tbuckley/cabot-search huggingface dataset:
Interleukin-10 Inhibits Bone Marrow Fibroblast Progenitor Cell–Mediated Cardiac Fibrosis in Pressure-Overloaded Myocardium
Authors: Suresh K. Verma, Venkata N.S. Garikipati, Prasanna Krishnamurthy, Sarah M. Schumacher, Laurel A. Grisanti, Maria Cimini, Zhongjian Cheng, Mohsin Khan, Yujia Yue, Cindy Benedict, May M. Truongcao, Joseph E. Rabinowitz, David A. Goukassian, Douglas Tilley, Walter J. Koch, Raj Kishore
Journal: Circulation (2017)

Background: Activated fibroblasts (myofibroblasts) play a critical role in cardiac fibrosis; however, their origin in the diseased heart remains unclear, warranting further investigation. Recent studies suggest the contribution of bone marrow fibroblast progenitor cells (BM-FPCs) in pressure overload–induced cardiac fibrosis. We have previously shown that interleukin-10 (IL10) suppresses pressure overload–induced cardiac fibrosis; however, the role of IL10 in inhibition of BM-FPC–mediated cardiac fibrosis is not known. We hypothesized that IL10 inhibits pressure overload–induced homing of BM-FPCs to the heart and their transdifferentiation to myofibroblasts and thus attenuates cardiac fibrosis. Methods: Pressure overload was induced in wild-type (WT) and IL10 knockout (IL10KO) mice by transverse aortic constriction. To determine the bone marrow origin, chimeric mice were created with enhanced green fluorescent protein WT mice marrow to the IL10KO mice. For mechanistic studies, FPCs were isolated from mouse bone marrow. Results: Pressure overload enhanced BM-FPC mobilization and homing in IL10KO mice compared with WT mice. Furthermore, WT bone marrow (from enhanced green fluorescent protein mice) transplantation in bone marrow–depleted IL10KO mice (IL10KO chimeric mice) reduced transverse aortic constriction–induced BM-FPC mobilization compared with IL10KO mice. Green fluorescent protein costaining with α-smooth muscle actin or collagen 1α in left ventricular tissue sections of IL10KO chimeric mice suggests that myofibroblasts were derived from bone marrow after transverse aortic constriction. Finally, WT bone marrow transplantation in IL10KO mice inhibited transverse aortic constriction–induced cardiac fibrosis and improved heart function. At the molecular level, IL10 treatment significantly inhibited transforming growth factor-β–induced transdifferentiation and fibrotic signaling in WT BM-FPCs in vitro. Furthermore, fibrosis-associated microRNA (miRNA) expression was highly upregulated in IL10KO-FPCs compared with WT-FPCs. Polymerase chain reaction–based selective miRNA analysis revealed that transforming growth factor-β–induced enhanced expression of fibrosis-associated miRNAs (miRNA-21, -145, and -208) was significantly inhibited by IL10. Restoration of miRNA-21 levels suppressed the IL10 effects on transforming growth factor-β–induced fibrotic signaling in BM-FPCs. Conclusions: Our findings suggest that IL10 inhibits BM-FPC homing and transdifferentiation to myofibroblasts in pressure-overloaded myocardium. Mechanistically, we show for the first time that IL10 suppresses Smad–miRNA-21–mediated activation of BM-FPCs and thus modulates cardiac fibrosis.
A phase 1/2 study of metronomic 5-fluorouracil (5-FU) plus nab-paclitaxel, bevacizumab, leucovorin, and oxaliplatin (FABLOx) in patients with metastatic pancreatic cancer
Authors: Vincent Picozzi, Vaibhav Sahai, Diane Simeone, Caio Rocha Lima, Allyson Ocean, Philip Philip, Wasif Saif, Aparna Kalyan, Michael Ondovik, Jack Shiansong Li, Chrystal Louis
Journal: Annals of Oncology (2017)
Predictive role of FAS for trabectedin in second lines of advanced soft tissue sarcoma (ASTS): A Spanish group for research on sarcoma (GEIS) study.
Authors: Javier Martin Broto, David Marcilla, Rafael Ramos, David Silva Moura, Ramiro Alvarez, Nieves Hernandez, Carolina Agra Pujol, Empar Mayordomo, Cleofe Romagosa, Silvia Bague, Eugenia Reguero, Julia Cruz, Francisco Javier Martin, Antonio Gutierrez, Josefina Cruz, Rosa Maria Alvarez Alvarez, Robert Diaz Beveridge, Claudia Maria Valverde Morales, Antonio Lopez-Pousa, Javier Martinez-Trufero
Journal: Journal of Clinical Oncology (2017)

