tbuckley/cabot-search huggingface dataset:
Diabetes and Endothelial Dysfunction: A Clinical Perspective
Authors: Jorge Calles-Escandon, Marilyn Cipolla
Journal: Endocrine Reviews (2001)

The main etiology for mortality and a great percent of morbidity in patients with diabetes mellitus is atherosclerosis. A hypothesis for the initial lesion of atherosclerosis is endothelial dysfunction, defined pragmatically as changes in the concentration of the chemical messengers produced by the endothelial cell and/or by blunting of the nitric oxide-dependent vasodilatory response to acetylcholine or hyperemia. Endothelial dysfunction has been documented in patients with diabetes and in individuals with insulin resistance or at high risk for developing type 2 diabetes. Factors associated with endothelial dysfunction in diabetes include activation of protein kinase C, overexpression of growth factors and/or cytokines, and oxidative stress. Several therapeutic interventions have been tested in clinical trials aimed at improving endothelial function in patients with diabetes. Insulin sensitizers may have a beneficial effect in the short term, but the virtual absence of trials with cardiovascular end-points preclude any definitive conclusion. Two trials offer optimism that treatment with ACE inhibitors may have a positive impact on the progression of atherosclerosis. Although widely used, the effect of hypolipidemic agents on endothelial function in diabetes is not clear. The role of antioxidant therapy is controversial. No data have been published regarding the effects of hormonal replacement therapy on endothelial dysfunction in postmenopausal women with type 2 diabetes.
Adenovirus-Mediated Gene Transfer of VEGF <sub>121</sub> Improves Lower-Extremity Endothelial Function and Flow Reserve
Authors: Sanjay Rajagopalan, Manan Shah, Ann Luciano, Ronald Crystal, Elizabeth G. Nabel
Journal: Circulation (2001)

Background Vascular endothelial growth factor (VEGF) currently is being evaluated in clinical angiogenesis trials involving patients with peripheral arterial disease. We hypothesized that delivery of VEGF to the skeletal muscle of the lower extremity using an adenoviral vector (Ad GV VEGF 121.10 ) would improve peripheral endothelial function. Accordingly, we investigated lower-extremity endothelial function in patients enrolled in a Phase I adenovirus-mediated gene delivery trial of VEGF 121.10 . Methods and Results Blood flow to the index extremity was measured by thermodilution at baseline and 30 days after administration of Ad GV VEGF 121.10 , in response to the infusion of endothelium-dependent and -independent agonists (acetylcholine and nitroglycerin, respectively) into the ipsilateral femoral artery. There was no difference in basal flow before or after treatment with Ad GV VEGF 121.10 . In response to acetylcholine (150 μg/min and 300 μg/min), there was a 0.9-fold (0.33±0.03 to 0.32±0.03 L/min) and 1.2-fold (0.33±0.03 to 0.490±0.02 L/min) change in flow before Ad GV VEGF 121.10 treatment. After Ad GV VEGF 121.10 treatment, flow increased 2.4-fold (0.310±0.04 to 0.730±0.10 L/min) and 2.3-fold (0.31±0.04 to 0.7±0.08 L/min), respectively ( P &lt;0.05 before Ad GV VEGF 121.10 treatment versus after Ad GV VEGF 121.10 for both doses). Infusion of nitroglycerin resulted in a 1.8-fold increase in flow before Ad GV VEGF 121.10 (0.33±0.03 to 0.58±0.06 L/min) compared with a 2.4-fold increase (0.31±0.04 to 0.73±0.09 L/min) after Ad GV VEGF 121.10 ( P =NS before Ad GV VEGF 121.10 versus after Ad GV VEGF 121.10 ). Lower-extremity flow reserve increased in all patients in response to at least 1 dose of acetylcholine. Peak walking times increased concomitant with improvement in endothelial function. Conclusions Adenoviral gene transfer of VEGF 121.10 appears to modulate endothelial function and lower-extremity flow reserve in patients with peripheral arterial disease.
T Lymphocytes and mononuclear phagocytes in the skin infiltrate of systemic and discoid lupus erythematosus and Jessner's lymphocytic infiltrate
Authors: Y. T. KONTTINEN, S. REITAMO, A. RANKI, M. SEGERBERG-KONTTINEN
Journal: British Journal of Dermatology (1981)

