tbuckley/cabot-search huggingface dataset:
Behavioural outcomes of subthalamic stimulation and medical therapy versus medical therapy alone for Parkinson's disease with early motor complications (EARLYSTIM trial): secondary analysis of an open-label randomised trial
Authors: Eugénie Lhommée, Lars Wojtecki, Virginie Czernecki, Karsten Witt, Franziska Maier, Lisa Tonder, Lars Timmermann, Thomas D Hälbig, Fanny Pineau, Franck Durif, Tatiana Witjas, Marcus Pinsker, Maximilian Mehdorn, Friederike Sixel-Döring, Andreas Kupsch, Rejko Krüger, Saskia Elben, Stephan Chabardès, Stéphane Thobois, Christine Brefel-Courbon, Fabienne Ory-Magne, Jean-Marie Regis, David Maltête, Anne Sauvaget, Jörn Rau, Alfons Schnitzler, Michael Schüpbach, Carmen Schade-Brittinger, Gunther Deuschl, Jean-Luc Houeto, Paul Krack, Velina Negovanska, Marie-Laure Welter, Jean-Christophe Corvol, Yves Agid, Soledad Navarro, Niklaus Meier, Andreas Hartmann, Helke Hesekamp, Philippe Cornu, Bettina Möller, Adelheid Nebel, Jan Raethjen, Karina Knudsen, Jens Volkmann, Daniela Falk, Steffen Paschen, Ingo Meister, Jens Kuhn, Kerstin Donner, Josef Kessler, Michael Barbe, Gereon Fink, Mohammad Maarouf, Andrea Kühn, Bianca Müller, Katharina Faust, Doreen Gruber, Gerd-H. Schneider, Eric Seigneuret, Pierre Pollak, Valerie Fraix, Andrea Kistner, Olivier Rascol, Christophe Arbus, Lola Danet, Patrick Chaynes, Stefan J. Groiss, Christian Hartmann, Martin Südmeyer, Mahnaz Partowinia-Peters, Jan Vesper, Severine Ledily, Philippe Damier, Sylvie Raoul, Claudia Trenkwalder, Wenke Richter-Dreske, Tobias Wächter, Daniel Weiss, Alexandro Eusebio, Jean Philippe Azulay, Gustavo Polo, Serge Pinto, Johannes Levin, Stephanie Dornier, Fredy Pene, Delphine Hourton, Mathieu Quintin, Cecile Hoffart-Jourdain, Helene Brocvielle, Kerstin Balthasar, Meryem Stein, Susanne Harnisch, Alexander Reuss, Behnaz Aminossadati, Christian Nasemann, Wolfgang Oertel, Benoit Bataille, Dieter Hellwig, Alireza Gharabaghi, Florian Amtage, Patrick Mertens, Manja Kloss, Bart Post, Hans Speelman
Journal: The Lancet Neurology (2018)
Dasatibib-induced authophagy is synergistically enhanced in combination with temozolomide and is further augmented in PTEN-functional glioma
Authors: Vanessa Milano, Tiffany LaFortune, John de Groot
Journal: Cancer Research (2008)

1325   Glioblastoma is defined by its high cellularity and mitotic activity, aggressive invasiveness, microvascular proliferation, and central necrosis. BMS-354825 (dasatinib) is an ATP-competitive small-molecule inhibitor effective in treating drug-resistant tumors with mutant BCR-ABL, KIT, and EGFR by blocking tyrosine phosphorylation sites that are critical in tumorigenesis. In studying the action of dasatinib in human glioblastoma, we found that levels of phosphorylated SRC, AKT, and ribosomal protein S6 were decreased in cell lines treated with low-nanomolar concentrations of dasatinib at baseline and following stimulation with epidermal growth factor. Furthermore, an increased sensitivity to dasatinib was noted in glioma cells with functional PTEN. These data indicate that the assessment of PTEN, MAPK, AKT, and rpS6 in glioblastoma treatment may provide a guide on which optimal therapeutic solutions can be based. Reduction of invasive potential was observed  in vitro  at concentrations well below dasatinib’s IC 50 , which was corroborated by immunofluorescence staining showing disruption of paxillin localization to focal adhesions and decreases in FAK autophosphorylation. Cell cycle analysis revealed modest levels of G 1  arrest but a significant increase in autophagic cell death in glioma cells treated with dasatinib as assessed by acridine orange staining and a concomitant increase in LC3 expression and processing. Combination treatment of glioma cells with dasatinib and temozolomide resulted in a highly significant increase in cell cycle disruption and autophagic cell death, notably increasing the therapeutic efficacy of temozolomide. These results strongly support the use of dasatinib in the treatment of glioblastoma and provide a rationale for combination therapy with dasatinib and temozolomide.
