tbuckley/cabot-search huggingface dataset:
AT-16 * PHASE II STUDY OF TIVOZANIB, AN ORAL VEGFR INHIBITOR, IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: V. Chandra, Y. Ou, J. Evans, J. Kalpathy-Cramer, J. Dietrich, A. Chi, P. Wen, B. Rosen, T. Batchelor, E. Gerstner
Journal: Neuro-Oncology (2014)

BACKGROUND: Bevacizumab, a monoclonal antibody against VEGF-A, is approved for recurrent glioblastoma (GBM) but must be administered as an intravenous infusion twice a month. We designed a Phase II study of oral tivozanib, a VEGFR tyrosine kinase inhibitor, to determine if an oral substitute could be found. METHODS: A two-stage, Phase II study of tivozanib monotherapy was conducted in patients with recurrent GBM. Standard eligibility criteria were included and all patients had at least 1 cm of residual disease to assess radiographic tumor response. The primary endpoint was the proportion of patients progression-free at 6 months (PFS6). Secondary endpoints included median PFS, OS, toxicity, radiographic response (RR), and exploratory analyses of perfusion, permeability, diffusion MRI as well as blood biomarkers of angiogenesis. RESULTS: Ten patients were enrolled in stage 1 with a median age of 62 (51-73). Best MacDonald criteria responses were: CR (1), PR (1), SD (4), PD (4). By volume measurements, 8 patients exhibited a >20% decrease in tumor size. Median duration of response was 3.6 mo (1.7-3.8mo). One patient was taken off study for skin toxicity/fatigue and 8 patients were taken off study for PD. There were no patients progression-free at 6 months although 1 patient remains on treatment at 5 months. Since it was not possible to achieve the pre-specified PFS6 the study was terminated after stage 1. One patient experienced grade 3 hypertension probably related to tivozanib. Two of 4 patients who were on steroids at the start of treatment were able to decrease or discontinue steroids. CONCLUSION: Tivozanib was well tolerated but the PFS6 did not meet the pre-specified efficacy threshold for further analysis. Ongoing analysis of the correlative imaging (perfusion, diffusion, permeability) and blood biomarkers may shed light on why this oral VEGFR inhibitor was ineffective in this patient population.
Colonic duplication with heterotopy of gastric mucosa
Authors: A. Madro, K. Celinski, B. Prozorow-Krol, C. Lozowski, L. Buk, J. Swatek, J. Pilat, M. Slomka
Journal: Endoscopy (2013)

Gastrointestinal duplications are rare congenital anomalies, occurring in 1/5000 livebirths [1] [2]. However, colonic duplications are extremely rare with only 7 % of duplications involving the colon [3]. Heterotopy of gastric mucosa is a congenital lesion that often accompanies intestinal duplication [4]. In the case of symptomatic duplications, surgery is the treatment of choice, especially when complicated by ileus or hemorrhage [5]. Here we present an unusual case of large-bowel duplication in a patient with chronic diarrhea.
Abstract 4223: Gamma-tocotrienol and simvastatin target TIC and EMT populations in drug-resistant breast cancer
Authors: Archana Gopalan, Weiping Yu, Bob G. Sanders, Kimberly Kline
Journal: Cancer Research (2012)