T Lymphocytes and mononuclear phagocytes were measured quantitatively with the histochemical acid alpha-naphthyl acetate esterase (ANAE) method from paraffin sections of skin affected by systemic and discoid lupus erythematosus and by Jessner's lymphocytic infiltrate. The composition of the patchy cutaneous mononuclear cell infiltrates was similar in these three disorders.
Multicenter Phase III Randomized Trial Comparing Docetaxel and Trastuzumab With Docetaxel, Carboplatin, and Trastuzumab As First-Line Chemotherapy for Patients With <i>HER2-</i>Gene-Amplified Metastatic Breast Cancer (BCIRG 007 Study): Two Highly Active Therapeutic Regimens
Authors: Vicente Valero, John Forbes, Mark D. Pegram, Tadeusz Pienkowski, Wolfgang Eiermann, Gunter von Minckwitz, Henri Roche, Miguel Martin, John Crown, John R. Mackey, Pierre Fumoleau, Janusz Rolski, Zrinka Mrsic-Krmpotic, Agnieszka Jagiello-Gruszfeld, Alessandro Riva, Marc Buyse, Henry Taupin, Guido Sauter, Michael F. Press, Dennis J. Slamon
Journal: Journal of Clinical Oncology (2010)

Docetaxel-trastuzumab (TH) is effective therapy for HER2-amplified metastatic breast cancer (MBC). Preclinical findings of synergy between docetaxel, carboplatin, and trastuzumab (TCH) prompted a phase III randomized trial comparing TCH with TH in patients with HER2-amplified MBC.Two hundred sixty-three patients were randomly assigned to receive eight 3-week cycles of TH (trastuzumab plus docetaxel 100 mg/m(2)) or TCH (trastuzumab plus carboplatin at area under the serum concentration-time curve 6 and docetaxel 75 mg/m(2)). Trastuzumab was given at 4 mg/kg loading dose followed by a 2 mg/kg dose once per week during chemotherapy, and then 6 mg/kg once every 3 weeks until progression.Patient characteristics were balanced between groups. There was no significant difference between TH and TCH in terms of the primary end point, time to progression (medians of 11.1 and 10.4 months, respectively; hazard ratio, 0.914; 95% CI, 0.694 to 1.203; P = .57), response rate (72% for both groups), or overall survival (medians of 37.1 and 37.4 months, respectively; P = .99). Rates of grades 3 or 4 adverse effects for TH and TCH, respectively, were neutropenic-related complications, 29% and 23%; thrombocytopenia, 2% and 15%; anemia, 5% and 11%; sensory neuropathy, 3% and 0.8%; fatigue, 5% and 12%; peripheral edema, 3.8% and 1.5%; and diarrhea, 2% and 10%. Two patients given TCH died of sepsis, and one patient given TH experienced sudden cardiac death. Absolute left ventricular ejection fraction decline > 15% was seen in 5.5% of patients on the TH arm and 6.7% of patients on the TCH arm.Adding carboplatin did not enhance TH antitumor activity.TH (docetaxel, 100 mg/m(2)) and TCH (docetaxel, 75 mg/m(2)) demonstrated efficacy with acceptable toxicity in women with HER2-amplified MBC.
Late-Stage Cancer Patients Remain Highly Responsive to Immune Activation by the Selective TLR8 Agonist Motolimod (VTX-2337)
Authors: Gregory N. Dietsch, Tressa D. Randall, Raphael Gottardo, Donald W. Northfelt, Ramesh K. Ramanathan, Peter A. Cohen, Kristi L. Manjarrez, Mona Newkirk, James Kyle Bryan, Robert M. Hershberg
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Immunotherapy as a treatment for cancer holds the promise of complete and durable tumor remission, yet the immunosuppressive environment created by many tumors, advanced patient age, and previous treatments with cytotoxic agents may limit the approach. The activity of motolimod (VTX-2337), a potent and selective Toll-like receptor 8 (TLR8) agonist, was therefore assessed in the context of advanced, late-stage cancer patients. Experimental Design: The repertoire of mediators induced from human peripheral blood mononuclear cells in response to motolimod was characterized. Translational studies in cynomolgus monkeys elucidated the activity of motolimod on an intact immune system, identified biomarkers of TLR8 activation, and defined the relationship between the pharmacokinetic and pharmacodynamic (PK/PD) response. The PK/PD relationship for motolimod in cancer patients was assessed, compared with preclinical findings, and contrasted with activity in healthy volunteers. Results: In late-stage cancer patients, plasma levels of multiple biomarkers, including IL6, G-CSF, MCP-1, and MIP1-β, increased with increasing motolimod dose. The magnitude and breadth of the biomarker response closely aligned with the response seen in preclinical studies, demonstrating that advanced cancer patients remained responsive to TLR8 activation. In addition, the PK/PD response in cancer patients closely aligned with the activity of motolimod seen in healthy volunteers. Conclusions: Late-stage cancer patients are highly sensitive to TLR8 activation by motolimod. Tumor burden, advanced age, and prior treatment history with cytotoxic agents did not moderate or modify the response predicted by nonclinical studies and confirmed in healthy volunteers. Clin Cancer Res; 21(24); 5445–52. ©2015 AACR.
Developmental regulation of lck gene expression in T lymphocytes.
Authors: R S Wildin, A M Garvin, S Pawar, D B Lewis, K M Abraham, K A Forbush, S F Ziegler, J M Allen, R M Perlmutter
Journal: The Journal of Experimental Medicine (1991)

