tbuckley/cabot-search huggingface dataset:
A3.04 Stromal cell metabolism; the reverse warburg effect in the inflamed synovium
Authors: JL Marshall, J Falconer, S Kapoor, A Filer, K Raza, SP Young, CD Buckley
Journal: Annals of the Rheumatic Diseases (2016)

<h3></h3> Reprogramming of stromal cell metabolism toward glycolysis in cancerous tissue provides a source of high-energy metabolic intermediates which support proliferation, invasion and metastasis of invading tumour cells; a phenomenon known as the 'Reverse Warburg' effect. We have explored whether a similar interplay may fuel pathogenic processes in autoinflammatory diseases such as rheumatoid arthritis (RA). In RA, fibroblasts are themselves transformed to an aggressive, tumour-like phenotype and also reside in close proximity to energetically demanding immune cells including resident macrophages, infiltrating neutrophils and autoaggressive lymphocytes. We used nuclear magnetic resonance spectroscopy and metabolic flux analysis to identify pathological changes to metabolism in both primary human RA synovial cells, and murine cells from TNF-ΔARE and collagen-induced models of arthritis. We have shown that the fibroblast metabotype correlates with C-reactive protein as a systemic marker of inflammation, and can predict resolution of acute synovitis or progression to chronic RA prior. We have confirmed the clinical prognostic potential of metabolic profiling in inflammatory diseases and demonstrated that synovial fibroblasts increase glycolysis but not mitochondrial respiration in response to inflammatory cues such as tumour necrosis factor-α. Furthermore, analysis of monocarboxylate transporters (MCT-4) supports the likelihood that increased glycolytic products such as lactate may be shuttled between fibroblasts and myeloid cells <i>in situ</i>. Our findings shed light on the metabolic relationships between cells at sites of autoinflammatory pathology and support the therapeutic targeting of the glycolytic pathway beyond oncology. European Union9s FP7 Health Programme FP7-HEALTH-F2–2012–305549 AR UK Rheumatoid Arthritis Pathogenesis Centre of Excellence 20298
Characterization of the colon by endoscopic ultrasonography
Authors: F Castro-Poças, P Lago, M Mascarenhas, E Santos, C Chaves, J Areias
Journal: Endoscopy (2006)

Introduction: indications to EUS of the colon are emerging. Aims: (1) characterization by EUS of colonic/rectal walls and peri-colonic/rectal spaces; (2) compare 12 and 20MHz probes; (3) create an EUS data base of the colon/rectum in healthy to compare with patients. Material: Study of 60 healthy;30 females;20 between 18–39 years old;20, 40–59; 20, 60–80; in each of this age groups 50% female. EUS was performed with 12 and 20MHz; in each age groups half of the cases evaluated with 12MHz and half with 20MHz. We evaluated the right colon (RC), transverse (TC), descending (DC), sigmoide (SC) and rectum (RE). Parameters: (1) nº of layers; (2) thickness: mucosa, subm., m. propria, entire wall; (3) regularity of mucosal surface and interface between layers; (4) pattern of different layers; (5) vessels in submucosa; (6) peri-intestinal lymph nodes. Results: (1) (p<0.05) nº of layers identified in the submucosa and m. propria comparing 12 and 20MHz; the RE and DC presented the highest median; (2) thickness of the entire wall and of it's layers (p<0.05): entire wall and m. propria thicker in RE and SC; subm. thinner in TC; mucosa thinner in DC and SC; (3) larger m. propria thickness in DC and RE in the age 40–59 years; (4) high regularity of mucosal surface and interface between layers (>90%); (5) homogeneous pattern in >90% of the cases in wall layers; (6) presence of subm. vessels in 30% of cases in DC and RE and fewer in RC (11.7%); (7) presence of lymph nodes in 10% of cases. Conclusions:(1)20MHz identifies higher nº of layers than 12MHz; (2) nº of layers higher in DC and RE; (3) rectal wall is thicker than colon; (4) differences in thickness of the various layers between different colonic segments (5) there are differences in thickness of m. propria and of entire wall depending on age; (6) wall and it's different layers present a high regularity and homogeneity.
PWE-089 Outcomes of Patients with Crohn’S Disease: Azathioprine Tolerant and Azathioprine Intolerant: Abstract PWE-089 Table
Authors: L Lee, A Gardezi, G Macfaul, S Lanzon-Miller
Journal: Gut (2013)

