tbuckley/cabot-search huggingface dataset:
The Harveian Lectures ON THE TREATMENT OF SOME ACUTE VISCERAL INFLAMMATIONS: Delivered before the Harveian Society of London, November 5th, 12th, and 19th, 1903
Authors: D. B. Lees
Journal: BMJ (1903)

The goal of this study was to elucidate the mechanisms of 17β-estradiol (E<sub>2</sub>) antioxidant and neuroprotective actions in stroke. The results reveal a novel extranuclear receptor-mediated antioxidant mechanism for E<sub>2</sub> during stroke, as well as a hypersensitivity of the CA3/CA4 region to ischemic injury after prolonged hypoestrogenicity. E<sub>2</sub> neuroprotection was shown to involve a profound attenuation of NADPH oxidase activation and superoxide production in hippocampal CA1 pyramidal neurons after stroke, an effect mediated by extranuclear estrogen receptor α (ERα)-mediated nongenomic signaling, involving Akt activation and subsequent phosphorylation/inactivation of Rac1, a factor critical for activation of NOX2 NADPH oxidase. Intriguingly, E<sub>2</sub> nongenomic signaling, antioxidant action, and neuroprotection in the CA1 region were lost after long-term E<sub>2</sub> deprivation, and this loss was tissue specific because the uterus remained responsive to E<sub>2</sub>. Correspondingly, a remarkable loss of ERα, but not ERβ, was observed in the CA1 after long-term E<sub>2</sub> deprivation, with no change observed in the uterus. As a whole, the study reveals a novel, membrane-mediated antioxidant mechanism in neurons by E<sub>2</sub> provides support and mechanistic insights for a “critical period” of E<sub>2</sub> replacement in the hippocampus and demonstrates a heretofore unknown hypersensitivity of the CA3/CA4 to ischemic injury after prolonged hypoestrogenicity.
A Phase I Study of the Multi-Targeted Tyrosine Kinase Inhibitor Cabozantinib in Patients with Acute Myeloid Leukemia
Authors: Amir T. Fathi, Traci M. Blonquist, Mark J. Levis, Daniela Hernandez, Karen K. Ballen, David E. Avigan, Robin Joyce, Malgorzata McMasters, Emma Logan, Gabriela S. Hobbs, Andrew M. Brunner, Christine Connolly, Ashley M. Perry, Christelle Joseph, Tina T. Som, Aura Y. Ramos, Donna S. Neuberg, Philip C. Amrein
Journal: Blood (2016)
HGG-02. DIANHYDROGALACTITOL (VAL-083) OVERCOMES MGMT- AND P53-MEDIATED CHEMO-RESISTANCE AND DISPLAYS SYNERGY WITH TOPOISOMERASE INHIBITORS
Authors: Beibei Zhai, Anne Steino, Jeffrey Bacha, Dennis Brown, Mads Daugaard, Theodore Nicolaides
Journal: Neuro-Oncology (2017)

The mortality rate of pediatric CNS cancer has not decreased as other pediatric cancers, and high-grade gliomas (HGG) are the main cause of death in children with brain tumors. Children with HGG have few therapeutic options and 5-year survival is less than 20%. Relapsed HGG have a uniformly fatal outcome despite all available treatments. The standard treatment for HGG is surgery followed by radiotherapy and temozolomide (TMZ) although the efficacy of TMZ in children is negligible. DNA repair protein O6-Methyl-Guanine-DNA-MethylTransferase (MGMT) is expressed in most pediatric HGG and expression is correlated with resistance to TMZ and nitrosoureas and dismal prognosis. VAL-083 is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity in pediatric brain tumors as well as a favorable safety profile in prior NCI-sponsored clinical trials. VAL-083 induces interstrand cross-links at guanine-N7 causing DNA double-strand breaks and cancer cell death. VAL-083 overcomes TMZ-resistance and is equally active against GBM cancer stem cells (CSCs) and non-CSCs independent of MGMT status, in vitro. We recently showed that VAL-083 leads to irreversible S/G2-phase cell cycle arrest and persistent activation of the homologous recombination DNA repair pathway. This mechanism-of-action of VAL-083 suggests the potential for synergy with topoisomerase inhibitors (TOPi), commonly used in the treatment of pediatric HGG, which require cancer cells to be in S-phase for optimal efficacy. Here, VAL-083 cytotoxicity and DNA damage-response was evaluated in SF188, Med8a, A549 and PC3 cell-lines. We report strong activity in p53-mutated Med8a and SF188 cells known to be radio- and chemo-resistant. Further, we report synergy between VAL-083 and both topoisomerase I and II inhibitors (camptothecin and etoposide) in both A549 and PC3 cell-lines. Our results support a distinct anti-cancer mechanism for VAL-083 compared to standard HGG chemotherapy, resulting in the ability to overcome chemo-resistance and exhibiting synergy with TOPi.
Стеатоз печени и стеатогепатит — неизбежность смешанного генеза
Authors: Yu.M. Stepanov
Journal: GASTROENTEROLOGY (2014)

