tbuckley/cabot-search huggingface dataset:
DiSCoVERing Innovative Therapies for Rare Tumors: Combining Genetically Accurate Disease Models with<i>In Silico</i>Analysis to Identify Novel Therapeutic Targets
Authors: Allison R. Hanaford, Tenley C. Archer, Antoinette Price, Ulf D. Kahlert, Jarek Maciaczyk, Guido Nikkhah, Jong Wook Kim, Tobias Ehrenberger, Paul A. Clemons, Vlado Dančík, Brinton Seashore-Ludlow, Vasanthi Viswanathan, Michelle L. Stewart, Matthew G. Rees, Alykhan Shamji, Stuart Schreiber, Ernest Fraenkel, Scott L. Pomeroy, Jill P. Mesirov, Pablo Tamayo, Charles G. Eberhart, Eric H. Raabe
Journal: Clinical Cancer Research (2016)

Abstract Purpose: We used human stem and progenitor cells to develop a genetically accurate novel model of MYC-driven Group 3 medulloblastoma. We also developed a new informatics method, Disease-model Signature versus Compound-Variety Enriched Response (“DiSCoVER”), to identify novel therapeutics that target this specific disease subtype. Experimental Design: Human neural stem and progenitor cells derived from the cerebellar anlage were transduced with oncogenic elements associated with aggressive medulloblastoma. An in silico analysis method for screening drug sensitivity databases (DiSCoVER) was used in multiple drug sensitivity datasets. We validated the top hits from this analysis in vitro and in vivo. Results: Human neural stem and progenitor cells transformed with c-MYC, dominant-negative p53, constitutively active AKT and hTERT formed tumors in mice that recapitulated Group 3 medulloblastoma in terms of pathology and expression profile. DiSCoVER analysis predicted that aggressive MYC-driven Group 3 medulloblastoma would be sensitive to cyclin-dependent kinase (CDK) inhibitors. The CDK 4/6 inhibitor palbociclib decreased proliferation, increased apoptosis, and significantly extended the survival of mice with orthotopic medulloblastoma xenografts. Conclusions: We present a new method to generate genetically accurate models of rare tumors, and a companion computational methodology to find therapeutic interventions that target them. We validated our human neural stem cell model of MYC-driven Group 3 medulloblastoma and showed that CDK 4/6 inhibitors are active against this subgroup. Our results suggest that palbociclib is a potential effective treatment for poor prognosis MYC-driven Group 3 medulloblastoma tumors in carefully selected patients. Clin Cancer Res; 22(15); 3903–14. ©2016 AACR.
Prostate Cancer Early Detection
Authors: Richard J Babaian, Alan W Partin
Journal: Journal of the National Comprehensive Cancer Network (2010)

ogy: Prostate Cancer Early Detection (to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org)provide a set of sequential recommendations detailing a screening and subsequent workup strategy for maximizing the detection of prostate cancer in an early, organconfined state and attempting to minimize unnecessary procedures.These guidelines were developed for men who have elected to participate in prostate cancer screening; they are not meant to address the controversy regarding population screening.
Familial (genetic) subtypes of pure depressive disease
Authors: G Winokur
Journal: American Journal of Psychiatry (1979)

The author reviewed data from five studies and found that depressed patients with a history of depression in a parent or child have more sibships containing depression than depressed patients without this family history. Thus, there is a clustering of depressions in certain families. Sporadic pure depressive disease (PDD), where no depressive illness exists in a first-degree family member of a depressed proband, is associated with a later age of onset than familial PDD, where depressive illness does exist in a first-degree relationship. The possibility exists that familial PDD and sporadic PDD are autonomous illnesses. The presence of a family history of depression may be predictive to some extent of a good response to adequate tricyclic medication or ECT.
PTH-336 Effects of lower doses of dca on radiosensitisation of colorectal cancer cells in vitro
Authors: S Shaikh, B San Juan, T Hughes, SL Perry, T Maisey, DG Jayne
Journal: Gut (2015)

