tbuckley/cabot-search huggingface dataset:
Modulation of Redox Homeostasis by Inhibition of MTHFD2 in Colorectal Cancer: Mechanisms and Therapeutic Implications
Authors: Huai-Qiang Ju, Yun-Xin Lu, Dong-Liang Chen, Zhi-Xiang Zuo, Ze-Xian Liu, Qi-Nian Wu, Hai-Yu Mo, Zi-Xian Wang, De-Shen Wang, Heng-Ying Pu, Zhao-Lei Zeng, Bo Li, Dan Xie, Peng Huang, Mien-Chie Hung, Paul J Chiao, Rui-Hua Xu
Journal: JNCI Journal of the National Cancer Institute (2018)

Overcoming oxidative stress is a critical step for tumor progression; however, the underlying mechanisms in colorectal cancer (CRC) remain unclear.We investigated nicotinamide adenine dinucleotide (phosphate) (NAD(P))-dependent enzyme methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) expression, clinical relevance, redox modification, and molecular mechanisms using the CRC cells and tissues (n = 462 paired samples). The antitumor effects of MTHFD2 inhibitor LY345899 on CRC tumorigenesis and metastasis were evaluated in vitro and in vivo. Data analysis used Kaplan-Meier, Pearson's correlation, and Student t test where appropriate. All statistical tests were two-sided.Here, we report that the patients with high expression of MTHFD2 have a shorter overall survival (HR = 1.62, 95% CI = 1.12 to 2.36, P = .01) and disease-free survival (HR = 1.55, 95% CI = 1.07 to 2.27, P = .02) than patients with low MTHFD2 expression. Suppression of MTHFD2 disturbs NADPH and redox homeostasis and accelerates cell death under oxidative stress, such as hypoxia or anchorage independence (P ≤ .01 for all). Also, genetic or pharmacological inhibition of MTHFD2 suppresses CRC cell growth and lung and peritoneal metastasis in cell-based xenografts (n = 5-8 mice per group). Importantly, LY345899 treatment statistically significantly suppresses tumor growth and decreases the tumor weight in CRC patient-derived xenograft models (n = 10 mice per group, mean [SD] tumor weight of the vehicle-treated group was 1.83 [0.19] mg vs 0.74 [0.30] mg for the LY345899-treated group, P < .001).Our study presents evidence that MTHFD2 confers redox homeostasis and promotes CRC cell growth and metastasis. The folate analog LY345899 as MTHFD2 inhibitor displays therapeutic activity against CRC and warrants further clinical investigation for CRC treatment.
A Microwell‐Assisted Multiaptamer Immunomagnetic Platform for Capture and Genetic Analysis of Circulating Tumor Cells
Authors: Zaizai Dong, Chuanhao Tang, Libo Zhao, Jiachao Xu, Yayun Wu, Xiaojun Tang, Wei Zhou, Rongxiang He, Rong Zhao, Li Xu, Zhen Zhang, Xiaohong Fang
Journal: Advanced Healthcare Materials (2018)

Abstract Detection of circulating tumor cells (CTCs) in peripheral blood is of paramount significance for cancer diagnosis, progress evaluation, and individualized therapy. However, the rareness and heterogeneity of CTCs introduces significant challenges in the capture of cancer cells as well as downstream genetic analysis. In this work, a microwell‐assisted multiaptamer immunomagnetic platform (MMAIP) is proposed for highly efficient capture of CTCs with minimum influence of heterogeneity. Assisted by a microwell chip, the purity of CTCs is greatly improved, thus meeting the requirement of downstream gene analysis. This is, as far as is known, the first aptamer based platform enabling mutation analysis of the captured CTCs from cancer patients, which will contribute to the practical application of aptamers in clinics.
Abstract 15480: The Efficacy and Safety of More Potent Antiplatelet Therapy With Vorapaxar in Patients With Impaired Renal Function: Insights From the TRA 2P-TIMI 50 Trial
Authors: Simon Correa Gaviria, Eugene Braunwald, Marc P Bonaca, Sabina A Murphy, Erica L Goodrich, David A Morrow, Michelle L O'Donoghue
Journal: Circulation (2017)