Представлен анализ этиологических и патогенетических механизмов формирования стеатоза и стеатогепатита смешанного генеза. Показано, что одним из основных этиопатогенетических факторов развития стеатоза печени и стеатогепатита остается алкоголь, роль которого прослеживается у 46–65 % пациентов. Накоплены убедительные данные, свидетельствующие о том, что ожирение, инсулинорезистентность представляют собой факторы прогрессирования стеатоза и стеатогепатита алкогольной, неалкогольной и смешанной этиологии. Одновременное влияние нескольких этиологических факторов приводит к незамедлительному развитию стеатоза и стеатогепатита у 95 % пациентов. Многие триггерные факторы можно рассматривать как взаимодополняющие факторы поражения печени смешанного генеза. Приведены общие подходы к диагностике, лечению, представлены основные группы лекарственных препаратов для коррекции стеатоза и стеатогепатита смешанного генеза.
DIPG-15. EFFECTIVE PRECLINICAL TREATMENT OF DIFFUSE INTRINSIC PONTINE GLIOMA BY MELK INHIBITION
Authors: Michaël H Meel, Miriam Guillén-Navarro, Mark C de Gooijer, Piotr Waranecki, Levi CM Buijl, Olaf van Tellingen, Dannis G van Vuurden, Gertjan JL Kaspers, Esther Hulleman
Journal: Neuro-Oncology (2017)

Maternal embryonic leucine zipper kinase (MELK) is the second highest expressed kinase in diffuse intrinsic pontine glioma (DIPG). Inhibition of MELK by the small molecule OTSSP167 effectively reduces proliferation and induces cell death in primary DIPG cell lines at low nanomolar concentrations. RNA sequencing of DIPG cells treated with OTSSP167 reveals upregulation of genes associated with the PPAR transcription factors as well as upregulation of PPAR target genes. Western blot and immunofluorescence demonstrates reduced inhibitory phosphorylation and increased nuclear localization of PPARγ upon MELK inhibition. Combined treatment of DIPG cells with OTSSP167 and PPARγ agonists synergistically reduced cell survival. Given the importance of the blood-brain barrier in DIPG, brain penetration of OTSSP167 was investigated by administration of the compound to wild-type, Abcb1a/b -/-, Abcg2-/- and Abcb1a/b -/-; Abcg2-/- mice. Brain bioavailability was severely reduced by both Abcb1a/b and Abcg2 efflux activity. To demonstrate the potential of MELK inhibition for the treatment of DIPG, Abcb1a/b -/-; Abcg2-/- athymic nude mice were xenografted with primary DIPG tumors and treated with a low dose of OTSSP167 for six weeks. After 15 days of treatment, half the mice carrying DIPG xenografts showed remission of the tumors, with several showing long-term stable disease even after cessation of treatment. To our knowledge, this is the first time treatment of DIPG xenografts resulted in remissions, urging the development of brain penetrable MELK inhibitors for clinical trials.
Abstract 325: miR-223 Negatively Regulate Ischemia/Reperfusion-induced Cardiac Necroptosis
Authors: Guo-Chang Fan, Dongze Qin, Xiaohong Wang, Liwang Yang, Wei Huang, Yigang Wang
Journal: Circulation Research (2015)