11071 Background: There are currently several second-line options for the treatment of ASTS as gemcitabine combinations, trabectedin, pazopanib, eribulin or olaratumab plus doxorubicin in cases where anthracyclins are still possible. There is an unmet need for predictive biomarkers which hinders the rational selection of the best sequence in second line. We already published the prognostic value of FAS in first line of ASTS while this study analyzes its predictive role in different second line schemes. Methods: Most relevant selection criteria for this study were having received trabectedin in 2 nd line or beyond for ASTS, progressive disease after at least one previous line for ASTS and signed CI. A TMA was set up for FAS staining (Cell Signaling) with blocks from diagnostic time. Two expert blinded pathologists reviewed and classified the cases as negative, weak or strong. Kaplan–Meier estimations were used for time-to-event variables and the log-rank test was used to compare groups. Results: A series of 198 patients accomplished selection criteria. Metastases at diagnosis occurred in 46 (24%) and median time to metastases was 18.8 months (CI 16,3; 21.3). Previous line to trabectedin consisted of gemcitabine combination 83 (42%), Doxorubicin-based 65 (33%) and others 50 (25%). Median PFS for previous and trabectedin lines were 3.5 (2.8-4.2) and 3.4 (2.8-4) months respectively. FAS positive entailed significantly better PFS for the previous trabectedin line: 4.1 (1.5-6.7) vs 3.0 (2.5-3.5) months, p = 0.01 whereas FAS positive was related with worse PFS for the trabectedin line 2.5 (2.2-2.8) vs 3.7 (2.7-4.8) months, p = 0.028. These results were more notorious for L-sarcoma cases: 7.0 (3.6-10.5) vs 4.3 (1.9-6.6) months, p = 0.017 in previous line and 2.4 (2.2-2.6) vs 6.5 (3.8-9.3) months, p &lt; 0.001 in trabectedin. From trabectedin administration, FAS+ had significantly worse OS especially in L-sarcomas: 11.9 (5.2-18.7) vs 21.7 (12.7-30.8) months, p = 0.002. Conclusions: FAS showed predictive value in PFS and OS for trabectedin administration in ASTS. The different prognostic role of FAS across distinct lines and its relevance in L-sarcomas deserve further attention.
An mTORC1/AKT1/Cathepsin H axis controls filaggrin expression and processing in skin, a novel mechanism for skin barrier disruption in Atopic Dermatitis
Authors: Aishath S. Naeem, Cristina Tommasi, Christian Cole, Stuart J. Brown, Yanan Zhu, Benjamin Way, Saffron Ag. Willis Owen, Miriam Moffatt, William O. Cookson, John I. Harper, Di Wl, Sara J. Brown, Thomas Reinheckel, Ryan F.L. O’Shaughnessy
Journal: Journal of Allergy and Clinical Immunology (2016)
Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Final results for the AVAST-M trial.
Authors: Philippa Corrie, Andrea Marshall, Paul Lorigan, Martin Eric Gore, Saad Tahir, Guy Faust, Charles G. Kelly, Maria Marples, Sarah Danson, Ernest Marshall, Stephen Houston, Ruth E. Board, Ashita Marie Waterston, Jenny Penelope Nobes, Mark Harries, Satish Kumar, Gemma Young, Emily Barker, Janet Dunn, Mark R. Middleton
Journal: Journal of Clinical Oncology (2017)