<h3>Introduction</h3> Azathioprine is well established for the maintenance of remission in patients with Crohn’s disease and 87% patients on maintenance therapy are able to reduce steroid consumption. However, azathioprine is less effective at treating disease recurrence and seven patients need to be treated to prevent one recurrence (1). Intolerance to azathioprine occurs in almost a third of patients and it has been proposed that the intolerance to azathioprine is a poor prognostic marker that may predispose patients to a more aggressive disease course. <h3>Methods</h3> A cross sectional study was performed using the Milton Keynes Hospital IBD database to compare outcomes of patients that were azathioprine intolerant and those that were azathioprine tolerant. A descriptive analysis of clinical features and outcomes of these two groups was performed. <h3>Results</h3> 141 patients were included for analysis of which 24.8% were intolerant to azathioprine. The median age of azathioprine intolerant patients was 47 and 31.4% were male. In the azathioprine tolerant cohort, the median age was 36 and 41.5% were male. Azathioprine was not tolerated due to gastrointestinal side effects in 53.6%, neurological effects (depression/headaches/vertigo) in 17.9%, deranged LFTs in 17.9% and the arthralgia/neutropenia and cutaneous side effects making up the remaining cases. <h3>Conclusion</h3> Azathioprine is a drug that is not tolerated in nearly a quarter of Crohn’s disease patients and this effect demonstrated a sex bias towards females. Patients who were intolerant to azathioprine were not more likely to undergo surgery or to have more strictures or fistulas. However, azathioprine-intolerant patients were considerably more likely to have more active disease, to require monoclonal antibody therapy and steroids. Compared to patients who are able to use azathioprine, for every 100 patients who are intolerant, 24 less will be in remission and 20 more will have moderate to severe disease. We conclude that patients with azathioprine intolerance will have poorer symptom control, but does not predispose to a more aggressive disease course. <h3>Disclosure of Interest</h3> None Declared. <h3>Reference</h3> Pearson D, May G, Fick G, Sutherland L. Azathioprine for maintenance of remission in Crohn’s disease. Cochrane Database of Systematic Reviews
Effects of Testosterone Treatment in Older Men
Authors: Peter J. Snyder, Shalender Bhasin, Glenn R. Cunningham, Alvin M. Matsumoto, Alisa J. Stephens-Shields, Jane A. Cauley, Thomas M. Gill, Elizabeth Barrett-Connor, Ronald S. Swerdloff, Christina Wang, Kristine E. Ensrud, Cora E. Lewis, John T. Farrar, David Cella, Raymond C. Rosen, Marco Pahor, Jill P. Crandall, Mark E. Molitch, Denise Cifelli, Darlene Dougar, Laura Fluharty, Susan M. Resnick, Thomas W. Storer, Stephen Anton, Shehzad Basaria, Susan J. Diem, Xiaoling Hou, Emile R. Mohler, J. Kellogg Parsons, Nanette K. Wenger, Bret Zeldow, J. Richard Landis, Susan S. Ellenberg
Journal: New England Journal of Medicine (2016)

Serum testosterone concentrations decrease as men age, but benefits of raising testosterone levels in older men have not been established.
Acute stroke due to air embolism complicating ERCP
Authors: D. Chavalitdhamrong, P. Draganov
Journal: Endoscopy (2013)

Air embolism is a rare, but severe complication of endoscopic retrograde cholangiopancreatography (ERCP). We present two cases of acute stroke after ERCP due to intracranial and spinal air embolism. Our second case is the first report of spinal cord air embolism.
Abstract 5575: Strigolactones: a novel class of plant hormones inhibit cancer cell and cancer stem-like cell growth and survival.
Authors: Ronit I. Yarden, Claire B. Pollock
Journal: Cancer Research (2013)

