tbuckley/cabot-search huggingface dataset:
Getting the Lay of the Land: Human and Animal Evidence on Environmental Chemicals and Autism
Authors: Wendee Nicole
Journal: Environmental Health Perspectives (2019)

Autism spectrum disorder (ASD)-a neurobehavioral condition with multiple levels of expression and severity-touches the lives of many individuals and their families.In the United States alone, ASD diagnoses have risen from 1 in 150 in 2002 to 1 in 59 in 2014. 1 Estimated costs for medical care, lost parental work time, and special education range from $11.5 billion to $60.9 billion. 1 Although the reasons for this climb are not completely understood, "the increase in the prevalence of autism in such a short span of time is certainly alarming," says Katherine Pelch, senior scientist at the Endocrine Disruption Exchange.Pelch is lead author of a new scoping review on autism and environmental chemicals published in Environmental Health Perspectives. 2 The review comprehensively combs the literature for both human and animal studies looking at ASD and early-life environmental exposures-the most vulnerable window of time for the developing brain.The authors' goal was to identify gaps in the research, propose specific exposures for systematic review with respect to ASD, and recommend future research priorities.
Syndecan-Mediated Ligation of ECM Proteins Triggers Proliferative Arrest of Disseminated Tumor Cells
Authors: Tsukasa Shibue, Ferenc Reinhardt, Robert A. Weinberg
Journal: Cancer Research (2019)

Systemic dissemination of tumor cells often begins long before the development of overt metastases, revealing the inefficient nature of the metastatic process. Thus, already at the time of initial clinical presentation, many patients with cancer harbor a myriad disseminated tumor cells (DTC) throughout the body, most of which are found as mitotically quiescent solitary cells. This indicates that the majority of DTCs fail, for still unknown reasons, to initiate rapid proliferation after entering foreign tissue, which likely contributes significantly to the inefficiency of metastasis formation. Here, we showed that extracellular matrix (ECM) components of the host parenchyma prevented proliferation of DTCs that had recently infiltrated foreign tissue by binding to syndecan receptors expressed on the surface of these cells. This led to the recruitment of the Par-3:Par-6:atypical PKC protein complex, a critical regulator of cell polarity, to the plasma membrane and release of Par-1 kinase into the cytosol. Cytosolic Par-1 bound, phosphorylated, and inactivated KSR scaffolding proteins ultimately inhibited Ras/ERK signaling and, in turn, cell proliferation. Inhibition of the syndecan-mediated signaling restored the proliferation of otherwise dormant DTCs, enabling these cells to efficiently colonize foreign tissues. Intriguingly, naturally aggressive cancer cells overcame the antiproliferative effect of syndecan-mediated signaling either by shutting down this signaling pathway or by activating a proproliferative signaling pathway that works independent of syndecan-mediated signaling. Collectively, these observations indicate that the proliferative arrest of DTCs is attributable, in part, to the syndecan-mediated ligation of ECM proteins. SIGNIFICANCE: This study identifies a novel signaling pathway that regulates the proliferative dormancy of individual disseminated tumor cells.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/23/5944/F1.large.jpg.
Comparative analysis of molecular aberration in different genders for identification of key pathways in hepatocellular carcinoma.