In the mouse and human, mRNA transcripts encoding the lymphocyte-specific protein tyrosine kinase p56lck are derived from two separate promoters resulting in heterogeneity in the 5' untranslated region sequence. The proximal promoter lies just 5' to the coding region for the gene and is active only in thymocytes. In contrast, the distal promoter lies 34 kilobases (kb) 5' in the human, and is active both in thymocytes and mature peripheral T cells. As previously reported, transgenic mice bearing functional proximal promoter sequence juxtaposed with the SV40 large T antigen gene invariably develop lymphoid tumors confined to the thymus. In the current work, transgenic mice bearing a 2.6-kb fragment of the human distal promoter fused to the SV40 large T antigen gene express large T antigen in thymocytes and in peripheral lymphoid cells, and develop tumors of both the thymus and the peripheral lymphoid organs. The ability of the human distal promoter to function appropriately in transgenic mice is consistent with the strong similarity observed between the mouse and human distal promoter sequences. With the exception of a single short interval that serves as a target for binding of nuclear factors, significant sequence similarity is not seen when the distal and proximal promoter sequences are compared. Hence, developmentally regulated, lineage-specific transcription of the lck gene is mediated by distinct promoter sequences that appear to be capable of functioning independently.
Is there a future for extracorporeal photochemotherapy in the treatment of the rheumatological diseases?
Authors: M R HOLBROOK, R J POWELL
Journal: Annals of the Rheumatic Diseases (1997)

The list of so called ‘disease modifying agents’ in rheumatoid arthritis now includes methotrexate and cyclosporin A. The efficacy of certain speculative treatments in the rheumatic diseases including antibody based therapies such as anti-tumour necrosis factor1 and anti-ICAM,2 cytokine toxic fusion proteins,3 oral administration of antigens,4 stem cell therapy,5 and cytokine receptor antagonists6 are being investigated. After the reported success of extracorporeal photochemotherapy (ECP) in systemically disseminated cutaneous T cell lymphoma7 in 1987 its benefits are also being explored in rheumatological conditions.

Two hours after oral methoxypsoralen, blood is removed from the patient, exposed to ultraviolet A light at room temperature, and then reinfused. This procedure can either be done as a continuous flow or by concentrating the lymphocytes and reinfusing as a bolus, and is usually performed on two consecutive days each month. In the initial group of 37 patients with therapy resistant cutaneous T cell lymphoma 27 improved with ECP, and over the past 10 years ECP has been adopted increasingly for this condition.

