tbuckley/cabot-search huggingface dataset:
Effects of bariatric surgery on gout incidence in the Swedish Obese Subjects study: a non-randomised, prospective, controlled intervention trial
Authors: Cristina Maglio, Markku Peltonen, Martin Neovius, Peter Jacobson, Lennart Jacobsson, Anna Rudin, Lena M S Carlsson
Journal: Annals of the Rheumatic Diseases (2016)

Objectives To assess the long-term effect of bariatric surgery on the incidence of gout and hyperuricaemia in participants of the Swedish Obese Subjects (SOS) study. Methods This report includes 1982 subjects who underwent bariatric surgery and 1999 obese controls from the SOS study, a prospective intervention trial designed to assess the effect of bariatric surgery compared with conventional treatment. None of the subjects had gout at baseline. An endpoint on gout incidence was created based on information on gout diagnosis and use of gout medications through national registers and questionnaires. Median follow-up for the incidence of gout was about 19 years for both groups. Moreover, the incidence of hyperuricaemia over up to 20 years was examined in a subgroup of participants having baseline uric acid levels &lt;6.8 mg/dL. Results Bariatric surgery was associated with a reduced incidence of gout compared with usual care (adjusted HR 0.60, 95% CI 0.48 to 0.75, p&lt;0.001). The difference in absolute risk between groups was 3 percentage points at 15 years, and the number of subjects needed to be treated by bariatric surgery to prevent one incident gout event was 32 (95% CI 22 to 59). The effect of bariatric surgery on gout incidence was not influenced by baseline risk factors, including body mass index. During follow-up, the surgery group had a lower incidence of hyperuricaemia (adjusted HR 0.47, 95% CI 0.39 to 0.58, p&lt;0.001). The difference in absolute risk between groups was 12 percentage points at 15 years, and the number of participants needed to be treated by bariatric surgery to prevent hyperuricaemia was 8 (95% CI 6 to 13). Conclusions Bariatric surgery prevents gout and hyperuricaemia in obese subjects. Trial registration number NCT01479452 ; Results.
Weight Loss Decreases Magnetic Resonance Elastography Estimated Liver Stiffness in Nonalcoholic Fatty Liver Disease
Authors: Niraj S. Patel, Jonathan Hooker, Monica Gonzalez, Archana Bhatt, Phirum Nguyen, Kimberly Ramirez, Lisa Richards, Emily Rizo, Carolyn Hernandez, Tatiana Kisseleva, Bernd Schnabl, David Brenner, Claude B. Sirlin, Rohit Loomba
Journal: Clinical Gastroenterology and Hepatology (2016)
Infographic. Golf and health
Authors: A D Murray, L Daines, D Archibald, R A Hawkes, C Schiphorst, P Kelly, L Grant, N Mutrie
Journal: British Journal of Sports Medicine (2016)

Extract Download figure Open in new tab Download powerpoint GolfHealthPublic healthSportReviewThis is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/
Toll-Like Receptor 4/MyD88–Mediated Signaling of Hepcidin Expression Causing Brain Iron Accumulation, Oxidative Injury, and Cognitive Impairment After Intracerebral Hemorrhage
Authors: Xiao-Yi Xiong, Liang Liu, Fa-Xiang Wang, Yuan-Rui Yang, Jun-Wei Hao, Peng-Fei Wang, Qi Zhong, Kai Zhou, Ao Xiong, Wen-Yao Zhu, Ting Zhao, Zhao-You Meng, Yan-Chun Wang, Qiu-Wen Gong, Mao-Fan Liao, Jian Wang, Qing-Wu Yang
Journal: Circulation (2016)

