tbuckley/cabot-search huggingface dataset:
Local hypersensitivity reaction in transgenic mice with squamous epithelial IL-5 overexpression provides a novel model of eosinophilic oesophagitis
Authors: Joanne C Masterson, Eóin N McNamee, Lindsay Hosford, Kelley E Capocelli, Joseph Ruybal, Sophie A Fillon, Alfred D Doyle, Holger K Eltzschig, Anil K Rustgi, Cheryl A Protheroe, Nancy A Lee, James J Lee, Glenn T Furuta
Journal: Gut (2012)

Eosinophilic oesophagitis (EoE) is a chronic inflammatory condition of the oesophagus with limited treatment options. No previous transgenic model has specifically targeted the oesophageal mucosa to induce oesophageal eosinophilia.We developed a mouse model that closely resembles EoE by utilising oxazolone haptenation in mice with transgenic overexpression of an eosinophil poietic and survival factor (interleukin (IL)-5) in resident squamous oesophageal epithelia.Overexpression of IL-5 in the healthy oesophagus was achieved in transgenic mice (L2-IL5) using the squamous epithelial promoter Epstein-Barr virus ED-L2. Oxazolone-challenged L2-IL5 mice developed dose-dependent pan-oesophageal eosinophilia, including eosinophil microabscess formation and degranulation as well as basal cell hyperplasia. Moreover, oesophagi expressed increased IL-13 and the eosinophil agonist chemokine eotaxin-1. Treatment of these mice with corticosteroids significantly reduced eosinophilia and epithelial inflammation.L2-IL5 mice provide a novel experimental model that can potentially be used in preclinical testing of EoE-related therapeutics and mechanistic studies identifying pathogenetic features associated with mucosal eosinophilia.
Results of a Phase II Upfront Window of Pharmacokinetically Guided Topotecan in High-Risk Medulloblastoma and Supratentorial Primitive Neuroectodermal Tumor
Authors: Clinton F. Stewart, Lisa C. Iacono, Murali Chintagumpala, Stewart J. Kellie, David Ashley, W.C. Zamboni, M.N. Kirstein, Maryam Fouladi, Louis G. Seele, Dana Wallace, Peter J. Houghton, Amar Gajjar
Journal: Journal of Clinical Oncology (2004)

To assess the antitumor efficacy of pharmacokinetically guided topotecan dosing in previously untreated patients with medulloblastoma and supratentorial primitive neuroectodermal tumors, and to evaluate plasma and CSF disposition of topotecan in these patients.After maximal surgical resection, 44 children with previously untreated high-risk medulloblastoma were enrolled, of which 36 were assessable for response. The topotecan window consisted of two cycles, administered initially as a 30-minute infusion daily for 5 days, lasting 6 weeks. Pharmacokinetic studies were conducted on day 1 to attain a topotecan lactone area under the plasma concentration-time curve (AUC) of 120 to 160 ng/mL.h. After 10 patients were enrolled, the infusion was modified to 4 hours, with dosage individualization.Of 36 assessable patients, four patients (11.1%) had a complete response and six (16.6%) showed a partial response, and disease was stable in 17 patients (47.2%). Toxicity was mostly hematologic, with only one patient experiencing treatment delay. The target plasma AUC was achieved in 24 of 32 studies (75%) in the 30-minute infusion group, and in 58 of 93 studies (62%) in the 4-hour infusion group. The desired CSF topotecan exposure was achieved in seven of eight pharmacokinetic studies when the topotecan plasma AUC was within target range.Topotecan is an effective agent against pediatric medulloblastoma in patients who have received no therapy other than surgery. Pharmacokinetically guided dosing achieved the target plasma AUC in the majority of patients. This drug warrants testing as part of standard postradiation chemotherapeutic regimens. Furthermore, these results emphasize the importance of translational research in drug development, which in this case identified an effective drug.
Magnetic Nanoparticle-Based Hyperthermia for Head &amp; Neck Cancer in Mouse Models
Authors: Qun Zhao, Luning Wang, Rui Cheng, Leidong Mao, Robert D. Arnold, Elizabeth W. Howerth, Zhuo G. Chen, Simon Platt
Journal: Theranostics (2012)

