tbuckley/cabot-search huggingface dataset:
Abstract 3522: BET and BRAF inhibitors act synergistically against BRAF mutant melanoma
Authors: Luca Paoluzzi, Douglas Hanniford, Elena Sokolova, Iman Osman, Farbod Darvishian, Jinhua Wang, James E. Bradner, Eva Hernando
Journal: Cancer Research (2015)

Abstract Purpose: Despite major advances in the treatment of metastatic melanoma, treatment failure is still inevitable in most cases. Manipulation of key epigenetic regulators, including inhibition of Bromodomain and extra-terminal domain (BET) family members impairs cell proliferation in vitro and tumor growth in vivo in different cancers, including melanoma. BET inhibition is thought to impair downstream transcriptional activity of the MAPK (MAPK) pathway and other key oncogenic signaling pathways, suggesting complementarity with MAPK inhibition. Here, we investigated the effect of combining the BET inhibitor JQ1 with the BRAF inhibitor Vemurafenib in in vitro and in vivo models of BRAF-mutant melanoma. We additionally screened potential synergism of JQ-1 with 27 additional compounds including inhibitors of the proteasome, histone deacetylases (HDACi) and MEK. Methods: We performed cytotoxicity and apoptosis assays, and a xenograft mouse model to determine the in vitro and in vivo efficacy of JQ1 in combination with Vemurafenib against BRAF-mutant melanoma cell lines. Further, to investigate the molecular mechanisms underlying the effects of this combined treatment, we conducted antibody arrays of in vitro drug-treated cell lines and RNA sequencing of drug-treated xenograft tumors. Synergism between JQ1 and other targeted compounds was examined by in vitro cytotoxicity assays. Results: The combination of JQ1 and Vemurafenib acted synergistically in BRAF-mutant cell lines. Additional combinations that were found synergistic included JQ-1 plus proteasome inhibitors (carfilzomib and marizomib, HDAC inhibitors (romidepsin and panobinostat), or anti-Bcl2 small molecules (Obatoclax and TW-37). The combination of JQ-1 and Vemurafenib resulted in marked apoptosis in vitro, with up-regulation of several pro-apoptotic proteins involved in both the intrinsic and extrinsic pathways of apoptosis. In vivo, this combination treatment suppressed tumor growth and significantly improved survival compared to either drug alone. RNA sequencing of tumor tissues revealed almost four thousand genes that were uniquely modulated by the combination. Furthermore, several anti-apoptotic genes such as MCL-1, BCL-XL and BCL-2 were significantly down-regulated. Conclusions: Collectively, our data provide a rationale for combinations of BET inhibitors with additional compounds including BRAF inhibitors, as a novel strategy for the treatment of melanoma. Citation Format: Luca Paoluzzi, Douglas Hanniford, Elena Sokolova, Iman Osman, Farbod Darvishian, Jinhua Wang, James E. Bradner, Eva Hernando. BET and BRAF inhibitors act synergistically against BRAF mutant melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3522. doi:10.1158/1538-7445.AM2015-3522
On the Transmission of the Lactic Dehydrogenase Agent From Mother to Offspring&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Charles G. Crispens, Jr.
Journal: JNCI Journal of the National Cancer Institute (1965)

Transmission of the lactic dehydrogenase (LDH) agent from mother to offspring occurs across the placenta when female mice are infected before conception or during gestation. If mothers are inoculated with this virus within 24 hours after giving birth, transmission to progeny may occur in the milk. That 5-week-old mice, assumed to be uninfected because their serum LDH levels were normal, may carry the virus in their blood is of interest in regard to the possibility that an accurate estimate of infectivity among offspring is not obtained by the standard assay method. The finding may also be useful in future experiments with the LDH agent. Excretion of the LDH agent in semen was demonstrable as early as 24 hours and as late as 70 days after inoculation.
Use of genomic signatures to predict response to histone deacetylase inhibitors and correlation with tumor subtypes and molecular pathways.
Authors: A. L. Cohen, R. Soldi, A. Bild
Journal: Journal of Clinical Oncology (2010)