Abstract Strigolactones (SLs) are a novel class of plant hormones produced in roots and regulate new above ground shoot branching, by inhibiting self-renewal of undifferentiated meristem cells. Here we show that Strigolactone analogues are able to inhibit proliferation and induce apoptosis of several different types of cancer cells including breast, prostate, lung, colon and osteosarcoma cells but not ‘non-cancer’ lines. Given the therapeutic problem of cancer recurrence which is hypothesized to be due to drug resistant cancer stem cells, we also tested the ability of Strigolactone analogues to inhibit cancer stem cell growth. We show that Strigolactones are potent inhibitors of self-renewal and survival of breast cancer cell lines grown as cancer stem cell enriched mammospheres and even a short exposure leads to irreversible effects on mammosphere dissociation and cell death. Cell cycle analysis showed that all five strigolactone analogues induced G2/M arrest, coupled with increased percentages of cells in the sub-G1 fraction. AnnexinV staining confirmed that Strigolactone treatment induced apoptosis. Strigolactone treatment was hallmarked by increased expression of genes involved in stress signaling, as well as apoptosis, metabolic function and cellular adhesion. Immunoblot analysis of strigolactone treated cells also revealed increased phosphorylation of the stress activated MAPKs: p38 and JNK1/2 and decreased phospho-ERK1/2 and phospho-AKT. In summary, Strigolactones are promising candidates for anticancer therapy by their ability to induce cell cycle arrest and apoptosis in cell lines derived from a wide array of different cancers. Citation Format: Ronit I. Yarden, Claire B. Pollock. Strigolactones: a novel class of plant hormones inhibit cancer cell and cancer stem-like cell growth and survival. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5575. doi:10.1158/1538-7445.AM2013-5575 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
FACTORS ASSOCIATED WITH HIGH PATIENT RADIATION DOSE DURING CHRONIC TOTAL OCCLUSION PERCUTANEOUS CORONARY INTERVENTION: INSIGHTS FROM A CONTEMPORARY MULTICENTER REGISTRY
Authors: Georgios Christakopoulos, Georgios Christopoulos, Dimitrios Karmpaliotis, Khaldoon Alaswad, Robert Yeh, Farouc Jaffer, R. Michael Wyman, William Lombardi, Muhammad Nauman Tarar, Aaron Grantham, David Kandzari, Nicholas Lembo, Jeffrey Moses, Ajay Kirtane, Manish Parikh, Phillip Green, Matthew Finn, Santiago Garcia, Anthony Doing, Craig A. Thompson, Subhash Banerjee, Emmanouil Brilakis
Journal: Journal of the American College of Cardiology (2016)
NT-36 * FOCUSED ULTRASOUND ENHANCED CHEMOTHERAPEUTIC AGENT (TEMOZOLOMIDE) DELIVERY FOR BRAIN TUMOR TREATMENT: A PRECLINICAL INVESTIGATION
Authors: K.-C. Wei, J.-Y. Chen, C.-Y. Huang, P.-Y. Chen, H.-Y. J. Wang, H.-L. Liu
Journal: Neuro-Oncology (2014)

Malignant brain tumor is highly aggressive disease with high recurrence and motility rate. Current therapeutic approaches including surgery, radiation and chemotherapy only provide limited disease progression control. One of the major issues results its poor outcome is the blockade of chemotherapeutic agent delivery by the blood-brain barrier (BBB). Recently, focused ultrasound (FUS) with the presence of microbubbles has been confirmed its feasibility in transient and local BBB opening, demonstrated the potential in performing noninvasive brain drug delivery. Therefore, the use of FUS for enhancement of drug delivery to brain parenchyma may serve as a possible treatment of brain tumors. The objective of this study is to investigate the potential in combining the FUS-induced BBB opening with the Temozolomide (TMZ), the first-line brain tumor chemotherapeutic agent, to improve the brain tumor treatment. Brain tumor bearing mice were served as the animal model. Evans-blue was administered to demonstrate the blood-brain BBB-opened site, quantification of TMZ concentration in brain and tumor tissue was performed by high performance liquid chromatography (HPLC) and electrospray ion trap mass spectrum. Our results revealed the accumulation of TMZ in tissue or cerebrospinal fluid of FUS exposed groups is significantly increased as compared with controlled group, which demonstrates the efficacy of FUS-BBB opening for enhancement of local TMZ delivery in brain. Furthermore, FUS-BBB opening combines TMZ treatment significantly inhibits the tumor growth rate and prolongs the median survival of brain tumor animals. Our study provide evidences supporting the effect of FUS-BBB opening in enhancement of local delivery of chemotherapeutic agent to brain and the potential for future clinical application.
SAT0218 Clinical phenotypes in NPSLE; data from the leiden NPSLE clinic
Authors: E. Zirkzee, G.M. Steup-Beekman, E. Bollen, R. van der Mast, N. van der Wee, M. Huisman, H. Middelkoop, M. van Buchem, T. Huizinga
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Therapeutic decisions in NPSLE are made on a patient-by-patient basis guided by the severity of symptoms and the suspected underlying pathogenetic mechanism. Evidence for therapeutic decisions is scanty as is data on clinical phenotypes in NPSLE. <h3>Objectives</h3> To describe clinical phenotypes per suspected pathogenetic mechanism in NPSLE. <h3>Methods</h3> The Leiden NPSLE clinic is a tertiary referral centre that evaluates patients suspected of NPSLE and leads to a prospectively collected database. Standardized evaluation including serological, imaging, clinical and neuropsychological testing is followed by a multidisciplinary consensus meeting. Diagnosis and therapeutic decisions based on the suspected pathogenetic mechanism are made by consensus of all participating medical specialists. We describe clinical phenotypes with sociodemographic and clinical characteristics per pathogenetic mechanism. <h3>Results</h3> One hundred consecutive patients were evaluated in the Leiden NPSLE clinic. Three clinical phenotypes could be differentiated in primary NPSLE; 55% inflammatory NPSLE in patients who were advised immunosuppressive therapy, 32% ischemic NPSLE in patients who were advised anticoagulant therapy and 13% undefined NPSLE in patients who were advised symptomatic treatment. Age and disease duration in each group were 42 and 8, 47 and 9, 45 and 2 years, respectively. MRI abnormalities were present in 72%, 100% and 80% of respective phenotypes and SLEDAI scores were 10, 7 and 6. IgG anticardiolipin antibodies and lupus anticoagulans were present in respectively 33% and 48% of inflammatory and in 58% and 67% of ischemic NPSLE and were absent in undefined NPSLE patients. Twenty-five percent of ischemic NPSLE-patients reported transient ischemic attacks oppose to none in other groups. Cognitive dysfunction was present in 62% of inflammatory, 50% of ischemic and 20% of undefined NPSLE patients. As a fourth group secondary NPSLE was recognized in 11% of patients, in this group 75% of patients had a renal disorder and 88% of patients used steroids. <h3>Conclusions</h3> To the best of our kowledge this is the first prospective evaluation of a standardized multidisciplinary assessment of neuropsychiatric symptoms in SLE-patients. A remarkable feature of inflammatory NPSLE is a high SLEDAI and high prevalence of cognitive dysfunction. Whereas in ischemic NPSLE IgG anticardiolipin antibodies and lupus anticoagulans are highly prevalent and patients are distinguished by the report of TIA’s, also in this group all patients had abnormalities on MRI of the brain. <h3>Disclosure of Interest</h3> None Declared
Intramural hematoma of the colon caused by double-balloon enteroscopy in a patient with chronic disseminated intravascular coagulation
Authors: Yasuaki Nagami, Yasuhiro Fujiwara, Masafumi Yamamura, Masatsugu Shiba, Toshio Watanabe, Kazunari Tominaga, Tetsuo Arakawa
Journal: Endoscopy (2016)