9501 Background: Bevacizumab (Bev) is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumours. As VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in melanoma patients at high risk of recurrence. Methods: AVAST-M (ISRCTN81261306) is a randomised phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy after resection of AJCC stage IIB, IIC and III cutaneous melanoma compared to standard observation (Obs). 1320 patients were needed to detect 8% differences in 5 year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint was OS; secondary endpoints included disease free interval (DFI), distant-metastasis free interval (DMFI). BRAF and NRASmutation status were obtained in 682 patients in a translational sub-study. Results: From July 2007 to March 2012, 1343 patients were recruited (671 to Bev; 672 to Obs). 56% were male, median age was 56 years (range 18-88 years), 14% were stage IIIA and 59% were stage IIIB/C. With 6 years median follow-up, 505 (38%) patients had died (251 [37%] on Bev; 254 [38%] on Obs); 699 (52%) patients had recurred (335 [50%] on Bev, 369 [55%] on Obs). OS at 5 years was 64% on Bev versus 63% on Obs (Hazard ratio [HR] 0.99; 95% confidence interval [CI] 0.84-1.18, p=0.96). At 5 years, 51% were disease free on Bev versus 45% on Obs (HR 0.85; 95% CI 0.74-0.99, p=0.04) and 59% were distant metastasis free on Bev versus 54% on Obs (HR 0.91; 95% CI 0.77-1.07, p=0.24). A BRAF V600 mutation was found in 44% of tumours assessed; 20% were NRAS mutant. BRAF mutant patients treated with Bev tended to have better DFI (HR=0.79 95% CI 0.58-1.08, p=0.14) and OS (HR=0.79; 95% CI 0.55-1.13, p=0.20); this was not evident for BRAF WT. NRAS mutant patients tended to have worse DFI (HR=1.39; 95% CI 1.03-1.88; p=0.03) and OS (HR=1.18; 95% CI 0.85-1.62, p=0.20) than NRASWT patients. Conclusions: This large, multi-centre trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev improves DFI, but this does not translate into an overall survival benefit. Funding:Cancer Research UK; drug supplied by Roche Products Ltd. Clinical trial information: ISRCTN81261306.
Authors’ reply to Evans
Authors: Michèle Bally, James M Brophy
Journal: BMJ (2017)

We do not agree that immediate onset of a notably increased risk is explained by failure to adequately adjust for confounding or by reverse causation.12 Aside from matching and multivariable regression, a key reason why early risk is not just confounding is that we restricted the inclusion of studies to those done before rofecoxib was withdrawn. Confounding by indication or by contraindication is unlikely to have occurred because before September 2004 the choice of non-steroidal anti-inflammatory drug (NSAID) by …
Chondroitin sulfate for knee osteoarthritis
Authors: Donald M Marcus
Journal: Annals of the Rheumatic Diseases (2017)

The apparent efficacy of chondroitin sulfate in treating knee osteoarthritis reported by Reginster et al 1 must be considered in the context of the literature on this subject. The results of trials of chondroitin and/or glucosamine for relief of pain caused by osteoarthritis of the knee and hip have been …
Abstract P135: Hyperpolarized Carbon-13 Magnetic Resonance Reveals Early- and Late-Onset Changes to Metabolism in the Failing Heart
Authors: Marie Schroeder, Angus Z Lau, Albert P Chen, Jennifer Barry, Damian J Tyler, Kieran Clarke, Kim A Connelly, Graham Wright, Charles H Cunningham
Journal: Circulation Research (2011)