Authors: Li Yu, Feng Tieshan, Lifeng Li, Shifu Chen, Liu Xiaoliang
Journal: Journal of Clinical Oncology (2019)

e23192 Background: The incidence rate of hepatocellular carcinoma (HCC) varies significantly between genders, being higher in men than in women. While the molecular mechanisms remain unexplored, we systematically analyzed the gene expression and SNV signature to identify key molecular aberrations and pathways. Methods: Gene expression and simple nucleotide variation data of 407 HCC patients with HCC including 140 females and 267 males were collected. We identified genes with differential mutation frequency in two cohorts using Fisher’s exact test (p-value &lt; 0.05), and Deseq2 to identify differential expression genes (FDR &lt; 0.05 and fold change &gt; 2). Enrichment analysis was applied using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Reactome database (p adjust &lt; 0.05). Results: In total, 103 genes with differential mutation frequency in two cohorts were identified. Of these genes, 57 genes were differentially expressed, and the number of up-regulated genes in males and females were 21 and 36, respectively. The genes that show significant up-regulation in males are KDM5D and ANKFN1 which have the log 2 (fold change) of 7.49 and 4.45. The genes that show significant up-regulation in females are SYT13 and SCD5 which have the log 2 (fold change) of 2.33 and 2.29. The result of enrichment analysis showed that the up-regulated genes in males and females were involved in different biological pathways. In males, the up-regulated genes mainly participated in the PPAR signaling pathway. In females, the up-regulated genes mainly participated in the Rho GTPase cycle, regulation of insulin secretion and integration of energy metabolism. Conclusions: In this study, 57 genes with differential mutation frequency and differential expression between males and females with HCC were identified based on TCGA dataset. Enrichment analysis result indicated that these genes are mainly involved in signaling pathways relevant to carcinogenesis and metabolism.
P14.43 Histone H3F3A and HIST1H3B K27M mutations in pediatric high-grade gliomas: the Florentine experience
Authors: M Guidi
Journal: Neuro-Oncology (2019)

Abstract Background Pediatric high- grade gliomas (HGGs) represent a malignancy with a poor survival. The genetic analysis of these entities has identified useful mutations for an improved prognostic framing. The research of mutations in all H3 histone variants (HIST1H3B and H3F3A) could be usefull to define tumors with different prognosis and phenotypes inasmuch they seems to drive two distinct oncogenic programmes. MATERIALS E METHODS We performed a retrospective analysis of pediatric HGGs. We evaluated the type of histone H3 mutated and we performed a meta-analysis comparing our results with literature data. RESULTS We evaluated 41 cases of pediatric HGGs (median age of patients: 7 years old, range: 0–32):): 32 anaplastic astrocytoma (78,5%), 9 glioblastoma multiforme (25,9%), We have researched the K27M mutations in the distinct histone H3 variants (i.e. HIST1H3B and H3F3A). The mutation H3F3A K27M was found in 6 patients instead HIST1H3B K27 mutations was found in a single patient with GBM. All the patients with H3F3A K27M mutation had a progression disease but without statistical correlation (p:0,07). They had a worse prognosis with a median overall survival of 15,5 months (p: 0.0014) versus wild type patients (not reached). H3.3K27M mutation status is a signiﬁcant predictor of OS with a hazard ratio of 4.499 (p = 0.0001). The patient with HIST1H3B K27 mutation died after first line of therapy. Conclusions Due to the low incidence of the mutation HIST1H3B in our series we can’t define the difference with two variants. However, the research of K27M mutation in HGGs has diagnostic and prognostic role. The role of histone H3 mutated could predict the outcome in HGGs patients and it could give us more informations compared to the clinic and radiological characteristic of the tumors.