Case of paediatric neuromuscular disease with a surprising clinical outcome: time to challenge the dogma?
Authors: Marie Wright, Adnan Manzur, Andy Bush
Journal: Thorax (2018)

A 4-month-old female infant was referred with a 4-week history of tachypnoea and faltering growth.She was the first child of healthy unrelated parents, and was conceived following two early miscarriages.Noteworthy family history included the unexplained sudden deaths of her mother's sibling aged 8 months and a 12-year-old first cousin.The pregnancy was complicated by intrauterine growth restriction, and birth weight at 37 weeks' gestation was 2.5 kg (second centile).She had no respiratory compromise in the neonatal period, and initially established good weight gain and met developmental milestones age appropriately.At 12 weeks old, she was observed by her parents to be tachypnoeic.Her work of breathing gradually increased over the next month, but was not associated with cough, stridor or systemic symptoms.Simultaneously, her weight drifted to below the 0.4th centile.At first presentation, the infant appeared malnourished but was alert and interactive.She had marked respiratory distress and a paradoxical breathing pattern with indrawing of the abdomen on inspiration, but respiratory examination was otherwise unremarkable.Muscle strength and tone were normal, but she had positional talipes and correctable flexion deformities of her fingers.Oxygen saturation was 95% in air, and gas exchange was normal on capillary blood gas analysis (pH 7.44, pCO 2 4.66 kPa, HCO 3 24 mmol/L, BE -0.2 mmol/L).ECG and echocardiogram were normal.Chest X-ray showed an elevated right hemidiaphragm (figure 1), and unilateral diaphragmatic paralysis was confirmed on fluoroscopic ultrasound.Rhinovirus and Adenovirus were detected on nasopharyngeal aspirate viral PCR.Andy Bush (Professor of Respiratory Paediatrics): These clinical features are suggestive of a progressive neuromuscular disorder with relative preservation of limb muscle function and early respiratory muscle involvement.There are several possible causes; the likeliest diagnosis is spinal muscular atrophy with respiratory distress type 1 (SMARD1), and the differential diagnosis includes nemaline rod myopathy, subtypes of congenital muscular dystrophy, and congenital myopathies including MEGF10 gene-related early-onset myopathy, areflexia, respiratory distress and dysphagia.SMARD1 is a neuromuscular disorder characterised by early diaphragm weakness and is caused by mutations of the Provenance and peer review not commissioned; externally peer reviewed.
Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial
Authors: Michael B Atkins, Elizabeth R Plimack, Igor Puzanov, Mayer N Fishman, David F McDermott, Daniel C Cho, Ulka Vaishampayan, Saby George, Thomas E Olencki, Jamal C Tarazi, Brad Rosbrook, Kathrine C Fernandez, Mariajose Lechuga, Toni K Choueiri
Journal: The Lancet Oncology (2018)
Italian perspective bone metastases (BM) database: The first one-year experience.