Disordered metabolic substrate utilisation has been implicated in the pathogenesis of heart failure (HF). Hyperpolarised (HYP) 13C magnetic resonance, a technique in which the fate of 13C-labelled metabolites can be followed using MR imaging or spectroscopy, has enabled non-invasive assessment of metabolism. The aim of this study was to monitor carbohydrate metabolism alongside cardiac structure, function, and energetics, throughout HF progression. HF was induced in pigs (n=5) by right ventricular pacing at 188 bpm for 5 weeks. Pigs were examined at weekly time points: cine MRI assessed cardiac structure and function, HYP 13C2-pyruvate was administered intravenously and 13C MRS was used to assess 13C-glutamate production via Krebs cycle, 31P MRS assessed myocardial energetics, and HYP 13C1-pyruvate was administered to enable MRI of H13CO3- production from pyruvate dehydrogenase (PDH). At baseline, pigs had a normal left ventricular (LV) cardiac index (CI) and end diastolic volume (EDVi). The PCr/ATP was 2.3 ± 0.2. The 13C-glutamate/13C2-pyruvate was 4.3 ± 0.9%, and the H13CO3-/13C1-pyruvate ratio was 1.6 ± 0.2%. After 1–2 weeks of pacing, CI decreased to 3.3 ± 0.5 l/min/m2, PCr/ATP decreased to 1.7 ± 0.1, and 13C-glutamate/13C2-pyruvate decreased to 2.1 ± 0.6%. With the onset of HF, EDVi increased to 140.3 ± 14.1 ml/m2 and H13CO3-/13C1-pyruvate decreased to 0.5 ± 0.2%. In conclusion, we observed an early defect in Krebs' cycle that occurred alongside impaired cardiac energetics and function. Carbohydrate oxidation via PDH was maintained until the onset of HF. These results encourage use of metabolic therapies to delay/prevent the onset of heart failure in patients.
Prediction of local and metastatic recurrence in solitary fibrous tumor: construction of a risk calculator in a multicenter cohort from the French Sarcoma Group (FSG) database
Authors: S. Salas, N. Resseguier, J.Y. Blay, A. Le Cesne, A. Italiano, C. Chevreau, P. Rosset, N. Isambert, P. Soulie, D. Cupissol, C. Delcambre, J.O. Bay, P. Dubray-Longeras, M. Krengli, B. De Bari, S. Villa, J.H.A.M. Kaanders, S. Torrente, D. Pasquier, J.O. Thariat, L. Myroslav, C.V. Sole, H.F. Dincbas, J.Y. Habboush, T. Zilli, T. Dragan, K. Khanﬁr, G. Ugurluer, T. Cena, F. Duffaud, N. Penel, F. Bertucci, D. Ranchere-Vince, P. Terrier, S. Bonvalot, N. Macagno, C. Lemoine, M. Lae, J.M. Coindre, C. Bouvier
Journal: Annals of Oncology (2017)
Role of Shelterin Complex and Alternative Telomere Lengthening in Genomic Instability and Disease Progression in Chronic Myeloid Leukemia
Authors: Tomasz Stoklosa, Anna Deregowska, Katarzyna Pruszczyk, Iwona Solarska, Marcin M Machnicki, Jagoda Adamczyk, Ilona Seferynska, Anna Lewinska, Maciej Wnuk
Journal: Blood (2016)
Abstract 368: Structural and Molecular Mechanisms of Excitation-contraction Uncoupling in Heart Failure
Authors: Ming Xu, Hao-Di Wu, Rong-Chang Li, Su-Fang Li, Shao-Ting Lai, You-Yi Zhang, Shi-Qiang Wang
Journal: Circulation Research (2012)