It is well known that myocardial ischemia/reperfusion (I/R) causes myocyte apoptosis and necrosis. For many years, apoptosis was considered to be the only form of gene-regulated cell death, whereas necrosis was thought as a passive accidental cell death. Recent studies, however, clearly indicate that necrosis can be controlled by multiple genes, and RIPK1/3-regulated necrosis, called necroptosis, has gained well attention. We and others previously showed that miR-223, an anti-inflammatory miRNA, was greatly up-regulated in the infarcted heart. To test whether miR-223 regulates I/R-induced cardiac necroptosis, transgenic (TG) mice with cardiac-specific overexpression of miR-223 and miR-223 knockout (KO) mice were used and underwent global no-flow I/R (30min/1h). We observed that TG hearts displayed the better recovery of contractile function (+dP/dt: 92±4%), compared with wild-type (WT) hearts (65±3%). This improvement was accompanied with a 2.4-fold decrease in lactate dehydrogenase (LDH), a marker of necrosis, released from TG hearts, comparable to WTs. By contrast, KO-hearts showed the worse recovery of contractile function (+dP/dt: 41± 3%) than WTs (+dP/dt: 70±4%), and increased LDH release (3-fold). Notably, both TUNEL-staining and DNA fragmentation analysis for cardiac apoptosis showed no difference between groups. Western-blotting assays showed that protein levels of RIPK1, RIPK3 and MLKL, three known mediators in the necroptotic pathway, were reduced in TG hearts, whereas they were increased in KOs, compared to respective WT controls upon I/R. Furthermore, pre-injection of NEC-1s (1.65mg/kg), a specific inhibitor of necroptosis, into miR-223-KO mice, significantly improved cardiac function recovery during I/R, compared to saline-injected KOs. To elucidate the mechanisms underlying the miR-223-mediated cardiac necroptosis, we performed a series of experiments (bioinformatics, luciferase report assay, and western-blotting). Our results showed that miR-223 negatively regulated the expression of TNFR1 and death receptor 6 (DR6), two activators of the necroptotic pathway. Put together, this study indicates that miR-223 could control I/R-induced cardiac necroptosis via targeting the DR6/TNFR1-RIP1/3-MLKL pathway.
Sofosbuvir, Velpatasvir, and Voxilaprevir for Previously Treated HCV Infection
Authors: Marc Bourlière, Stuart C. Gordon, Steven L. Flamm, Curtis L. Cooper, Alnoor Ramji, Myron Tong, Natarajan Ravendhran, John M. Vierling, Tram T. Tran, Stephen Pianko, Meena B. Bansal, Victor de Lédinghen, Robert H. Hyland, Luisa M. Stamm, Hadas Dvory-Sobol, Evguenia Svarovskaia, Jie Zhang, K.C. Huang, G. Mani Subramanian, Diana M. Brainard, John G. McHutchison, Elizabeth C. Verna, Peter Buggisch, Charles S. Landis, Ziad H. Younes, Michael P. Curry, Simone I. Strasser, Eugene R. Schiff, K. Rajender Reddy, Michael P. Manns, Kris V. Kowdley, Stefan Zeuzem
Journal: New England Journal of Medicine (2017)

Patients who are chronically infected with hepatitis C virus (HCV) and who do not have a sustained virologic response after treatment with regimens containing direct-acting antiviral agents (DAAs) have limited retreatment options.We conducted two phase 3 trials involving patients who had been previously treated with a DAA-containing regimen. In POLARIS-1, patients with HCV genotype 1 infection who had previously received a regimen containing an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive either the nucleotide polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir, and the protease inhibitor voxilaprevir (150 patients) or matching placebo (150 patients) once daily for 12 weeks. Patients who were infected with HCV of other genotypes (114 patients) were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group. In POLARIS-4, patients with HCV genotype 1, 2, or 3 infection who had previously received a DAA regimen but not an NS5A inhibitor were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir-voxilaprevir (163 patients) or sofosbuvir-velpatasvir (151 patients) for 12 weeks. An additional 19 patients with HCV genotype 4 infection were enrolled in the sofosbuvir-velpatasvir-voxilaprevir group.In the three active-treatment groups, 46% of the patients had compensated cirrhosis. In POLARIS-1, the rate of sustained virologic response was 96% with sofosbuvir-velpatasvir-voxilaprevir, as compared with 0% with placebo. In POLARIS-4, the rate of response was 98% with sofosbuvir-velpatasvir-voxilaprevir and 90% with sofosbuvir-velpatasvir. The most common adverse events were headache, fatigue, diarrhea, and nausea. In the active-treatment groups in both trials, the percentage of patients who discontinued treatment owing to adverse events was 1% or lower.Sofosbuvir-velpatasvir-voxilaprevir taken for 12 weeks provided high rates of sustained virologic response among patients across HCV genotypes in whom treatment with a DAA regimen had previously failed. (Funded by Gilead Sciences; POLARIS-1 and POLARIS-4 ClinicalTrials.gov numbers, NCT02607735 and NCT02639247 .).
TMOD-09. A PATIENT-DERIVED XENOGRAFT MODEL MIMICKING RECURRENT PEDIATRIC MALIGNANT GLIOMA
Authors: Mona M. Al-Gizawiy, Ninh B. Doan, Robert T. Wujek, Hisham S. Alhajala, Shama P. Mirza, Christopher R. Chitambar, Kathleen M. Schmainda
Journal: Neuro-Oncology (2017)