In this study, magnetic iron oxide nanoparticle induced hyperthermia is applied for treatment of head and neck cancer using a mouse xenograft model of human head and neck cancer (Tu212 cell line).A hyperthermia system for heating iron oxide nanoparticles was developed by using alternating magnetic fields.Both theoretical simulation and experimental studies were performed to verify the thermotherapy effect.Experimental results showed that the temperature of the tumor center has dramatically elevated from around the room temperature to about 40 o C within the first 5-10 minutes.Pathological studies demonstrate epithelial tumor cell destruction associated with the hyperthermia treatment.
Genome-wide Methylation Analysis Identifies Genes Specific to Breast Cancer Hormone Receptor Status and Risk of Recurrence
Authors: Mary Jo Fackler, Christopher B. Umbricht, Danielle Williams, Pedram Argani, Leigh-Ann Cruz, Vanessa F. Merino, Wei Wen Teo, Zhe Zhang, Peng Huang, Kala Visvananthan, Jeffrey Marks, Stephen Ethier, Joe W. Gray, Antonio C. Wolff, Leslie M. Cope, Saraswati Sukumar
Journal: Cancer Research (2011)

To better understand the biology of hormone receptor-positive and-negative breast cancer and to identify methylated gene markers of disease progression, we carried out a genome-wide methylation array analysis on 103 primary invasive breast cancers and 21 normal breast samples, using the Illumina Infinium HumanMethylation27 array that queried 27,578 CpG loci. Estrogen and/or progesterone receptor-positive tumors displayed more hypermethylated loci than estrogen receptor (ER)-negative tumors. However, the hypermethylated loci in ER-negative tumors were clustered closer to the transcriptional start site compared with ER-positive tumors. An ER-classifier set of CpG loci was identified, which independently partitioned primary tumors into ER subtypes. A total of 40 (32 novel and 8 previously known) CpG loci showed differential methylation specific to either ER-positive or ER-negative tumors. Each of the 40 ER subtype-specific loci was validated in silico, using an independent, publicly available methylome dataset from the Cancer Genome Atlas. In addition, we identified 100 methylated CpG loci that were significantly associated with disease progression; the majority of these loci were informative particularly in ER-negative breast cancer. Overall, the set was highly enriched in homeobox containing genes. This pilot study shows the robustness of the breast cancer methylome and illustrates its potential to stratify and reveal biological differences between ER subtypes of breast cancer. Furthermore, it defines candidate ER-specific markers and identifies potential markers predictive of outcome within ER subgroups.
Structural Domains in Phospholemman
Authors: Zhenhui Chen, Larry R. Jones, Jeffrey J. O’Brian, J. Randall Moorman, Steven E. Cala
Journal: Circulation Research (1998)

Abstract —Phospholemman (PLM) is a small (72–amino acid) transmembrane protein found in cardiac sarcolemma that is a major substrate for several protein kinases in vivo. Detailed structural data for PLM is lacking, but several studies have described an ion conductance that results from PLM expression in oocytes. Moreover, addition of purified PLM to lipid bilayers generates similar ion currents, suggesting that the PLM molecule itself might be sufficient for channel formation. To provide a framework for understanding the function of PLM, we investigated PLM topology and structure in sarcolemmal membrane vesicles and analyzed purified recombinant PLM. Immunoblot analyses with site-specific antibodies revealed that the extracellular segment (residues 1 to 17) exists in a protected configuration highly resistant to proteases, even in detergent solutions. The intracellular portion of the molecule (residues 38 to 72), in contrast, was highly susceptible to proteases. Trypsin treatment produced a limit peptide (residues 1 to 43), which showed little change in electrophoretic mobility in SDS gels and retained the ion-channel activity in lipid bilayers that is characteristic of the full-length protein. In addition, we found that conductance through PLM channels exhibited rapid inactivation during depolarizing ramps at voltages greater than ±50 mV, Channels formed by trypsinized PLM or recombinant PLM 1–43 exhibited dramatic reductions in voltage-dependent inactivations. Our data point to distinct domains within the PLM molecule that may correlate with functional properties of channel activity observed in oocytes and lipid bilayers.
Plasma Asymmetric Dimethylarginine and Incidence of Cardiovascular Disease and Death in the Community
Authors: Rainer H. Böger, Lisa M. Sullivan, Edzard Schwedhelm, Thomas J. Wang, Renke Maas, Emelia J. Benjamin, Friedrich Schulze, Vanessa Xanthakis, Ralf A. Benndorf, Ramachandran S. Vasan
Journal: Circulation (2009)

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, induces endothelial dysfunction. Although elevated ADMA has been associated with an increased risk of cardiovascular disease events and death in referral samples, the prognostic significance of ADMA in the community has not been adequately evaluated.
Hybrid Cell–Gene Therapy for Pulmonary Hypertension Based on Phagocytosing Action of Endothelial Progenitor Cells
Authors: Noritoshi Nagaya, Kenji Kangawa, Munetake Kanda, Masaaki Uematsu, Takeshi Horio, Naoto Fukuyama, Jun Hino, Mariko Harada-Shiba, Hiroyuki Okumura, Yasuhiko Tabata, Naoki Mochizuki, Yoshihide Chiba, Keisuke Nishioka, Kunio Miyatake, Takayuki Asahara, Hiroshi Hara, Hidezo Mori
Journal: Circulation (2003)