The excitation-contraction (E-C) coupling in heart cells governed by L-type Ca 2+ channels (LCCs) in the cell membrane/T-tubules (TTs) and ryanodine receptors (RyRs) in the junctional sarcoplasmic reticulum (JSR). During heart failure, LCC-RyR signaling became defective, leading to degraded Ca 2+ transients and compromised contractile strength. In the present study, we investigated the structural and molecular mechanisms underlying the compromised LCC-RyR signaling in rat heart failure models produced by transverse aortic constriction surgery. Stereological analysis of transmission electron microscopic images showed that the volume density and the surface area of JSRs and those of JSR-coupled TTs were both decreased in failing heart cells. The TT-JSR junctional structures, known as couplons, were displaced or missing from the Z-line areas. Moreover, the spatial span of individual couplons was markedly reduced in failing heart cells. Knockdown of junctophilin-2 (JP2), a TT-SR linker protein down-regulated in heart failure, fully reproduced the structural deformation and decreased/desynchronized Ca 2+ release, indicating that JP2 down-regulation is at least partially responsible for the structural and functional defects of E-C coupling in heart failure. In searching for upstream regulator of JP2, we found that microRNA-mediated suppression of JP2 expression underlied both TT-SR structural uncoupling and LCC-RyR functional uncoupling. These results revealed molecular and structural mechanisms underlying the defective E-C coupling in failing heart cells, and suggested new therapeutic targets against heart failure.
A New Method to Evaluate the Oesophagogastric Junction – The Functional Imaging Probe (FLIP)
Authors: BP McMahon, JB Frokjaer, P Kunwald, D Liao, P Funch-Jensen, H Gregersen, AM Drewes
Journal: Endoscopy (2006)

Aims: To verify the efficacy of a new probe FLIP for measuring geometric changes in the OGJ on healthy controls (HCs) and on a classical achalasia patient.
Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus
Authors: Md Yuzaiful Md Yusof, Daniel Shaw, Yasser M El-Sherbiny, Emma Dunn, Andy C Rawstron, Paul Emery, Edward M Vital
Journal: Annals of the Rheumatic Diseases (2017)

To assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab.117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Complete depletion was predicted by normal complement and lower pre-rituximab plasmablasts and was not associated with increased serious infection post-rituximab. Seventy-seven (with data on 72) C1 responders were retreated on clinical relapse. Of these, 61/72 (85%) responded in cycle 2 (C2). Of the 11 C2 non-responders, nine met 2NDNR criteria (incidence=12%) and tested positive for anti-rituximab antibodies. Lack of concomitant immunosuppressant and higher pre-rituximab plasmablasts predicted 2NDNR. Five were switched to ocrelizumab/ofatumumab, and all depleted and responded.Treatment with anti-CD20 agents can be guided by B-cell monitoring and should aim to achieve complete depletion. 2NDNR is associated with anti-rituximab antibodies, and switching to humanised agents restores depletion and response. In SLE, alternative anti-CD20 antibodies may be more consistently effective.
Pattern of liver-directed therapies and outcomes in cancer patients hospitalized in the United States.
Authors: Olatunji Boladale Alese, Sungjin Kim, Zhengjia Chen, Taofeek Kunle Owonikoko, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2015)

