tbuckley/cabot-search huggingface dataset:
PHY906 as a broad-spectrum enhancer in cancer therapy: Clinical and preclinical results in hepatocellular carcinoma
Authors: Shwu-Huey Liu, Angeline Foo, Zaoli Jiang, Rajendra Marathe, Jing Guan, Tah-Mun Su, Robert Tilton, Yun Yen, Michal Rose, Samuel So, Edward Chu, Yung-Chi Cheng
Journal: Cancer Research (2006)

2145  PHY906, a traditional Chinese botanical formulation, was first described 1800 years ago for common gastrointestinal distress. Currently, PHY906 is being developed for FDA approval as a botanical prescription medicine offering a new approach to cancer supportive care. The preclinical data indicates that PHY906 can reduce chemo-induced gastrointestinal toxicity while simultaneously enhancing the therapeutic efficacy of a broad-spectrum of common anticancer agents, including CPT-11, 5-FU, capecitabine, oxaliplatin, VP-16, taxol, and gemcitabine in a variety of tumor-implanted in vivo animal models. The mechanism of PHY906 antitumor activity is multifarious, including inhibitory activities of NF-κB, matrix metalloproteases (MMPs), multi-drug resistant protein (MDR), and CYP450 and modulation of numerous cytokines. Possible mechanisms of action for the reduction of gastrointestinal toxicity are the inhibition of Tachykinin NK-1 and Opiate δ receptors and modulation of inflammatory cytokines. A phase I/II, multicenter, open-label, dose-escalation, safety and efficacy study of PHY906 plus capecitabine in patients with unresectable hepatocellular carcinoma is presently underway. The main objective of phase I is to define the safety, tolerability, and effective dose of PHY906 when co-administered with capecitabine. Three doses have been studied. Cohort I: PHY906 (1000mg, bid, D1-4 and 8-11) plus capecitabine (1000 mg/m2,bid, D1-14); cohort II: PHY906 (600mg, bid, D1-4 and 8-11) plus capecitabine (750 mg/m2, bid, D1-14); and cohort III: PHY906 (800mg, bid, D1-4 and 8-11) plus capecitabine (750 mg/m2, bid, D1-14). The cohort I dose regimen has resulted in unacceptable dose-limiting toxicities while the dosing in cohorts II and III were both well tolerated. Stable disease after two cycles of study-drug treatment for cohorts II (N=4) and III (N=6) are 75% and 67%, respectively. The median time to disease progression (TTP) is 26.5 weeks and the median survival time is greater than 44.5 weeks for Cohort II. The majority of the patients in Cohort III remain on study. The primary objective for the current phase II is determining the objective antitumor response rate while the secondary objectives are determining TTP, overall survival time, and quality of life (QoL). While clinical trials address efficacy and safety of the drug, chemical and biological analytic methods have been developed to address drug consistency and quality control. Comprehensive molecular resolution chemical fingerprints utilizing a three-dimensional LC/MS profile and a sensitive cellular bioresponse genomic profile to generate a quantitative signature pattern for comparing and confirming batch-to-batch similarity of study drug. These studies offer a modern approach to the study of ancient botanicals that may represent novel regimens for cancer treatment.
Toxi-infections alimentaires collectives à Norovirus, liées à la consommation d'huitres de l'étang de Thau, France, décembre 2002
Authors: A Doyle, D Barataud, A Gallay, J M Thiolet, S Le Guyaguer, E Kohli, V Vaillant
Journal: Eurosurveillance (2004)

