tbuckley/cabot-search huggingface dataset:
Melatonin Treatment Improves Mesenchymal Stem Cells Therapy by Preserving Stemness during Long-term <i>In Vitro</i> Expansion
Authors: Yi Shuai, Li Liao, Xiaoxia Su, Yang Yu, Bingyi Shao, Huan Jing, Xinjing Zhang, Zhihong Deng, Yan Jin
Journal: Theranostics (2016)

Mesenchymal stem cells (MSCs) are promising candidates for tissue regeneration and disease treatment. However, long-term in vitro passaging leads to stemness loss of MSCs, resulting in failure of MSCs therapy. Here, we report a melatonin-based strategy to improve cell therapy of in vitro cultured MSCs. Among four small molecules with anti-aging and stem cell-protection properties (rapamycin, resveratrol, quercetin and melatonin), colony forming, proliferation, and osteogenic differentiation assay showed that melatonin was the most efficient to preserve self-renewal and differentiation properties of rat bone marrow MSCs (BMMSCs) after long-term passaging. Functional assays confirmed melatonin treatment did not affect the colony forming, proliferation and osteogenic differentiation of BMMSCs cultured for 1 or 4 passages, but largely prevented the decline of self-renew and differentiation capacity of BMMSCs cultured for 15 passages in vitro. Furthermore, heterotopic osteogenesis assay, critical size calvarial defects repair assay, osteoporosis treatment and experimental colitis therapy assay strongly certified that melatonin preserved the therapeutic effect of long-term passaged BMMSCs on bone regeneration and immunotherapy in vivo. Mechanistically, melatonin functioned by activating antioxidant defense system, inhibiting the pathway of cell senescence, and preserving the expression of gene governing the stemness. Taken together, our findings showed that melatonin treatment efficiently prevented the dysfunction and therapeutic failure of BMMSCs after long-term passaging, providing a practical strategy to improve the application of BMMSCs in tissue engineering and cytotherapy.
Dramatic Down-Regulation Of MNDA Expression In CP-CML Cells From The LSC Compartment
Authors: Céline Bourgne, Alexandre Janel, Juliette Berger, Agnès Guerci, Caroline Jamot, Nathalie Chaudagne, Sylvie Deurveilher, Pascale Pigeon, Eric Hermet, Nathalie Boiret-Dupré, Pierre Verrelle, Philippe Arnaud, Eric Milot, Marc G Berger
Journal: Blood (2013)
Molecular testing prior to first-line therapy in patients with stage IV nonsquamous non-small cell lung cancer (NSCLC): A survey of U.S. medical oncologists.
Authors: Mark R. Green, Joanne Willey, Arden Buettner, Maria Lankford, Doug B. Neely, Suresh S. Ramalingam
Journal: Journal of Clinical Oncology (2014)

8097 Background: Current ASCO, CAP/IASLC/AMP, and NCCN guidelines recommend testing tumor specimens from all patients with advanced non-squamous NSCLC for EGFR mutation status and ALK fusion gene rearrangement. Clearly defining actual rates of oncogene mutation testing among US medical oncologists (MO’s) has been challenging. During 2013, we used a live, case-based, market-research vehicle to document estimated rates of oncogene testing for patients with advanced non-squamous NSCLC. Methods: Using unaided recall estimates, we quantitated testing rates of 385 US MO’s. Response options included specified intervals between 0 and 100%. Assessments were done at 4 research events throughout 2013. Each MO participated in only one research assessment. Three questions were posed: 1) Think about the last 20 patients with stage IV non-squamous NSCLC seen by you for consideration of 1st line therapy. In what percentage of those 20 patients did you prescribe a 1stline anti-tumor therapy? 2) In thinking about those same patients, in what percentage did you (or someone prior to you) order testing for EGFR mutation status? 3) In those same patients, in what percentage did you or someone prior to you, order testing for ALK fusion gene rearrangement? Results: Shown in the Table are the results averaged across all events for treatment and testing for EGFR mutation status and ALK. No trends for increased rates of testing were seen over the assessment interval. Conclusions: Approximately 20% of US MO’s estimated their EGFR and ALK testing rates as being < 40% in patients with advanced non-squamous NSCLC. Our findings demonstrate an urgent need to educate physicians on the role of molecular testing in NSCLC. % of last 20 pts Q1: first-line therapy rate N=366 Q2: EGFR testing rate N=368 Q3: ALK testing rate N=379 100% 10% 25% 17% 80 - 99% 59% 35% 32% 60 - 79% 21% 14% 18% 40 - 59% 4% 8% 10% 30 - 39% 3% 3% 6% < 30% 2% 14% 17% Can’t estimate 1% 1% 1%
Effect of Folic Acid Food Fortification in Canada on Congenital Heart Disease Subtypes
Authors: Shiliang Liu, K.S. Joseph, Wei Luo, Juan Andrés León, Sarka Lisonkova, Michiel Van den Hof, Jane Evans, Ken Lim, Julian Little, Reg Sauve, Michael S. Kramer
Journal: Circulation (2016)

