tbuckley/cabot-search huggingface dataset:
Tissue Gene Expression of Renin-Angiotensin System in Human Type 2 Diabetic Nephropathy
Authors: Tadashi Konoshita, Shigeyuki Wakahara, Shinichi Mizuno, Makoto Motomura, Chikako Aoyama, Yasukazu Makino, Yasuyuki Kawai, Norihiro Kato, Ichiro Koni, Isamu Miyamori, Hiroshi Mabuchi
Journal: Diabetes Care (2006)

OBJECTIVE—Recent studies have proved that blockade of the renin-angiotensin system (RAS) retards the progression of diabetic nephropathy, whereas hyporeninemia is known as a typical state in diabetic subjects. The purpose of this study is to determine whether expression levels of RAS differ between nondiabetic and diabetic renal tissues with accurate quantitative method. RESEARCH DESIGN AND METHODS—Subjects were 66 nondiabetic and 8 diabetic patients with biopsy-proven renal diseases. The eight diabetic subjects suffered from type 2 diabetes with overt proteinuria. Renal histology revealed typical diffuse or nodular lesions with linear IgG deposit on immunofluorescent staining and thickened basement membrane on electronic microscopy. Total RNA from a small part of the renal cortical biopsy specimens was reverse-transcribed, and the resultant cDNA was amplified for new major components of RAS (i.e., renin, renin receptor, angiotensinogen, ACE, ACE2, angiotensin II type 1 receptor, and angiotensin II type 2 receptor) and measured. RESULTS—Among these components, a significant upregulation was observed in the ACE gene in diabetic renal tissue. CONCLUSIONS—The results suggest that renal tissue RAS might be activated in the respect that ACE gene expression is upregulated in spite of a tendency to low renin expression in type 2 diabetic nephropathy.
Pathogenesis of NUT Midline Carcinoma
Authors: Christopher A. French
Journal: Annual Review of Pathology Mechanisms of Disease (2011)

NUT midline carcinoma (NMC), an aggressive form of squamous cell carcinoma, is defined by the presence of acquired chromosomal rearrangements involving NUT, usually BRD4-NUT fusion genes and, less commonly, NUT-variant fusion genes involving BRD3 or still-uncharacterized genes. Improved diagnostic tests reveal that although rare, NMCs occur in people of any age and may be indistinguishable from more common squamous cell carcinomas of adulthood. NMCs have simple karyotypes whose hallmark is genomic instability, suggesting that NMC arises through a distinct pathogenic pathway representing a genetic shortcut to the phenotype of squamous cell carcinoma. Mechanistically, BRD-NUT fusion proteins appear to act by blocking differentiation, possibly by sequestering histone acetyltransferase activity. Accordingly, histone deacetylase inhibitors or BET inhibitors, the latter of which inhibit binding of BRD-NUT proteins to chromatin, induce terminal differentiation of NMC cells. These insights provide a rationale for targeted therapy of NMC, which is almost uniformly refractory to conventional chemotherapy and radiotherapy.
The ingestion and digestion of human lactoferrin by mouse peritoneal macrophages and the transfer of its iron into ferritin.
Authors: J L van Snick, B Markowetz, P L Masson
Journal: The Journal of Experimental Medicine (1977)

Human lactoferrin (Lf) labeled with 125I and/or 59Fe was found to be ingested in vitro by mouse peritoneal macrophages (MPM). The uptake measured after 15 h incubation reached a saturation point at a concentration of 200 microgram/ml in the culture medium, whatever was the iron content of Lf. In such conditions, the uptake of transferrin (Tf) used as a control was 10 times lower. At a concentration of 80 microgram/ml in the medium, one cell picked up about 0.7 X 10(6) molecules of Lf per hour, and 0.13 X 10(6) molecules of Tf per hour. Iron-saturated Lf disappeared from MPM with a half life of 14.5 h, whereas the halflife of iron-free Lf was 4.2 h. Concomitant with the intracellular digestion of Lf, the iron was transmitted to ferritin. These data provide additional support for the hypothesis that Lf plays a key role in iron turnover, especially at the level of the reticuloendothelial system where iron is recovered from the catabolism of erythrocytes.
The Evolution of Antibodies into Versatile Tumor-Targeting Agents
Authors: Michael Z. Lin, Michael A. Teitell, Gary J. Schiller
Journal: Clinical Cancer Research (2005)