<h3>Introduction</h3> Neoadjuvant radiotherapy confers a well-established benefit in locoregional recurrence for patients with locally invasive rectal cancer. However, only around 50% experience significant downstaging of their tumour. Radiation-associated toxicity renders dose escalation unachievable. Dichloroacetate (DCA) is a generic drug shown to modify tumour metabolism reversing the Warburg effect and inducing apoptosis and may potentially enhance the effect of radiation. This study aimed to investigate the effects of DCA at lower doses in combination with radiotherapy on the survival of CRC cell lines, and any possible synergistic DNA damage. <h3>Method</h3> CRC cells (LoVo) and control cells (HEK 293) treated with DCA (2,5,10 mM) and irradiation (0,4,8 Gy). Influences of the combination treatment on cell survival were analysed using MTT assays and clonogenic assays and the induction of DNA damage by quantifying gamma-H2AX foci. Statistical analyses were performed using GraphPad, differences between DCA-treated and vehicle control groups were assessed using the Mann-Whitney U test. <h3>Results</h3> DCA (5 mM) significantly reduced the survival of CRC cells in combination with 4 Gy and 8 Gy (P = 0.0244, 0.0078, respectively). DCA (10 mM) significantly reduced survival of CRC cells in in combination with 4 Gy and 8 Gy (P &lt; 0.0001, &lt;0.0001, respectively). DCA (5 mM) significantly increased the mean number of DNA double-strand breaks (DSB) per CRC cell in combination with 4 Gy and 8 Gy (P = 0.0041, 0.023, respectively). In unirradiated CRC cells, all the DCA doses (2, 5, 10 mM) significantly increased the mean number of DSB’s per CRC cell (P &lt; 0.0014). In the control cell line DCA (5, 10 mM) significantly increased the mean number of DSB’s per cell induced at 4 Gy (P &lt; 0.0001). <h3>Conclusion</h3> Lower doses of DCA may have an additive killing effect in combination with radiation in CRC cells. A similar picture of sensitivity was seen in normal cell line demonstrating that DCA is not completely harmless. Increasing doses of DCA associated with increased levels of DSB’s in CRC cells and it may be a potential mechanism behind DCA. Further research is warranted exploring the mechanism behind the effects of DCA and as a potential adjunct in the management of rectal cancers. <h3>Disclosure of interest</h3> None Declared.
Phase I/II study of vicinium given by intravesical administration in patients with superficial transitional cell carcinoma of the bladder: Phase I results
Authors: D. Fitsialos, S. Seitz, E. Wiecek, M. Rasamoelisolo, J. Entwistle, M. Jewett, G. C. MacDonald, N. Glover
Journal: Journal of Clinical Oncology (2006)