Previous studies have yielded inconsistent results for the effects of periconceptional multivitamins containing folic acid and of folic acid food fortification on congenital heart defects (CHDs).
Activation of tumor infiltrating lymphocytes from colorectal cancer and colorectal liver metastasis patients by anti-human PD-1 Antibody BGB-A317 in a 3D spheroid system.
Authors: Xiaoran Wu, Tong Zhang, Chunyan Fu, Yanjuan Zhang, Amy Guo, lian Hai Zhang, Kun Wang, Baocai Xing, Jiafu Ji, Lai Wang, Kang Li, Lusong Luo
Journal: Journal of Clinical Oncology (2016)

e14560 Background: Blockade of the PD-1 pathway with anti-PD-1 antibody, such as nivolumab (nivo) and pembrolizumab (pembro), has led to remarkable clinical responses in patients (Pts) with many different cancer types. BGB-A317, currently under clinical development, is a novel humanized IgG4 anti-PD-1 antibody. BGB-A317 has a unique binding signature to PD-1 with high affinity. Additionally, it is engineered to remove Fc gamma receptor (FcγR) binding, including FcγRI, FcγRIIA, FcγRIIB and FcγRIIIA. In this study, we investigated the activation of tumor infiltrating lymphocytes (TILs) from Pts with colorectal cancer (CRC) and colorectal liver metastasis (CLM) by BGB-A317 treatment and compared it with nivo and pembro. Methods: TCR signal-initiating cells were used to generate a single spheroid. TILs, isolated from fresh CRC (23 Pts) and CLM (17 Pts) tumor tissues, were co-cultured with the spheroid in an ex vivo 3D assay to assess the immunomodulatory functions of BGB-A317, nivo, and pembro. The treatment-mediated activation of TILs was evaluated by IFN-γ production and TILs proliferation. Flow cytometry and IHC were used to detect different immune cell subsets in tumor microenvironment (TME) of CRC and CLM Pts. The correlations between the immune cell subsets and the activation of TILs were also investigated. Results: BGB-A317, nivo, and pembro all induced activation of TILs in a 3D ex vivo spheroid model. All three anti-PD-1 antibodies showed significant increases in IFN-γ and TILs proliferation in this model. Of note, in both CRC and CLM Pts, BGB-A317 treatment led to significantly higher IFN-γ production than that in nivo and pembro treated groups at concentration levels of 0.1, 1 and 10 μg/mL. The enhanced TILs function was associated with a high density of CD8+ T cells, but inversely correlated with the percentage of CD11b+myeloid cells in CRC tumors. Of interest, BGB-A317 showed better activation of TILs in the liver metastasis TME where macrophages were more abundant. Conclusions: These findings demonstrated that BGB-A317 exhibits potent TILs activation in ex vivo assay, which support its clinical development for the treatment of human cancers.
CD8+ /ICOS+ /CXCR5+ Tumor Infiltrating T-CELLS (CD8fc) Sharing Functional Similarities With TFH CELLS ARE Present In Classical Hodgkin’S Lymphoma Tissues Displaying A Specific “MIXED NODULARITY” Pattern
Authors: Suong Le Thi, Florence Broussais, Reda Bouabdallah, Françoise gondois-Rey, Luc Xerri, Daniel Olive
Journal: Blood (2013)
P0276 : HIF2-alpha neddylation as a selective SerpinB3-dependent mechanism leading to its increase
Authors: S. Cannito, G. Villano, C. Turato, E. Morello, C. Paternostro, S. Quarta, S. Colombatto, F. Lopitz-Otsoa, M.L. Martinez-Chantar, P. Pontisso, M. Parola
Journal: Journal of Hepatology (2015)
LP52 : Nonalcoholic fatty liver disease (NAFLD) as potential risk factor of cardiovascular disease and oncological disease in diabetic type 2 patients
Authors: D. Caroli, A. Nogara, E. Rosa-Rizzotto, A. Boscolo Bariga, S. Zanoni, S. De Boni, G. Cavallarin, C. Marafin, M. Inglese, M. Della Loggia, L. Peraro, S. Lobello, F. De Lazzari
Journal: Journal of Hepatology (2015)
Hyperfibrinolysis increases blood–brain barrier permeability by a plasmin- and bradykinin-dependent mechanism
Authors: Oscar A. Marcos-Contreras, Sara Martinez de Lizarrondo, Isabelle Bardou, Cyrille Orset, Mathilde Pruvost, Antoine Anfray, Yvann Frigout, Yannick Hommet, Laurent Lebouvier, Joan Montaner, Denis Vivien, Maxime Gauberti
Journal: Blood (2016)

