitis in RA, suggesting distinct interplay between glucose availability and inflammation in RA. Furthermore, the effect of metformin on proinflammatory mechanisms suggests a role for AMPK-modifying compounds in the treatment of RA.
Early-life programming of mesenteric lymph node stromal cell identity by the lymphotoxin pathway regulates adult mucosal immunity
Authors: Conglei Li, Evelyn Lam, Christian Perez-Shibayama, Lesley A. Ward, Jianbo Zhang, Dennis Lee, Albert Nguyen, Musaddeque Ahmed, Emma Brownlie, Kirill V. Korneev, Olga Rojas, Tian Sun, William Navarre, Housheng Hansen He, Shan Liao, Alberto Martin, Burkhard Ludewig, Jennifer L. Gommerman
Journal: Science Immunology (2019)

Early-life LTβR signaling programs the mesenteric lymph node stromal cell environment, optimizing gut IgA responses in the adult mouse.
Suppression of ILC2 differentiation from committed T cell precursors by E protein transcription factors
Authors: Liangyue Qian, Sandra Bajana, Constantin Georgescu, Vincent Peng, Hong-Cheng Wang, Indra Adrianto, Marco Colonna, Jose Alberola-Ila, Jonathan D. Wren, Xiao-Hong Sun
Journal: The Journal of Experimental Medicine (2019)

Current models propose that group 2 innate lymphoid cells (ILC2s) are generated in the bone marrow. Here, we demonstrate that subsets of these cells can differentiate from multipotent progenitors and committed T cell precursors in the thymus, both in vivo and in vitro. These thymic ILC2s exit the thymus, circulate in the blood, and home to peripheral tissues. Ablation of E protein transcription factors greatly promotes the ILC fate while impairing B and T cell development. Consistently, a transcriptional network centered on the ZBTB16 transcription factor and IL-4 signaling pathway is highly up-regulated due to E protein deficiency. Our results show that ILC2 can still arise from what are normally considered to be committed T cell precursors, and that this alternative cell fate is restrained by high levels of E protein activity in these cells. Thymus-derived lung ILC2s of E protein–deficient mice show different transcriptomes, proliferative properties, and cytokine responses from wild-type counterparts, suggesting potentially distinct functions.
Deubiquitinase Activity Profiling Identifies UCHL1 as a Candidate Oncoprotein That Promotes TGFβ-Induced Breast Cancer Metastasis
Authors: Sijia Liu, Román González-Prieto, Mengdi Zhang, Paul P. Geurink, Raymond Kooij, Prasanna Vasudevan Iyengar, Maarten van Dinther, Erik Bos, Xiaobing Zhang, Sylvia E. Le Dévédec, Bob van de Water, Roman I. Koning, Hong-Jian Zhu, Wilma E. Mesker, Alfred C.O. Vertegaal, Huib Ovaa, Long Zhang, John W.M. Martens, Peter ten Dijke
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Therapies directed to specific molecular targets are still unmet for patients with triple-negative breast cancer (TNBC). Deubiquitinases (DUB) are emerging drug targets. The identification of highly active DUBs in TNBC may lead to novel therapies. Experimental Design: Using DUB activity probes, we profiled global DUB activities in 52 breast cancer cell lines and 52 patients' tumor tissues. To validate our findings in vivo, we employed both zebrafish and murine breast cancer xenograft models. Cellular and molecular mechanisms were elucidated using in vivo and in vitro biochemical methods. A specific inhibitor was synthesized, and its biochemical and biological functions were assessed in a range of assays. Finally, we used patient sera samples to investigate clinical correlations. Results: Two DUB activity profiling approaches identified UCHL1 as being highly active in TNBC cell lines and aggressive tumors. Functionally, UCHL1 promoted metastasis in zebrafish and murine breast cancer xenograft models. Mechanistically, UCHL1 facilitates TGFβ signaling–induced metastasis by protecting TGFβ type I receptor and SMAD2 from ubiquitination. We found that these responses are potently suppressed by the specific UCHL1 inhibitor, 6RK73. Furthermore, UCHL1 levels were significantly increased in sera of patients with TNBC, and highly enriched in sera exosomes as well as TNBC cell–conditioned media. UCHL1-enriched exosomes stimulated breast cancer migration and extravasation, suggesting that UCHL1 may act in a paracrine manner to promote tumor progression. Conclusions: Our DUB activity profiling identified UCHL1 as a candidate oncoprotein that promotes TGFβ-induced breast cancer metastasis and may provide a potential target for TNBC treatment.
Estimating Pangenomes with Roary
Authors: Farrah Sitto, Fabia U Battistuzzi
Journal: Molecular Biology and Evolution (2019)