Methoxypsoralen is a photoreactive agent that is temporarily transformed into its active form on exposure to ultraviolet A light before reverting in a fraction of a second to its inactive state. While ultraviolet A activated psoralens have a direct effect on intracellular DNA8 leading to cell death, this alone is unlikely to account for the …
Transcriptional Regulation During Development of the Ductus Arteriosus
Authors: Kathryn N. Ivey, David Sutcliffe, James Richardson, Ronald I. Clyman, Joseph A. Garcia, Deepak Srivastava
Journal: Circulation Research (2008)

The ductus arteriosus is a specialized blood vessel containing highly differentiated and contractile vascular smooth muscle, derived largely from neural crest cells, that is essential for fetal life but typically closes after birth. Impaired development of the ductus arteriosus or disruption of signaling pathways that initiate postnatal closure can result in persistent patency of the ductus arteriosus, the third most common congenital heart defect. We found that Tfap2beta, a transcription factor associated with patent ductus arteriosus in humans, was uniquely expressed in mouse ductal smooth muscle. Endothelin-1 and the hypoxia-induced transcription factor, Hif2alpha were also highly enriched in ductal smooth muscle at embryonic day 13.5 and were dependent on Tfap2beta for their expression in this domain. Hif2alpha functioned as a negative regulator of Tfap2beta-induced transcription by disrupting protein-DNA interactions, suggesting a negative feedback loop regulating Tfap2beta activity. Our data indicate that Tfap2beta, Et-1, and Hif2alpha act in a transcriptional network during ductal smooth muscle development and that disruption of this pathway may contribute to patent ductus arteriosus by affecting the development of smooth muscle within the ductus arteriosus.
Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci
Authors: Andre Franke, Dermot P B McGovern, Jeffrey C Barrett, Kai Wang, Graham L Radford-Smith, Tariq Ahmad, Charlie W Lees, Tobias Balschun, James Lee, Rebecca Roberts, Carl A Anderson, Joshua C Bis, Suzanne Bumpstead, David Ellinghaus, Eleonora M Festen, Michel Georges, Todd Green, Talin Haritunians, Luke Jostins, Anna Latiano, Christopher G Mathew, Grant W Montgomery, Natalie J Prescott, Soumya Raychaudhuri, Jerome I Rotter, Philip Schumm, Yashoda Sharma, Lisa A Simms, Kent D Taylor, David Whiteman, Cisca Wijmenga, Robert N Baldassano, Murray Barclay, Theodore M Bayless, Stephan Brand, Carsten Büning, Albert Cohen, Jean-Frederick Colombel, Mario Cottone, Laura Stronati, Ted Denson, Martine De Vos, Renata D'Inca, Marla Dubinsky, Cathryn Edwards, Tim Florin, Denis Franchimont, Richard Gearry, Jürgen Glas, Andre Van Gossum, Stephen L Guthery, Jonas Halfvarson, Hein W Verspaget, Jean-Pierre Hugot, Amir Karban, Debby Laukens, Ian Lawrance, Marc Lemann, Arie Levine, Cecile Libioulle, Edouard Louis, Craig Mowat, William Newman, Julián Panés, Anne Phillips, Deborah D Proctor, Miguel Regueiro, Richard Russell, Paul Rutgeerts, Jeremy Sanderson, Miquel Sans, Frank Seibold, A Hillary Steinhart, Pieter C F Stokkers, Leif Torkvist, Gerd Kullak-Ublick, David Wilson, Thomas Walters, Stephan R Targan, Steven R Brant, John D Rioux, Mauro D'Amato, Rinse K Weersma, Subra Kugathasan, Anne M Griffiths, John C Mansfield, Severine Vermeire, Richard H Duerr, Mark S Silverberg, Jack Satsangi, Stefan Schreiber, Judy H Cho, Vito Annese, Hakon Hakonarson, Mark J Daly, Miles Parkes
Journal: Nature Genetics (2010)
Systems and Capacity to Address Noncommunicable Diseases in Low- and Middle-Income Countries
Authors: Mohammed K. Ali, Cristina Rabadán-Diehl, John Flanigan, Claire Blanchard, K. M. Venkat Narayan, Michael Engelgau
Journal: Science Translational Medicine (2013)