Hyperfibrinolysis is a systemic condition occurring in various clinical disorders such as trauma, liver cirrhosis, and leukemia. Apart from increased bleeding tendency, the pathophysiological consequences of hyperfibrinolysis remain largely unknown. Our aim was to develop an experimental model of hyperfibrinolysis and to study its effects on the homeostasis of the blood-brain barrier (BBB). We induced a sustained hyperfibrinolytic state in mice by hydrodynamic transfection of a plasmid encoding for tissue-type plasminogen activator (tPA). As revealed by near-infrared fluorescence imaging, hyperfibrinolytic mice presented a significant increase in BBB permeability. Using a set of deletion variants of tPA and pharmacological approaches, we demonstrated that this effect was independent of N-methyl-D-aspartate receptor, low-density lipoprotein-related protein, protease-activated receptor-1, or matrix metalloproteinases. In contrast, we provide evidence that hyperfibrinolysis-induced BBB leakage is dependent on plasmin-mediated generation of bradykinin and subsequent activation of bradykinin B2 receptors. Accordingly, this effect was prevented by icatibant, a clinically available B2 receptor antagonist. In agreement with these preclinical data, bradykinin generation was also observed in humans in a context of acute pharmacological hyperfibrinolysis. Altogether, these results suggest that B2 receptor blockade may be a promising strategy to prevent the deleterious effects of hyperfibrinolysis on the homeostasis of the BBB.
Thyroid Disorders in Children and Adolescents
Authors: Patrick Hanley, Katherine Lord, Andrew J. Bauer
Journal: JAMA Pediatrics (2016)

Normal thyroid gland function is critical for early neurocognitive development, as well as for growth and development throughout childhood and adolescence. Thyroid disorders are common, and attention to physical examination findings, combined with selected laboratory and radiologic tools, aids in the early diagnosis and treatment.To provide a practical review of the presentation, evaluation, and treatment of thyroid disorders commonly encountered in a primary care practice.We performed a literature review using the PubMed database. Results focused on reviews and articles published from January 1, 2010, through December 31, 2015. Articles published earlier than 2010 were included when appropriate for historical perspective. Our review emphasized evidence-based management practices for the clinician, as well as consensus statements and guidelines. A total of 479 articles for critical review were selected based on their relevance to the incidence, pathophysiology, laboratory evaluation, radiological assessment, and treatment of hypothyroidism, hyperthyroidism, thyroid nodules, and thyroid cancer in children and adolescents. Eighty-three publications were selected for inclusion in this article based on their relevance to these topics.The primary care physician is often the first health care professional responsible for initiating the evaluation of a thyroid disorder in children and adolescents. Patients may be referred secondary to an abnormal newborn screening, self-referred after a caregiver raises concern, or identified to be at risk of a thyroid disorder based on findings from a routine well-child visit. Irrespective of the path of referral, knowledge of the signs and symptoms of hypothyroidism, hyperthyroidism, and thyroid nodules, as well as the general approach to evaluation and management, will help the primary care physician complete an initial assessment and determine which patients would benefit from referral to a pediatric endocrinologist.Early identification and treatment of thyroid disease in children and adolescents is critical to optimize growth and development. The primary care physician plays a critical role in identifying patients at risk. An understanding of risk factors, clinical signs and symptoms, and interpretation of screening laboratories ensures an efficient and accurate diagnosis of these common disorders. Regular communication between the primary care physician and the subspecialist is critical to optimize outcome because the majority of patients with thyroid disorders will require long-term to lifelong medical therapy and/or surveillance.
Comparative impact of treatment on clinical benefit in patients with glioblastoma (GBM) enrolled in the phase II trial of ICT-107.
Authors: Terri S. Armstrong, Patrick Y. Wen, David A. Reardon, Surasak Phuphanich, Robert Aiken, Joseph C. Landolfi, William T. Curry, Jay-Jiguang Zhu, Michael J. Glantz, David M. Peereboom, James Markert, Renato V. LaRocca, Donald O'Rourke, Karen L. Fink, Lyndon J. Kim, Michael L. Gruber, Glenn Jay Lesser, Edward Pan, Santosh Kesari, John Yu
Journal: Journal of Clinical Oncology (2015)