Authors: Alberto Bongiovanni, Flavia Foca, Manuela Fantini, Rosachiara Forcignano, Francesco Silvestris, Fabrizio Artioli, Enrico Campadelli, Bruno Daniele, Francesca Ciotti, Giulia Marcantognini, Federica Recine, Valentina Fausti, Roberto Vespignani, Dino Amadori, Toni Ibrahim
Journal: Journal of Clinical Oncology (2016)

e13075 Background: BM are still the main cause of morbidity and morbility in cancer patients, mostly due to their complications defined as skeletal-related event (SRE). SRE reduce patients’quality of life and are a serious health problem from clinical and economical point of view. The majority of data concerning BM patients are obtained from retrospective experiences. The aims are to collect prospective data on the natural history of BM and SREs, and to evaluate clinical and biological factors (as objective response, bone pain, biomarker value) related both to the primary tumors and to BM. Methods: BM Database is a multicenter Italian prospective observational study that takes advantage of a web-based software supported by an open source package (Xampp). Demographic, clinical and pathological information were recorded, and updated every 6 months by the participating centers. In order to verify the feasibility, for the first 3 years it will be recorded data from 5 primary tumors: Breast, Prostate, Gastrointestinal, Lung and urinary tract. Results: From September 2014, a total of 262 patients have been included, from 7 centers. For 173 patients (102 female and 71 male) data on BM were available. Median age was 62 years. ECOG Performance status was 0-1 in 67% of the patients. About 49% of cases had breast as primary tumor, 21% lung, 17% prostate, 5% urinary tract and 8% other sites. About 54% had visceral metastases. At diagnosis 53% of cases had multiple BM( > 6), 31% were oligometastatic (2-6) and 16% had solitary lesions. Metastasis were axial in 45%, appendicular in 5%, and both in 42%. BM were widely lytic (39%), while 24% were sclerotic and 14% mixed. BM were histologically confirmed in 14% of cases. Seventy-three SREs were recorded: 71% radiotherapy, 22% pathological fractures, 4% surgery, 3% bone marrow suppression. Conclusions: BM Data Base is the first Italian multicenter and perspective experience to study the natural history of BM from different tumors. The quality of collected data is the key element of this project. The data analysis will provide relevant information to better understand the natural history of BM, as well the patients’quality of life prognosis and treatment. y of BM, as well the patients’quality of life prognosis and treatment
Intralesional rose bengal for treatment of melanoma.
Authors: Sanjiv S. Agarwala, Robert Hans Ingemar Andtbacka, Kristen N. Rice, Merrick I. Ross, Charles Raben Scoggins, Bernard Mark Smithers, Eric D. Whitman, Eric Andrew Wachter
Journal: Journal of Clinical Oncology (2016)

TPS9600 Background: Intralesional rose bengal (PV-10) is an investigational small molecule ablative immunotherapy that can elicit primary ablation of injected tumors and secondary T-cell activation. Phase 2 testing in Stage III-IV melanoma yielded a 51% objective response rate (ORR) with 50% complete response (CR) when all disease was injected. PV-10 is currently undergoing phase 3 testing as a single agent in patients with locally advanced cutaneous melanoma and phase 1b testing in combination with immune checkpoint inhibition for more advanced disease. Methods: Study PV-10-MM-31 (NCT02288897) is an international multicenter, open-label, randomized controlled trial of PV-10 versus investigator’s choice of chemotherapy (dacarbazine or temozolomide) or oncolytic viral therapy (talimogene laherparepvec). A total of 225 subjects with locally advanced cutaneous melanoma (Stage IIIB or Stage IIIC recurrent, satellite or in-transit melanoma) randomized 2:1 will be assessed for progression free survival (PFS) by RECIST 1.1 (using blinded Independent Review Committee assessment of study photography and radiology data). Comprehensive disease assessments, including review of photography and radiology data, are performed at 12 week intervals; clinical assessments of progression status are performed at 28-day intervals. Study PV-10-MM-1201 (NCT02557321) is an international multicenter, open-label, sequential phase study of PV-10 in combination with pembrolizumab. Stage IV metastatic melanoma patients with at least one injectable cutaneous or subcutaneous lesion who are candidates for pembrolizumab are eligible. In the current phase 1b portion of the study, up to 24 subjects will receive the combination of PV-10 and pembrolizumab (PV-10 + standard of care). In phase 2 an estimated 120 participants will be randomized 1:1 to receive either PV-10 and pembrolizumab or pembrolizumab alone. The primary endpoint for phase 1b is safety and tolerability with PFS a key secondary endpoint; PFS is the primary endpoint for phase 2. Clinical trial information: NCT02288897.