4580 Background: Vicinium is a fusion protein comprised of a humanized scFv, specific for Ep-CAM (epithelial cell adhesion molecule), and a truncated fragment of Pseudomonas exotoxin A. Ep-CAM is highly expressed on carcinoma cells including superficial transitional cell carcinomas (TCC) of the bladder. Vicinium targets and kills Ep-CAM-positive tumors. Results from the Phase I arm of a Phase I/II trial where Vicinium was instilled into the bladders of patients with superficial TCC of the bladder showed the drug to be very well tolerated and showed promising clinical results. Methods: 64 patients with Ep-CAM positive superficial TCC of the bladder, Ta, Tis or T1, Grades 2 or 3 who were refractory or intolerant to BCG therapy were admitted into the study. Dosing comprised a minimum of 3 subjects per dose level through 12 escalating doses. Vicinium was given once/week for 6 consecutive weeks by intravesical administration into the bladder via a catheter at escalating dose levels of 0.1, 0.2, 0.33, 0.66, 1.32, 2.64, 5.28, 10.56, 13.73, 17.85, 23.2 and 30.16 mg/week. All toxicities were assessed according to the NCI CTC v3. Blood samples were collected at different times in the study to determine systemic drug exposure and to assess immunogenicity. Efficacy was explored via biopsy, cystoscopy, urine cytology and FISH. Results: Vicinium was very well tolerated at all doses. Almost all (64/65) patients were positive for the Ep-CAM antigen. Pharmacokinetic analysis showed no evidence of Vicinium in the circulation of any of the patients; however, the majority of patients developed an anti-Vicinium response. Most patients, in particular at the higher doses, showed decreased tumor cell numbers by FISH analysis by the final day of treatment with the greatest sustained effect being observed in patients with the higher percentage Ep-CAM-positive tumors. Conclusions: Vicinium dosed on a weekly basis for 6 weeks was very well tolerated at all dose levels. The early clinical benefit observed with Vicinium strongly supports its development as a promising therapy for superficial transitional cell carcinoma of the bladder. The phase II arm of the trial will confirm the safety and further assess the efficacy of Vicinium at a recommended Phase II dose. [Table: see text]
Effects of a potent CYP3A inhibitor on the pharmacokinetics and safety of enzastaurin
Authors: L. Musib, C. Darstein, J. Suico, J. Baldwin, P. Welch
Journal: Journal of Clinical Oncology (2007)

2572 Background: Enzastaurin (ENZ) targets the PKCβ and PI3K/AKT pathways to induce tumor cell apoptosis, reduce proliferation, and suppress tumor-induced angiogenesis. ENZ is metabolized by CYP3A in vitro. This study examined the potential clinical effects of a potent CYP3A4 inhibitor, ketoconazole (KETO), on the pharmacokinetics and safety of ENZ. Methods: In this open-label, fixed-sequence, three-period, crossover study (duration = 6 weeks), healthy subjects received an oral, 200- mg, single dose of ENZ (period 1); 400-mg daily doses of KETO for 4 days to assess QT (period 2); and 400-mg daily doses of KETO for 14 days, with a 200-mg single dose of ENZ given on day 4 (period 3). Plasma samples for PK analysis were collected predose and after ENZ administration in periods 1 and 3 at scheduled intervals. Results: Of the 16 women enrolled, 13 completed the study. Changes in PK parameters of ENZ and its metabolite, LY326020, in the presence of KETO are summarized in the table . No serious adverse events (AEs) occurred. A similar number of AEs possibly related to enzastaurin occurred in period 1 (6) and period 3 (7). Headache (n=4) and nausea (n=3) were more frequent in period 3, but were also the most common AEs related to KETO. Three patients had hepatic transaminase elevations, but no consistent pattern with dosing period or ENZ exposures was observed. At 4 hours post-dose, QT intervals were prolonged by a mean 5.88 (95% CI: 1.767–10.00) msec after four daily doses of KETO and by a mean 9.29 (95% CI: 5.165–13.41) msec when coadministered with ENZ. Conclusion: In the presence of KETO, plasma concentrations of ENZ and its metabolites increased significantly. ENZ alone did not increase QT intervals. Ketoconazole plus ENZ caused a slightly greater increase in QT intervals compared to KETO alone, but this very small change may not be clinically significant. ENZ was generally well tolerated, alone or with KETO. [Table: see text] No significant financial relationships to disclose.
Study of Oxidative Metabolism in Tumor Tissues of Squamous Cell Lung Cancer and Adenocarcinoma
Authors: E. Shalashnaya, I. Goroshinskaya, S. Chilingaryants, E.I. Surikova, P.S. Kachesova, L.A. Nemashkalova, A. Leonova
Journal: Annals of Oncology (2014)
PTU-022 Caecal location is associated with increased lesion recurrence following endoscopic mucosal resection of large non-pedunculated colorectal polyps: Abstract PTU-022 Table 1
Authors: A Chattree, MD Rutter
Journal: Gut (2015)