2036 Background: This study was a randomized double blind placebo-controlled phase 2 trial of dendritic cell(DC) Vaccine ICT-107 following standard treatment in newly diagnosed patients with GBM. Although OS was not different, PFS was longer in those receiving the vaccine. To evaluate the clinical benefit of this prolonged PFS, Karnofsky Performance Status (KPS) and steroid dosing, as well as patient reported QOL using the Functional Assessment of Cancer Therapy –Brain (FACT-BR) were evaluated during the progression free period. Methods: The FACT-BR was completed by patients at baseline, and longitudinally during the maintenance phase after four induction vaccinations and at the end of study visit. Corticosteroid dosing and KPS were evaluated throughout the progression free period at monthly timepoints for 12 months and every 6 months thereafter. Between arm differences were evaluated using Fisher test or ANOVA statistics. A p-value of 0.05 was considered significant when comparing the two treatment groups for all analyses. Results: Participants (81 patients in the ICT-107 arm and 43 patients in the control arm) completed baseline FACT-BR assessment (97% compliance), with 84% and 68% completing end of cycle 1 and end of study assessments respectively. Quality of life, as measured by the FACT-BR, was maintained equally until progression for ICT-107 and control patients. Performance level, as measured by KPS, was significantly higher during the treatment period in those receiving ICT-107 (p,0.05, Cycles 1-4 or maintenance phase). There was a trend for less steroid usage over time in the ICT-107 arm (30%) versus the control (44%) (p = 0.1, log rank). Conclusions: Based on these initial analyses of clinical benefit, increased PFS time with ICT-107 is not associated with a detrimental impact on self-report of QOL, and is associated with retention of performance capacity as measured by KPS, and may be associated with a longer corticosteroid free period than those receiving standard treatment. Clinical trial information: NCT01280552.
Case 25-2016
Authors: Jessica A. Zeidman, Paul C. Shellito, Benjamin T. Davis, Lawrence R. Zukerberg
Journal: New England Journal of Medicine (2016)

A 33-year-old man presented with painful bowel movements and rectal bleeding. Physical examination and sigmoidoscopy revealed sentinel skin tags, multiple fissures, and mucosal inflammation of the distal rectum. A diagnosis was made.
Abstract A49: WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis
Authors: Gangarao Davuluri, William P. Schiemann, Edward F. Plow, Khalid Sossey-Alaoui
Journal: Cancer Research (2016)

Abstract Chemoresistance allows for disease to recur and ultimately causes the death of most breast cancer patients. This scenario is particularly relevant in patients harboring triple-negative breast cancer (TNBC) tumors for which there are no effective FDA-approved drugs. However, a recent study determined that TNBCs can be segregated into 6 genetically distinct subtypes that do in fact exhibit differential rates of pathological complete response (pCR) to standard-of-care chemotherapies. Of these, the mesenchymal and mesenchymal stem-like subtypes of TNBCs exhibit the lowest rates of pCR when treated with standard-of-care chemotherapies. WAVE3 is an actin-cytoskeleton remodeling protein, and recent studies have highlighted a potential role for WAVE3 in promoting tumor progression and metastasis in TNBC. However, whether WAVE3 activity is involved in the development of chemoresistance in TNBCs remains unclear. Here we show that loss of WAVE3 expression resensitizes human TNBC cells to doxorubicin and docetaxel, as measured by increased apoptosis and cell death. We also show that WAVE3 knockdown in the chemotherapy-treated TNBC cells results in inhibition of STAT1 phosphorylation, as well as a significant decrease in expression levels of its downstream effector HIF-1α. Since HIF-1α is a major activator of VEGF-A production, and therefore a stimulator of tumor angiogenesis, loss of HIF-1α in the WAVE3-knockdown cells resulted in the inhibition the chemotherapy-mediated VEGF-A secretion and the downstream activation of angiogenesis, a phenomenon that often accompanies chemoresistance. Our data identify a critical role of WAVE3 in sensitizing TNBC to chemotherapy by inhibiting the STAT1/HIF-1α/VEGF-A signaling axis, and support the possibility that WAVE3 inhibition may be a promising target for TNBC cancer therapy. Citation Format: Gangarao Davuluri, William P. Schiemann, Edward F. Plow, Khalid Sossey-Alaoui. WAVE3 modulates sensitivity of TNBCs to chemotherapeutics by inhibiting the STAT-HIF-1α-mediated angiogenesis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A49.
Spatially selective depletion of tumor-associated regulatory T cells with near-infrared photoimmunotherapy
Authors: Kazuhide Sato, Noriko Sato, Biying Xu, Yuko Nakamura, Tadanobu Nagaya, Peter L. Choyke, Yoshinori Hasegawa, Hisataka Kobayashi
Journal: Science Translational Medicine (2016)