Abstract Background and significance: Breast cancer (BC) is the second leading cause of cancer deaths in women. Despite great advances in treatment of early and advanced BC, relapse with drug resistance and metastasis is the biggest impediment to successful remission. Accumulating evidence supports the emerging concept that cancer stem cells (CSCs, also called tumor initiating cells, TICs), a rare tumor cell population that exhibits self-renewal and differentiation properties, are responsible for tumor relapse and metastasis. Hence, identifying molecular mediators responsible for maintenance of TICs and metastasis in drug resistant breast cancer is important to develop better and successful therapeutic strategies. Model system and methods: Acquired tamoxifen resistant (MCF-7/TamR) and doxorubicin resistant (MCF-7/ADR) cell lines as well as their isogenic parental counterparts MCF-7/S and MCF-7/WT, respectively were used in this study. ALDH activity assay was used for characterization and enrichment of TIC population. Immuno-staining/FACS of CD44+/CD24- was used to determine the metastasis potential in-vitro. Western blot analyses were used to detect signal transduction mediators known to be important for maintenance of TIC and EMT populations. Results: Both drug resistant cell lines expressed a higher percentage of TIC population as detected by ALDH activity and elevated EMT population as detected by CD44+/CD24- and increased EMT marker Vimentin and decreased MET marker E-cadherin in comparison with the isogenic sensitive cell lines. Both drug resistant cell lines uniformly expressed higher levels of pStat-3, c-Myc and CyclinD1 in comparison with their respective parental cell lines. Knockdown of Stat-3 using siRNA and Stat-3 inhibitor reduced TIC populations, reduced EMT populations, and decreased c-Myc and CyclinD1, but did not affect Vimentin and E-cadherin protein expression. γT3 and SVA alone and in combination reduced TIC populations as measured by reduced ALDH population and inhibition of mammospheres. Both agents alone and in combination reduced the EMT populations and reduced the levels of p-Stat3, c-Myc and CyclinD1expressed in drug-resistant breast cancer cell lines. Conclusion: These in vitro data demonstrate that drug resistant breast cancer cell lines contain high levels of TIC and EMT sub-populations that are in part controlled by the Stat-3 pathway. Furthermore, αT3 and SVA alone and in combination show the ability to target TIC population and metastasis associated mediators. Supported by the Clayton Foundation for Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4223. doi:1538-7445.AM2012-4223
Abstract 3373: Clinical trial simulation for the individualization of docetaxel dosing.
Authors: Carlos Perez-Ruixo, Belen Valenzuela, Mario González-Sales, Emiliano Calvo
Journal: Cancer Research (2013)

Abstract Background and objective: To evaluate if docetaxel severe neutropenia can be reduced by pharmacokinetic (PK) and absolute neutrophils counts (ANC) guided dose individualization. Methods: The incidence of Grade 4 neutropenia following docetaxel 75 mg/m2 every 3 weeks (Arm A) or docetaxel individualized dose (Arm B) was predicted on the basis of the model proposed by Bruno [1] and Quartino [2]. Optimal sampling times for PK and ANC assessments after an initial test dose were determined. The individual model parameters estimated using the maximum a posteriori estimation in NONMEM 7 were used to determine the individualized docetaxel dose, defined as the maximum dose that yields a probability of neutropenia Grade 4 lower than 30%. Results: An initial dose of 50 mg/m2 at least 2 weeks earlier, plasma concentrations collected at 1, 3 and 7 h after the start of the infusion, and ANC measurements determine at 0, 7, 14, and 21 days were adequate to determine the individualized dose, without any carry-over effect. The neutropenia Grade 4 incidence was 55% and 45% in arms A and B, respectively. A sample size of 154 patients per arm was need to have a 82% power of detecting the effect of dose individualization. The average docetaxel individualized dose was 55 mg/m2. Conclusions: Docetaxel PKPD guided dose individualization is potentially useful in controlling the PKPD variability and decreasing the incidence of neutropenia Grade 4. 1.Bruno R, Vivier N, Vergniol JC, De Phillips SL, Montay G, Sheiner LB.A population pharmacokinetic model for docetaxel (Taxotere): model building and validation. J Pharmacokinet Biopharm. 1996; 24: 153-172. 2.Quartino AL, Friberg LE, Karlsson MO. A simultaneous analysis of the time-course of leukocytes and neutrophils following docetaxel administration using a semi-mechanistic myelosuppression model. Invest New Drugs. 2012; 30: 833-845. Citation Format: Carlos Perez-Ruixo, Belen Valenzuela, Mario González-Sales, Emiliano Calvo. Clinical trial simulation for the individualization of docetaxel dosing. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3373. doi:10.1158/1538-7445.AM2013-3373
INTRACRANIAL NEOPLASMS IN PSYCHOTIC PATIENTS
Authors: NAOMI RASKIN
Journal: American Journal of Psychiatry (1956)