e13596 Background: Histone deacetylase (HDAC) inhibitors are a promising class of cancer drugs. The ability to predict which tumors are likely to respond helps in planning clinical trials and delivering treatment. Methods: We developed gene expression signatures using cell lines before and after treatment with valproic acid (VPA), trichostatin A (TSA), and suberoylanilide hydroxamic acid (SAHA). Gene expression signatures for pathway activation were developed using induction of genes regulating epigenetic processes (HDAC1, HDAC4, SIRT1, DNMT2, and EZH2). Using logistic regression we predicted drug sensitivity and epigenetic signaling pathways in subtypes of cancers using data from 32 public datasets. Prediction of pathway activity and drug responsiveness was validated using human tumor cells grown in 3D culture or mouse xenografts. Results: Pathway activation patterns and drug sensitivity vary across tumor types and subtypes. Thyroid and GI cancers and mesothelioma are predicted to have highest response to HDAC inhibitors (p<0.0001). There were significant differences in HDAC pathway activity and drug response within tumor subtypes. For example, glioblastoma, particularly Freije class HC2A and HC2B, are more likely to be sensitive to HDAC inhibitors than lower grade gliomas, which have lower HDAC4 and EZH2 activation (p<0.0001). Basal and HER2-positive breast tumors have higher HDAC4 activity and sensitivity to HDAC inhibitors than ER-positive tumors (p<0.0005). We saw correlation between components of the epigenetic machinery. HDAC inhibitor sensitivity correlates with MYC and EZH2 activation, particularly in ovarian tumors, mesotheliomas, basal breast cancer, and gliomas (p<0.001). Preclinical drug studies in cell lines and patient tumors grown in 3D culture and orthotopic models validate our genomic analyses. Conclusions: Epigenetic pathway activity and sensitivity to epigenetic modifiers vary across tumor types and subtypes. High-throughput expression profiling can impact cancer drug selection. Pre-identification of patient response may improve response rates and assist in identifying optimal inclusion criteria for clinical trials. No significant financial relationships to disclose.
APACHE II: Prediction of outcome of 451 ICU oncology admissions in a community hospital
Authors: R.R. Abbott, M. Setter, S. Chan, K. Choi
Journal: Annals of Oncology (1991)

The APACHE II system has been shown to be a reliable and useful means of evaluating patient outcome from the intensive care unit when applied to a broad spectrum of diagnoses. The major purpose of this study was to determine the use of APACHE II as a means of predicting outcome of ICU oncology patients. Data were retrospectively collected for 451 ICU oncology admissions. A direct relationship between severity of physiologic derangement and patient risk of death was demonstrated. Patients with scores of 30 or greater had hospital mortality rates of 100% for postoperative and 92.6% for nonoperative patients. The APACHE II was a useful means of predicting the outcome of ICU oncology patients. This potentially provides the patient, family, and physician an objective dimension in making decisions whether to transfer the oncology patient.
PTU-047 Tolerability of thiopurines in a UK South Asian inflammatory bowel disease population
Authors: D G Walker, H R T Williams, T R Orchard
Journal: Gut (2010)

<h3>Introduction</h3> The thiopurine drugs, azathioprine and mercaptopurine are commonly used in the treatment of both Crohn9s disease (CD) and ulcerative colitis (UC). In general, they are well tolerated and safe. However, side effects, serious enough to warrant drug withdrawal, are reported in up to 24% of patients.1 Common reasons for thiopurine withdrawal include gastric intolerance, leucopaenia and deranged liver function tests. Previous studies in the UK have concentrated on Caucasian IBD populations; there are no previous studies of the tolerability of thiopurine drugs in the UK South Asian IBD population. <h3>Methods</h3> The aim of this study was to determine the frequency of thiopurine withdrawal in a UK South Asian IBD cohort. The medical notes of South Asian inflammatory bowel disease patients attending clinic in five North West London hospitals between 2007 and 2009 were reviewed. Any patients treated with thiopurines were noted and patients withdrawing from treatment within 6 months of starting treatment were recorded. <h3>Results</h3> Three hundred and seventy-one South Asian IBD patients were identified. One hundred and fifty-one patients (41%) were started on a thiopurine. In 34.4% of cases (52/151) South Asian patients stopped first-line immunosuppression with a thiopurine within 6 months of starting. In five cases the reason for drug withdrawal was not documented. In the remaining 47 cases, the reasons reported for stopping the drug included gastric intolerance (17), flu-like symptoms (3), pancreatitis (5), hepatitis (3), rash (3), myelotoxicity (3) and non-specific symptoms (including headache, itching, increased urinary frequency and paraesthesia) (13). <h3>Conclusion</h3> This study has revealed a high level of thiopurine withdrawal in a cohort of South Asian IBD patients. Although TPMT levels were not available for all South Asian patients in our study, previous research has shown that TPMT polymorphisms are of a similar frequency in British Caucasians and South Asians. A high proportion of South Asian patients stopped thiopurine treatment for non-specific symptoms (13/47; 28%). A possible reason to explain this could be difficulty in communication with non-English speaking patients, in particular a lack of drug information leaflets translated into other languages. This may mean that patients do not know what to expect when starting thiopurines. Clinicians need to be aware of this and information leaflets on thiopurines should be translated for ethnic minorities who are unable to read English.
Brief Communication: Antitumor Action of Vitamin A in Mice Inoculated With Adenocarcinoma Cells2
Authors: Giuseppe Rettura, Anton Schittek, Mark Hardy, Stanley M. Levenson, Achilles Demetriou, Eli Seifter
Journal: JNCI Journal of the National Cancer Institute (1975)