Introduction: Patients with renal disease are often undertreated with antiplatelet therapy due to concerns about bleeding. Vorapaxar, an antiplatelet therapy that blocks platelet activation via PAR...
Anxiety, Depression, and Insomnia Among Adults With Opioid Dependence Treated With Extended-Release Naltrexone vs Buprenorphine-Naloxone
Authors: Zill-e-Huma Latif, Jurate Šaltyte Benth, Kristin Klemmetsby Solli, Arild Opheim, Nikolaj Kunoe, Peter Krajci, Kamni Sharma-Haase, Lars Tanum
Journal: JAMA Psychiatry (2018)

IMPORTANCE Extended-release naltrexone (XR-NTX) is a promising alternative treatment of opioid addiction but has never been compared with opioid agonist treatment for effects on symptoms of anxiety, depression, and insomnia.OBJECTIVE To investigate whether XR-NTX unmasks or reinforces current comorbid symptoms of anxiety, depression, or insomnia compared with opioid agonist treatment. DESIGN, SETTING, AND PARTICIPANTSIn this prospective randomized clinical trial, 159 men and women aged 18 to 60 years with opioid dependence were randomized to 12 weeks of treatment with either XR-NTX or combined buprenorphine-naloxone (BP-NLX) followed by a 9-month, open-label treatment study with participant choice of 1 of these 2 drugs.The study was conducted at outpatient addiction clinics in 5 urban hospitals in Norway, with the clinical trial performed from November 1, 2012, to October 23, 2015, and the follow-up study completed on July 23, 2016.All analyses were conducted using an intention-to-treat sample.INTERVENTIONS Extended-release naltrexone hydrochloride, 380 mg, administered as an injection every 4 weeks or flexible doses (4-24 mg; target dosage 16 mg/d) of daily oral combined BP-NLX.MAIN OUTCOMES AND MEASURES Every 4 weeks, symptoms of anxiety and depression were assessed using the 25-item Hopkins Symptom Checklist, and symptoms of insomnia were assessed using the Insomnia Severity Index. RESULTSIn total, 159 participants were randomized to treatment with either XR-NTX (n = 80) or BP-NLX (n = 79), and 105 participants (66.0%) completed the trial.The treatment groups showed similar distributions of age (mean [SD], 36.4 [8.8] vs 35.7 [8.5] years), sex (61 [76.3%] women and 54 [68.4%] men), and duration of heroin use (mean [SD], 6.9 [5.8] vs 6.7 [5.2] years).For the clinical trial period, no overall differences were detected between treatment groups for anxiety (effect size [95% CI], -0.14 [-0.47 to 0.19]) or depression (effect size [95% CI], -0.12 [-0.45 to 0.21]) scores, but the insomnia score was significantly lower in the XR-NTX group (effect size [95% CI], -0.32 [-0.61 to -0.02]; P = .008).In the follow-up period, no overall differences could be detected in the effect size [95% CI] of scores for anxiety (0.04 [-0.34 to 0.42]), depression (-0.04 [-0.42 to 0.33]), or insomnia (0.04 [-0.33 to 0.42]) between participants continuing with and participants switching to XR-NTX.No significant sex differences between the 2 treatment groups were detected.CONCLUSIONS AND RELEVANCE Comorbid symptoms of anxiety, depression, or insomnia in abstinence-motivated persons with opioid dependence should not prevent switching from treatment with an opioid agonist to treatment with XR-NTX.
Engineering Controlled Peritumoral Inflammation to Constrain Brain Tumor Growth
Authors: Tarun Saxena, Johnathan G. Lyon, S. Balakrishna Pai, Daniel Pare, Jessica Amero, Lohitash Karumbaiah, Sheridan L. Carroll, Eric Gaupp, Ravi V. Bellamkonda
Journal: Advanced Healthcare Materials (2018)

