tbuckley/cabot-search huggingface dataset:
A phase Ib/II study of cancer stemness inhibitor napabucasin (BBI-608) in combination with gemcitabine (gem) and nab-paclitaxel (nabPTX) in metastatic pancreatic adenocarcinoma (mPDAC) patients (pts).
Authors: Tanios S. Bekaii-Saab, Alexander Starodub, Bassel F. El-Rayes, Bert H. O'Neil, Safi Shahda, Kristen Keon Ciombor, Anne M. Noonan, Wahid Tewfik Hanna, Amikar Sehdev, Walid Labib Shaib, Sameh Mikhail, Anterpreet S. Neki, Cindy Oh, Youzhi Li, Wei Li, Laura Borodyansky, Chiang Li
Journal: Journal of Clinical Oncology (2017)

4106 Background: Cancer stem cells are fundamentally important for resistance to therapy, recurrence and metastasis. Napabucasin is a first-in-class cancer stemness inhibitor in development identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al, PNAS 112(6):1839, 2015). Preclinical studies suggest that napabucasin sensitizes heterogeneous cancer cells to chemotherapy and targeted agents. Methods: A phase Ib/II multi-center study in mPDAC pts was performed to confirm the RP2D, PK profile and evidence of anticancer activity of napabucasin in combination with nabPTX and Gem. Pts received napabucasin 240 mg BID with weekly nabPTX 125 mg/m 2 and gem 1000 mg/m 2 for 3 out of every 4 weeks until disease progression (PD) or other discontinuation criterion. Results: Of 71 intent to treat (ITT) pts enrolled, 49 (69%) were treatment-naïve and 22 (31%) received neoadjuvant treatment. There were no significant PK interactions, dose-limiting or unexpected toxicities. Most common adverse events (AEs) included grade 1 diarrhea/cramping, nausea and fatigue with grade 3 AEs noted in 12 pts: fatigue (8), electrolyte imbalance (2), diarrhea (1), dehydration (1), nausea (1) and weight loss (1). Among pts who received RECIST evaluation (60), disease control (DCR; CR+PR+SD) was observed in 55 (92%), with 1 CR (2%) and 26 PR (43%) (31 - 78% regression). Of 11 pts with non-evaluable disease, treatment stopped due to compliance (4), consent withdrawal (3), clinical PD (1), toxicity (1), insurance (1) and death (1). Among 71 ITT pts, DCR was observed in 55 (77%), with 1 CR (1.4%) and 26 PR (37%). Maturing median progression free survival and overall survival (OS) in ITT pts is &gt;7.1 and &gt;10.4 m, respectively. Conclusions: This study showed that napabucasin can be combined with nabPTX and gem, with encouraging signs of efficacy in mPDAC now being confirmed in a phase 3 study. Clinical trial information: NCT02231723. [Table: see text]
Diagnostic Nuclear Medicine.
Authors: A Baert, F Leuven, Stuttgart Heuck, W Becker, S Gambhir, C Jamar, F Keng, G Lucignani, G Luker, K Luker, H Nadel, J Nuyts, H Schelbert, V Schiepers, M.-C Urbain, Christiaan Schiepers
Journal: Annals of Internal Medicine (1971)
Brief Report: Treatment of Tumor Necrosis Factor–Transgenic Mice With Anti–Tumor Necrosis Factor Restores Lymphatic Contractions, Repairs Lymphatic Vessels, and May Increase Monocyte/Macrophage Egress
Authors: Echoe M. Bouta, Igor Kuzin, Karen de Mesy Bentley, Ronald W. Wood, Homaira Rahimi, Rui‐Cheng Ji, Christopher T. Ritchlin, Andrea Bottaro, Lianping Xing, Edward M. Schwarz
Journal: Arthritis & Rheumatology (2017)