A 63-year-old man with a history of surgery for thoracic aortic dissection was transferred to our hospital with obscure gastrointestinal bleeding (OGIB) and bloody stools. Laboratory examination revealed the following results: hemoglobin, 9.9 g/dL; platelets, 94 000/µL; creatinine, 1.29 mg/dL. Video capsule endoscopy following anterograde and retrograde double-balloon enteroscopy (DBE) could not identify the bleeding source.
Malignant Melanoma in Patients Treated for Psoriasis with Methoxsalen (Psoralen) and Ultraviolet A Radiation (PUVA)
Authors: Robert S. Stern, Khanh T. Nichols, Liisa H. Väkevä
Journal: New England Journal of Medicine (1997)

Photochemotherapy with oral methoxsalen (psoralen) and ultraviolet A radiation (PUVA) is an effective treatment for psoriasis. However, PUVA is mutagenic, increases the risk of squamous-cell skin cancer, and can cause irregular, pigmented skin lesions. We studied the occurrence of melanoma among patients treated with PUVA.We prospectively identified cases of melanoma and documented the extent of exposure to PUVA among 1380 patients with psoriasis who were first treated with PUVA in 1975 or 1976. Using incidence data, we calculated the expected incidence of melanoma in this cohort and compared it with the observed incidence. Using regression models, we assessed the risks of melanoma associated with a long time (> or = 15 years) since the first treatment and with a large number of PUVA treatments (> or = 250).From 1975 through 1990, we detected four malignant melanomas, about the number expected in the overall population (relative risk, 1.1). From 1991 through 1996, we detected seven malignant melanomas (relative risk, 5.4; 95 percent confidence interval, 2.2 to 11.1). The risk of melanoma was higher in the later period than in the earlier one (incidence-rate ratio, 3.8) and higher among patients who received at least 250 PUVA treatments than among those who received fewer treatments (incidence-rate ratio, 3.1).About 15 years after the first treatment with PUVA, the risk of malignant melanoma increases, especially among patients who receive 250 treatments or more.
Abstract 337: A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib.
Authors: Jie Cai, Mengmeng Yang, Jianyun Deng, Xiaoming Song, Xuesong Huang, Taiping Chen, Jean Pierre Wery, Yiyou Chen, Henry QX Li
Journal: Cancer Research (2013)