P04.18 Management of diffuse gliomas using hypnosis-aided awake surgery: oncological and functional preliminary results in a series of 16 cases
Authors: T Picart, G Pardey Bracho, R Ameli, L Berner, L Thomas, S Cartalat, J Honnorat, F Ducray, J Guyotat
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Awake resection of diffuse gliomas aims to find a tailored onco-functional balance for each patient. Hypnosis represents an innovative technique able to optimize the comfort and well-being of the patient during such procedures. The aim of the present study is to analyse the oncological and functional outcome in a cohort of patients operated on with hypnosis-aided awake surgery. MATERIAL AND METHODS All consecutive adult patients that underwent hypnosis-aided resection for a diffuse glioma between January 2018 and January 2019 were recorded. Neurological and cognitive status were assessed preoperatively and at 3 months postoperatively. Extent of tumor resection was quantified by a radiologist on magnetic resonance imaging. RESULTS Sixteen patients (6 males and 10 females), with a mean age of 39 years, were included. Gliomas were revealed by epileptic seizures (62.5%), motor deficit (6.25%) or incidentally discovered (31.25%) and were either located in the right hemisphere (50%) or in the left hemisphere (50%), with a mean initial volume of 42 mL. Histologically, there were six grade II-astrocytomas, three grade III-astrocytomas, five grade II-oligodendroglioma, one grade III-oligodendroglioma and one ganglioglioma. Under HAS, the awake-time after the anaesthesia drugs stop was short, because low doses of drugs were required thanks to the hypnotic state. All patients were able to reliably performed the different tests until functional subcortical limits were reached. Postoperative magnetic resonance imaging showed complete resection in 8 cases (50%), subtotal resection in 2 cases (12.5%) and partial resection in 6 cases (37.5%), with a mean resection rate of 84.6%. At 3 months after surgery, there was only a new motor deficit (6.25%). The language and neuropsychological assessments were improved in 7 patients (43.75%), stable in 7 patients (43.75%) and deteriorated in some tests in 2 patients (12.5%). After surgery, no patient reported negative emotion concerning the awake glioma resection and all patient declared being ready for a second awake resection in the future, if indicated. CONCLUSION According to these preliminary results, hypnosis-aided awake resection of diffuse gliomas appears to be safe and effective from an onco-functional viewpoint and parallelly contributes to decrease intra-operative pain, anxiety and major discomfort.
The most troublesome aspects of quality of life for people with advanced cancer in a supportive care trial
Authors: A. K. Nowak
Journal: Journal of Clinical Oncology (2006)

18527 Background: ZEST is a placebo-controlled trial of sertraline for people with advanced cancer who feel depressed, anxious or tired but do not have a clear indication for antidepressants. We describe here the aspects of quality of life (QL) rated most troublesome at baseline by the first 150 subjects. Methods: Subjects completed a battery of QL questionnaires including the CES-D, HADS, FACT-G, FACT-Fatigue, and the Patient Disease and Treatment Assessment Form (Pt DATA Form). The Pt DATA Form assesses pertinent symptoms and concerns using 40 single items with a uniform response scale from 0 (no trouble at all) to 10 (worst I can imagine). Test-retest reliability was assessed with the intraclass correlation coefficient (ICC). Convergent validity was assessed by testing correlations between single items from the PT DATA Form and the corresponding, validated, multi-item scales. Results: The median age was 66 (IQR 59 to 73); median Karnofsky Perfomance Status was 80 (IQR 70 to 90); 63% were male; commonest primaries were colorectal (17%), lung (16%), prostate, (14%), breast (13%), and gynaecologic (10%). The aspects rated worst (mean score, proportion scoring &gt;3) were: Fatigue (5.5, 90%), Problems with sex (4.1, 51%), Trouble sleeping (3.6, 49%), Drowsiness (3.5, 54%), Not feeling myself (3.5, 51%), Pain (3.4, 45%), Shortness of breath (3.4, 47%), Problems doing what I wanted (3.1, 45%), Anxiety (3.0, 40%), Depression (2.7, 36%), Dry mouth (2.7, 38%), Trouble concentrating (2.7, 30%), Irritability (2.6, 32%), Altered sense of taste (2.5, 34%), Difficulty walking (2.4, 32%), and Constipation (2.1, 24%). Mean scores were higher in men than women for Problems with sex (5.0 v 2.4, p &lt; 0.001); and, in subjects aged 65 or younger for Hair loss (2.4 v 1.1, p = .01). There were no other significant differences by gender or age. Correlations supported the validity of the single item scales for depression, anxiety, fatigue; and for physical, emotional and overall well-being. The test-retest reliability of the Pt DATA Form was good (ICC &gt;0.5 for 34 of 40 items). Conclusions: Pertinent aspects of QL were validly measured with single item scales. Insomnia, dry mouth, altered sense of taste and irritability were more troublesome than many other, better studied symptoms. No significant financial relationships to disclose.