1. This study indicates that, as found in routine autopsies at the state hospitals, there are many more meningiomas, more pituitary and metastatic tumors, somewhat fewer granulomatous tumors and considerably fewer gliomas than in a general hospital. 2. Most of the undiagnosed intracranial tumors were found in aged patients with severe cerebral arteriosclerosis.
Ryk controls remapping of motor cortex during functional recovery after spinal cord injury
Authors: Edmund R Hollis, Nao Ishiko, Ting Yu, Chin-Chun Lu, Ariela Haimovich, Kristine Tolentino, Alisha Richman, Anna Tury, Shih-Hsiu Wang, Maysam Pessian, Euna Jo, Alex Kolodkin, Yimin Zou
Journal: Nature Neuroscience (2016)
AB0002 Structural analysis of the SPRY domain of pyrin protein by bioinformatics and thermodynamics methods: Implications for the pathogenesis of familial mediterranean fever
Authors: A. Gul, B. Erman
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Familial Mediterranean fever (FMF), the most common hereditary autoinflammatory disorder, is associated with variations in the MEFV gene, which encodes the pyrin protein. The majority of the amino acid substitutions in pyrin are located at the C-terminal <i>SPRY</i> domain, but functional consequences of these variations have yet to be identified. <h3>Objectives</h3> This study aimed to analyze the <i>SPRY</i> domain structure by using a bioinformatics and thermodynamics approach for the prediction of ligand binding sites, energy pathways and their relationship with known FMF-related variations. <h3>Methods</h3> We used the elastic net model for the structural analysis of SPRY, which assumes that fluctuations of the energy are related to fluctuations of residue positions and the connectivity matrix of the protein. This model establishes a connection between energy fluctuation pathways and protein architecture. This model helps to predict the locations of hotspots for ligand binding and identifies the pathways of energy conduction within the protein. We also assessed the possible binding sites of caspase 1 to SPRY domain of pyrin, as one of the few known interacting proteins, using the elastic net model together with molecular docking software GOLD. <h3>Results</h3> Elastic net model analysis of SPRY of pyrin revealed the energy responsive pathway of the domain, which starts with the residue Tyr608 and ends at Phe721 and Tyr732. The residues on this pathway are overlapped with evolutionarily conserved amino acids of the SPRY domain. Tyr608 residue interacted strongly with Gln753, which is located at the bottom of the possible ligand-binding shallow cavity on one side of the SPRY domain. The most penetrant FMF-related variations, Met680Ile and Met694Val, are located at the either sides of this cavity. Molecular docking analyses suggested a strong binding affinity for caspase 1 to the domain through Met680, with a 5-residue tail of caspase 1 interacting with the cavity and energy pathways. <h3>Conclusions</h3> These computational analyses support the critical role of the shallow cavity on one side of the <i>SPRY</i> domain as the ligand-binding site, which connects the ligand binding to the energy-transmission to the neighboring domains. This work reveals possible binding sites of caspase 1 on the SPRY domain and its interaction with the energy transmission pathway. Positioning the most penetrant MEFV variations around this region warrants further investigations for the clarification of their effects on the ligand binding and energy transmission. <h3>Disclosure of Interest</h3> None Declared
ESTABLISHMENT OF NORMAL VALUES FOR HEPATIC EXTRACTION FRACTION (HEF) AND EXCRETION T 1/2 WITH Tc-99m LABELED MEBROFENIN AND DISOFENIN USING A SEMIAUTOMATIC NEW COMPUTER SOFTWARE.
Authors: E. Doo, M. J. Eklem, M. E. Slauson, G. T. Krishnamurthy
Journal: Clinical Nuclear Medicine (1988)
Abstract 2059: HO-3867-induced apoptosis in hypoxic ovarian cancer cells occurs via ubiquitin-dependent degradation of signal transducer and activator of transcription 3 (STAT3)
Authors: Georgia McCann, David Cohn, Kalman Hideg, Periannan Kuppusamy, Selvendiran Karuppaiyah
Journal: Cancer Research (2011)