Disturbance of brain iron metabolism after intracerebral hemorrhage (ICH) results in oxidative brain injury and cognition impairment. Hepcidin plays an important role in regulating iron metabolism, and we have reported that serum hepcidin is positively correlated with poor outcomes in patients with ICH. However, the roles of hepcidin in brain iron metabolism after ICH remain largely unknown.Parabiosis and ICH models combined with in vivo and in vitro experiments were used to investigate the roles of hepcidin in brain iron metabolism after ICH.Increased hepcidin-25 was found in serum and primarily in astrocytes after ICH. The brain iron efflux, oxidative brain injury, and cognition impairment were improved in Hepc-/- ICH mice but aggravated by the human hepcidin-25 peptide in C57BL/6 ICH mice. Data obtained in in vitro studies showed that increased hepcidin inhibited the intracellular iron efflux of brain microvascular endothelial cells but was rescued by a hepcidin antagonist, fursultiamine. Using parabiosis ICH models also shows that increased serum hepcidin prevents brain iron efflux. In addition, Toll-like receptor 4 (TLR4)/MyD88 signaling pathway increased hepcidin expression by promoting interleukin-6 expression and signal transducer and activator of transcription 3 phosphorylation. TLR4-/- and MyD88-/- mice exhibited improvement in brain iron efflux at 7, 14, and 28 days after ICH, and the TLR4 antagonist (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1-carboxylate significantly decreased brain iron levels at days 14 and 28 after ICH and improved cognition impairment at day 28.The results presented here show that increased hepcidin expression caused by inflammation prevents brain iron efflux via inhibition of the intracellular iron efflux of brain microvascular endothelial cells entering into circulation and aggravating oxidative brain injury and cognition impairment, which identifies a mechanistic target for muting inflammation to promote brain iron efflux and to attenuate oxidative brain injury after ICH.
AMG 479 in relapsed or refractory Ewing's family tumors (EFT) or desmoplastic small round cell tumors (DSRCT): Phase II results.
Authors: W. D. Tap, G. D. Demetri, P. Barnette, J. Desai, P. Kavan, R. Tozer, G. R. Friberg, H. Deng, I. McCaffery, A. W. Tolcher
Journal: Journal of Clinical Oncology (2010)

10001 Background: IGF1 signaling is implicated in the pathobiology of EFT and DSRCT. AMG 479 is a fully human monoclonal antibody antagonist of IGF1R that induced a complete response (CR) in 1 EFT patient (pt) in the phase I trial (Tolcher JCO 2009;27:5800-7). This phase II study evaluated the safety and efficacy of AMG 479 in pts with refractory EFT or DSRCT. Methods: This single-arm, multicenter, open-label study had ∼90% power to identify objective response rates (ORR) of 10-30% with a maximum alpha level of 0.05. A futility boundary was developed using a Bayesian approach to stop if either the ORR (CR + partial response [PR]) or clinical benefit rate (CR + PR + stable disease [SD] > 24 wks) was unlikely to be ≥ 10%. Key eligibility: clinical diagnosis of refractory EFT or DSRCT, ≥ 16 years old, no previous anti-IGF1R therapy, ECOG PS ≤ 2, archival tumor tissue, adequate organ function. Pts received 12 mg/kg AMG 479 IV Q2W. ORR (RECIST 1.0) was the primary endpoint. Archival tumor samples were analyzed for EWS gene translocations. Results: 35 pts (19 EFT [54%]; 16 DSRCT [46%]) enrolled (9/07 - 3/09) and received AMG 479. Median age = 31 (range 19-77) years; 80% male; ECOG PS 0/1/2 = 46%/46%/9%. ORR = 6%: there were 2 PRs by central analysis (1 EFT censored at 47 wks; 1 DSRCT censored at 12 wks). 7 pts (20%) had a clinical benefit (2 PR + 5 SD > 24 weeks). Central volumetric CT analysis confirmed tumor shrinkage ≥ 10% in 10 pts (29%). The most common toxicities (any grade) were fatigue (46%), nausea (34%), dyspnea (31%), and peripheral edema (29%). Grade 3/4 toxicities (worst grade) observed in 37% of pts included thrombocytopenia (14%), neutropenia (9%), and hyperglycemia (6%). There were 8 deaths on study due to disease progression. EWS genotyping data (27 available pts) displayed significant heterogeneity. No apparent pattern was observed between any specific EWS translocation and tumor response. Conclusions: AMG 479 monotherapy in these heavily pretreated pts with advanced relapsed or refractory EFT/DSRCT had an ORR of 6%. Although limited RECIST responses were seen in this heterogeneous population, 20% of pts experienced a clinical benefit. Efforts to characterize responsive subsets and predictive biomarkers are ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen, ARIAD, Genentech/Roche, Pfizer Amgen Amgen, Chemotherapy Foundation, Pfizer Amgen, ARIAD, Pfizer
Phase I trial of obatoclax mesylate in combination with bortezomib for treatment of relapsed multiple myeloma.
Authors: A. Keith Stewart, Suzanne Trudel, Jeffrey A. Zonder, Suzanne R. Hayman, Charles Erlichman, Briant Fruth, Betsy LaPlant, Daniel Sullivan
Journal: Journal of Clinical Oncology (2012)