<h3>Introduction</h3> Large caecal polyps over 2 cm in size are considered amongst the most complex lesions to achieve successful endoscopic resection, with recent data suggesting a significantly increased risk of post procedure bleeding and perforation associated with their endoscopic removal compared with elsewhere in the colon.<sup>1,2</sup>There is however a paucity of data assessing whether caecal location affects successful (R<sub>0</sub>) clearance of lesions. <h3>Method</h3> Retrospective analysis was conducted on large non-pedunculated colorectal polyps (LNPCPs) managed with endoscopic mucosal resection in the North East Bowel Cancer Screening Programme (BCSP) between 2011–12. A comparison of 12 month recurrence rates, an internationally recognised marker of treatment success,<sup>3</sup>was made between caecal and non-caecal LNPCP groups. Statistical analysis was performed using the chi-squared test. <h3>Results</h3> A total of 135 lesions were identified, with 12 month recurrence identified in 8.1% of cases. Caecal location demonstrated a strongly significant association with recurrence compared with non-caecal location (27.8% vs 5.1%, p = 0.007) <h3>Conclusion</h3> Caecal location was associated with over a 5-fold increase (28.7% vs 5.1%) in the incidence of 12 month recurrence. The results from this series confirm the increased technical demands associated with the endoscopic resection of caecal LNPCPs, especially considering our study involved experienced BCSP endoscopists. In view of the increased risk of endoscopic treatment failure, in addition to the established increased risk of adverse endoscopic events, we feel that caecal LNPCPs may benefit from multidisciplinary discussion and should only be managed by experienced clinicians. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Rutter MD, Nickerson C, Rees CJ, <i>et al</i>. Risk factors for adverse events related to polypectomy in the English Bowel Cancer Screening Programme. Endoscopy 2014;46:90–7 Metz AJ, Bourke MJ, Moss A, <i>et al</i>. Factors that predict bleeding following endoscopic mucosal resection of large colonic lesions. Endoscopy 2011;43:506–11 Moss A, Bourke MJ, Williams SJ, <i>et al</i>. Endoscopic mucosal resection outcomes and prediction of submucosal cancer from advanced colonic mucosal neoplasia. Gastroenterology 2011;140:1909–18
Spontaneous Lymphomas in Mice Genetically Selected for High or Low Phytohemagglutinin Responsiveness&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: V Covelli, V Di Majo, B Bassani, C Mancini, L Adorini, G Doria
Journal: JNCI Journal of the National Cancer Institute (1985)

Biozzi mice selected for high (Hi) or low (Lo) responsiveness to phytohemagglutinin (PHA) have been followed for their entire life-span to examine their pathology at death. Spontaneous lymphomas were found to exhibit higher incidence and faster development in Lo/PHA than in Hi/PHA females, whereas a similar difference between the two lines did not attain the level of statistical significance in male mice. The incidence of solid tumors was higher in Lo/PHA than in Hi/PHA males but the same in females of the two lines, yet the probability of dying from solid tumors was slightly increased in Lo/PHA mice of both sexes. All these results indicate that T-cell-mediated immunity influences mainly the spontaneous incidence of lymphomas and, to a lesser degree, the appearance of other solid tumors.
Lung transplantation for pulmonary sarcoidosis. Twenty-five years of experience in the USA
Authors: Ziad Taimeh, Marshall I Hertz, Sara Shumway, Marc Pritzker
Journal: Thorax (2016)