En janvier 2003, l'Institut de Veille Sanitaire a ete alerte de l'existence de foyers de gastroenterites vraisemblablement associes a la consommation d'huitres elevees dans l'etang de Thau, au sud de la France. Au cours de la meme periode, une epidemie de plus de 200 cas, associee a des huitres en provenance de l'etang de Thau etait declaree en Italie. Une enquete a ete menee pour determiner la source et le vehicule de ces epidemies. Une analyse descriptive des foyers declares en France, une analyse microbiologique des prelevements de selles et d'huitres, un genotypage des norovirus, ainsi qu'une investigation environnementale de l'etang de Thau ont ete menes. Une etude de cohorte retrospective a egalement ete realisee parmi les personnes ayant participe a des repas familiaux a Paris. 
D'apres les resultats de l'analyse descriptive, treize foyers familiaux dans quatre departements (69 cas) ont pu etre attribues a la consommation des huitres de Thau. Les huitres, distribuees sur le lieu de travail et puis consommees lors de 14 repas en famille entre le 19 et le 24 decembre ont cause une autre epidemie. Le taux d'attaque etait de 21/36 (58%) chez ceux qui avaient consomme des huitres et de 0/22 chez ceux qui n'en avaient pas consomme (p=0.00002). Des norovirus (genogroupes I et II) ont ete identifies dans les prelevements de selles de quatre foyers d'infection, et dans les huitres de trois foyers d'infection (dont Paris). Les investigations environnementales ont mis en cause les fortes precipitations, le debordement des stations d'epuration, et la contamination fecale de l'etang de Thau au mois de decembre.
Les huitres de l'etang de Thau ont ete responsables d'un nombre de foyers de gastroenterites a norovirus au cours de l'hiver 2002 en France et en Italie. Une demande officielle de purification des huitres avant distribution a ete prise au vu des niveaux eleves de E.Coli retrouves dans l'eau de l'etang et dans les coquillages. Cette mesure n'a pas pu etre mise en oeuvre en raison d'un equipement insuffisant. Cette investigation a permis de changer la maniere dont les zones d'elevage des coquillages sont classees en France.
GENE-02. PERIPHERAL BLOOD DNA METHYLATION PROFILES IDENTIFY IDH1/2 MUTATION STATUS IN ADULTS WITH DIFFUSE GLIOMA
Authors: Andreas Kloetgen, Jonathan Serrano, Seema Patel, Christopher Bowman, Guomiao Shen, David Zagzag, Matthias Karajannis, John Golfinos, Dimitris Placantonakis, Aristotelis Tsirigos, Andrew S Chi, Matija Snuderl
Journal: Neuro-Oncology (2017)

Identification of IDH1/2 mutations and association with better outcome revolutionized diagnosis and management of patients with gliomas. Liquid biopsy allows identification of driver mutations from blood; however detection of circulating tumor DNA or circulating tumor cells from patients with brain tumors is difficult due to the low amount of tumor material in the peripheral blood. We hypothesized that brain tumors alter the epigenetic profiles of circulating leukocytes and sought to identify DNA methylation patterns in peripheral blood that would identify molecular subtypes of glioma. We analyzed brain tumors and matched whole peripheral blood collected in EDTA tubes from 63 patients with newly diagnosed diffuse glioma and whole peripheral blood from 40 individuals with no known history of brain tumor. Tumor IDH1/2 mutation status was analyzed using next-generation sequencing and circulating leukocyte genomic DNA methylation was analyzed using Illumina 850k EPIC array. Methylation data were analyzed with the R Bioconductor package minfi, including quality control, data normalization and differentially methylated CpG site analysis. Subsequent filtering was performed using a p-value cutoff = 0.01 and a minimal mean difference of the Beta-value of = 0.1. Peripheral blood methylation profiles of patients with brain tumors were distinctly different from controls. DNA methylation profiles from peripheral leukocytes identified a total of 222 differentially methylated CpG sites in males and 515 CpG sites in females between IDH mutated versus wild-type diffuse glioma patients. Blood DNA methylation distinguished patients with IDH mutant and wildtype diffuse gliomas with 98% accuracy, nearly perfectly separating groups by clustering. Diffuse gliomas induce epigenetic changes in the methylome of the circulating leukocytes. IDH wildtype and mutant gliomas can be distinguished with high accuracy by profiling the epigenome of circulating leukocytes. Our study demonstrates the potential of peripheral blood DNA methylation assessment for non-invasive diagnosis of brain tumors.
NCMP-01. SEIZURE CONTROL AFTER INITIAL PRESENTATION IN IDH MUTATED GLIOMA PATIENTS
Authors: Byram Ozer, Yvonne Bui, Daniela Markovic, Huytram Nguyen, Linda Liau, Phioanh Nghiemphu, Timothy Cloughesy, Albert Lai
Journal: Neuro-Oncology (2017)