8013 Background: Obatoclax mesylate (GX15-070MS) is a BH3 mimetic that inhibits Bcl-2 protein family members including MCL-1, a dominant target in myeloma (MM). Obatoclax (OBX) inhibited viability of 14 MM cell lines (mean IC 50 215 nM) and primary MM samples while exhibiting pre clinical synergy with bortezomib (BTZ). Sensitivity correlated with basal levels of Mcl-1 and Bcl- XL, but not Bcl2, Bim, Bax or Bak expression. Methods: We report a phase I trial of OBX in combination with BTZ. Eligibility required measureable disease, &gt; 1 prior MM therapy, ≤10 cycles of prior BTZ and did not progress on prior BTZ therapy, creatinine ≤2 ULN. Starting dose level 1 was OBX 14 mg/m 2 24-hour continuous iv. infusion days 1, 8, 15 of a 21-day cycle. BTZ given at 1.3mg/m 2 iv. days 1, 4, 8 and 11. After protocol amendment OBX level 1 dosing was 30 mg/m 2 , level 2 was 40 mg/m 2 IV both by continuous 3 hour infusion days 1, 8 and 15 on a 21 day schedule. Pre med. with famotidine was required. Results: Eleven patients were accrued, median age 62 (range: 46-77), median time from diagnosis was 4.7 years. Median of 2.5 cycles (range: 1-10). Median follow-up for patients still alive is 11.6 months (range: 0.9-35.5). At dose level 1, there were 2 DLTs. After amendment 8 patients were accrued (3 hour infusion): 4 at amended dose level 1 and 4 at dose level 2. All patients are now off treatment. 10 patients are evaluable for response: 2 patients at original dose level 1 (2 PR), 3 patients at dose level 1 (2 PR, 1 MR), no patients at dose level 2 responded: overall PR of 40%, clinical benefit response in 50% (95% CI: 19-81%). 6 patients had disease progression and 2 patients died. 4 DLTs were seen: at original dose level 1 grade 4 thrombocytopenia and delay of therapy &gt; 15 days. At dose level 2, 1 patient had grade 3 somnolence, a 2nd patient grade 3 euphoria and grade 4 thrombocytopenia. No DLTs were seen at amended dose level 1. Common adverse events of any grade included GI, hematologic and neurologic e.g. euphoria, decreased level of consciousness, psychosis, speech. Conclusions: In summary MTD is OBX 30mg/m 2 by 3 hour iv infusion once weekly, BTZ 1.3 mg/m 2 days 1,4,8, and 11. Major toxicities were central neurologic and hematologic. This P2C consortium study was supported by NCI N01-CM62205.
Active Vaccination with DKK1 Induces Protective and Therapeutic Antitumor Immunity In Multiple Myeloma
Authors: Jianfei Qian, Sungyoul Hong, Hong Qin, Ji Wang, Jinsong Wei, Liang Zhang, Haiyan Li, Yuhuan Zheng, Yongshen Lan, Jing Yang, Yong Lu, Larry W. Kwak, Qing Yi
Journal: Blood (2010)
Utility of susceptibility-weighted imaging in Parkinson’s disease and atypical Parkinsonian disorders
Authors: Zhibin Wang, Xiao-Guang Luo, Chao Gao
Journal: Translational Neurodegeneration (2016)

In the clinic, the diagnosis of Parkinson's disease (PD) largely depends on clinicians' experience. When the diagnosis is made, approximately 80% of dopaminergic cells in the substantia nigra (SN) have been lost. Additionally, it is rather challenging to differentiate PD from atypical parkinsonian disorders (APD). Clinially-available 3T conventional MRI contributes little to solve these problems. The pathologic alterations of parkinsonism show abnormal brain iron deposition, and therefore susceptibility-weighted imaging (SWI), which is sensitive to iron concentration, has been applied to find iron-related lesions for the diagnosis and differentiation of PD in recent decades. Until now, the majority of research has revealed that in SWI the signal intensity changes in deep brain nuclei, such as the SN, the putamen (PUT), the globus pallidus (GP), the thalamus (TH), the red nucleus (RN) and the caudate nucleus (CN), thereby raising the possibility of early diagnosis and differentiation. Furthermore, the signal changes in SN, PUT and TH sub-regions may settle the issues with higher accuracy. In this article, we review the brain iron deposition of PD, MSA-P and PSP in SWI in the hope of exhibiting a profile of SWI features in PD, MSA and PSP and its clinical values.
The gut microbiota contributes to a mouse model of spontaneous bile duct inflammation
Authors: Elisabeth Schrumpf, Martin Kummen, Laura Valestrand, Thomas U. Greiner, Kristian Holm, Velmurugesan Arulampalam, Henrik M. Reims, John Baines, Fredrik Bäckhed, Tom H. Karlsen, Richard S. Blumberg, Johannes R. Hov, Espen Melum
Journal: Journal of Hepatology (2016)
AUTHOR'S CORRECTION
Authors: Lippincott Williams Wilkins
Journal: Circulation Research (1965)