Abstract 225: Variations in Pharmacological Management of Children with Coronary Artery Aneurysms after Kawasaki Disease: A Study from the North American Kawasaki Disease Registry
Authors: Elif Seda Selamet Tierney, Andrew S Mackie, Brian W McCrindle, Mathew Mathew, Kathryn R Armstrong, Emily Williams, Deepika Thacker, Madisen Neufeld, Susan Nourse, Cedric Manlhiot, Geetha Raghuveer
Journal: Circulation (2015)

Background: The pharmacological management of coronary artery aneurysms (CAA) associated with Kawasaki disease (KD) is based on imperfect evidence, which may lead to considerable practice variation. Methods: Pharmacological management of patients included in the North American Kawasaki Disease Registry was reviewed. The Registry included data for 621 patients with CAA after KD (280 patients with maximum CAA z-score between 2.5-5.0, 139 with z-score 5.0-10.0 and 202 with z-score &gt;10.0) followed at 20 medical centers. Practice variation regarding acute treatment, anti-inflammatory agents, statins, beta-blockers, antiplatelet therapy and anticoagulation were assessed. Results: Considerable practice variation existed between centers. During the acute phase, 93% of patients received at least one dose of IVIG (range: 80-100%), with 23% (range: 12-50%) receiving additional immunomodulatory treatment (22% additional IVIG, 17% steroids, 4% infliximab). Use of a 3 rd course of IVIG was infrequent (2%). All centers reported using additional IVIG or steroids for IVIG-resistant patients, but only 6 centres reported any experience with infliximab (2 commonly, 4 infrequent). Routine use of non-steroidal anti-inflammatory agents was limited to 2 centres, with 4 additional sites reporting infrequent use (10% of patients). Statins (5%), beta blockers (4%) and abciximab (3%) were mostly used by a single centre and was limited to patients with giant CAAs. Aspirin was the primary antiplatelet modality for 97% of patients, clopidogrel (10% of all patients, 23% in giant CAA) was routinely prescribed to patients with giant CAAs at 6 centres, with 2 more centres reporting infrequent use and the remainder not reporting any use. For patients with giant CAA (z-score&gt;10.0), 46% were maintained on an antiplatelet agent alone, 17% additionally were on low molecular weight heparin(LMWH), 12% on warfarin and 25% had initially received LMWH and were later switched to warfarin. Conclusions: Given the important variations in management between centres and the poor evidence base, randomized controlled trials examining outcomes and nested in a high-quality collaborative registry may be an efficient strategy to address this gap.
Effect of Continuous B Cell Depletion With Rituximab on Pathogenic Autoantibodies and Total IgG Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis
Authors: Frank B. Cortazar, William F. Pendergraft, Julia Wenger, Charles T. Owens, Karen Laliberte, John L. Niles
Journal: Arthritis & Rheumatology (2016)

To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with continuous B cell depletion.We conducted a retrospective analysis of 239 patients with AAV treated with rituximab-induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed-effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression.During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval [95% CI] 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti-MPO) antibodies and those with anti-proteinase 3 (anti-PR3) antibodies, respectively. During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI -0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient-years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl.B cell-targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare.
Effectiveness of Family Integrated Care in neonatal intensive care units on infant and parent outcomes: a multicentre, multinational, cluster-randomised controlled trial