Brain tumors remain a great clinical challenge, in part due to their capacity to invade into eloquent, inoperable regions of the brain. In contrast, inflammation in the central nervous system (CNS) due to injuries activates microglia and astrocytes culminating in an astroglial scar that typically "walls-off" the injury site. Here, the hypothesis is tested that targeting peritumoral cells surrounding tumors to activate them via an inflammatory stimulus that recapitulates the sequelae of a traumatic CNS injury, could generate an environment that would wall-off and contain invasive tumors in the brain. Gold nanoparticles coated with inflammatory polypeptides to target stromal cells in close vicinity to glioblastoma (GBM) tumors, in order to activate these cells and stimulate stromal CNS inflammation, are engineered. It is reported that this approach significantly contains tumors in rodent models of GBM relative to control treatments (reduction in tumor volume by over 300% in comparison to controls), by the activation of the innate and adaptive immune response, and by triggering pathways related to cell clustering. Overall, this report outlines an approach to contain invasive tumors that can complement adjuvant interventions for invasive GBM such as radiation and chemotherapy.
Emerging Cellular Therapies for Cancer
Authors: Sonia Guedan, Marco Ruella, Carl H. June
Journal: Annual Review of Immunology (2018)

Genetically engineered T cells are powerful new medicines, offering hope for curative responses in patients with cancer. Chimeric antigen receptor (CAR) T cells were recently approved by the US Food and Drug Administration and are poised to enter the practice of medicine for leukemia and lymphoma, demonstrating that engineered immune cells can serve as a powerful new class of cancer therapeutics. The emergence of synthetic biology approaches for cellular engineering provides a broadly expanded set of tools for programming immune cells for enhanced function. Advances in T cell engineering, genetic editing, the selection of optimal lymphocytes, and cell manufacturing have the potential to broaden T cell-based therapies and foster new applications beyond oncology, in infectious diseases, organ transplantation, and autoimmunity.
Abstract 21097: Three-Dimensional Traction Stresses Facilitate Leukocyte Diapedesis
Authors: Yi-Ting Yeh, Serrano Ricardo, Joshua François, Jeng-Jiann Chiu, Juan Carlos del Álamo, Shu Chien, Juan Carlos Lasheras
Journal: Circulation (2017)

Objective: Leukocyte extravasation is critical in the immune response. Leukocytes transmigrate from apical to basal endothelium preferentially through VEC junctions three-dimensionally (3D), a process known as diapedesis. However, the precise biomechanical mechanisms by which the leukocyte-VEC interaction contributes to diapedesis remain elusive. Method: We conducted time-lapse imaging experiments to monitor the dynamics of VEC junctions during leukocyte diapedesis. We used 3D Traction Force Microscopy (3DTFM) and Monolayer Stress Microscopy to measure the spatiotemporal evolution of the traction stresses and intracellular tensions generated by the cells and to characterize the sequence of mechanical events during leukocyte diapedesis. We acquired 4-6 experiments for the statistical analysis. Results: We found that leukocyte firm adhesion caused the opening of junctional gaps before the initiation of leukocyte transmigration. We measured significant changes of in-plane stress and intracellular tension while the leukocyte firmly attached to VECs, and subsequently, the following increases of out-of-plane stress as the leukocyte migrates across the monolayer. Thrombin treatment increased the heterogeneity of VEC monolayer tensions, which created a VEC environment that facilitated leukocyte diapedesis. Subsequent treatment with Rho kinase inhibitor reversed the thrombin effect. Conclusion: The coordination between 3D traction stresses and VEC monolayer tensions, controls the dynamics of leukocyte diapedesis.
Youth With Type 1 Diabetes Taking Responsibility for Self-Management: The Importance of Executive Functioning in Achieving Glycemic Control
Authors: Anne F. Vloemans, Minke M.A. Eilander, Joost Rotteveel, Willie M. Bakker-van Waarde, Euphemia C.A.M. Houdijk, Roos Nuboer, Per Winterdijk, Frank J. Snoek, Maartje De Wit
Journal: Diabetes Care (2018)