Abstract Objectives: Hypoxia plays a role in tumorigenesis and the development of resistance to radio- and chemotherapy. We have shown that human xenograft tumors in mice are severely hypoxic and that hypoxic exposure increases the phosphorylation of STAT3 at the Tyr705 residue in A2780 cell lines and is associated with chemotherapeutic resistance. HO-3867, a novel curcumin analogue designed with our institution, induces cell cycle arrest and apoptosis via inhibition of the STAT3 signaling pathway. The goal of this study was to understand the mechanistic pathways involved. Methods: The study was performed using A2780 and SKOV3 human ovarian cancer cell lines grown under normoxic (21% O2) and hypoxic (1% O2) conditions for 24 hours. Hypoxia-exposed cells were subsequently treated with 10 or 20 uM of HO-3867 for 2 and 24 hours. The expression levels of pSTAT3, associated proteins, and apoptotic markers were evaluated by Western blot and RT-PCR. Quantification of apoptosis was performed by staining with Annexin V. We also examined cell viability and involvement of ubiquitin-dependent degradation of pSTAT3. Results: Treatment with HO-3867 under hypoxic conditions resulted in decreased protein expression of pSTAT3 Tyr705 and Ser727. Rapid downregulation of STAT3 correlated with accelerated ubiquitin-dependent degradation of Tyr705-phosphorylated STAT3. Treatment was associated with decreased levels of STAT3-targeting proteins VEGF, Bcl-2, Bcl-xL, and cyclin D1. RT-PCR revealed decreased BCL-2 mRNA expression with treatment. There was no change in expression of proteins upstream of STAT3 including pJAK1, JAK1, pTYK2, TYK2, SOCS1 and SOCS2. An induction in apoptosis contributed to inhibition of cell proliferation as HO-3867-exposed cells exhibited elevated levels of cleaved caspase-3, caspase-7, and PARP as well as an increase in apoptotic cell count measured by flow cytometry. Conclusion: Under hypoxic growth conditions, HO-3867 demonstrates cytotoxicity via inhibition of STAT3. The use of HO-3867 may be a potential adjunct in the treatment of hypoxia-mediated chemotherapy-resistant ovarian cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2059. doi:10.1158/1538-7445.AM2011-2059
TCT-535 I’ll Be Back – The Phenomenon of Recurrent Peripheral Vascular Interventions: Observations from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Vascular Interventions Collaborative (BMC2 VIC)
Authors: Yeo Jung Park, M Ashraf Mansour, Jeffrey Rubin, Tom P. Davis, Jihad A. Mustapha, Roberto A. Corpus, Hitinder S. Gurm, Peter Henke, Paul M. Grossman
Journal: Journal of the American College of Cardiology (2014)
Clinical workload in UK primary care: a retrospective analysis of 100 million consultations in England, 2007–14
Authors: F D Richard Hobbs, Clare Bankhead, Toqir Mukhtar, Sarah Stevens, Rafael Perera-Salazar, Tim Holt, Chris Salisbury
Journal: The Lancet (2016)

Primary care is the main source of health care in many health systems, including the UK National Health Service (NHS), but few objective data exist for the volume and nature of primary care activity. With rising concerns that NHS primary care workload has increased substantially, we aimed to assess the direct clinical workload of general practitioners (GPs) and practice nurses in primary care in the UK.We did a retrospective analysis of GP and nurse consultations of non-temporary patients registered at 398 English general practices between April, 2007, and March, 2014. We used data from electronic health records routinely entered in the Clinical Practice Research Datalink, and linked CPRD data to national datasets. Trends in age-standardised and sex-standardised consultation rates were modelled with joinpoint regression analysis.The dataset comprised 101,818,352 consultations and 20,626,297 person-years of observation. The crude annual consultation rate per person increased by 10·51%, from 4·67 in 2007-08, to 5·16 in 2013-14. Consultation rates were highest in infants (age 0-4 years) and elderly people (≥85 years), and were higher for female patients than for male patients of all ages. The greatest increases in age-standardised and sex-standardised rates were in GPs, with a rise of 12·36% per 10,000 person-years, compared with 0·9% for practice nurses. GP telephone consultation rates doubled, compared with a 5·20% rise in surgery consultations, which accounted for 90% of all consultations. The mean duration of GP surgery consultations increased by 6·7%, from 8·65 min (95% CI 8·64-8·65) to 9·22 min (9·22-9·23), and overall workload increased by 16%.Our findings show a substantial increase in practice consultation rates, average consultation duration, and total patient-facing clinical workload in English general practice. These results suggest that English primary care as currently delivered could be reaching saturation point. Notably, our data only explore direct clinical workload and not indirect activities and professional duties, which have probably also increased. This and additional research questions, including the outcomes of workload changes on other sectors of health care, need urgent answers for primary care provision internationally.Department of Health Policy Research Programme.
EICOSAPENTAENOIC ACID AND ATORVASTATIN ACTIVE METABOLITE, ALONE OR IN COMBINATION, REVERSED GLUCOSE- AND OXIDIZED LDL-INDUCED ENDOTHELIAL DYSFUNCTION MEASURED EX VIVO IN RATS
Authors: R. Preston Mason, Robert F. Jacob, Hazem Dawoud, Michael R. Wagner, Farina J. Mahmud, Samuel C.R. Sherratt, Tadeusz Malinski
Journal: Journal of the American College of Cardiology (2016)
Dissecting Aneurysm with Hemopericardium
Authors: Albert E. Hirst, Benjamin H. Barbour
Journal: New England Journal of Medicine (1958)