Objective Recent studies have demonstrated that there is an inverse relationship between lymphatic egress and inflammatory arthritis in affected joints. As a model, tumor necrosis factor (TNF)–transgenic mice develop advanced arthritis following draining lymph node (LN) collapse, and loss of lymphatic contractions downstream of inflamed joints. It is unknown if these lymphatic deficits are reversible. This study was undertaken to test the hypothesis that anti‐TNF therapy reduces advanced erosive inflammatory arthritis, associated with restoration of lymphatic contractions, repair of damaged lymphatic vessels, and evidence of increased monocyte egress. Methods TNF‐transgenic mice with advanced arthritis and collapsed popliteal LNs were treated with anti‐TNF monoclonal antibody (10 mg/kg weekly) or placebo for 6 weeks, and effects on knee synovitis, lymphatic vessel ultrastructure and function, and popliteal LN cellularity were assessed by ultrasound, histology, transmission electron microscopy (TEM), near‐infrared indocyanine green imaging, and flow cytometry. Results Anti‐TNF therapy significantly decreased synovitis (∼5‐fold; P &lt; 0.05 versus placebo), restored lymphatic contractions, and significantly increased the number of popliteal LN monocyte/macrophages (∼2‐fold; P &lt; 0.05 versus placebo). TEM demonstrated large activated macrophages attached to damaged lymphatic endothelium in mice with early arthritis, extensively damaged lymphatic vessels in placebo‐treated mice with advanced arthritis, and rolling leukocytes in repaired lymphatic vessels in mice responsive to anti‐TNF therapy. Conclusion These findings support the concept that anti‐TNF therapy ameliorates erosive inflammatory arthritis, in part via restoration of lymphatic vessel contractions and potential enhancement of inflammatory cell egress.
Mesenchymal stem/stromal cell extracellular vesicles: From active principle to next generation drug delivery system
Authors: Barbara Crivelli, Theodora Chlapanidas, Sara Perteghella, Enrico Lucarelli, Luisa Pascucci, Anna Teresa Brini, Ivana Ferrero, Mario Marazzi, Augusto Pessina, Maria Luisa Torre
Journal: Journal of Controlled Release (2017)
Abstract P116: The Physiological Ventricular Growth Signal Can Be Determined Using Infants with Congenital Heart Disease as Models
Authors: John E Foker, James M Berry, Brian A Harvey, Lee A Pyles
Journal: Circulation Research (2011)

Objectives The signal for ventricular growth has not been defined. This basic developmental question was studied using infants with congenital heart lesions as models. Our first hypothesis was that clinical ventricular hypoplasia is a developmental rather than a primarily genetic defect and, therefore, catch-up growth can be induced. Our clinical observations also led to the hypothesis that forward flow across the atrioventricular (AV) valve (mitral or tricuspid) is what generates the growth signal. To test these hypotheses we analyzed clinical data from infants with a variety of congenital defects including three groups of patients with a hypoplastic ventricle in whom a procedure was carried out to increase flow across the AV valve. Methods Infants with one of several congenital heart problems had right and left ventricular volumes (RV, LV) assessed by biplane echo and indexed to body surface area (m 2 ). The degree of hypoplasia was calculated using nomograms to determine the number of standard errors of the mean (SEM) below the expected volume (Table 1). Hypoplasia was considered significant when the SEM &lt; −2.0. The three groups were studied before and after (3–6 months) procedures which increased AV flow. Results Other possible growth mechanisms were assessed. (1) High wall stress with systemic or supra-systemic pressures produced no net cavitary growth unless AV valve flow was increased. (2) Significant retrograde flow from semilunar valve regurgitation did not increase ventricular size until failure developed. Therefore, no evidence was found for other growth mechanisms. Conclusions 1) Patients with congenital heart disease have a variety of defects, some of which can serve as models to answer basic developmental questions. 2) Increased AV valve flow provides the signal which induces ventricular growth. 3) Operations which increased AV valve flow induced catch-up growth of hypoplastic ventricles and allowed beneficial two-ventricle repairs in these patients.
The DISC modification defines TRAIL resistance in glioblastoma cells
Authors: Anita Bellail, Margaret Tse, Chunhai Hao
Journal: Cancer Research (2008)