In recent years, monoclonal antibodies have become important weapons in the arsenal of anticancer drugs, and in select cases are now the drugs of choice due to their favorable toxicity profiles. Originally developed to confer passive immunity against tumor-specific antigens, clinical uses of monoclonal antibodies are expanding to include growth factor sequestration, signal transduction modulation, and tumor-specific drug delivery. In this review, we shall present the origins of antibody therapeutics within the field of immunotherapy and their evolution into effective anticancer agents, then discuss their multiple mechanisms of action, the basis of their tumor selectivity, and their therapeutic properties compared with traditional therapies. Antibodies are complex molecules whose efficacy and toxicity depend on the antigen, the antibody, any conjugated groups, and even the patient. Finally, we shall present new technologies being developed to increase the efficacy and selectivity of antibody-based therapeutics. Interestingly, many of the new approaches straddle the middle ground between immunotherapy and the traditional modalities of chemotherapy and radiotherapy, and can be seen as ways of combining the selectivity of the former with the efficacy of the latter.
Atrial wave propagation determining by color M-mode doppler in assessment of diastolic dysfunction
Authors: Alexandros P. Patrianakos, Frangiskos I. Parthenakis, Evanglos A. Papadimitriou, George F. Diakakis, Panagiotis G. Tzerakis, Panos E. Vardas
Journal: Journal of the American College of Cardiology (2003)
Morphologic and molecular characterization of ATRT xenografts adapted for orthotopic therapeutic testing
Authors: R. Hashizume, N. Gupta, M. S. Berger, A. Banerjee, M. D. Prados, J. Ayers-Ringler, C. D. James, S. R. VandenBerg
Journal: Neuro-Oncology (2010)

Atypical teratoid rhabdoid tumor (ATRT) is a malignant tumor of the central nervous system that most commonly arises in young children. The aggressive growth and propensity for early dissemination throughout the neuraxis confers a dismal prognosis. Large clinical trials that could test new therapeutic agents are difficult to conduct due to the low incidence of this cancer. For this reason, high throughput preclinical testing with suitable animal models for ATRT would serve a critical need for identifying the most efficacious treatments. In response to this need, we have adapted ATRT cell lines for bioluminescence imaging (BLI) of intracranial (orthotopic) xenografts established in athymic mice. Our results indicate that following supratentorial or infratentorial injection in athymic mice, ATRT cells produce rapidly growing tumors, often with intraventricular spread or neuraxis dissemination. When established as orthotopic xenografts, the tumors predominantly display cells with a rhabdoid-like cellular morphology that show a spectrum of immunophenotypes similar to primary ATRT tumors. To demonstrate the feasibility of this orthotopic ATRT xenograft model for therapeutic testing with correlation to biomarker analysis, we examined the responses of luciferase-modified ATRT cells to temozolomide (TMZ). These xenografts, which highly express MGMT, are resistant to TMZ treatment when compared with an orthotopic glioblastoma xenograft that is MGMT deficient and responsive to TMZ. These data suggest that an orthotopic ATRT xenograft model, in which BLI is used for monitoring tumor growth and response to therapy, should contribute to the identification of effective therapeutics and regimens for treating this highly aggressive pediatric brain tumor.
Statistical model for assessing the proportion of subjects with subjective sensitisations in adverse reactions to foods
Authors: David Briggs, Laurence Aspinall, Andrea Dickens, Carsten Bindslev‐Jensen
Journal: Allergy (2001)