OBJECTIVE Successful self-management of type 1 diabetes requires cognitive skills such as executive functioning (EF). In the transition to adolescence, youth take over responsibility for diabetes management. We set out to test: 1) the association between EF and glycemic control over time and 2) whether this association was moderated by: a) youth, shared, or parent responsibility for diabetes management and b) youth’s age. RESEARCH DESIGN AND METHODS Within the Diabetes IN DevelOpment study (DINO), parents of youth with type 1 diabetes (8–15 years at baseline; N = 174) completed a yearly assessment over 4 years. Glycemic control (HbA1c) was derived from hospital charts. Youth’s EF was measured using the Behavior Rating Inventory of Executive Functioning (BRIEF)-parent report. The Diabetes Family Responsibility Questionnaire (DFRQ)-parent report was used to assess diabetes responsibility (youth, shared, and parent). Linear generalized estimating equations were used to analyze data including youth’s sex, age, and age of diabetes onset as covariates. RESULTS Relatively more EF problems are significantly associated with higher HbA1c over time (β = 0.190; P = 0.002). More EF problems in combination with less youth responsibility (β = 0.501; P = 0.048) or more parental responsibility (β = −0.767; P = 0.006) are significantly associated with better glycemic control over time. Only age significantly moderates the relationship among EF problems, shared responsibility, and glycemic control (β = −0.024; P = 0.019). CONCLUSIONS Poorer EF is associated with worse glycemic control over time, and this association is moderated by responsibility for diabetes management tasks. This points to the importance of EF when youth take over responsibility for diabetes management in order to achieve glycemic control.
Abstract 13698: Does Obesity Impact Left Ventricular Thickness in Children With Hypertrophic Cardiomyopathy?
Authors: Seshadri Balaji, Michael P DeLorenzo, Frank A Fish, Susan P Etheridge, Peter F Aziz, Mark W Russell, Svjetlana Tisma, Andreas Pflaumer, Narayanswami Sreeram, Peter Kubus, Ian H Law, Michal J Kantoch, Naomi J Kertesz, Margaret J Strieper, Christopher C Erickson, Jeremy P Moore, Stephanie J Nakano, Harinder R Singh, Philip Chang, Mitchell I Cohen, Anne Fournier, Maria V Ilina, Richard T Smith, Frank Zimmerman, Michaela Horndasch, Walter Li, Anjan Batra, Leo Liberman, Robert M Hamilton, Christopher M Janson, Shubayan Sanatani, Ilana Zeltser, George McDaniel, Jason M Garnreiter, Hannah Katcoff, Maully Shah
Journal: Circulation (2017)

Introduction: Hypertrophic cardiomyopathy (HCM) is a genetic heart disease with diverse natural history. The hallmark of HCM is severe left ventricular hypertrophy (LVH). In adults with HCM, obesit...
Abstract 16719: Withaferin a Attenuates Myocardial Ischemia/ Reperfusion Injury via Mitochondrial Death Cascade Blockade in an AMPK Dependent Manner
Authors: Rui Guo, Wayne Bond Lau, Zheyi Yan, Lu Gan, Wenjun Yan, Dajun Zhao, Dina Xie, Xinliang Ma, Erhe Gao, Yajing Wang
Journal: Circulation (2017)

Objective: Withaferin A (WFA) impedes cancer metastasis by exerting potent anti-invasive activity and anti-oxidative, anti-inflammatory properties. However, whether WFA attenuates myocardial ischem...
Intracellular Delivery of His‐Tagged Genome‐Editing Proteins Enabled by Nitrilotriacetic Acid–Containing Lipidoid Nanoparticles
Authors: Yamin Li, Alice Chukun Li, Qiaobing Xu
Journal: Advanced Healthcare Materials (2018)

Protein- and peptide-based therapeutics with high tolerance and specificity along with low off-target effects and genetic risks have attracted tremendous attention over the last three decades. Herein, a new type of noncationic lipidoid nanoparticle (LNP) is reported for His-tagged protein delivery. Active lipidoids are synthesized by conjugating a nitrilotriacetic acid group with hydrophobic tails (EC16, O16B, and O17O) and nanoparticles are formulated in the presence of nickel ions and helper lipids (cholesterol, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine, and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]). It is demonstrated that the newly developed LNPs are capable of delivering various His-tagged proteins including green fluorescent protein (GFP), (-30)GFP-Cre recombinase, and CRISPR/Cas9 ribonucleoprotein into mammalian cells.
The Kruppel-like factor 4 (KLF4) tumor suppressor gene is silenced by genetic and epigenetic mechanisms in medulloblastoma
Authors: Yukiko Nakahara, Paul Northcott, Paul Kongkham, John Peacock, Lars Feuk, Wiesia Grajkowska, Boleslaw Lach, Richard Grundy, Yancey Gillespie, Carlos Carlotti, Frederick Boop, Darell Bigner, Ian Pollack, Ronald Hamilton, Richard Gilbertson, Steven Scherer, James Rutka, Michael Taylor
Journal: Cancer Research (2007)