Authors: Karel O'Brien, Kate Robson, Marianne Bracht, Melinda Cruz, Kei Lui, Ruben Alvaro, Orlando da Silva, Luis Monterrosa, Michael Narvey, Eugene Ng, Amuchou Soraisham, Xiang Y Ye, Lucia Mirea, William Tarnow-Mordi, Shoo K Lee, Karel O'Brien, Shoo Lee, Marianne Bracht, Georges Caouette, Eugene Ng, Douglas McMillan, Linh Ly, Kimberly Dow, Richard Taylor, Luis Monterrosa, Roderick Canning, Koravangattu Sankaran, William Bingham, Amuchou Soraisham, Salhab el Helos, Ruben Alvaro, Michael Narvey, Orlando da Silva, Horacio Osiovich, Julie Emberley, Celine Catelin, Lucia St. Aubin, Tammy Warkentin, Zarin Kalapesi, Jaya Bodani, Kei Lui, Guan Kho, Zsuzsoka Kecskes, Jacqueline Stack, Peter Schmidt, Mary Paradisis, Roland Broadbent, Clare Raiman, Charlene Wong, Michele Cabot, Maryse L'Herault, Marie-Andree Gignac, Marie-Helene Marquis, Mylene Leblanc, Cathy Travell, Marlene Furlong, Annette Van Bergen, Maryanne Ottenhof, Heather Keron, Clare Bowley, Shannon Cross, Gillian Kozinka, Valerie Cobham-Richards, Kelly Northrup, Cindy Gilbert-Rogers, Pat Pidgeon, Kim McDuff, Norma Leger, Cindy Thiel, Shannon Willard, Evelyn Ma, Linda Kostecky, David Pogorzelski, Sherin Jacob, Kim Kwiatkowski, Valerie Cook, Naomi Granke, Nicola Geoghegan-Morphet, Hannah Bowell, Jennifer Claydon, Nicole Tucker, Thomas Lemaitre, Myriam Doyon, Candace Ryan, Joanne Sheils, Elizabeth Sibbons, Anne-Marie Feary, Ian Callander, Robyn Richard, Jennifer Orbeso, Margaret Broom, Alexis Fox, Jan Seuseu, Jack Hourigan, Cynthia Schaeffer, Ginette Mantha, Melanie Lataigne, Kate Robson, Leah Whitehead, Natasha Skinner, Rita Visconti, Deedee Crosland, Kate Griffin, Brandon Griffin, Lisa Collins, Kirsten Meyer, Ian Silver, Britt Burnham, Rachel Freeman, Kristi Muralt, Cara Ramsay, Pawulina McGrath, Michelle Munroe, Denise Hales
Journal: The Lancet Child & Adolescent Health (2018)
Stimulation of type I interferon production and increased expression of HLA-DR by human peripheral blood lymphocytes (PBL) following exposure to melphalan (MEL)
Authors: David A. Berd, Jason Kuchar, Takami Sato, Michael J. Mastrangelo
Journal: Cancer Research (2004)

656   Administration of cyclophosphamide can augment cell-mediated immunity in experimental animals and humans, but the mechanism is unknown. Consistent with published observations in murine systems, we reported that exposure of human PBL to activated forms of CY - MEL or hydroperoxycyclophosphamide - induced expression of mRNA for type I interferons (Proc. AACR, 2003). Here we demonstrate that the induction of mRNA is followed by the production of alpha interferon protein and then by enhanced expression of HLA-DR. PBL obtained from a normal donor were exposed to various concentrations of MEL for 1 hour, then washed and incubated at 37° in tissue culture medium; then they were analyzed by flow cytometry for intracellular alpha interferon and for surface antigens. Cytoplasmic alpha interferon was detected after 16 hours and the fluorescence intensity was highest in PBL that had been exposed to MEL at concentrations of 0.1-1.0 uM. In contrast, MEL-treated PBL did not exhibit cytoplasmic staining for the cyokines, gamma interferon or interleukin-2. After 48-72 hours incubation of MEL-treated PBL, there was an increase in the percentage expressing HLA-DR: 5-15% in diluent-treated controls versus 25-50% in MEL-treated; the optimal MEL concentration was 1 uM. These PBL were separated into CD3+ and CD3(-) populations using antibody-coated magnetic beads and were analyzed by two-color flow cytometry. In both the CD3+ fraction (T cells) and the CD3(-) fraction (B cells and monocytes) MEL treatment resulted in an increased number of cells expressing HLA-DR: CD3+ fraction: diluent=4%, MEL=25%; CD3(-) fraction: saline=17%, MEL=50%). Moreover, in the MEL-treated CD3+ fraction there was an increase in the percentage of cells (diluent=3%, MEL=13%) expressing CD20, a traditional B-cell marker that is known to be co-expressed by a small subpopulation of T cells. Since the expression of both HLA-DR and CD20 is increased by alpha interferon, it is possible that this cytokine was the mediator of both phenotypic changes. Moreover, it is plausible that these  in vitro  observations reflect the physiologic effects of melphalan and cyclophosphamide after  in vivo  administration.
Control of Renin Secretion in the Anesthetized Dog : 1) Relationship between Renin Secretion and Plasma Sodium Concentration in the Peritoneal Dialyzed Dog
Authors: Kenjiro Yamamoto, Takamichi Hasegawa, Hiroshi Tanaka, Juro Ueda
Journal: Circulation (1968)

The present study was made on the influence of acute change in plasma sodium level on the renin secretion in the anesthetized dog. Plasma sodium concentration was reduced by a peritoneal dialysis with low sodium lavage solution, and was returned by administration of hypertonic saline solution. The renin secretion markedly increased following a reduction of the plasma sodium level, and decreased following administration of hypertonic saline solution.