818    BACKGROUND:  TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) is capable of inducing apoptosis; however, its death machinery is inhibited in the majority of human cancers. TRAIL-induced apoptosis occurs through its binding on the receptors and subsequent formation of intracellular DISC (death-inducing signaling complex). Here, we report that the DISC modification determines TRAIL resistance in glioblastoma cells.  METHODS AND RESULTS:  TRAIL has four membrane associated receptors: two death receptor DR4/5 and two decoy receptors DcR1/2. Western blot and flow cytometry analysis of nine glioblastoma cell lines and ten tumor tissues detected no DcR1/2 proteins; the result rules out the possible role of DcR1/2 in TRAIL signaling in the tumor. DR5 was detected in all the cell lines and tumor tissues; in contrast, however, DR4 was seen only in a few cell lines and tumor tissues. Non-reducing and reducing Western blots revealed the homotrimer formation of DR5 but not DR4; immunoprecipitation with Flag-TRAIL and anti-Flag M2 antibody identified DR5 but not DR4 in the cell lines. These results indicate that DR5 is the only functional TRAIL receptor in glioblastoma cells. Of the nine cell lines, four were TRAIL sensitive and five were resistant. The sensitive and resistant cells were treated with Flag-TRAIL and anti-Flag M2 antibody and the Flag-TRAIL-induced DISC was immunoprecipitated with anti-M2 antibody agarose. DR5, FADD (Fas-associated death domain) and caspase-8 cleavage products were detected in the DISC in the sensitive cells. Lipid rafts were required for the DISC assembly as inhibition of lipid raft formation prevented TRAIL-induced apoptosis. In addition to DR5, FADD, and caspase-8, RIP (receptorr-interacting protein), c-FLIP (cellular FADD-like interleukin-1β-converting enzyme-inhibitory protein) and PED (phosphoprotein enriched in diabetes) were detected in the non-raft fraction of the resistant cells, leading the inhibition of caspase-8 cleavage and activation of NF-κB. Treatment of the resistant cells with I-κB inhibitor parthenolide eliminated TRAIL-induced NF-κB signaling but not TRAIL resistance. In contrast, however, targeting of either RIP, c-FLIP or PED with siRNA led to the redistribution of the DISC from non-rafts to lipid rafts and thereby eliminated both TRAIL-induced NF-κB signaling and TRAIL resistance in the resistant cells.  Conclusions:  This study identifies two types of the DISC in glioblastoma cells: i) the DISC formed with DR5, FADD and caspase-8 for TRAIL-induced apoptosis, and ii) the DISC composed of DR5, RIP, c-FLIP, PED, FADD and caspase-8 in TRAIL-resistance. Targeting of either RIP, FLIP or PED eliminates TRAIL resistance and thus provides therapeutic strategies that can overcome the TRAIL resistance in glioblastomas.
Quality-of-Life and Health Behaviors in Survivors of Acute Leukemia Compared with the General Population: A Population-Based Matched Case-Control Study
Authors: Koung Jin Suh, Dong-Yeop Shin, Inho Kim, Sung-Soo Yoon, Jeong-Ok Lee, Soo-Mee Bang, Ki Hwan Kim, Jin Hyun Park, Sang Min Park, Youngae Kim, Young Ho Yun, Youngil Koh
Journal: Blood (2016)
A phase 2 study of galunisertib (TGF-Β R1 inhibitor) and sorafenib in patients with advanced hepatocellular carcinoma (HCC).
Authors: Robin Kate Kelley, Edward Gane, Eric Assenat, Jurgen Siebler, Peter R. Galle, Philippe Merle, Isabelle Ollivier-Hourmand, Ann Cleverly, Ivelina Gueorguieva, Michael M. F. Lahn, Sandrine J. Faivre, Karim A. Benhadji, Gianluigi Giannelli
Journal: Journal of Clinical Oncology (2017)