Circulating endothelial progenitor cells (EPCs) migrate to injured vascular endothelium and differentiate into mature endothelial cells. We investigated whether transplantation of vasodilator gene-transduced EPCs ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats.We obtained EPCs from cultured human umbilical cord blood mononuclear cells and constructed plasmid DNA of adrenomedullin (AM), a potent vasodilator peptide. We used cationic gelatin to produce ionically linked DNA-gelatin complexes. Interestingly, EPCs phagocytosed plasmid DNA-gelatin complexes, which allowed nonviral, highly efficient gene transfer into EPCs. Intravenously administered EPCs were incorporated into the pulmonary vasculature of immunodeficient nude rats given MCT. Transplantation of EPCs alone modestly attenuated MCT-induced pulmonary hypertension (16% decrease in pulmonary vascular resistance). Furthermore, transplantation of AM DNA-transduced EPCs markedly ameliorated pulmonary hypertension in MCT rats (39% decrease in pulmonary vascular resistance). MCT rats transplanted with AM-expressing EPCs had a significantly higher survival rate than those given culture medium or EPCs alone.Umbilical cord blood-derived EPCs had a phagocytosing action that allowed nonviral, highly efficient gene transfer into EPCs. Transplantation of AM gene-transduced EPCs caused significantly greater improvement in pulmonary hypertension in MCT rats than transplantation of EPCs alone. Thus, a novel hybrid cell-gene therapy based on the phagocytosing action of EPCs may be a new therapeutic strategy for the treatment of pulmonary hypertension.
Post-extubation outcomes in a tertiary referral cardio-thoracic intensive care unit (CICU)
Authors: Charlotte Pereira, Martin Rooms, Rakhee Shah, Layla Meshykhi, Grainne Gallagher, Kat Elliott, Sunny Kaul
Journal: European Respiratory Journal (2013)

Extubation failure is associated with increased length of stay (LOS) and higher mortality rate. There is little published data (Thille et al. Crit Care Med 2011; 39:2612-2618) on modifiable risk factors.

Aim: Record outcomes of all patients extubated in a tertiary referral CICU and identify risk factors predicting poorer outcomes.

Hypothesis: Re-admissions, re-intubations and tracheostomies will be associated with poorer outcomes.

Method/Design & Setting : Prospective 1-year observational study in a 25 bedded level 3 CICU facility. Data retrieved from paperless patient record system and patients followed up till discharge or death. The first 6 months data is reported here.

Results: Total number of admissions is 650, (43 re-admissions); 70 % male, mean age 64 years (SD 15). Indications for admission: post-cardiac surgery (71%) transplant (8%) ventricular assist device insertion (4.5%) thoracic surgery (3.5%) cardiology (12%) thoracic medicine (1%). Table 1 shows the outcomes.

View this table:

Table 1





Conclusion: This is the first known report of post-extubation outcomes in a CICU setting. Re-intubation, re-admission, tracheostomy and higher baseline serum creatinine (Cr) are all associated with poor outcomes. Further data collection is underway to identify cardio-respiratory modifiable factors and report 1 year LOS and mortality.
Targeting Sonic Hedgehog-Associated Medulloblastoma through Inhibition of Aurora and Polo-like Kinases
Authors: Shirley L. Markant, Lourdes Adriana Esparza, Jesse Sun, Kelly L. Barton, Lisa M. McCoig, Gerald A. Grant, John R. Crawford, Michael L. Levy, Paul A. Northcott, David Shih, Marc Remke, Michael D. Taylor, Robert J. Wechsler-Reya
Journal: Cancer Research (2013)

Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma.
Atypical Antipsychotics: New Directions and New Challenges in the Treatment of Schizophrenia
Authors: Shitij Kapur, Gary Remington
Journal: Annual Review of Medicine (2001)