P11.25 Assessing electrical properties of cells as predictive marker for patient-specific TTFields response and optimal frequency
Authors: A Kinzel, E Zeevi, K Gotlib, C Wenger, A Naveh, Z Bomzon, E Kirson, U Weinberg, Y Palti
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Tumor treating fields (TTFields) are currently approved for the treatment of glioblastoma multiforme (GBM, using 200 kHz), and being tested in other tumor types such as non-small cell lung cancer and brain metastases occurring in this indication (LUNAR and METIS trials, using 150 kHz). Response to TTFields in cancer cells was empirically shown to be frequency-dependent specific for cell type; however, there are no markers available predicting optimal frequency or response in different cancer types or individual patients to date. There is evidence indicating electrical properties determine the optimal anti-mitotic frequency. This study analyzed the correlation of electrical properties of cells with their optimal TTFields frequency and sensitivity using the 3DEP reader (LabTech) to determine the electrical properties with the help of Dielectrophoresis (DEP) force. With this technique, cell movements within electric fields of different frequencies can by analyzed based on the physical effect of DEP, exercising a force on polarizable particles inside a non-homogeneous electric field. MATERIAL AND METHODS We used the 3DEP reader to obtain baseline properties (permittivity and conductivity) of 17 different cell lines of several tumor types. The resulting curves were analyzed by a 2-way ANOVA. Additionally, we determined the optimal frequency for maximum cytotoxic effect for each cell line using the inovitroTM system and eventually compared with the detected electrical properties. RESULTS We found cell lines with an optimal TTFields frequency of 150 kHz (corresponding to cells with a membrane capacitance in the lower range of the observed 3DEP curves, n=9) to possess significantly different (p&lt;0.001) electrical properties from cells with an optimal TTFields frequency of 200 kHz (n=8). According to the curve differences in the lower frequency range, the measure of membrane capacitance served as a good predictor for TTFields response. CONCLUSION This study showed a correlation of cell membrane capacitance and optimal TTFields frequency and response. Our results provide a substantial rationale for further studies investigating the predictive potential of electrical properties of tumor cells as a measure for the optimal frequency and sensitivity to TTFields in individual patients.
Challenges of Suicide Outcomes Ascertainment in Administrative Claims Databases—Reply
Authors: David A. Brent, Kwan Hur, Robert D. Gibbons
Journal: JAMA Psychiatry (2019)

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P14.45 Primary diffuse large B-cell CNS lymphoma over 80 years: an analysis of 110 patients from the french Oculo-Cerebral Lymphoma (LOC) network
Authors: A MAAREK, D Maucort-Boulch, C Houillier, K Hoang-Xuan, C Soussain, H Ghesquières
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND in large unselected series, the median age of Primary CNS Lymphoma (PCNSL) patients (pts) is about 70 years. In one USA cancer registry study for PCNSL patients older than 65 years, 14% of them are older than 80 years. Data on clinical characteristics, therapeutical management, toxicity of treatment and outcome of these very elderly pts are limited. MATERIAL AND METHODS we reviewed PCNSL pts aged of 80 years or older included in the database of the French Oculo-Cerebral lymphoma (LOC) network. From January 2011, this network prospectively recorded all newly diagnosed PCNSL from 22 regional expert centers in France. RESULTS 110 pts with a DLBCL PCNSL aged of 80 years or older were diagnosed between January 2011 and January 2018 representing 8% of pts available in the LOC database. The clinical characteristics were as follows: 63% of females; median age: 83y (80–92); performance status (PS) ≥3, 55% of pts. Median creatinine clearance (CKD.EPI) was 70ml/min. Treatment was initiated either by a neuro-oncology or a hematology team in 35% and 65% of cases, respectively. First line treatment was high-dose (HD) methotrexate (MTX) based chemotherapy (CT) in 85 pts (77%), other chemotherapy regimen in 13 pts (12%) and palliative care in 12 pts (11%). Interestingly, no difference of distribution for the main clinical and biological characteristics was observed between these three groups. After first-line induction chemotherapy, response rate for evaluable patients (n=85) were as follows: 37% of complete response, 9% of partial response, 54% of stable or progressive disease. Rituximab was used in combination with CT in 53/98 treated pts (54%). For toxicity, among the 351 infusions performed for the 85 pts who received MTX-based CT, grade 3–4 toxicities were: 46% of any events, 15% of infection, 13% of cytopenia, 11% of acute renal failure and 8% of elevated liver enzymes. 13% of pts presented toxic death. Median progression free survival (PFS) and overall survival (OS) were 5 months and 8 months, respectively. Pts treated with MTX-based CT had a significantly prolonged PFS and OS. In the univariate analysis performed for the 85 pts treated with MTX-based CT, no initial clinical and biological influenced PFS or OS. Intravenous rituximab used in first line therapy significantly improved PFS and OS. CONCLUSION in this large series of consecutive PCNSL pts aged of 80y or over prospectively recorded in a national database, we showed that the prognosis remains poor with major toxicity under conventional treatment. No clinical predictor of survival was highlighted in our series. Patients initially treated with MTX-based CT in combination with rituximab had an improved outcome. The development of target and innovative therapies is needed for this category of patients representing 8% of all PCNSL in the database of the LOC network.​
PL1.2 Multiparametric assessment of factors influencing 2 HG accumulation in diffuse brain gliomas
Authors: L Nichelli, F Branzoli, R Valabregue, L Capelle, C Ottolenghi, F Bielle, J Lerond, M Giry, C Villa, D Galanaud, S Lehéricy, M Marjańska, M Sanson, A Di Stefano
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND 2-hydroxyglutarate (2HG) can be detected non-invasively in IDH-mutant gliomas by in vivo magnetic resonance spectroscopy (MRS). We investigated factors affecting 2 HG accumulation and explored the prognostic value of 2 HG detection in IDH mutant gliomas and 2 HG variations during anti-cancer therapies. MATERIAL AND METHODS We prospectively scanned by MEGA-PRESS 70 glioma patients (24 before surgery and 46 IDH mutant operated glioma) and measured 2HG. CRLB cut-off was 50%. We followed up 9 IDH mutant patients during radiotherapy and chemotherapy.We analyzed radiological parameters (tumor and cystic/necrotic volumes, fractions of VOI filled with tumor, spectroscopic profile, “infiltrative” versus “expansive” morphology, contrast-enhancement) and genetic profile (IDH1, IDH2, 1p19q codeletion). 2HG concentrations in plasma, urine, and surgical obtained samples were measured by gas chromatography-mass spectrometry (GC-MS). RESULTS MEGA-PRESS sequence detected 2HG with a sensitivity of 95% in untreated patients, and of 69% in pre-treated patient. Positive predictive value was 100% in both groups. 2HG was lower in pre-treated IDH mutant gliomas (1.1 versus 2.3 mM, P=0.02) and decreased rapidly during radiotherapy and chemotherapy before any radiological change. 2HG detection was positively correlated with tumor volume (P=0.02), choline measurements (r=0.58 P&lt;0.0001), cellular density (measured by restricted diffusivity, Pearson r -0.40 P=0.01), “expansive” presentation, mutated reads/total reads ratio by NGS and was inversely correlated with Myo-inositol (Pearson R -0.29 P=0.03) and cystic/necrotic areas (P=0.04). 2HG by MRS positively correlated with urine 2HG (r=0.80 P=0.003). 2 HG was higher in IDH2 mutant (4.7 versus 2.4 Mm, P=0.02) and lower in non R132H IDH1 mutant (1.12 mM P=0.004). Among IDH mutant glioma patients, 2 HG detection was associated with longer survival (HR 0.09; 95%CI 0.018–0.52). CONCLUSION Tumor volume, cellular density, previous radio- and chemotherapy and genetic features determine 2 HG detection in IDH mutant gliomas. 2 HG detection is associated with better outcome and can be reliably monitored during anti-cancer treatments.