Wolinsky, H., and Glagov, S.: Structural Basis for the Static Mechanical Properties of the Aortic Media, Circulation Research, 14: 400-413, 1964. An error was made in the calculation of the data for figure 4. The statements and conclusions in the text, when based on correct calculations, are not modified. The correct figure and legend are given here.
Deferral of rectal surgery following a continued response to preoperative chemoradiotherapy (Watch and Wait) study: A phase II multicenter study in the United Kingdom.
Authors: S. K. Yu, G. Brown, R. J. Heald, S. Chua, G. Cook, Y. Barbachano, I. Chau, A. Wotherspoon, D. M. Tait
Journal: Journal of Clinical Oncology (2011)

489 Background: Neoadjuvant chemoradiotherapy (CRT) and surgical resection are standard components of therapy for patients locally advanced rectal cancer (T3,T4 or N+) in UK. In 15%-30% of patients treated pre-operatively with CRT will develop pathological complete response (CR). The time from completion of CRT to maximal tumour response is as yet unknown. This study is the first prospective study to attempt to identify the percentage of patients who can safely omit surgery and the safety of deferred surgery in patients who achieve clinical complete response post CRT. Of the 59 patients required for the study, this provides an update on 19 patients entered. Methods: Patients with locally advanced rectal cancer requiring neoadjuvant treatment are identified in the multidisciplinary meet (MDT). Patients undergo CRT using a minimum of 50.4Gy in 28 # daily conformal CT planned CRT with concomitant Capecitabine at 825mg/m 2 BD. MRI pelvis and body CT are repeated 4 weeks post CRT and rediscussed at MDT. If there is a good partial response or CR, patients are considered for Deferral of Surgery Study. Based on the pre treatment clinical staging, patients are considered for adjuvant chemotherapy as per NICE guidance. At any point of the study, if there is histology proven tumour regrowth or progression, patient undergo surgery. Results: 10 (53%) patients remain in CR. 6 (32%) patients underwent surgical resection with clear margin after detection of tumour regrowth at from 2-23 months post CRT. 5 out of 6 of the patients with tumour regrowth underwent PET CT as per protocol, and all tumour regrowth in those 5 patients were detected by PET CT, i.e. FDG avid disease. The pathological stages on these 6 patients were ypT2N0 CRM negative in 5 and ypT3N0 CRM negative in 1. 3 (15%) patients with tumour regrowth refused surgery. Conclusions: In the 19 recruited patients, all the patients with tumour regrowth underwent surgical resection with clear margins. PET CT appears a useful tool for detecting tumour regrowth. The median time for tumour regrowth is 17.5 months post CRT. The trial will be successful if at least 11/59 patients are able to safely omit surgery. Accrual of patients continues. No significant financial relationships to disclose.
LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer.
Authors: Amita Patnaik, Lee S. Rosen, Sara M. Tolaney, Anthony W. Tolcher, Jonathan Wade Goldman, Leena Gandhi, Kyriakos P. Papadopoulos, Muralidhar Beeram, Drew Warren Rasco, Scott P. Myrand, Palaniappan Kulanthaivel, Joan M. Andrews, Martin Frenzel, Damien Cronier, Edward M. Chan, Keith Flaherty, Patrick Y. Wen, Geoffrey Shapiro
Journal: Journal of Clinical Oncology (2014)