Vitamin A palmitate was incorporated into a laboratory chow (150,000 IU/kg diet) and fed ad libitum to C3H/HeJ female mice inoculated with 1 × 106 C3HBA tumor cells, beginning the day of inoculation. Control female mice of the same strain similarly inoculated were fed the laboratory chow alone. Vitamin A did not affect tumor incidence, but it did decrease the tumor growth rate for the first 19 days, after which growth rates were independent of treatment. Vitamin A-treated mice survived for significantly longer times than did control mice.
C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury
Authors: Sean M. Silverman, Byung-Jin Kim, Garreth R. Howell, Joselyn Miller, Simon W. M. John, Robert J. Wordinger, Abbot F. Clark
Journal: Molecular Neurodegeneration (2016)

C1q represents the initiating protein of the classical complement cascade, however recent findings indicate pathway independent roles such as developmental pruning of retinal ganglion cell (RGC) axons. Furthermore, chronic neuroinflammation, including increased expression of C1q and activation of microglia and astrocytes, appears to be a common finding among many neurodegenerative disease models. Here we compare the effects of a retinal ischemia/reperfusion (I/R) injury on glial activation and neurodegeneration in wild type (WT) and C1qa-deficient mice in the retina and superior colliculus (SC). Retinal I/R was induced in mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. Glial cell activation and population changes were assessed using immunofluorescence. Neuroprotection was determined using histological measurements of retinal layer thickness, RGC counts, and visual function by flash electroretinography (ERG).Retinal I/R injury significantly upregulated C1q expression in the retina as early as 72 h and within 7 days in the superficial SC, and was sustained as long as 28 days. Accompanying increased C1q expression was activation of microglia and astrocytes as well as a significantly increased glial population density observed in the retina and SC. Microglial activation and changes in density were completely ablated in C1qa-deficient mice, interestingly however there was no effect on astrocytes. Furthermore, loss of C1qa significantly rescued I/R-induced loss of RGCs and protected against retinal layer thinning in comparison to WT mice. ERG assessment revealed early preservation of b-wave amplitude deficits from retinal I/R injury due to C1qa-deficiency that was lost by day 28.Our results for the first time demonstrate the spatiotemporal changes in the neuroinflammatory response following retinal I/R injury at both local and distal sites of injury. In addition, we have shown a role for C1q as a primary mediator of microglial activation and pathological damage. This suggests developmental mechanisms of C1q may be re-engaged during injury response, modulation of which may be beneficial for neuroprotection.
The diagnostic implications of formal thought disorder in mania and schizophrenia: a reassessment
Authors: V C Jampala, M A Taylor, R Abrams
Journal: American Journal of Psychiatry (1989)