Abstract Non-small cell lung cancer (NSCLC) has the highest mortality among all malignances while with limited treatment options. Among the most significant treatment advancement in recent years are the introduction of target therapies of EGFR-TKIs (Erlotinib and Gefitinib) for adenocarcinoma with EGFR activating mutations, and Crizotinib for NSCLC with ALK activation (EML4-ALK fusion)1. ALK activation are associated with a subset of NSCLC patients (3∼5%).Crizotinib is considered not a particularly potent ALK inhibitor, with IC50 at range of tens of nanomoles. It may not be an ideal agent for treating NSCLC with activating ALK. Therefore, a new ALK inhibitor with better potency and specificity could be of particularly medical importance. Currently, the industry is actively searching for such new agents. A relevant experimental model could also greatly facilitate evaluating and validating these new drug candidates. Patient derived xenografts (PDX) (including NSCLC PDX) mirror patients’ histopathology and genetic profiles2, thus known as “patient avatar”. It has improved predictive power as preclinical cancer models, and enables discovery of predictive biomarkers for targeted therapeutics. We have established a large collection of NSCLC PDX models (NSCLC-HuPrime®) by engrafting naïve patient tumor tissues into immune-compromised mice2. Among these models, we have identified one model, LU1656, of NSCL carcinosarcoma histology and with EML4-ALK fusion mutation. This mutation apparently causes over-expression of ALK as measured at mRNA level. This model has wild-type KRAS, c-MET and EGFR genes. Treatment of LU1656 with Crizotinib caused significant but not complete tumor response, suggesting ALK activation is one of the oncogenic drivers of this model. In addition, LU1656 also responded to Cetuximab, but respond poorly to Erlotinib. It would be interesting to examine the combination of these treatments. This model is, to our knowledge, the first reported PDX model with EML4-ALK fusion mutation. We believe that LU1656 would be a useful model to evaluate investigational ALK inhibitors, and new combination treatment regimens of Crizotinib and standard of care chemotherapies. Citation Format: Jie Cai, Mengmeng Yang, Jianyun Deng, Xiaoming Song, Xuesong Huang, Taiping Chen, Jean Pierre Wery, Yiyou Chen, Henry QX Li. A NSCLC PDX with EML4-ALK fusion mutation responds to crizotinib. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 337. doi:10.1158/1538-7445.AM2013-337
Cholesterol Crystals and the Formation of Cholesterol Gallstones
Authors: Abbas Sedaghat, Scott M. Grundy
Journal: New England Journal of Medicine (1980)

To examine the relation of cholesterol crystallization to the formation of gallstones, gallbladder bile was obtained by means of duodenal intubation in 54 patients (eight with asymptomatic gallstones) and from 17 patients undergoing cholecystectomy for cholelithiasis. Hepatic bile was obtained from nine patients with common-duct stones. Bile samples were examined for cholesterol monohydrate crystals and analyzed to determine the percentage of cholesterol saturation. Intubation in the eight patients with asymptomatic gallstones revealed a cholesterol saturation of 142±42 per cent (mean ±S.D.) and crystals in five patients. Crystals were absent in the other 36 patients with supersaturated bile (cholesterol saturation, 166±44 per cent) and in the 10 patients with undersaturated bile (cholesterol saturation, 81±24 per cent). In the 26 patients with symptomatic cholelithiasis or common-duct stones, crystals were not seen in the bile of the seven patients with pigment stones but were present in the bile of all 19 patients with cholesterol stones. (In some cases crystals appeared only after 24 to 48 hours of incubation.) Cholesterol crystallization is probably a prerequisite for the formation of cholesterol gallstones; however, many subjects have no crystallization despite marked supersaturation. (N Engl J Med. 1980; 302: 1274–7.)
Inhaled Nitric Oxide and Persistent Pulmonary Hypertension of the Newborn
Authors: Jesse D. Roberts, Jeffrey R. Fineman, Frederick C. Morin, Philip W. Shaul, Stephen Rimar, Michael D. Schreiber, Richard A. Polin, Maurice S. Zwass, Michael M. Zayek, Ian Gross, Michael A. Heymann, Warren M. Zapol, Kajori G. Thusu, Thomas M. Zellers, Mark E. Wylam, Alan Zaslavsky
Journal: New England Journal of Medicine (1997)

Persistent pulmonary hypertension of the newborn causes systemic arterial hypoxemia because of increased pulmonary vascular resistance and right-to-left shunting of deoxygenated blood. Inhaled nitric oxide decreases pulmonary vascular resistance in newborns. We studied whether inhaled nitric oxide decreases severe hypoxemia in infants with persistent pulmonary hypertension.