534 Background: Cyclin-dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to enable cell proliferation. LY2835219, a small molecule inhibitor of CDK4/6, has shown antitumor activity in xenograft models of multiple cancers. In a cohort of 47 patients (pts) with metastatic breast cancer (MBC) treated with LY2835219, there were 8 confirmed and 3 unconfirmed partial responses (PRs) among 36 pts with HR+ MBC. Fulvestrant is an anti-estrogen used to treat HR+ MBC. Thus, we expanded the Phase I study to evaluate LY2835219 plus fulvestrant for pts with HR+ MBC. Methods: We conducted a Phase I study to evaluate the safety, pharmacokinetics, and antitumor activity of LY2835219 in 5 different tumor types. For breast cancer, there were cohorts for both LY2835219 in MBC (n=47) and the combination of LY2835219 plus fulvestrant in HR+ MBC (n=13). Patients in the HR+ MBC combination cohort received LY2835219 at 200mg orally every 12 hours on Days 1-28 of a 28-day cycle plus fulvestrant at 500mg IM once monthly. CTCAE v4.02 was used to grade adverse events (AEs). RECIST v1.1 was used to assess tumor response. Results: In the HR+ MBC combination cohort, 13 pts with a median of 4 prior systemic therapies (range 2-8) received LY2835219 plus fulvestrant. Among these pts, the most common possibly related treatment-emergent AEs across all grades were diarrhea (including 8% G3), fatigue (8% G3), neutropenia (31% G3), nausea (no G3), vomiting (no G3), and leukopenia (23% G3); there were no Grade 4 events. LY2835219 dose reductions from 200mg to 150mg occurred in 8 pts, including 2 pts for diarrhea and 1 pt each for fatigue and neutropenia. Importantly, febrile neutropenia was not observed and there were no discontinuations due to toxicity. No serious AEs or deaths were reported. In HR+ MBC, LY2835219 demonstrated clinical activity (8 confirmed and 3 unconfirmed PRs) and also acceptable safety in combination with fulvestrant. Conclusions: LY2835219 demonstrates single-agent activity in MBC. For patients with HR+ MBC, the combination of LY2835219 plus fulvestrant shows acceptable safety and merits further clinical investigation for efficacy. Clinical trial information: NCT01394016.
Platelet Functions and Risk Prognosis in Myelodysplastic Syndromes,
Authors: Nora V. Butta, Mónica Martín Salces, Raquel de Paz, Elena G. Arias Salgado, Ihosvany Fernández Bello, Mayte Álvarez Román, Isabel Rivas, Miguel Canales, Víctor Jiménez-Yuste
Journal: Blood (2011)
Protein signal pathway mapping of human breast cancer from I-SPY: Correlations with response and genomic subtyping.
Authors: J. D. Wulfkuhle, M. E. Lenburg, M. Pierobon, J. Illi, J. Zhu, A. DeMichele, V. A. Espina, L. A. Liotta, L. Esserman, E. Petricoin
Journal: Journal of Clinical Oncology (2010)

10512 Background: Profiling signaling pathway activation in cancer is critical as these pathways represent targets for new molecular guided therapeutics. The I-SPY TRIAL (CALGB 150007/150012, ACRIN 6657) is a trial of neoadjuvant anthracycline- and taxane-based chemotherapy that provides a unique series of biopsy specimens that have been subjected to extensive and detailed molecular characterization, together with detailed clinical and radiographic information. Methods: Purified tumor epithelium from 149 frozen pre-treatment biopsy specimens were procured via laser capture microdissection. Reverse phase protein microarray (RPMA) technology was used to quantitatively measure the activation of 40 key signaling proteins including components of pathways of interest for targeted therapy in breast cancer (HER2, IGFR, EGFR, mTOR, AKT and PLK1). Association between pathway activation and genomic subtype, pCR, residual cancer burden (RCB), and other clinical measures including tumor size, and nodal involvement was examined. Results: Protein pathway activation measured in pretreatment samples divided patients into 5 groups by hierarchical clustering. Activation of HER2 and AKT pathways was associated with pCR and minimal residual disease following neoadjuvant chemotherapy (p < 0.05). Activation of HER2, AKT, PLK1 and EGFR were each associated with HER2 positivity as measured by IHC and/or FISH. Individual pathway activation levels were not observed to be associated with tumor molecular subtype as determined by transcriptome profiling. Patients with global signaling activation had higher rates of cancer recurrence. Conclusions: Using RPMA technology and minimal tissue from core biopsies, it is possible to measure functional pathway activation for which targeted therapies are available. The clinical significance of the five pathway activation subtypes and the activity of individual pathways will be prospectively tested in I-SPY 2, where agents targeted to these pathways will be introduced in the neoadjuvant setting. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Theranostics Health Theranostics Health Theranostics Health
Fibrinogen scaffolds with immunomodulatory properties promote in vivo bone regeneration
Authors: Daniel M. Vasconcelos, Raquel M. Gonçalves, Catarina R. Almeida, Inês O. Pereira, Marta I. Oliveira, Nuno Neves, Andreia M. Silva, António C. Ribeiro, Carla Cunha, Ana R. Almeida, Cristina C. Ribeiro, Ana M. Gil, Elisabeth Seebach, Katharina L. Kynast, Wiltrud Richter, Meriem Lamghari, Susana G. Santos, Mário A. Barbosa
Journal: Biomaterials (2016)