The outcome from a Double-Blind Placebo-Controlled Food Challenge is often of a subjective nature and cannot be measured directly. Reactions to placebo challenges are frequently observed, implying that some of the responses in the study are in fact 'false responses'. In order to adjust for these false responses, previous studies have used various methods, including removing subjects from the analysis who reacted to the placebo. Simply ignoring the false responses can lead to misleading estimates for the true proportion of sensitised individuals. This paper outlines two models which can account for these false responses. In the single challenge study, a simple model is developed which enables the estimation of the rate of false responses in the study, as well as the true proportion of sensitised subjects. This model is very easy to apply in practice. For a repeated challenge study, a more complicated model is developed which again enables the estimation of the rate of false responses and the true proportion of sensitised subjects.
Identification and Prognostic Significance of an Epithelial-Mesenchymal Transition Expression Profile in Human Bladder Tumors
Authors: Egbert Baumgart, Michael S. Cohen, Brasil Silva Neto, Micah A. Jacobs, Chad Wotkowicz, Kimberly M. Rieger-Christ, Andreia Biolo, Ron Zeheb, Massimo Loda, John A. Libertino, Ian C. Summerhayes
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Epithelial to mesenchymal transition (EMT) is reportedly an important transition in cancer progression in which the underlying cellular changes have been identified mainly using in vitro models. In this study, we examined the expression pattern of EMT markers in vivo and determined the occurrence and clinical significance of these events in a series of bladder carcinomas. Experimental Design: Eight hundred and twenty-five tumor samples from 572 bladder cancer patients were assembled in 10 tissue microarrays. Paraffin sections from each tissue microarray were subjected to antigen retrieval and processed by immunohistochemistry for the expression of E-cadherin, plakoglobin, β-catenin, N-cadherin, and vimentin. Results: Pathologic expression of E-cadherin, β-catenin, plakoglobin, and vimentin were associated with the clinicopathologic variables of grade and stage with only the cytoplasmic localization of plakoglobin found associated with lymph node status. Associations between the aforementioned markers were found significant as determined by the Spearman correlation coefficient with N-cadherin showing no associations in this analysis. In univariate survival analysis involving patients who underwent cystectomy, the reduction or loss of plakoglobin significantly influenced overall survival (P = 0.02) in which the median time to death was 2 years compared with 4 years when a normal level of plakoglobin was recorded. When the analysis was done for cancer-specific survival, low levels of both plakoglobin (P = 0.02) and β-catenin (P = 0.02) significantly influenced survival. Conclusion: The putative markers of EMT defined within a panel of bladder carcinoma cell lines were recorded in vivo, frequently associated with tumors of high grade and stage. Although multivariate analysis showed no significant influence of the EMT biomarkers on survival, alterations associated with plakoglobin were identified as significant prognostic features in these tumors.
Analysis of lung function and survival in RECAP: An open-label extension study of pirfenidone (PFD) in patients with idiopathic pulmonary fibrosis (IPF)
Authors: Ulrich Costabel, Carlo Albera, Williamson Bradford, Phil Hormel, Talmadge King, Paul Noble, Steven Sahn, Dominique Valeyre, Roland du Bois
Journal: European Respiratory Journal (2012)

Introduction:  RECAP is an open-label extension study evaluating long-term treatment with PFD in IPF patients who completed one of the CAPACITY (CAP) trials.   Objective:  Further examine the effect of PFD on lung function and survival in patients with IPF.   Methods:  PFD 2403 mg/d was administered orally in 3 equally divided doses. Forced vital capacity (FVC) was measured at baseline and Wks 12, 36, and 60. To facilitate comparison with CAP outcomes, analyses were based on patients newly-treated with PFD in RECAP who had baseline FVC and DLco values that met CAP entry criteria.   Results:  A total of 178 patients were newly-treated with PFD in RECAP and had baseline values that met CAP entry criteria. The mean change from baseline to Wk 60 in %FVC in this group was –5.8%; mean change over the corresponding period in CAP was –7.0% in the PFD group (N=345) and –9.4% in the placebo group (N=347). The percentage of patients with an FVC decline ≥10% was 16.6% in RECAP, compared with 16.8% and 24.8%, respectively, in the PFD and placebo groups in CAP. Overall survival in newly-treated patients in RECAP was similar to that of PFD patients in CAP ( Figure 1 ).  Conclusions:  FVC and survival outcomes in IPF patients newly treated with PFD in RECAP were similar to those in PFD-treated patients in CAP. These data provide further evidence to support the use of PFD in patients with IPF.
Modeling Infection Transmission
Authors: Jim Koopman
Journal: Annual Review of Public Health (2004)

Understanding what determines patterns of infection spread in populations is important for controlling infection transmission. The science that advances this understanding uses mathematical and computer models that vary from deterministic models of continuous populations to models of dynamically evolving contact networks between individuals. These provide insight, serve as scientific theories, help design studies, and help analyze data. The key to their use lies in assessing the robustness of inferences made using them to violation of their simplifying assumptions. This involves changing model forms from deterministic to stochastic and from compartmental to network, as well as adding realistic detail and changing parameter values. Currently inferences about infection transmission are often made using stratified rate or risk comparisons, logistic regression models, or proportionate hazards models that assume an absence of transmission. Robustness assessment will show many of these inferences to be wrong. A community of epidemiologist modelers is needed for effective robustness assessment.
Hypoxic induction of vascular endothelial growth factor is markedly decreased in diabetic individuals who do not develop retinopathy.
Authors: S Marsh, F M Nakhoul, K Skorecki, A Rubin, B P Miller, R Leibu, N S Levy, A P Levy
Journal: Diabetes Care (2000)