Abstract A description of the genetic makeup of a species based on a single genome is often insufficient because it ignores the variability in gene repertoire among multiple strains. The estimation of the pangenome of a species is a solution to this issue as it provides an overview of genes that are shared by all strains and genes that are present in only some of the genomes. These different sets of genes can then be analyzed functionally to explore correlations with unique phenotypes and adaptations. This protocol presents the usage of Roary, a Linux-native pangenome application. Roary is a straightforward software that provides 1) an overview about core and accessory genes for those interested in general trends and, also, 2) detailed information on gene presence/absence in each genome for in-depth analyses. Results are provided both in text and graphic format.
Pembrolizumab as a Cause of Cholangiopathy in a Patient With Metastatic Melanoma
Authors: Laura Stuart, Beth Lambourne, Paul Turner, David E.J. Jones, Ruth Plummer, Nicola Cresti, Jessica K. Dyson
Journal: Hepatology (2019)

Stuart, Laura; Lambourne, Beth; Turner, Paul; Jones, David E.J.; Plummer, Ruth; Cresti, Nicola; Dyson, Jessica K. Author Information
A First-in-Human Phase I Study to Evaluate the ERK1/2 Inhibitor GDC-0994 in Patients with Advanced Solid Tumors
Authors: Andrea Varga, Jean-Charles Soria, Antoine Hollebecque, Patricia LoRusso, Johanna Bendell, Shih-Min A. Huang, Marie-Claire Wagle, Kwame Okrah, Lichuan Liu, Elaine Murray, Sandra M. Sanabria-Bohorquez, Michael Tagen, Hatem Dokainish, Lars Mueller, Howard Burris
Journal: Clinical Cancer Research (2019)

ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors.GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled in the expansion stage.Forty-seven patients were enrolled in six successive cohorts (50-800 mg). A single DLT of grade 3 rash occurred at 600 mg. The most common drug-related adverse events (AE) were diarrhea, rash, nausea, fatigue, and vomiting. Pharmacokinetic data showed dose-proportional increases in exposure, with a mean half-life of 23 hours, supportive of once daily dosing. In evaluable paired biopsies, MAPK pathway inhibition ranged from 19% to 51%. Partial metabolic responses by FDG-PET were observed in 11 of 20 patients across dose levels in multiple tumor types. Overall, 15 of 45 (33%) patients had a best overall response of stable disease and 2 patients with BRAF-mutant colorectal cancer had a confirmed partial response.GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single-agent activity was observed in 2 patients with BRAF-mutant colorectal cancer.
Resistance to immunotherapy is associated with high parenchymal PD1+CD8+/CD8+ T cells (PD1tR) driven by tumour CD155
Authors: A. Lepletier de Oliveira, J. Madore, J.S. O’donnell, R.L. Johnston, M. Eastgate, D. Mallardo, P.A. Ascierto, D. Massi, B. Merelli, M. Mandala, J.S. Wilmott, T. Bald, J. Stagg, B. Routy, G.V. Long, R.A. Scolyer, N. Waddell, W.C. Dougall, M.W.L. Teng, M. Smyth
Journal: Annals of Oncology (2019)
Comparison of breast magnetic resonance imaging, mammography, and clinical breast exam for surveillance of women at high risk for hereditary breast cancer
Authors: Rebecca Sutphen, Tuya Pal, Jennifer Pickard, Joann Runk, Elissa Clayton, Melissa Cochran, A. Pat Romilly, Margaret Szabunio, Joanne Cressman, John Beauchamp, Sadie Aguila, Claudia Berman, Robert Clark
Journal: Cancer Research (2004)