▪ Abstract “Atypical” antipsychotics represent a new generation of antipsychotics with a significantly lower incidence of extrapyramidal side effects (EPS), as well as little or no effect on prolactin elevation. These advantages constitute a major improvement in the treatment of patients with schizophrenia. The exact mechanisms that make these drugs atypical is not clear. However, a preferential action on serotonin 5-HT 2 or D 4 receptors, or a more rapid dissociation from the dopamine D 2 receptor, may account for atypicality. Although the atypical antipsychotics have overcome EPS, other side effects such as weight gain and impaired glucose tolerance/lipid abnormalities have come to the fore. Thus, the challenges are far from over. The current atypicals are much more effective against the psychosis of schizophrenia than against the other, more enduring aspects of this disorder, e.g. negative symptoms and cognitive dysfunction. At present, the atypicals use a “pharmacological shotgun” strategy to treat aspects of the disease in all patients. A more sophisticated and perhaps effective approach to schizophrenia may lie in independently targeting the pathophysiological mechanisms of each clinical dimension (i.e. positive, negative, cognitive, and affective) with more selective drugs that can be combined and individually titrated to the needs of each patient.
Adjunctive Versus Monotherapeutic Treatment for Schizophrenia: Addressing Antipsychotic Side Effects
Authors: MONICA HAZRA, DAVID C. MAMO, GARY REMINGTON
Journal: American Journal of Psychiatry (2008)

aripiprazole was added to haloperidol to evaluate the beneficial effects on haloperidol-induced hyperprolactinemia.The authors pointed out that switching is "not always possible in clinical practice, especially if the patient has responded well to the antipsychotic that produced the hyperprolactinemia" (1, p. 1404).The addition of aripiprazole significantly decreased prolactin levels and improved negative symptoms, sleep, and extrapyramidal side effects.The authors attributed these effects to aripiprazole's unique mechanism(s) of action (2).We do not take issue with the scientific merit of this study but are concerned with the clinical implications, specifically the apparent promotion and justification of the adjunctive use of aripiprazole.Well-controlled clinical studies have not supported the use of antipsychotic polypharmacy, and this practice has been associated with increased adverse effects (3, 4), premature death (5), and unnecessary economic demands (6).Good clinical practice argues for the fewest medications possible and, in the case of treatment with antipsychotics, advocates for the adjunctive use of antipsychotics as a last resort (7).As a class, the newer antipsychotics have afforded us advantages in decreasing extrapyramidal symptoms, lowering prolactin
Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas
Authors: Dariush Etemadmoghadam, Anna deFazio, Rameen Beroukhim, Craig Mermel, Joshy George, Gad Getz, Richard Tothill, Aikou Okamoto, Maria B. Raeder, Paul Harnett, Stephen Lade, Lars A. Akslen, Anna V. Tinker, Bianca Locandro, Kathryn Alsop, Yoke-Eng Chiew, Nadia Traficante, Sian Fereday, Daryl Johnson, Stephen Fox, William Sellers, Mitsuyoshi Urashima, Helga B. Salvesen, Matthew Meyerson, David Bowtell
Journal: Clinical Cancer Research (2009)

A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advanced-stage serous cancers.Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling.Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition.We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.
<i>XRCC1</i> Genotype and Breast Cancer: Functional Studies and Epidemiologic Data Show Interactions between <i>XRCC1</i> Codon 280 His and Smoking
Authors: Brian F. Pachkowski, Scott Winkel, Yoshiko Kubota, James A. Swenberg, Robert C. Millikan, Jun Nakamura
Journal: Cancer Research (2006)

Abstract Tobacco smoke produces oxidative and alkylative DNA damage that necessitates repair by base excision repair coordinated by X-ray cross-complementing gene 1 (XRCC1). We investigated whether polymorphisms in XRCC1 alter DNA repair capacity and modify breast cancer risk associated with smoking. To show the functionality of the 280His variant, we evaluated single-strand break (SSB) repair capacity of isogenic Chinese hamster ovary cells expressing human forms of XRCC1 after exposure to hydrogen peroxide (H2O2), methyl methanesulfonate (MMS), or camptothecin by monitoring NAD(P)H. We used data from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study that included 2,077 cases (786 African Americans and 1,281 Whites) and 1,818 controls (681 African Americans and 1,137 Whites), to examine associations among XRCC1 codon 194, 280, and 399 genotypes, breast cancer, and smoking. Odds ratios and 95% confidence intervals (95% CI) were calculated by unconditional logistic regression. Only cells expressing the 280His protein accumulated SSB, indicated by NAD(P)H depletion, from both H2O2 and MMS exposures. In the CBCS, positive associations were observed between breast cancer and smoking dose for participants with XRCC1 codon 194 Arg/Arg (Ptrend = 0.046), 399 Arg/Arg (Ptrend = 0.012), and 280 His/His or His/Arg (Ptrend = 0.047) genotypes. The 280His allele was in strong linkage disequilibrium with 194Arg (Lewontin's D′ = 1.0) and 399Arg (D′ = 1.0). These data suggest that less common, functional polymorphisms may lie within common haplotypes and drive gene-environment interactions. (Cancer Res 2006; 66(5): 2860-8)