4097 Background: TGFβ signaling is associated with HCC progression. Inhibition of TGFβ R1 potentiates activity of sorafenib in in-vitro and in-vivo models. Here we report the clinical activity of galunisertib (G) plus sorafenib (S) in pts with incurable HCC and no prior systemic therapy. Methods: Eligibility criteria included incurable HCC with measurable disease per RECIST 1.1, no prior systemic therapy, Child Pugh A, ECOG PS ≤1.G was administered as 80 mg PO BID (lead-in Cohort 1) or 150 mg PO BID (lead-in Cohort 2 and expansion cohort), as intermittent dosing of 14 days on/off (28 days = 1 cycle). S was administered continuously as a 400 mg PO BID. Primary objective was to characterize time-to-progression (TTP) and biomarker changes in pts. Secondary objectives included evaluation of OS, PK, and toxicity (CTCAE v 4.0). Results: 47 pts were enrolled (Cohort 1 = 3, Cohort 2 and expansion cohort = 44). In the 150 mg BID cohort: Male = 88.6%; median age = 64 years; PS = 0/1, 81.8%/18.2%; etiology: hepatitis C = 34.1%, hepatitis B = 18.2%, alcohol = 20.5%, multiple = 13.6%; AFP≥200 µg/L = 50%; portal vein invasion = 34.1%. Incidence of AEs was similar between G dose levels. Overall in the 150mg BID cohort, treatment related AEs ( &gt; 15%) were hand and foot syndrome (61.4%), diarrhea (40.9%), pruritus (22.7%), anemia and weight loss (20.5%), fatigue (29.5%), alopecia (18.2%), myalgia (22.7%), decrease in platelet count and nausea (15.9%). Two pts on 150 mg BID discontinued treatment due to study drug related AEs (anemia and weight loss). PK of G at 150 mg BID (n = 12) when co-administered with S, was similar to that observed in the G monotherapy study. G was rapidly absorbed and had an elimination half-life of approximately 8h. Median TTP (RECIST) was 4.1 (2.8, 5.5) months. OS, with a high censor rate of 55% was not mature at the time of this data cutoff. Median OS was 17.9 (14.8, NE) months. Conclusions: The combination of G plus S demonstrated acceptable safety and a meaningful OS of 17.9 months in an advanced HCC population. TTP was similar to S monotherapy in contemporary clinical trials though interpretation is limited by single arm design. Clinical trial information: NCT01246986.
Abstract P224: Connective Tissue Growth Factor Plays a Key Role in Myocardial Fibrosis After Angiotensin II Exposure
Authors: Nicole L Rosin, Jean-François Légaré, Timothy D Lee
Journal: Circulation Research (2011)

Background: AngiotensinII (AngII) exposure to rodents is a common model of fibrosis, characterized by hypertension, hypertrophy and eventual deposition of excess extracellular matrix (ECM) proteins resulting in organ dysfunction. We have previously shown that cellular infiltration of bone marrow derived progenitor cells (fibrocytes) occurs prior to ECM deposition and is associated with production of the connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β). The objective of this project was to characterize the role of CTGF in promoting fibrocyte recruitment and subsequent fibrosis after AngII exposure. Methods: Mice were treated with AngII or saline using an osmotic mini-pump at 2.8mg/kg/day. After 6hr to 7d hearts were excised and embedded in paraffin or prepared for mRNA isolation. Immunohistochemistry was used to determine extent and localization of CTGF protein. Quantitative RT-PCR was used to determine relative CTGF and TGF-β mRNA levels. Primary cardiomyocyte and fibrocyte cultures were isolated from neonatal or 3d AngII exposed animals respectively. Primary cultures were stimulated to determine the source (qRT-PCR) and function (proliferation, migration and differentiation) of CTGF. Results: In animals exposed to AngII, CTGF mRNA peaked the earliest at 6hr (21-fold; p&lt;0.01) when compared to TGFbeta, which peaked at 3d (5-fold; p&lt;0.05). Concurrent CTGF protein expression was evident by 3d of AngII exposure and appeared localized to the cardiomyocytes. Findings were confirmed using isolated cardiomyocytes, which significantly increased expression of CTGF in response to AngII (2-fold; p&lt;0.05). While CTGF did not promote fibrocyte migration in transwell chamber assay it promoted significant fibrocyte proliferation in vitro (2-fold; p&lt;0.05). Conclusion: We provide strong evidence that AngII exposure first results in the production of CTGF by cardiomyocytes. Furthermore, we have shown that CTGF does not promote migration as a chemokine but instead contributes to proliferation of fibrocytes once recruited from the bone marrow into the myocardium.
Cover image: Intralymphatic histiocytosis with giant blanching violaceous plaques
Authors: E.N. Ergen, J.P. Zwerner
Journal: British Journal of Dermatology (2017)