BACKGROUND: Pediatric high grade glioma (pHGG) is a devastating cancer of the central nervous system. The prognosis of this most malignant form of brain tumor remains poor, largely due to the inherent resistance of pHGG to therapy, and inevitably leads to recurrence. Unfortunately, because recurrent glioma, or glioma remaining after conventional therapy, frequently has very different molecular characteristics from the original tumor in addition to a vastly different biological behavior, recurrent pHGG has proven exceedingly difficult to treat, with very few treatment options providing clinically meaningful outcomes. As part of the NCI Pediatric Preclinical Testing Program, several pediatric brain cancer cell lines, including the ones used in this study, were developed and characterized. However, to our knowledge, none have been utilized in development of a rat xenograft model of recurrent pHGG. METHODS: Pediatric glioblastoma cells (SJ-GBM2) were obtained from the Children’s Oncology Group Cell Culture and Xenograft Repository. Irradiated SJGBM2-10gy cells were generated by exposure to a total radiation dose of 10 Gy. Following irradiation, the resultant SJGBM2-10gy cells were tested for cell viability and allowed to reach confluence prior to stereotactical implantation into the right striatum of male athymic rats. RESULTS: Less than 1% of total cells survived radiation. Both irradiated and parental cell lines formed tumors in 100% of the animals following intracranial implantation. Irradiated SJGBM2-10gy cells exhibited a more aggressive tumor growth than the parental SJ-GBM2 cell line, resulting in mortality on average 14 days earlier. Histopathological analysis is underway and more advanced imaging studies are planned. CONCLUSION: To our knowledge this is the first report of an intracranial rat xenograft model mimicking recurrent pHGG using irradiated cell lines. It represents a robust and expedient in vivo model for studying recurrent pHGG biology.
Racial Disparity in Drug Utilization Among Multiple Myeloma Patients: A SEER Medicare Analysis
Authors: Sikander Ailawadhi, Ryan D Frank, Richa Menghani, Mayank Sharma, M'hamed Temkit, Shumail M. Paulus, Nandita Khera, Shahrukh K. Hashmi, Pooja Advani, Abhisek Swaika, Aneel Paulus, Vivek Roy, Gerardo Colon-Otero, Asher A. Chanan-Khan
Journal: Blood (2016)
Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study
Authors: Oliver J Brady, Hannah C Slater, Peter Pemberton-Ross, Edward Wenger, Richard J Maude, Azra C Ghani, Melissa A Penny, Jaline Gerardin, Lisa J White, Nakul Chitnis, Ricardo Aguas, Simon I Hay, David L Smith, Erin M Stuckey, Emelda A Okiro, Thomas A Smith, Lucy C Okell
Journal: The Lancet Global Health (2017)

Mass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.We collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.The models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.Mass drug administration has the potential to reduce transmission for a limited time, but is not an effective replacement for existing vector control. Unless elimination is achieved, mass drug administration has to be repeated regularly for sustained effect.Bill & Melinda Gates Foundation.
Language readiness and learning among deaf children
Authors: Anne E Pfister, Daniel H Lende
Journal: Behavioral and Brain Sciences (2017)

Abstract We applaud Goldin-Meadow &amp; Brentari's (G-M&amp;B's) significant efforts to consider the linkages between sign, gesture, and language. Research on deaf children and sign language acquisition can broaden the G-M&amp;B approach by considering how language readiness is also a social phenomenon and that distinctions between imagistic and categorical formats rely on language practices and contexts.
High court judge quashes decision to strike off gynaecologist for dishonesty
Authors: Clare Dyer
Journal: BMJ (2017)

A medical practitioners tribunal which decided that a doctor was dishonest in treating a couple who were friends for free and later sending them an invoice, had reached a conclusion that “no reasonable tribunal could conceivably have reached,” a High Court judge has ruled.