A substantial portion of the care of glioma patients involves seizure control. The risk of seizure at presentation is most strongly associated with low grade gliomas, which are often IDH mutated, and some literature suggests that IDH mutation may be causative. However, little is known about long-term seizure control in gliomas and whether IDH status can help clarify seizure risk. To determine whether IDH status in gliomas is associated with long-term seizure control. A retrospective chart review of 1097 adult patients seen at UCLA and Kaiser Permanente Los Angeles between 1995 and 2015 was performed. A cohort of 874 patients possessed sufficient records to correlate IDH status with primary outcomes of seizure control, including seizures at presentation, time to first seizure, annual seizure burden, seizure medication usage, and clinical events in proximity to seizures. Seizure outcomes were analyzed with Kaplan-Meier and Cox Proportional Hazard Modeling using a competing risks model, while post seizure control was evaluated with multivariate linear regression modeling. 37% of IDH WT gliomas and 66% of IDH mutant gliomas presented with seizures, but the effect was strongly correlated with grade. Seizure at presentation (HR 2.1, p<0.001) and IDH status independently predict likelihood of disease-course seizure. Specifically, IDH WT tumors evidenced shorter time to seizure development (HR 1.3, p=0.05) and proximity to a clinical event such as progression or death (HR 1.5, p=0.03). IDH mutant gliomas had longer interval time until seizure and were less frequently associated with a clinical event, but instead were more likely associated with parameters of refractoriness once seizures developed. IDH WT gliomas more rapidly develop disease-course seizures, usually due to clinical progression, whereas IDH mutant gliomas occur more randomly and with higher refractoriness. This may help clinicians stratify seizure risk based on IDH status and seizure presentation history.
How to approach psychotic symptoms in a non-specialist setting
Authors: Musa Basseer Sami, David Shiers, Saqib Latif, Sagnik Bhattacharyya
Journal: BMJ (2017)

#### What you need to know



Fig 1  Puppet Schizophrene by Bryan Charnley (1949-1991), who had schizophrenia (www.bryancharnley.info). © The estate of Bryan Charnley, reproduced with permission



Identification of psychotic symptoms in non-specialist settings is key to initiating timely pathways to care. A systematic review of 30 observational studies of pathways to care of first-episode psychosis showed that first contact was more usually through a physician than through emergency services.1 This article is aimed at generalists, primary care physicians, and hospital doctors, who play a critical role and who require a low threshold for referral for specialist assessment, sometimes before diagnosis is certain.2

Prompt intervention is key to improving outcome. However, patients rarely present complaining of hallucinations or delusions. Concerns that something is not quite right may first be raised to the generalist by family members, friends, neighbours, and school teachers.1

In very early stages, perceptual abnormalities and thought disorder may not be apparent, nor delusions well formed. Features may include:

Hallmark features are increasing distress and decline in functioning.456

An overview of symptoms is shown in figure 2⇓. Psychosis maybe preceded by …
CSIG-19. FHL2 INTERACTS WITH EGFRVIII TO PROMOTE GLIOBLASTOMA GROWTH
Authors: Lili Sun, Qing Lan, Ming Li
Journal: Neuro-Oncology (2017)