Funding sources: none. Conflicts of interest: none declared. Dear Editor, A 73‐year‐old man presented with a 2‐month history of fatigue and bruising. Physical examination revealed a blanching violaceous exanthem (a–c). Haematological work‐up revealed thrombocytopenia (11 × 109 platelets L−1), anaemia (haemoglobin 9 g dL−1) and an IgG‐kappa monoclonal gammopathy. Skin histology revealed intralymphatic histiocytosis (endothelial cells stained for CD31 and CD34, intraluminal cells stained with CD45 and CD68; d, e). The patient was treated for immune thrombocytopenic purpura with intravenous immunoglobulin and prednisone, with improvement. No progression occurred after 1 year on prednisone. Intravascular histiocytosis is a benign inflammatory skin condition characterized by lymphangiectasias in the reticular dermis containing aggregates of macrophages. The clinical manifestations include erythematous and violaceous patches, infiltrated plaques and nodules. Published cases suggest associations with rheumatoid arthritis and possibly joint replacement, diabetes and cancer. A case comparable in severity or with similar systemic disease associations could not be found.1 ...
Prescription medicine use by pedestrians and the risk of injurious road traffic crashes: A case-crossover study
Authors: Mélanie Née, Marta Avalos, Audrey Luxcey, Benjamin Contrand, Louis-Rachid Salmi, Annie Fourrier-Réglat, Blandine Gadegbeku, Emmanuel Lagarde, Ludivine Orriols
Journal: PLoS Medicine (2017)

While some medicinal drugs have been found to affect driving ability, no study has investigated whether a relationship exists between these medicines and crashes involving pedestrians. The aim of this study was to explore the association between the use of medicinal drugs and the risk of being involved in a road traffic crash as a pedestrian.Data from 3 French nationwide databases were matched. We used the case-crossover design to control for time-invariant factors by using each case as its own control. To perform multivariable analysis and limit false-positive results, we implemented a bootstrap version of Lasso. To avoid the effect of unmeasured time-varying factors, we varied the length of the washout period from 30 to 119 days before the crash. The matching procedure led to the inclusion of 16,458 pedestrians involved in an injurious road traffic crash from 1 July 2005 to 31 December 2011. We found 48 medicine classes with a positive association with the risk of crash, with median odds ratios ranging from 1.12 to 2.98. Among these, benzodiazepines and benzodiazepine-related drugs, antihistamines, and anti-inflammatory and antirheumatic drugs were among the 10 medicines most consumed by the 16,458 pedestrians. Study limitations included slight overrepresentation of pedestrians injured in more severe crashes, lack of information about self-medication and the use of over-the-counter drugs, and lack of data on amount of walking.Therapeutic classes already identified as impacting the ability to drive, such as benzodiazepines and antihistamines, are also associated with an increased risk of pedestrians being involved in a road traffic crash. This study on pedestrians highlights the necessity of improving awareness of the effect of these medicines on this category of road user.
Abstract 220: Induction of Heme Oxygenase-1 Enhances Matrix Metalloproteinase-9 Secretion and Myocardial Fibrosis
Authors: Muneyoshi Okada, Shiro Ikeda, Hideyuki Yamawaki, Yukio Hara
Journal: Circulation Research (2012)