OBJECTIVE: A small percentage of patients do not develop any evidence of diabetic retinopathy (DR) even after many years of diabetes. Vascular endothelial growth factor (VEGF) has been implicated in the development of DR. Therefore, we sought to determine if the regulation of VEGF differs in those patients who develop DR after many years of diabetes compared with those who do not develop DR. RESEARCH DESIGN AND METHODS: We performed standard 7-field stereoscopic fundus photography on 95 consecutive patients with type 1 and type 2 diabetes. Patients were categorized into 3 groups according to the presence or absence of DR and the duration of diabetes: group 1 was defined by presence of DR, group 2 was defined by absence of DR after &amp;gt;10 years duration of diabetes, and group 3 was defined by absence of DR with long-standing diabetes (&amp;gt; or =20 years for type 1 diabetes and &amp;gt; or =15 years for type 2 diabetes). Monocytes from 40 ml peripheral blood were isolated from all patients, and the hypoxic induction of VEGF was determined in vitro. RESULTS: We found no significant difference in the basal level of VEGF in patients with and without DR. However, we did find a markedly significant difference in the hypoxic induction of VEGF between patients from group 1 and group 3 (4.35+/-0.55 vs. 1.87+/-0.3, P&amp;lt;0.00013). CONCLUSIONS: This study suggests that 1 mechanism for the absence of DR in patients with long-standing diabetes is a decreased hypoxic induction of VEGF.
Lens Epithelium-derived Growth Factor/p75 Qualifies as a Target for HIV Gene Therapy in the NSG Mouse Model
Authors: Sofie Vets, Janine Kimpel, Andreas Volk, Jan De Rijck, Rik Schrijvers, Bert Verbinnen, Wim Maes, Dorothee Von Laer, Zeger Debyser, Rik Gijsbers
Journal: Molecular Therapy (2012)

Lens epithelium-derived growth factor (LEDGF/p75) is an essential cofactor of HIV integration. Both stable overexpression of the C-terminal part of LEDGF/p75 (LEDGF(325-530)) containing the integrase (IN)-binding domain (IBD) and stable knockdown (KD) of LEDGF/p75 are known to inhibit HIV infection in laboratory cell lines. Here, primary human CD(4)(+) T-cells were transduced with lentiviral vectors encoding LEDGF(325-530), the interaction-deficient mutant LEDGF(325-530)D366N, or a hairpin depleting LEDGF/p75 and challenged with HIV. Maximal protection of primary T-cells from HIV infection was obtained after LEDGF(325-530) overexpression reducing HIV replication 40-fold without evidence of cellular toxicity. This strategy was subsequently evaluated in the NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ (NSG) mouse model. Threefold reduction in mean plasma viral load was obtained in mice engrafted with CD(4)(+) T-cells expressing LEDGF(325-530) in comparison with engraftment with LEDGF(325-530)D366N cells. Four weeks after transplantation with LEDGF(325-530)D366N cells, 70% of the CD(4)(+) cells were lost due to ongoing HIV replication. However, in mice transplanted with LEDGF(325-530) cells only a 20% decrease in CD(4)(+) cells was measured. Liver and spleen sections of LEDGF(325-530) mice contained less HIV than LEDGF(325-530)D366N mice as measured by p24 antigen detection. LEDGF(325-530) overexpression potently inhibits HIV replication in vivo and protects against HIV mediated cell killing of primary CD(4)(+) T-cells.
Fibromyalgia: a randomised, controlled trial of a treatment programme based on self management
Authors: C Cedraschi
Journal: Annals of the Rheumatic Diseases (2004)