4733  Purpose: Recommended surveillance for women at high risk for breast cancer, including BRCA1 and BRCA2 mutation carriers, includes regular mammography and clinical breast examination, although the effectiveness of these screening techniques in these women has not been established. The purpose of the present study was to compare breast magnetic resonance imaging (MRI) with mammography, and physical examination in women at high risk for hereditary breast cancer. Patients and Methods: A total of 178 women, aged 22-74 years, of which 51 had proven BRCA1 or BRCA2 mutations and the remainder had a strong family histories of breast or ovarian cancer. These women underwent clinical breast exam, and if this was normal, mammography and MRI were done on the same day. A biopsy was performed when either mammography or breast MRI investigations were judged to be suspicious for malignancy. Results: Three women required a biopsy based on abnormal results. The only invasive breast cancer occurred in a mutation carrier with a history of right-sided breast cancer and was only detected by MRI. This breast cancer was in the left breast, measured l.2 cm in diameter and all nodes were negative. Conclusion: Breast MRI only detected one invasive breast cancer in this series of 178 women at high risk for hereditary breast cancer. As this study contains preliminary data, conclusions regarding the use of MRI as a screening tool in women at high-risk for breast cancer cannot be drawn until appropriate follow-up is performed with these women.
Postoperative fluid collections: a new indication for interventional endoscopic ultrasound?
Authors: Yaqi Zhai, Ningli Chai, Enqiang Linghu
Journal: Endoscopy (2019)

See also:Safety and efficacy of the use of lumen-apposing metal stents in the management of postoperative fluid collections: a large, international, multicenter studyEndoscopy 2019; 51(08): 715-721DOI: 10.1055/a-0924-5591See also:Reply to Zhai et al.Endoscopy 2020; 52(01): 79-79DOI: 10.1055/a-1041-3083
Abstract 11932: Whole Exome Sequencing in a Cardiovascular Cohort Identifies Previously Undiagnosed Monogenic Cardiovascular Diseases
Authors: Jawan W Abdulrahim, Lydia C Kwee, Fawaz Alenezi, Aris Baras, Teminioluwa Ajayi, Christopher L Holley, Robert W McGarrah, James P Daubert, Lauren K Truby, Sreekanth Vemulapalli, Andrew Wang, Svati H Shah
Journal: Circulation (2019)

Monogenic diseases are individually rare but collectively common, and are likely underdiagnosed. Thus, we sought to determine the prevalence of monogenic cardiovascular (CV) diseases in a cohort of...
Promiscuous Mutations Frequently Activate the Non-Canonical NFkB Pathway in Multiple Myeloma (MM).
Authors: Peter Leif Bergsagel, John Carpten, Marta Chesi, Scott VanWier, Jonathan J. Keats, Michael Sebag, Wee-Joo Chng, Roelandt Schop, Angela Baker, Tae-Hoon Chng, Homer Fogle, Yuan Xiao Zhu, Chang Xin Shi, Laura Kay Bruhn, Michael Barrett, Catherine Mancini, Tammy Price-Troska, Gergory Ahmann, Kim Henderson, Philip R. Greipp, Angela Dispenzieri, Jeff Trent, Keith Stewart, Rafael Fonseca
Journal: Blood (2006)
Matters of the Mind—Bedtime Procrastination, Relaxation-Induced Anxiety, Lonely Tweeters
Authors: Rita Rubin
Journal: JAMA (2019)

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Delegation of flu jabs: pharmacists are trained and vigilant
Authors: Sarah D A Friend
Journal: BMJ (2019)