Background: Heme oxygenase (HO)-1 is a stress-inducible rate-limiting enzyme in heme catabolism into carbon monoxide, biliverdin and free iron. Whereas HO-1 exerts cardioprotective effect, such as anti-hypertrophic and anti-apoptotic effect in cardiomyocytes, the influence of HO-1 on cardiac fibroblasts has not been clarified. We examined the effect of HO-1 induced by cobalt protoporphyrin IX (CoPPIX) on matrix metalloproteinase (MMP)-9 secretion, a biomarker of cardiac remodeling, in cardiac fibroblasts. Methods and Results: Cardiac fibroblasts were isolated from male Wistar rats. Secreted MMP-9 protein into culture medium and HO-1 expression in cell lysates were measured by Western blotting. CoPPIX (0.1-1 μ M) increased HO-1 expression and enhanced interleukin (IL)-1β (4 ng/ml, 24 h)-induced MMP-9 secretion (n=4). Mn 2 (CO) 10 (0.3-10 μ M), a carbon monoxide donor, increased IL-1β-induced MMP-9 secretion (n=4), although bilirubin (0.3-10 μ M), a metabolite of biliverdin, and FeSO 4 (0.3-10 μ M), a free iron donor, had no effect. Mn 2 (CO) 10 increased reactive oxygen species (ROS) generation and the enhanced effect of Mn 2 (CO) 10 on IL-1β-induced MMP-9 secretion was abolished by an antioxidant EUK-134 (10 μ M, n=4). We also examined the effect of CoPPIX on isoproterenol (5 mg/kg/day, subcutaneous injection, for 1 or 7 days)-induced cardiac remodeling in male Wistar rats. CoPPIX (1 mg/kg) was administered intraperitoneally every 2 days and this treatment increased HO-1 expression. Hearts were excised at the day 2 or day 8. Myocardial fibrosis was evaluated by Azan staining. At the day 8, CoPPIX worsened isoproterenol-induced myocardial fibrosis significantly (n=6), but had no effect on the increase of heart weight. CoPPIX also enhanced isoproterenol-induced MMP-9 expression at the day 2 (n=10). Conclusion: Induction of HO-1 by CoPPIX enhances IL-1β-induced MMP-9 secretion via ROS generation through heme-derived carbon monoxide in cardiac fibroblasts and isoproterenol-induced myocardial fibrosis and MMP-9 expression. These findings suggest that HO-1 induction does not necessarily exert cardioprotective effects.
Parkinson’s disease: summary of updated NICE guidance
Authors: Gabriel Rogers, Debbie Davies, Joshua Pink, Paul Cooper
Journal: BMJ (2017)

#### What you need to know

Parkinson’s disease is one of the most common neurological conditions, estimated to affect around 250 people per 100 000 in the UK.1 People with Parkinson’s disease classically present with motor symptoms including bradykinesia, rigidity, rest tremor, and postural instability; however, non-motor symptoms may also be prominent, including depression, cognitive impairment, and autonomic disturbances.

This article summarises the most recent update to the National Institute for Health and Care Excellence (NICE) guideline for the diagnosis and management of Parkinson’s disease in adults.2 This NICE guideline provides an update on most aspects of managing Parkinson’s disease, incorporating knowledge generated by a series of recent, large scale, independently funded, randomised trials in Parkinson’s therapy, and replaces guidance published in 2006. The update reflects emerging experience in areas such as impulse control disorders that may coexist with Parkinson’s disease and provides recommendations on the use of treatments that may provide some relief from the distressing symptoms of advanced Parkinson’s disease. The guideline update has not changed the suggested approach to the diagnosis of Parkinson’s disease, communication with people with Parkinson’s disease and their carers, pharmacological neuroprotective therapy, and interventions by Parkinson’s disease nurse specialists. Recommendations, full details of evidence, and the NICE pathway are available via the NICE website (www.nice.org.uk/guidance/ng71).

NICE recommendations are …
A Retrospective Analysis of Ultra Low-Dose Decitabine Combined with Gha Regimen in Patients with Middle and High Risk Myelodysplastic Syndrome
Authors: Wang Xiaman, Ju Bai, Yun Yang, Jianli Wang, Wanggang Zhang, Xingmei Cao, Yinxia Chen, Yanping Song, Hongli Chen, Yue Peng, Aili He, Fangxia Wang
Journal: Blood (2016)