HEALING of a dissecting aneurysm of the aorta is not uncommon. Shennan1 observed 79 cases of "healed" dissecting aneurysm among a total of 300 cases in his exhaustive review. Levinson and his associates2 found that 26 per cent of a series of 58 patients survived for three months or longer.Healing typically results in a "double aorta." In such cases the aneurysmal sac usually communicates with the original lumen at its origin and termination, allowing a free flow of blood through both channels. Healing in the sense that thrombosis and complete organization have obliterated the dissected segment has been reported . . .
Compensatory Asymmetric Hemidiaphragmatic Uptake Secondary to Contralateral Hemidiaphragmatic Paresis
Authors: Yingbing Wang, Mannudeep Kalra, James Scott
Journal: Clinical Nuclear Medicine (2012)

A 59-year-old man with diffuse large B-cell lymphoma presenting as an anterior mediastinal mass underwent PET/CT after 2 cycles of chemotherapy. PET/CT shows moderately increased FDG uptake in a predominantly left prevascular mass, consistent with partially treated lymphoma. The left hemidiaphragm is elevated. PET shows asymmetric uptake along the right hemidiaphragm, which is hypothesized to represent compensatory increased workload related to contralateral left diaphragmatic paresis. The left diaphragmatic paresis is likely caused by phrenic nerve involvement by left prevascular mass.
Abstract 3129: COX2 overexpression increases malignant potential of human glioma cells through Id1.
Authors: Kaiming Xu, Hui-Kuo G. Shu
Journal: Cancer Research (2013)

Abstract Increased COX2 expression directly correlates with glioma grade and is also associated with shorter survival in malignant glioma patients. Id1 is similarly overexpressed in higher grade gliomas. Id1 is a member of the helix-loop-helix (HLH) family of transcriptional repressors that act as dominant-negative inhibitors of basic-HLH factors. Recent studies indicate that Id1 may be involved in the genesis/progression of gliomas. Here, we find that COX2 overexpression in human glioma cells correlates with increased Id1 protein levels. We further find that forced expression of COX2 and Id1 enhances soft agar colony formation. In cell invasion assay, both COX2 and Id1 expression in LN229 human glioma cells (LN/COX2 and LN/Id1) increase migration through matrigel. These cells also showed more tumorigenic potential with development of significantly larger subcutaneous tumors compared with controls. Of note, tumors expressing COX2 or Id1 had higher microvessel density than control tumors. Next, the effect of COX2 and Id1 overexpression was assessed in an orthotopic intracranial model. Here, nude mice injected with LN/COX2 or LN/Id1 cells had significantly decreased survival times compared with corresponding controls (Table 1). To assess the role of Id1 induction on the malignant potential of COX2-expressing glioma cells, LN/COX2 cells with shRNA against Id1 were intracranially injected and found to have a statistically significant increase in survival compared to those injected with control shRNA LN/COX2 cells (Table 1). Finally, to test a COX2-targeting therapy, we used the COX2 inhibitor celecoxib in our xenograft model and found inhibition of growth of flank tumors derived from glioma cells overexpressing COX2. In conclusion, COX2 overexpression in human glioma cells results in elevated Id1 protein level, which, in turn, enhances the transformation and invasiveness of human glioma cells, promotes microvessel formation and enhances xenograft tumor growth subcutaneously and intracranially. Table 1. Survival of nude mice injected intracranially with the indicated glioma cells. Expt. 1 Expt. 2 Expt. 3 Cell type N Median Survival (days) N Median Survival (days) N Median Survival (days) LN/Ctrl 10 71 8 78 LN/COX2 10 40 9 53 LN/Id1 9 22 11 21 LN/COX2 shCtrl 10 75 LN/COX2 shId1 10 56 p-value by logrank &amp;lt;0.001 &amp;lt;0.001 0.011 Citation Format: Kaiming Xu, Hui-Kuo G. Shu. COX2 overexpression increases malignant potential of human glioma cells through Id1. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3129. doi:10.1158/1538-7445.AM2013-3129