Mr Justice Collins quashed the decision, made last December, to strike consultant gynaecologist Joseph Onwude from the medical register, subject to his right of appeal.1

Collins held that the tribunal’s decision that …
IMMU-04. HIGH FREQUENCY OF PROGRAMMED DEATH LIGAND 1 EXPRESSION IN PEDIATRIC CENTRAL NERVOUS SYSTEM TUMORS
Authors: Farha Sherani, Benjamin Liechty, Matija Snuderl, Sharon Gardner
Journal: Neuro-Oncology (2017)

Tumors escape immune surveillance by activating the inhibitory checkpoint programmed death 1 (PD-1)/programmed death ligand 1 (PDL-1) pathway to attenuate T cell responses and render them functionally exhausted. Antibodies targeting the PD-1/PDL-1 immune checkpoint pathway rescue anti-tumor function and have shown remarkable success in treating several adult cancers, with PDL-1 positive tumors demonstrating the most objective responses. There are limited data on PDL-1 expression in pediatric central nervous system (CNS) tumors. We evaluated PDL-1 expression in formalin-fixed, paraffin-embedded tumor specimens from 37 pediatric patients via immunohistochemistry. We used a rabbit anti-human monoclonal anti PDL-1 antibody by Spring BioSciences (M4424). PDL-1+ positivity was quantified as either <1%, 1–5%, 6–25%, 26–50% or >50% membrane staining. Tumors with >5% membrane staining were scored as positive. The proportion of PDL-1+ tumors was 100% for anaplastic pleomorphic xanthoastrocytoma (4/4), 80% for pilocytic astrocytoma (4/5), 67% for glioblastoma (4/6), 67% for ependymoma (2/3), 50% for anaplastic astrocytoma (1/2), 50% for primitive neuroectodermal tumor (1/2), 25% for medulloblastoma (1/4), and 0% for pineoblastoma (0/6). Of the remaining 5 tumors tested, 2 were PDL-1+ (anaplastic ganglioglioma, anaplastic oligodendroglioma), and 3 were negative for PDL-1 expression (recurrent astrocytoma, atypical choroid plexus papilloma, choroid plexus carcinoma). Interestingly, all glioblastoma tumors (4/4) had >50% PDL-1 expression, whereas all pineoblastoma (6/6) tumors had <1%, showing trends even in a small cohort. Overall, of the 37 tumors tested, 51% (19/37) were PDL-1+. Our study reveals strong evidence for an active PD-1/PDL-1 pathway in a high proportion of pediatric CNS tumors. Our next steps are to increase sample size, and evaluate the tumor microenvironment by quantifying tumor infiltrating lymphocytes and regulatory T cells in pediatric CNS tumors to provide support for expediting this targeted immunotherapy in children.
LGG-05. SINGLE-CELL RNA SEQUENCING OF PEDIATRIC LOW-GRADE GLIOMAS REVEALS INTRATUMORAL HETEROGENEITY
Authors: Brenton Paolella, Pratiti Bandopadhayay, Guillaume Bergthold, Alex Shalek, Kristine Pelton, Shakti Ramkissoon, Claire Sinai, Hayley Malkin, Zach Herbert, Yu Sun, John Alberta, Meredith Brown, John Daley, Suzan Lazo-Kallanian, Liliana Goumnerova, Mark Kieran, Keith Ligon, Rameen Beroukhim
Journal: Neuro-Oncology (2017)

Pediatric low-grade gliomas (PLGGs) are slow growing tumors that result in neurologic defects due to both disease burden and therapeutic complications. We have previously performed FFPE bulk expression profiling on more than 150 PLGGs that revealed substantial tumor heterogeneity on the level of gene expression. One limitation of bulk expression profiling is the presence of normal cells along with tumor cells that confound the overall expression signal in a tumor. We therefore analyzed gene expression profiles of individual cells from dissociated tumors obtained by flow cytometry. Single cells from freshly dissociated PLGGs were sorted by flow cytometry into distinct populations using the glial progenitor marker A2B5. Individual A2B5-negative and A2B5-positive cells were processed by ultra-low input RNA sequencing. We analyzed between 30–283 cells per tumor. RNA-sequencing of bulk sorted populations were processed in parallel as controls. We observed high correlations between the bulk control populations and the average of the single cell populations derived from the same tumor at the RNA expression level. In all tumors analyzed, consensus clustering distinguished two major sub-populations of single cells; one predominantly composed by A2B5 positive cells and the other exclusively by A2B5 negative cells. Principle component analyses also demonstrated distinct clustering between A2B5-positive and A2B5-negative cells. These data suggest that intratumoral heterogeneity observed at the population level can be reduced by analyzing individual cells. Importantly, we can identify specific gene expression signatures that distinguish these populations to enhance our understanding of PLGGs. Single cell transcriptome profiling of freshly dissociated PLGGs revealed unique subpopulations of cells within these tumors. A2B5 positive cells generally cluster separately from A2B5 negative cells, suggesting that key differences exist between cells within individual PLGGs. Further analysis may reveal biological pathways specifically operative in PLGG tumor cells or non-transformed cells that can inform our understanding of PLGGs.