Four-and-a-half LIM protein2 (FHL2) is a member of the LIM-only protein family, which plays a critical role in tumorigenesis. We previously reported that FHL2 is upregulated and plays an oncogenic role in glioblastoma (GBM), the most common and aggressive brain tumor. GBM is also marked by common mutations in the epidermal growth factor receptor (EGFR) gene, most notably the EGFRvIII mutation found in approximately 20–30% of GBM. Here we report in GBM cells that FHL2 physically interacts with EGFRvIII through its four and a half LIM domains. The expression of FHL2 increased EGFRvIII protein levels, and, importantly this effect was due to an increase in protein stability and not due to an increase in EGFR mRNA expression. In contrast, FHL2 knockdown using RNA interference reduced EGFRvIII and EGFR protein expression and the phosphorylation levels of EGFR and AKT. Consistently, the expression of EGFR is significantly lower in mouse FHL2-null astrocytes, and reintroduction of FHL2 is able to rescue EGFR levels. Functionally, targeting FHL2 inhibited EGFRvIII-promoted cellular proliferation and colony-forming cell production through increasing cell apoptosis. FHL2 silencing prevented tumor growth and significantly prolonged the survival time of the mice bearing EGFRvIII-expressing GBM cells. Clinically, FHL2 expression is positively correlated with EGFR expression in GBM patient specimens. Taken together, our results demonstrate that FHL2 interacts with EGFRvIII to regulate EGFRvIII-mediated glioma growth, which will help to understand the molecular pathogenesis of gliomagenesis and possibly to develop a novel approach to treat GBM with EGFRvIII.
Transcriptomic and morphophysiological evidence for a specialized human cortical GABAergic cell type
Authors: Eszter Boldog, Trygve E. Bakken, Rebecca D. Hodge, Mark Novotny, Brian D. Aevermann, Judith Baka, Sándor Bordé, Jennie L. Close, Francisco Diez-Fuertes, Song-Lin Ding, Nóra Faragó, Ágnes K. Kocsis, Balázs Kovács, Zoe Maltzer, Jamison M. McCorrison, Jeremy A. Miller, Gábor Molnár, Gáspár Oláh, Attila Ozsvár, Márton Rózsa, Soraya I. Shehata, Kimberly A. Smith, Susan M. Sunkin, Danny N. Tran, Pratap Venepally, Abby Wall, László G. Puskás, Pál Barzó, Frank J. Steemers, Nicholas J. Schork, Richard H. Scheuermann, Roger S. Lasken, Ed S. Lein, Gábor Tamás
Journal: Nature Neuroscience (2018)
P2.09-008 Usefulness of Immunohistochemistry in the Differential Diagnosis of Epithelioid Mesothelioma and Lung Squamous Cell Carcinoma
Authors: K. Kushitani, V. Amatya, Y. Okada, Y. Katayama, A. Mawas, Y. Miyata, M. Okada, K. Inai, T. Kishimoto, Y. Takeshima
Journal: Journal of Thoracic Oncology (2017)
Reduced Expression of Glutathione S-Transferase α 4 Promotes Vascular Neointimal Hyperplasia in CKD
Authors: Jinlong Luo, Guang Chen, Ming Liang, Aini Xie, Qingtian Li, Qunying Guo, Rajendra Sharma, Jizhong Cheng
Journal: Journal of the American Society of Nephrology (2017)