CD25-targeted near-infrared photoimmunotherapy depletes T regs and promotes tumor regression.
The Unfolded Protein Response (UPR) Is Activated in Human Acute Myeloid Leukemia (AML) and Suppresses Translation of the CCAAT/Enhancer Binding Protein-Alpha (CEBPA) by Induction of the RNA-Binding Protein Calreticulin
Authors: Julian Schardt, Marianne Eyholzer, Beatrice U Mueller, Thomas Pabst
Journal: Blood (2008)
Whole Exome Sequencing Identifies Novel Lyst-Missense Mutations In Incomplete Childhood Chediak-Higashi-Syndrome Presenting As Hemphagocytic Lymphohistiocytosis (HLH)
Authors: Joachim Kunz, Tobias Rausch, Obul R Bandapalli, Adrian M Stuetz, Johann Greil, Ingrid Hausser, Jan Korbel, Andreas E Kulozik
Journal: Blood (2013)
US woman freed after court overturns 20 year sentence for causing death of her unborn baby
Authors: Owen Dyer
Journal: BMJ (2016)

A US woman, Purvi Patel, sentenced last year to 20 years in prison for using abortion drugs procured on the internet to end her pregnancy, has been freed after a court sentenced her to time already served on a lesser charge of neglect of a dependant.

Patel’s trial under Indiana’s feticide laws drew outrage from women’s groups who argued that state feticide legislation was never intended to be used against pregnant women, only against third parties …
A phase 2 study on efficacy, safety and intratumoral pharmacokinetics of oral selinexor (KPT-330) in patients with recurrent glioblastoma (GBM).
Authors: Morten Mau-Sørensen, Scott Randall Plotkin, Patrick Y. Wen, Andrew L. Kung, Ulrik Niels Lassen, Jean-Richard Saint-Martin, Greg Wright, Aleksander Chudnovsky, Joel Ellis, Sharon Friedlander, Bert van Eijk, Sharon Shacham, Michael G. Kauffman, Andrew B. Lassman
Journal: Journal of Clinical Oncology (2016)

2077 Background: The nuclear export protein exportin 1, (XPO1) is overexpressed in a wide variety of cancers, including GBM. Selinexor (SEL) is an oral Selective Inhibitor of Nuclear Export XPO1 antagonist with brain penetration. SEL forces the nuclear retention & activation of tumor suppressor proteins (TSPs) such as p53, IkB, & p21. Methods: We conducted an open label, 4-Arm Phase II trial enrolling adults with KPS ≥ 60 and recurrent, bevacizumab naïve, measurable GBM. Pts in Arm A received 50 mg/m2 of SEL BIW up to three times prior to resection of recurrent GBM to explore pharmacokinetic and pharmacodynamic effects of SEL in vivo; the other arms did not involve resection. Pts in Arm B received 50 mg/m2 SEL BIW, but the regimen was overly toxic. Therefore, arm B was closed and pts were randomized to either Arm C (60 mg, flat dose, BIW) or D (80 mg, flat dose, once weekly). Up to 30 pts will be accrued to arms C and D, each with a 30% target 6mPFS rate as the primary endpoint. Results: 7 pts (6/1 M/F, median age 57, 1–2 prior tx regimens (PTR)) were treated on Arm A, and 24 (19/5, M/F, median age 51; 1–3 PTR) on Arm B. Accrual to Arms C & D continues, with 4 pts (2/2 M/F, median age 42; 2-3 PTR) as of 20-Jan-2016. Commonly reported G1/2 AE’s (Arms B, C, D) included thrombocytopenia (49%) anorexia (41%), nausea (37%), & fatigue (33%). G3 AEs reported in ≥ 2 pts included fatigue (19%) & neutropenia (11%). One related G4 AE (hypophosphatemia) was reported in 1 pt. Mean tumor SEL concentration in Arm A was 136 nM vs. 985.5 nM in simultaneously collected plasma. Analyses of molecular predictors of response and effects during treatment are ongoing. RANO defined best response (investigator determined) among 27 evaluable pts were: 3 partial responses (11%), 6 stable disease (22%) & 18 progressive disease (67%). The 6-months-PFS rate is immature, although 4 pts were on SEL for ≥ 6 cycles. Conclusions: SEL’s concentration achieved in GBM tissue exceeds the IC50 in vitro. The main toxicities were thrombocytopenia, fatigue, and anorexia, which are mostly Grade 1/2. Partial responses & stable disease were observed. Accrual continues. Clinical trial information: NCT01986348.