Lung transplantation is the ultimate treatment for end-stage pulmonary sarcoidosis. Post-transplant survival outcomes remain unclear.Survival models were used to assess survival and graft outcomes in patients with sarcoid among 20,896 lung transplants performed in the USA.695 lung recipients were transplanted for pulmonary sarcoidosis. Sarcoid lung recipients had similar median survival rate (69.7 months (IQR 60.2-79.3)) compared with the non-sarcoid lung recipients (63.1 months (IQR 61.4-64.8), p=0.88). In multivariate Cox regression, sarcoidosis was not independently associated with worse mortality (HR 0.96 (95% CI 0.85 to 1.08), p=0.51). Among the sarcoid lung recipients, double lung transplantation (HR 0.76 (0.58 to 0.99), p=0.04) and lung allocation score era (HR 0.74 (0.56 to 0.97), p=0.03) were associated with improved survival.Recipients of lung transplants for pulmonary sarcoidosis had similar outcomes compared with non-sarcoid lung recipients.
Age-related differences in formal thought disorder in chronically hospitalized schizophrenic patients: a cross-sectional study across nine decades
Authors: P D Harvey, J Lombardi, M Leibman, M Parrella, L White, P Powchik, R C Mohs, M Davidson, K L Davis
Journal: American Journal of Psychiatry (1997)

This study used a cross-sectional design to examine the frequency of occurrence and severity of 10 different signs of thought disorder in schizophrenic patients across the lifespan.Schizophrenic patients, who ranged in age from 19 to 96 years (N = 392), were examined with the Scale for Assessment of Thought, Language, and Communication. The cognitive functioning of the geriatric patients (patients over the age of 64, N = 120) was also assessed.Poverty of speech was more common and more severe in geriatric patients, while four different signs of thought disorder that reflect disconnected speech were less common and less severe in geriatric patients. Analysis of covariance found that the lower severity of disconnection thought disorders in the older patients was not attributable to differences in the amount of speech produced.Aspects of disconnected speech were less severe in older patients, while the severity and frequency of poverty of speech were greater. These findings suggest that the two previously identified separate dimensions of communication disorder in schizophrenia vary differently with age and possibly in their cognitive and biological underpinnings.
PTH-065 The impact of changes to the nice guideline on the use of biologic agents in ulcerative colitis in a uk district general hospital: Abstract PTH-065 Table 1
Authors: R Mary Koshy, H Steed, R Nordon, MJ Brookes
Journal: Gut (2015)

<h3>Introduction</h3> After pressure from patient and clinical groups NICE have reversed their position on biologics<sup>1,2</sup>in subacute ulcerative colitis (UC) and it will be available to patients in 2015. <h3>Method</h3> A retrospective review of the use of infliximab for the treatment of UC in a single centre DGH between 2011 and 2014. <h3>Results</h3> Ten patients received infliximab for acute severe UC and ten for subacute UC. In the 12 months pre-infliximab these patients received 40 courses of prednisolone between them (Table 1). All subacute patients had received immunomodulators. All subacute patients had a partial or complete clinical (MAYO score) and biochemical response following infliximab induction, compared to 50% of the acute severe group. Two patients remain on long-term infliximab and in remission. Colectomy was required within 12 months for 55.6% of patients with acute severe disease and 44.4% of those with subacute activity. 60% of the remaining subacute patients (n = 3) have received steroids since infliximab. <h3>Conclusion</h3> NICE change of position<sup>2</sup>echos current practice in our centre and with the change in guidelines we may hope to see a reduction in steroid use prior to the use of biological treatment. However the long term success of infliximab in UC is limited. Subacute patients showed better immediate outcomes in terms of biochemical and clinical response, but at 12 months, outcomes were similar in both groups. Work is needed to identify the likely responders to make its use cost effective and evidence based guidance is needed on the clinical benefits of switching to alternative biological agents if infliximab fails. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Infliximab for acute exacerbations of ulcerative colitis. Available at: https://www.nice.org.uk/guidance/ta163. Accessed on 07/01/2015 Ulcerative colitis (moderate, severe) – infliximab (review TA140), adalimumab (review TA262) &amp; golimumab (2nd line) [ID695]. Available at: http://www.nice.org.uk/Guidance/InDevelopment/GID-TAG357. Accessed on 23/02/2015
Nephrin Tyrosine Phosphorylation Is Required to Stabilize and Restore Podocyte Foot Process Architecture
Authors: Laura A. New, Claire E. Martin, Rizaldy P. Scott, Mathew J. Platt, Ava Keyvani Chahi, Colin D. Stringer, Peihua Lu, Bozena Samborska, Vera Eremina, Tomoko Takano, Jeremy A. Simpson, Susan E. Quaggin, Nina Jones
Journal: Journal of the American Society of Nephrology (2016)