The authors compared nine manic patients exhibiting formal thought disorders (tangentiality, neologisms, drivelling, private use of words, and paraphasias) with 102 manic patients without these thought disorders and with 31 schizophrenic patients. Manic patients with formal thought disorders tended to have more "schizophrenic" symptoms than did manic patients without formal thought disorders, but both groups improved significantly more during the index episode than did the schizophrenic patients. Although the prevalence of flight of ideas was high in mania, narrowly defined formal thought disorder was rare, suggesting that precise definition and description of thought disorders would be helpful in distinguishing mania from schizophrenia.
Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease
Authors: Timothy Hardy, Mujdat Zeybel, Christopher P Day, Christian Dipper, Steven Masson, Stuart McPherson, Elsbeth Henderson, Dina Tiniakos, Steve White, Jeremy French, Derek A Mann, Quentin M Anstee, Jelena Mann
Journal: Gut (2016)

Liver biopsy is currently the most reliable way of evaluating liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD). Its inherent risks limit its widespread use. Differential liver DNA methylation of peroxisome proliferator-activated receptor gamma (PPARγ) gene promoter has recently been shown to stratify patients in terms of fibrosis severity but requires access to liver tissue. The aim of this study was to assess whether DNA methylation of circulating DNA could be detected in human plasma and potentially used to stratify liver fibrosis severity in patients with NAFLD.Patients with biopsy-proven NAFLD and age-matched controls were recruited from the liver and gastroenterology clinics at the Newcastle upon Tyne Hospitals NHS Foundation Trust. Plasma cell-free circulating DNA methylation of PPARγ was quantitatively assessed by pyrosequencing. Liver DNA methylation was quantitatively assessed by pyrosequencing NAFLD explant tissue, subjected to laser capture microdissection (LCM). Patients with alcoholic liver disease (ALD) were also subjected to plasma DNA and LCM pyrosequencing.26 patients with biopsy-proven NAFLD were included. Quantitative plasma DNA methylation of PPARγ stratified patients into mild (Kleiner 1-2) and severe (Kleiner 3-4) fibrosis (CpG1: 63% vs 86%, p<0.05; CpG2: 51% vs 65% p>0.05). Hypermethylation at the PPARγ promoter of plasma DNA correlated with changes in hepatocellular rather than myofibroblast DNA methylation. Similar results were demonstrated in patients with ALD cirrhosis.Differential DNA methylation at the PPARγ promoter can be detected within the pool of cell-free DNA of human plasma. With further validation, plasma DNA methylation of PPARγ could potentially be used to non-invasively stratify liver fibrosis severity in patients with NAFLD. Plasma DNA methylation signatures reflect the molecular pathology associated with fibrotic liver disease.
Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state
Authors: Stephanie L Padilla, Jian Qiu, Marta E Soden, Elisenda Sanz, Casey C Nestor, Forrest D Barker, Albert Quintana, Larry S Zweifel, Oline K Rønnekleiv, Martin J Kelly, Richard D Palmiter
Journal: Nature Neuroscience (2016)
Syndrome of Inappropriate Anti-Diuretic Hormone Secretion (Siadh) in Cancer Patients (Pts): Results of the First Multicenter Italian Survey
Authors: R. Berardi, M. Caramanti, E. Arvat, C. Mastroianni, F. Agustoni, M. Tiseo, B. Vincenzi, R. Buosi, R. Chiari, A. Camerini, A. Galeassi, M. Ghidini, V. De Marino, D. Ferrari, L. Doni, D. Fumagalli, L. Portalone, G. Schinzari, M. Tucci, S. Cascinu
Journal: Annals of Oncology (2014)
Does ischemia occur with panic attacks?
Authors: D W Lint, C B Taylor, L Fried-Behar, J Kenardy
Journal: American Journal of Psychiatry (1995)

The authors examined ambulatory ECG changes during panic attacks in patients with panic disorder.Ten otherwise healthy women with panic disorder and complaints of chest pain during panic attacks underwent a symptom-limited exercise test on a treadmill and then wore an ambulatory ECG monitor with software designed to detect and record ischemic events and used a hand-held computer for up to 6 days.Eight of the women had panic attacks while using the hand-held computer and the ECG monitor. No ischemic events occurred during any of the exercise tests. Twelve tachycardiac events occurred during panic attacks and 84 tachycardiac events occurred that were not associated with panic attacks. Panic attacks were associated with significantly more symptoms than were tachycardiac episodes.In this group of otherwise healthy women with panic disorder and chest pain, ambulatory ischemic changes were not recorded during panic attacks.
NTCT-02A COMMON AND LONG-LASTING PERIPHERAL NEUROPATHY IS ASSOCIATED WITH BRENTUXIMAB VEDOTIN TREATMENT OF MYCOSIS FUNGOIDES AND SÉZARY SYNDROME
Authors: Zachary Corbin, Annie Nguyen-Lin, Mahkam Tavallaee, Shufeng Li, Youn Kim, Seema Nagpal
Journal: Neuro-Oncology (2015)