<b>Objective:</b> To evaluate the efficacy of a treatment programme for patients with fibromyalgia (FM) based on self management, using pool exercises and education. <b>Methods:</b> Randomised controlled trial with a 6 month follow up to evaluate an outpatient multidisciplinary programme; 164 patients with FM were allocated to an immediate 6 week programme (n = 84) or to a waiting list control group (n = 80). The main outcomes were changes in quality of life, functional consequences, patient satisfaction and pain, using a combination of patient questionnaires and clinical examinations. The questionnaires included the Fibromyalgia Impact Questionnaire (FIQ), Psychological General Well-Being (PGWB) index, regional pain score diagrams, and patient satisfaction measures. <b>Results:</b> 61 participants in the treatment group and 68 controls completed the programme and 6 month follow up examinations. Six months after programme completion, significant improvements in quality of life and functional consequences of FM were seen in the treatment group as compared with the controls and as measured by scores on both the FIQ (total score p = 0.025; fatigue p = 0.003; depression p = 0.031) and PGWB (total score p = 0.032; anxiety p = 0.011; vitality p = 0.013,). All four major areas of patient satisfaction showed greater improvement in the treatment than the control groups; between-group differences were statistically significant for “control of symptoms”, “psychosocial factors”, and “physical therapy” No change in pain was seen. <b>Conclusion:</b> A 6 week self management based programme of pool exercises and education can improve the quality of life of patients with FM and their satisfaction with treatment. These improvements are sustained for at least 6 months after programme completion.
Demonstration of Re-entry within the His-Purkinje System in Man
Authors: MASOOD AKHTAR, ANTHONY N. DAMATO, WILLIAM P. BATSFORD, JEREMY N. RUSKIN, J. BIMBOLA OGUNKELU, GUILLERMO VARGAS
Journal: Circulation (1974)

Re-entry within the His-Purkinje system (HPS) was consistently observed in 15/24 consecutive patients in whom retrograde refractory period studies were performed using His bundle electrograms and the ventricular extrastimulus method. Within a narrow range of ventricular coupling intervals (V 1 V 2 ), V 2 retrogradely conducted to the bundle of His (H 2 ) with significant infra-His bundle conduction delay (V 2 H 2 interval). At critical V 2 H 2 delays another beat of ventricular origin (V 3 ) followed V 2 and was associated with H 2 V 3 intervals greater than the H-V intervals of sinus beat. It is postulated that V 2 retrogradely blocked within the right bundle branch and activated the bundle of His via the left bundle branch after which antegrade conduction occurred along the right bundle branch producing the V 3 response. In support of re-entry within the HPS are the following: 1) V 3 occurred in a narrow range of V 1 V 2 intervals and critical V 2 H 2 delays, 2) V 3 did not occur when V 2 retrogradely blocked below the bundle of His, 3) V 3 was independent of retrograde A-V nodal delay, 4) V 3 rarely occurred in patients with pre-existing complete right bundle branch block pattern. These results reasonably exclude local re-entry near the site of stimulation.
Phase II trial of 5-fluorouracil plus eniluracil in patients with advanced pancreatic cancer: a Southwest Oncology Group study
Authors: M.L. Rothenberg, J.K. Benedetti, J.S. Macdonald, T.E. Seay, M.A. Neubauer, C.S. George, M.S. Tanaka, J.K. Giguere, B.T. Pruitt, J.L. Abbruzzese
Journal: Annals of Oncology (2002)
Effect of the BH3 mimetic ABT-737 on human melanoma cells to apoptosis induced by selective BRAF inhibitors.
Authors: Peter Hersey, David Wroblewski, Branka Mijatov, Xu Dong Zhang, Nikolas Haass
Journal: Journal of Clinical Oncology (2012)

8553 Background: Although the introduction of selective BRAF inhibitors has been a major advance in treatment of metastatic melanoma, approximately 50% of patients have limited responses including stabilisation of disease or no response at all. The present study aims to identify a novel means of overcoming resistance of melanoma to killing by BRAF inhibitors. Methods: We examined the influence of the BH3 mimetic ABT-737 on induction of apoptosis by the selective BRAF inhibitor PLX4720 on a panel of melanoma cells with BRAF V600E mutations with or without mutations of CDK4 and BRAF wildtype cells with or without NRAS mutations. Included in the studies were cell lines established from 4 patients before and during treatment with selective BRAF inhibitors. Results: Cell lines with no or low sensitivity to PLX 4720 underwent synergistic increases and increased rates of apoptosis when combined with ABT-737. This degree of synergism was not seen in cell lines without BRAF V600E mutations. Apoptosis was mediated through the mitochondrial pathway and was due in part to upregulation of Bim as shown by inhibition of apoptosis following siRNA knockdown of Bim. Similar effects were seen in cell lines established from patients prior to treatment but not in lines from patients clinically resistant to the selective BRAF inhibitors. Conclusions: These results suggest that combination of selective BRAF inhibitors with ABT-737 or the oral form ABT-263 may increase the degree and rate of responses in previously untreated patients with V600E melanoma but not in those with acquired resistance to these agents.