1142  Medulloblastoma is a highly malignant embryonal tumor of the cerebellum that accounts for 20% to 25% of all primary brain tumors in children. Despite aggressive multimodal therapy, including surgery, irradiation, and chemotherapy, the 5-year survival rate is only 50% to 60%. The underlying genetic and epigenetic events that give rise to the majority of medulloblastomas are not known.  As part of a larger study to define genetic abnormalities in medulloblastoma, we identified in a single, primary medulloblastoma a discrete area of homozygous deletion on 9q31, a locus that shows frequent loss of heterozygosity in medulloblastoma. This 2.03 Mb deletion encompasses 8 known genes: ZNF462, RAD23B, KLF4, ACTL7B, ACTL7A, IKBKAP, C9orf6, and CTNNAL1. Exon re-sequencing of RAD23B (DNA repair)and KLF4 (known tumor suppressor gene) in a series of medulloblastomas with loss of heterozygosity on chromosome 9q did not reveal any mutations. However, treatment of medulloblastoma cell lines with 5-aza-deoxycytidine (5-Aza-C) resulted in greatly increased expression of KLF4 in 7/9 cell lines, suggesting that KLF4 is silenced by promotor methylation, and may be acting as a tumour suppressor gene. KLF4 is a zinc-finger transcription factor that is expressed primarily in post-mitotic, terminally differentiated epithelial cells of the skin, lungs, and gastrointestinal tract. KLF4, a known tumor suppressor gene regulates the expression of many genes, including those involved in differentiation and cell-cycle arrest. Recently, KLF4 has been shown to be epigenetically inactivated by promoter methylation in gastrointestinal cancer.  The transcription level of KLF4 was restored in 7/9 medulloblastoma cell lines after treatment with 5-Aza-C, as shown by real time RT-PCR. Bisulfite sequencing of multiple clones for each cell line demonstrated methylation of CpGs in the promoter region of KLF4, including 25 CpG sites (at -2168 to -1712) in those cell lines whose expression rose with 5-Aza-C; but no methylation was detected in cell lines where 5-Aza-C had no effect. Bisulfite sequencing of normal fetal and adult human cerebellum did not demonstrate any methylation of the KLF4 promotor, highly suggesting that methylation of KLF4 seen in medulloblastoma is abnormal. We examined the DNA methylation status of KLF4 in 45 primary pediatric medulloblastomas using methylation-specific PCR (MSP) and determined that 18% of primary medulloblastomas (7 of 45) are methylated at the KLF4 promoter region.  Our data suggest that the KLF4 tumour suppressor gene is inactivated by either genetic or epigenetic mechanisms in a significant subset of medulloblastoma. KLF4 may represent a novel target for the therapy of medulloblastoma.
Effect of interplay between age and low-flow duration on neurologic outcomes of extracorporeal cardiopulmonary resuscitation
Authors: Hsi-Yu Yu, Chih-Hsien Wang, Nai-Hsin Chi, Shu-Chien Huang, Heng-Wen Chou, Nai-Kuan Chou, Yih-Sharng Chen
Journal: Intensive Care Medicine (2018)