BACKGROUND: Brentuximab vedotin (BV) is an antibody-drug conjugate with a CD30 antibody linked to the microtubule inhibitor monomethyl auristatin E. The use of BV is being explored in Mycosis fungoides (MF) and Sezary syndrome (SS). In studies of BV treatment in other lymphomas, peripheral neuropathy was reported in 36% and 52% of patients, with resolution or improvement in 63% and 54%, respectively. METHODS: Patients were adults with good performance status in a phase II study of BV for MF/SS. A neurologist evaluated the patients at pre-defined intervals, and we employed the Total Neuropathy Score - clinical (TNSc) in a subset of the patients. Spearman's coefficient was used to measure correlations between CTCAE grade and TNSc scores. Logistic regression was used to evaluate the relationship between neuropathy grade and baseline neuropathy risk factors along with BV dose. RESULTS: Twenty-one (66%) of 32 patients developed worsening neuropathy, 9 (28%) CTCAE grade 1, 11 (34%) grade 2, and 1 (3%) grade 4. Seven (58%) of the patients with grades 2 or 4 progressed after the last dose of BV. Thirteen (62%) of patients showed improvement or resolution of the neuropathy. Risk factors of age, diabetes, alcoholism, and prior chemotherapy did not predict neuropathy. Total dose of BV predicted neuropathy (p < 0.0001). CTCAE grade correlated with TNSc (ρ = 0.75, p < 0.001), and grade 2 neuropathy occurred around a TNSc of 6 to 8. CONCLUSIONS: Our study reveals that a larger proportion of MF/SS patients treated with BV developed a long-lasting neuropathy than expected. The neuropathy has the pattern of a large fiber, sensory predominant syndrome, with generally negative symptoms. The TNSc provides a reliable measure of neuropathy with greater granularity. The ability to more clearly and objectively monitor such side effects is of paramount importance in the MF/SS population, given the chronic nature of their diagnosis.
Male psychological adaptation to unsuccessful medically assisted reproduction treatments: a systematic review
Authors: Mariana Veloso Martins, Miguel Basto-Pereira, Juliana Pedro, Brennan Peterson, Vasco Almeida, Lone Schmidt, Maria Emília Costa
Journal: Human Reproduction Update (2016)

Similarly to women, men suffer from engaging in fertility treatments, both physically and psychologically. Although there is a vast body of evidence on the emotional adjustment of women to infertility, there are no systematic reviews focusing on men's psychological adaptation to infertility and related treatments.The main research questions addressed in this review were 'Does male psychological adaptation to unsuccessful medically assisted reproduction (MAR) treatment vary over time?' and 'Which psychosocial variables act as protective or risk factors for psychological maladaptation?'A literature search was conducted from inception to September 2015 on five databases using combinations of MeSH terms and keywords. Eligible studies had to present quantitative prospective designs and samples including men who did not achieve pregnancy or parenthood at follow-up. A narrative synthesis approach was used to conduct the review.Twelve studies from three continents were eligible from 2534 records identified in the search. The results revealed that psychological symptoms of maladjustment significantly increased in men 1 year after the first fertility evaluation. No significant differences were found two or more years after the initial consultation. Evidence was found for anxiety, depression, active-avoidance coping, catastrophizing, difficulties in partner communication and the use of avoidance or religious coping from the wife as risk factors for psychological maladjustment. Protective factors were related to the use of coping strategies that involve seeking information and attribution of a positive meaning to infertility, having the support of others and of one's spouse, and engaging in open communication about the infertility problem.Our findings recommend an active involvement of men during the treatment process by health care professionals, and the inclusion of coping skills training and couple communication enhancement interventions in counselling. Further prospective large studies with high-quality design and power are warranted.