Podocytes are specialized epithelial cells of the kidney blood filtration barrier that contribute to permselectivity via a series of interdigitating actin-rich foot processes. Positioned between adjacent projections is a unique cell junction known as the slit diaphragm, which is physically connected to the actin cytoskeleton via the transmembrane protein nephrin. Evidence indicates that tyrosine phosphorylation of the intracellular tail of nephrin initiates signaling events, including recruitment of cytoplasmic adaptor proteins Nck1 and Nck2 that regulate actin cytoskeletal dynamics. Nephrin tyrosine phosphorylation is altered in human and experimental renal diseases characterized by pathologic foot process remodeling, prompting the hypothesis that phosphonephrin signaling directly influences podocyte morphology. To explore this possibility, we generated and analyzed knockin mice with mutations that disrupt nephrin tyrosine phosphorylation and Nck1/2 binding (nephrin(Y3F/Y3F) mice). Homozygous nephrin(Y3F/Y3F) mice developed progressive proteinuria accompanied by structural changes in the filtration barrier, including podocyte foot process effacement, irregular thickening of the glomerular basement membrane, and dilated capillary loops, with a similar but later onset phenotype in heterozygous animals. Furthermore, compared with wild-type mice, nephrin(Y3F/Y3F) mice displayed delayed recovery in podocyte injury models. Profiling of nephrin tyrosine phosphorylation dynamics in wild-type mice subjected to podocyte injury indicated site-specific differences in phosphorylation at baseline, injury, and recovery, which correlated with loss of nephrin-Nck1/2 association during foot process effacement. Our results define an essential requirement for nephrin tyrosine phosphorylation in stabilizing podocyte morphology and suggest a model in which dynamic changes in phosphotyrosine-based signaling confer plasticity to the podocyte actin cytoskeleton.
Lifestyle-focused text messages reduced LDL-C levels, systolic BP, and BMI in coronary heart disease
Authors: Hanna E. Bloomfield
Journal: Annals of Internal Medicine (2016)

Source Citation Chow CK, Redfern J, Hillis GS, et al. Effect of lifestyle-focused text messaging on risk factor modification in patients with coronary heart disease: a randomized clinical trial. JAMA. 2015;314:1255-63. 26393848
Factors Influencing Time to Seeking Medical Advice and Treatment Onset in Breast Cancer Patients in Serbia
Authors: L. Stamatovic, S.D. Mamula Masic, D. Vukotic, Z. Kovac, Z. Mihailovic, K. Zdravkovic, D. Petkovic, T. Bagi, N. Milic
Journal: Annals of Oncology (2014)
Comparison of PET measurement of local brain glucose metabolism and CAT measurement of brain atrophy in chronic schizophrenia and depression
Authors: A S Kling, E J Metter, W H Riege, D E Kuhl
Journal: American Journal of Psychiatry (1986)

Using [18F]fluorodeoxyglucose and positron emission tomography (PET), the authors examined the regional brain glucose metabolism of six patients with chronic schizophrenia, six patients with chronic depression, and 12 normal control subjects. Three schizophrenic and four depressive patients had CAT scans that showed enlarged ventricles (ventricle-brain ratios higher than 9.0) and widened sylvian fissures. The PET scans of the schizophrenic and depressed patients did not differ significantly from those of the age-matched controls, and a previously reported metabolic "hypofrontality" was not confirmed. The patients with enlarged ventricles and widened sylvian fissures tended to have lower global metabolism.