Caseloads of extracorporeal cardiopulmonary resuscitation (ECPR) have increased considerably, and hospital mortality rates remain high and unpredictable. The present study evaluated the effects of the interplay between age and prolonged low-flow duration (LFD) on hospital survival rates in elderly patients to identify subgroups that can benefit from ECPR.Adult patients who received ECPR in our institution (2006-2016) were classified into groups 1, 2, and 3 (18-65, 65-75, and > 75 years, respectively). Data regarding ECPR and adverse events during hospitalization were collected prospectively. The primary end point was favorable neurologic outcome (cerebral performance category 1 or 2) at hospital discharge.In total, 482 patients were divided into groups 1, 2, and 3 (70.5%, 19.3%, and 10.2%, respectively). LFDs were comparable among the groups (40.3, 41.0, and 44.3 min in groups 1, 2, and 3, P = 0.781, 0.231, and 0.382, respectively). Favorable neurologic outcome rates were nonsignificantly lower in group 3 than in the other groups (27.6%, 24.7%, and 18.4% for group 1, 2, and 3, respectively). Subgroup analysis revealed that the favorable neurologic outcome rates in group 1 were 36.7%, 25.4%, and 13.0% for LFDs of < 30, 30-60, and > 60 min, respectively (P = 0.005); in group 2, they were 32.1%, 21.2%, and 23.1%, respectively (P = 0.548); in group 3 they were 25.0%, 20.8%, and 0.0%, respectively (P = 0.274).On emergency consultation for ECPR, age and low-flow duration should be considered together to predict neurologic outcome.
Characterization of single microvesicles in plasma from glioblastoma patients
Authors: Kyle Fraser, Ala Jo, Jimmy Giedt, Claudio Vinegoni, Katherine S Yang, Pierepaolo Peruzzi, E Antonio Chiocca, Xandra O Breakefield, Hakho Lee, Ralph Weissleder
Journal: Neuro-Oncology (2018)

Extracellular vesicles (EV) are shed by tumor cells but little is known about their individual molecular phenotypes and heterogeneity. While exosomes have received considerable attention, much less is known about larger microvesicles. Here we profile single microvesicles (MV) and exosomes from glioblastoma (GB) cells and MV from the plasma of patients.
Phase I clinical study of NK105, paclitaxel-encapsulating micelles, on a weekly schedule, in patients with malignant tumors (dose-escalation phase).
Authors: Ken Kato, Hirofumi Mukai, Taito Esaki, Shozo Ohsumi, Yasuo Hozumi
Journal: Journal of Clinical Oncology (2013)

3082 Background: NK105 is the formulation of a novel drug delivery system that encapsulates paclitaxel (PTX) in polymeric micelles and possibly resolves the safety issues associated with the additives contained in the conventional PTX formulation. In the phase II study of NK105 administered to gastric cancer patients on a 150Emg/m 2 triweekly schedule, peripheral sensory neuropathy was mitigated compared to prior data for conventional PTX, without any reduction in efficacy. Based on the dose-density theory, we conducted a phase I study of NK105 on a weekly schedule to determine the dose-limiting toxicity (DLT) and recommended dosage (RD), and to evaluate the pharmacokinetic profile. Methods: Patients with advanced solid tumors refractory to standard therapy received NK105 at dosage levels of 50-100 mg/m 2 as a 30-min infusion without premedication, once a week for three weeks, followed by one week of rest. Pharmacokinetic analysis was conducted in cycles 1 and 2. Results: Sixteen patients were enrolled in the study. In the 100Emg/m 2 cohort (n=7), one patient experienced DLT (grade 4 neutropenia lasting 5 days), and dose reduction or delay was necessary in 4 of the 7 patients during the first course due to neutropenia. It was decided that 100 mg/m 2 was the maximum tolerated dosage, and the RD was set at 80 mg/m 2 . Grade 3 or more severe adverse drug reactions reported for the 80Emg/m 2 cohort were neutropenia, anemia, fatigue, hearing impaired and ataxia. Comparison of the pharmacokinetic parameters of NK105 with those of PTX at the same dosage (100 mg/m 2 ) showed that the AUC 0-inf. and Vdss of NK105 were approximately 50-fold and 1/15 of the reported PTX values, respectively. A refractory gastric cancer patient and an esophageal cancer patient each showed a partial response, at dosages of 80 mg/m 2 and 100 mg/m 2 , respectively. Conclusions: 80Emg/m 2 weekly administration of NK105 was well tolerated and showed anti-tumor activity, including partial responses and several occurrences of stable disease. The expansion phase of the study is ongoing at the RD of 80 mg/m 2 . Clinical trial information: JapicCTI-101233.