Clayton voices concerns about pharmacies giving flu jabs.1 NHS England is clear that pharmacists need suitable training to give flu vaccinations.2 Every year we are asked to make a declaration that our knowledge and skills are up to date, before providing the vaccination service. Pharmacy premises must keep emergency intramuscular adrenaline in case of an anaphylactic reaction to the flu …
Tucatinib, Trastuzumab, and Capecitabine for HER2-Positive Metastatic Breast Cancer
Authors: Rashmi K. Murthy, Sherene Loi, Alicia Okines, Elisavet Paplomata, Erika Hamilton, Sara A. Hurvitz, Nancy U. Lin, Virginia Borges, Vandana Abramson, Carey Anders, Philippe L. Bedard, Mafalda Oliveira, Erik Jakobsen, Thomas Bachelot, Shlomit S. Shachar, Volkmar Müller, Sofia Braga, Francois P. Duhoux, Richard Greil, David Cameron, Lisa A. Carey, Giuseppe Curigliano, Karen Gelmon, Gabriel Hortobagyi, Ian Krop, Sibylle Loibl, Mark Pegram, Dennis Slamon, M. Corinna Palanca-Wessels, Luke Walker, Wentao Feng, Eric P. Winer
Journal: New England Journal of Medicine (2019)

Patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer who have disease progression after therapy with multiple HER2-targeted agents have limited treatment options. Tucatinib is an investigational, oral, highly selective inhibitor of the HER2 tyrosine kinase. We randomly assigned patients with HER2-positive metastatic breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine, who had or did not have brain metastases, to receive either tucatinib or placebo, in combination with trastuzumab and capecitabine. The primary end point was progression-free survival among the first 480 patients who underwent randomization. Secondary end points, assessed in the total population (612 patients), included overall survival, progression-free survival among patients with brain metastases, confirmed objective response rate, and safety. Progression-free survival at 1 year was 33.1% in the tucatinib-combination group and 12.3% in the placebo-combination group (hazard ratio for disease progression or death, 0.54; 95% confidence interval [CI], 0.42 to 0.71; P<0.001), and the median duration of progression-free survival was 7.8 months and 5.6 months, respectively. Overall survival at 2 years was 44.9% in the tucatinib-combination group and 26.6% in the placebo-combination group (hazard ratio for death, 0.66; 95% CI, 0.50 to 0.88; P = 0.005), and the median overall survival was 21.9 months and 17.4 months, respectively. Among the patients with brain metastases, progression-free survival at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group (hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P<0.001), and the median progression-free survival was 7.6 months and 5.4 months, respectively. Common adverse events in the tucatinib group included diarrhea, palmar-plantar erythrodysesthesia syndrome, nausea, fatigue, and vomiting. Diarrhea and elevated aminotransferase levels of grade 3 or higher were more common in the tucatinib-combination group than in the placebo-combination group. In heavily pretreated patients with HER2-positive metastatic breast cancer, including those with brain metastases, adding tucatinib to trastuzumab and capecitabine resulted in better progression-free survival and overall survival outcomes than adding placebo; the risks of diarrhea and elevated aminotransferase levels were higher with tucatinib. (Funded by Seattle Genetics; HER2CLIMB ClinicalTrials.gov number, NCT02614794.).
Treatment of pediatric stage IA lymphocyte-predominant Hodgkin lymphoma with surgical resection alone: A report from the Children's Oncology Group.
Authors: Burton Appel, Peter Ehrlich, Lu Chen, Robert E. Hutchison, David C. Hodgson, Louis S. Constine, Cindy L. Schwartz
Journal: Journal of Clinical Oncology (2012)