e15112 Background: The liver is a common site of primary and metastatic cancer. Liver directed therapies are commonly used to treat cancer involving the liver. We report on the pattern and predictors of liver directed therapies in hospitalized cancer patients in the US. Methods: Data were obtained from all US states that contributed to the Nationwide Inpatient Sample by Agency for Health Care Research and Quality between 2006 and 2010. Univariate and multivariate testing was done to identify factors significantly associated with patient outcome. Results: 12,540 patients were identified for the five years of study. Mean age was 60 years (± 14). 70.5% had primary liver lesions (8,840) while the rest were liver metastases (3,700; 29.5%). 1,414 of the patients with metastases (11.3%) had tumors arising from gastrointestinal (GI) tract. The commonest procedure was partial hepatectomy (5352; 42.7%), followed by open (1251; 9.98%), percutaneous (908; 7.24%) or laparoscopic (632; 5.04%) ablation of liver lesions; embolization (1230; 9.8%), and liver transplants (331; 2.64%). There was a very low incidence of in-hospital mortality (2.4%), and a complication rate of 12.24%. 60% of in-hospital mortality was associated with acute liver necrosis (65; p < 0.001), ascites (60; p < 0.001), hepatic coma (30; p < 0.001), hepatorenal syndrome (23; p < 0.001), liver abscess (11; p = 0.012), and co-morbid illnesses >8 (p < 0.001). Complicated embolization had almost doubled risk of in-hospital mortality (OR 1.93; 1.12-3.33; p = 0.018), though it constitutes only 2.96% of overall mortality. Conclusions: The morbidity and mortality for hospitalized patients receiving liver directed therapies is relatively low, highlighting the potential utility of these procedures in the management of primary and metastatic liver cancer. Multivariate analysis of complications. Covariate Complication Level Odds Ratio (95% CI) OR P-value Primary tumor GI 1.59 (1.21-2.07) < .001 Non-GI 1 (Ref) - Metastases Yes 1.83 (1.56-2.16) < .001 No 1 (Ref) - Partial hepatectomy Yes 1.47 (1.28-1.70) < .001 No 1 (Ref) - Co-morbid diagnoses < 8 0.84 (0.83-0.85) < .001 > 8 1 (Ref) Ablation Yes 0.53 (0.41-0.67) < .001 No 1 (Ref) - Embolization Yes 0.54 (0.41-0.72) < .001 No 1 (Ref) -
Clinical and Incidental Perineural Invasion of Cutaneous Squamous Cell Carcinoma
Authors: Pritesh S. Karia, Frederick C. Morgan, Emily Stamell Ruiz, Chrysalyne D. Schmults
Journal: JAMA Dermatology (2017)

Perineural invasion (PNI) in cutaneous squamous cell carcinoma (CSCC) has been associated with an increased risk of poor outcomes. Patients with PNI may present with clinical symptoms and/or radiologic evidence of PNI (clinical PNI [CPNI]), yet most patients are asymptomatic and PNI is often found on histologic examination (incidental PNI [IPNI]). Evidence-based estimates of the risks of disease-related outcomes comparing IPNI and CPNI are limited in the dermatology literature.
RIG-I Activation Protects and Rescues from Lethal Influenza Virus Infection and Bacterial Superinfection
Authors: Christoph Coch, Jan Phillip Stümpel, Vanessa Lilien-Waldau, Dirk Wohlleber, Beate M. Kümmerer, Isabelle Bekeredjian-Ding, Georg Kochs, Natalio Garbi, Stephan Herberhold, Christine Schuberth-Wagner, Janos Ludwig, Winfried Barchet, Martin Schlee, Achim Hoerauf, Friedrich Bootz, Peter Staeheli, Gunther Hartmann, Evelyn Hartmann
Journal: Molecular Therapy (2017)

Influenza A virus infection causes substantial morbidity and mortality in seasonal epidemic outbreaks, and more efficient treatments are urgently needed. Innate immune sensing of viral nucleic acids stimulates antiviral immunity, including cell-autonomous antiviral defense mechanisms that restrict viral replication. RNA oligonucleotide ligands that potently activate the cytoplasmic helicase retinoic-acid-inducible gene I (RIG-I) are promising candidates for the development of new antiviral therapies. Here, we demonstrate in an Mx1-expressing mouse model of influenza A virus infection that a single intravenous injection of low-dose RIG-I ligand 5′-triphosphate RNA (3pRNA) completely protected mice from a lethal challenge with influenza A virus for at least 7 days. Furthermore, systemic administration of 3pRNA rescued mice with pre-established fulminant influenza infection and prevented the fatal effects of a streptococcal superinfection. Type I interferon, but not interferon-λ, was required for the therapeutic effect. Our results suggest that the use of RIG-I activating oligonucleotide ligands has the clinical potential to confine influenza epidemics when a strain-specific vaccine is not yet available and to reduce lethality of influenza in severely infected patients.