Neointima formation is the leading cause of arteriovenous fistula (AVF) failure. We have shown that CKD accelerates this process by transforming the vascular smooth muscle cells (SMCs) lining the AVF from a contractile to the synthetic phenotype. However, the underlying mechanisms affecting this transformation are not clear. Previous studies have shown that the α-class glutathione transferase isozymes have an important role in regulating 4-hydroxynonenal (4-HNE)-mediated proliferative signaling of cells. Here, using both the loss- and gain-of-function approaches, we investigated the role of glutathione S-transferase α4 (GSTA4) in modulating cellular 4-HNE levels for the transformation and proliferation of SMCs. Compared with non-CKD controls, mice with CKD had downregulated expression of GSTA4 at the mRNA and protein levels, with concomitant increase in 4-HNE in arteries and veins. This effect was associated with upregulated phosphorylation of MAPK signaling pathway proteins in proliferating SMCs. Overexpressing GSTA4 blocked 4-HNE-induced SMC proliferation. Additionally, inhibitors of MAPK signaling inhibited the 4-HNE-induced responses. Compared with wild-type mice, mice lacking GSTA4 exhibited increased CKD-induced neointima formation in AVF. Transient expression of an activated form of GSTA4, achieved using a combined Tet-On/Cre induction system in mice, lowered levels of 4-HNE and reduced the proliferation of SMCs. Together, these results demonstrate the critical role of GSTA4 in blocking CKD-induced neointima formation and AVF failure.
STEM-42. GENOME-WIDE CRISPR SCREENS IN BRAIN TUMOR INITIATING CELLS (BTICS) IDENTIFY POTENT SENSITIZERS OF CONVENTIONAL CHEMORADIOTHERAPY
Authors: Chirayu Chokshi, David Tieu, Parvez Vora, Chitra Venugopal, Katherine Chan, Amy Tong, Kevin Brown, Mohini Singh, Jason Moffat, Sheila Singh
Journal: Neuro-Oncology (2017)

Glioblastoma (GBM) is a highly aggressive and most common form of malignant primary brain tumor in adults (WHO grade IV). Despite surgical and adjuvant therapeutic interventions, including chemotherapy with the alkylating agent TMZ and cranial irradiation, GBM relapse is inevitable with a median survival of <15 months. Extensive intratumoral heterogeneity (ITH) in GBM is believed to be the leading cause of therapy resistance and disease relapse, suggesting that therapy acts as a selection pressure or bottleneck for tumor evolution from minority cell populations present at time of initial diagnosis. Recently, the advent of CRISPR-Cas9 technology has led to the development of genome-wide libraries of sgRNAs capable of introducing insertion-deletion (indels) within exons, leading to a frameshift mutation two-thirds of the time. Here, we present the first genome-wide CRISPR-Cas9 knockout screen in patient-derived GBM BTICs aimed to discover synthetic lethal sensitizers of conventional chemoradiotherapy. Briefly, we performed genome-wide CRISPR-Cas9 screens in treatment-naïve GBM BTICs subjected to in vitro chemotherapy with TMZ and irradiation. By comparing sgRNA dynamics at each doubling period, we were able to identify potent sensitizer genes exclusive to combined chemoradiotherapy, and not TMZ or irradiation alone. Candidate sensitizer genes were validated in an arrayed format to evaluate impact on GBM BTIC self renewal, proliferation, and sensitivity to TMZ and radiation. We aim to further validate these sensitizers of conventional chemoradiotherapy by performing a focused CRISPR-Cas9 genetic screen in our patient-derived xenograft model of treatment-refractory GBM. Ultimately, adjuvants targeting sensitizer genes could greatly enhance the impact of conventional chemoradiotherapy in GBM patients, leading to an increase in patient survival.
ACTR-52. CLINICAL IMPACT OF TERT PROMOTER DETECTION IN CIRCULATING CELL-FREE DNA OF PATIENTS WITH GLIOBLASTOMA – A PILOT STUDY
Authors: Tareq Juratli, Sebastian Stasik, Sven Richter, Amir Zolal, Gabriele Schackert, Dietmar Krex, Christian Thiede
Journal: Neuro-Oncology (2017)