9524 Background: Lymphocyte-predominant Hodgkin lymphoma (LPHL) is an uncommon histologic subtype comprising up to 10% of cases in pediatric series. Patients with LPHL typically present with low stage disease and are responsive to regimens used for classical HL. Recurrence is uncommon; secondary malignant neoplasms or evolution to non-Hodgkin lymphoma are more common events. Small retrospective studies have suggested that some patients with stage I LPHL can be cured with surgery alone. We report the results of a large prospective study using a treatment algorithm in which a selected subset of patients received surgery alone. Methods: Patients ages 0-21 years with newly-diagnosed, low risk LPHL were eligible for AHOD03P1. Low risk was defined as clinical Stage IA and IIA in the absence of bulk disease (a mediastinal mass &gt; 1/3 of the thoracic diameter or a nodal aggregate &gt; 6 cm). Central pathology review was performed to confirm LPHL histology. Baseline evaluations included CT and FDG-PET. Patients with Stage IA disease in a single node that was completely resected were observed without further therapy. Total resection (TR) was confirmed by rapid central review of CT and FDG-PET. In some cases the extent of resection was equivocal; repeat imaging 6-7 weeks after initial evaluation was used to allocate such patients to either observation or chemotherapy. Patients who recurred were assigned to treatment with 3 cycles of AV-PC (doxorubicin/vincristine/prednisone/cyclophosphamide). Results: Between January 2006 and November 2010, 52 patients with Stage IA, single node LPHL were enrolled with a confirmed TR. Nine patients have experienced a relapse; 8 were Stage I and 1 was Stage II at relapse. The median time to relapse was 10 (range 1-17) months. The median follow up among the 43 remaining patients is 26 (range 4-60) months. The current 2 year EFS estimate among these patients is 80.3% (95% CI: 65.3% -89.3%). Overall survival for the 52 patients is 100%. Conclusions: With this strategy of surgical resection followed by observation in a highly select cohort of pediatric LPHL, up to 80% of patients may be spared chemotherapy. Follow up is limited but overall survival to date is excellent.
Abstract 1669: Aprotinin Concentration Varies According To Cardiopulmonary Bypass Conditions
Authors: Toru Okamura, Nobuyuki Ishibashi, Yusuke Iwata, David Zurakowski, Richard Jonas
Journal: Circulation (2007)

Background: Aprotinin continues to be widely used in pediatric cardiac surgery although questions regarding renal toxicity in adults have been raised. This study tested the hypothesis that aprotini...
SGLT-2 inhibitors were not linked to severe or nonsevere UTIs vs DPP-4 inhibitors or GLP-1 agonists
Authors: Mayer B. Davidson
Journal: Annals of Internal Medicine (2019)

Source Citation Dave CV, Schneeweiss S, Kim D, et al. Sodium–glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med. 20...
Long-term follow-up of post-cardiac surgery Mycobacterium chimaera infections: A 5-center case series
Authors: Kathleen G. Julian, Tonya Crook, Eugene Curley, A. Ben Appenheimer, Catharine I. Paules, Barbara Hasse, Daniel J. Diekema, Charles L. Daley, Jorgelina de Sanctis, Walter C. Hellinger, Adrah Levin, George McSherry, Carol Freer, Cynthia J. Whitener
Journal: Journal of Infection (2019)
The impact of marijuana smoking on lung function
Authors: Robert J. Hancox, Malcolm R. Sears
Journal: European Respiratory Journal (2019)

As marijuana becomes more widely used, and is legalised in several jurisdictions, the question of whether regular marijuana smoking has a deleterious effect on respiratory health, similar to tobacco smoking, has been a major topic of investigation. While multiple studies indicate the potential for development of respiratory symptoms reflecting airway inflammation and chronic bronchitis (dominantly cough, wheeze, and sputum production), studies reporting detailed longitudinal lung function assessments have been substantially fewer. The effects of marijuana smoking on lung function remain to be fully elucidated <http://bit.ly/36unCEq>
Artificial Intelligence Classification of Central Visual Field Patterns in Glaucoma
Authors: Mengyu Wang, Lucy Q. Shen, Louis R. Pasquale, Michael V. Boland, Sarah R. Wellik, Carlos Gustavo De Moraes, Jonathan S. Myers, Thao D. Nguyen, Robert Ritch, Pradeep Ramulu, Hui Wang, Jorryt Tichelaar, Dian Li, Peter J. Bex, Tobias Elze
Journal: Ophthalmology (2019)