Detection of circulating cell-free tumor-derived DNA (cfDNA) has been shown to be of clinical value in monitoring cancer treatment. Having in mind that somatic TERT promoter (TERTp) mutations are clonal and frequent in IDH-wild-type glioblastoma (GBM), we conducted a pilot study to assess the clinical impact of TERTp-mutant cfDNA detection in CSF and plasma in GBM patient. A total of 30 GBM patients were prospectively enrolled. Matched plasma and CSF samples were collected before tumor resection in all patients. Using the IonTorrent PGM semiconductor sequencing platform, we analyzed the collected cfDNA and matched tumor DNA samples for hotspot mutations in the promoter region of TERT (C228 and C250). Logistic regression analysis was performed to evaluate the clinical impact of the variant allele frequency (VAF) of TERTp-mutant cfDNA in predicting patients’ overall (OS) and progression-free (PFS) survival. 25 patients had a TERTp-mutant GBM. The matched TERTp-CSF-derived cfDNA was successfully detected with 100% specificity and 92% sensitivity (23 patients). The median VAF of the CSF-cfDNA was 20.3% (0.08%-70.3%). In the plasma, the sensitivity of TERTp-mutant cfDNA detection was far lower (12%). There was a statistically significant linear relationship between the CSF-VAFs and PFS (R2 = 0.1615; p=0.0418). Strikingly, in the multivariate analysis, the median VAF for CSF-cfDNA was the best predictor for PFS (p=0.007, HR=4.1, 95% CI: 1.4–11.3) and OS (p=0.013, HR=4.7, 95% CI: 1.3–15.8). In contrast, all other included clinical parameters (age, tumor volume, extent of resection, MGMT promoter methylation status) did not appear as an independent prognostic factor. We propose that the detection and accurate quantification of TERTp-mutant CSF-cfDNA in GBM patients is feasible with a high sensitivity and specificity. Additionally, although generated on a small cohort, our findings indicate that pre-resection CSF-derived cfDNA might be a suitable marker to predict survival in TERTp-mutant GBM patients.
PATH-43. SHAPE-SHIFTERS IN GLIOBLASTOMA – SECONDARY GLIOSARCOMAS DIFFER BY TUMOR CELL INTRINSIC PROPERTIES INCLUDING AN INFLAMMATORY PHENOTYPE
Authors: Barbara Kiesel, Thomas Roetzer, Johanna Klughammer, Bernhard Baumann, Julia Furtner, Nadine Peter, Christine Marosi, Georg Widhalm, Adelheid Woehrer
Journal: Neuro-Oncology (2017)

Gliosarcoma constitutes a rare variant of IDH-wildtype glioblastoma that is characterized by a biphasic glial and mesenchymal differentiation. Gliosarcoma can be further classified into primary and secondary, with secondary types evolving from classic glioblastoma after receipt of therapy. They putatively show a worse prognosis. We screened a population-scale multicenter cohort of patients with glioblastoma, who underwent second surgery at time of relapse in order to identify patients with secondary gliosarcoma. We then integrated patient-level clinical data with quantitative pathology- and MR imaging-derived parameters, as well as DNA methylation patterns. Based on a total of 116 patients of glioblastoma with matched tissues at diagnosis and relapse, we observed a sarcoma-like shift in 12 individuals (9.5%, all treated with RT-TMZ). In all cases, the sarcomatous component with spindle-shaped tumor cells dominated as evidenced by increased morphometric tumor cell nuclear eccentricity (p<0.001). Nuclear eccentricity and its variability were predicted from DNA methylation patterns (ROC AUC=0.83, ROC AUC=0.76) while no differences in MR-imaging based volumes were noted. The sarcoma-like shift was accompanied by increased tumor cell proliferation (p=0.017) and relative non-necrotic tumor areas (p=0.014) upon relapse. In addition, an enhanced inflammatory phenotype including higher levels of CD8+ (p=0.008) and CD3+ (p=0.038) lymphocytes were present. Overall, median progression-free survival was significantly shorter (11 months, p=0.03) and overall survival tended to be unfavorable (24 months, p=0.11) as compared with glioblastomas that remained stable. In summary, we observed a shift towards a sarcoma-like phenotype in roughly 10% of patients with glioblastoma. This shift in morphology was evidenced by enhanced nuclear eccentricity that was predictable from DNA methylation patterns. Secondary gliosarcoma was characterized by higher tumor cell proliferation and immune infiltration and patients showed a significantly shorter time to progression.