Noncommunicable diseases (NCDs) are increasingly getting attention from different forums, including media outlets, health agencies, and the public and private sectors. Progress is being made in addressing NCDs, though more slowly in low- and middle-income countries (LMICs) as compared with high-income settings. Here, we offer an analysis of the challenges faced in LMICs. We discuss realistic strategies to understand and develop capacity needs (workforce, finances, and infrastructure) and systems (institutions and processes) to sustainably optimize NCD prevention and care in LMICs.
Manipulation of Human Ovarian Function: Physiological Concepts and Clinical Consequences*
Authors: Bart C. J. M. Fauser, Arne M. van Heusden
Journal: Endocrine Reviews (1997)

I. Introduction II. Dynamics of Normal Human Follicle Growth and Selection A. Gonadotropin-independent and -dependent follicle growth B. Intrafollicular endocrine changes C. Are estrogens needed for follicle development? D. In vivo regulation of follicle maturation in the monkey E. The FSH threshold and window concept for in vivo follicle growth 1. FSH threshold and follicle recruitment 2. FSH window and single dominant follicle selection 3. Dominant follicle development F. Modulation of FSH action 1. Heterogeneity of FSH 2. Direct interference with FSH action 3. Intraovarian interference with FSH action by growth factors III. Gonadotropin Induction of Ovulation A. The concept of monofollicle growth in anovulatory patients B. Conditions affecting treatment outcome 1. Patient-related factors 2. Hormone preparation-related factors 3. Other factors involved C. Commonly used step-up dose regimens 1. Conventional step-up protocol 2. Low-dose, step-up protocol D. Potential for a step-down dose regimen IV. Stero...
Identification of a Candidate Gene Panel for the Early Diagnosis of Prostate Cancer
Authors: Gisele H.J.M. Leyten, Daphne Hessels, Frank P. Smit, Sander A. Jannink, Hans de Jong, Willem J.G. Melchers, Erik B. Cornel, Theo M. de Reijke, Henk Vergunst, Paul Kil, Ben C. Knipscheer, Christina A. Hulsbergen-van de Kaa, Peter F.A. Mulders, Inge M. van Oort, Jack A. Schalken
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Serum PSA (sPSA) testing has led to the identification of patients with indolent prostate cancer, and inevitably overtreatment has become a concern. Progensa PCA3 urine testing was shown to improve the diagnosis of prostate cancer, but its diagnostic value for aggressive prostate cancer is limited. Therefore, urinary biomarkers that can be used for prediction of Gleason score ≥7 prostate cancer in biopsies are urgently needed. Experimental Design: Using gene expression profiling data, 39 prostate cancer biomarkers were identified. After quantitative PCR analysis on tissue specimens and urinary sediments, eight promising biomarkers for the urinary detection of prostate cancer were selected (ONECUT2, HOXC4, HOXC6, DLX1, TDRD1, NKAIN1, MS4A8B, PPFIA2). The hypothesis that biomarker combinations improve the diagnostic value for aggressive prostate cancer was tested on 358 urinary sediments of an intention-to-treat cohort. Results: A urinary three-gene panel (HOXC6, TDRD1, and DLX1) had higher accuracy [area under the curve (AUC), 0.77; 95% confidence interval (CI), 0.71–0.83] to predict Gleason score ≥7 prostate cancer in biopsies compared with Progensa PCA3 (AUC, 0.68; 95% CI, 0.62–0.75) or sPSA (AUC, 0.72; 95% CI, 0.65–0.78). Combining the three-gene panel with sPSA further improved the predictive accuracy (AUC, 0.81; 95% CI, 0.75–0.86). The accuracy of the three-gene predictive model was maintained in subgroups with low sPSA concentrations. Conclusions: The urinary three-gene panel (HOXC6, TDRD1, and DLX1) represents a promising tool to identify patients with aggressive prostate cancer, also in those with low sPSA values. The combination of the urinary three-gene panel with sPSA bears great potential for the early diagnosis of patients with clinically significant prostate cancer. Clin Cancer Res; 21(13); 3061–70. ©2015 AACR.
Detailed characterization of Act d 12 and Act d 13 from kiwi seeds: implication in IgE cross-reactivity with peanut and tree nuts
Authors: S. Sirvent, B. Cantó, F. Gómez, N. Blanca, J. Cuesta-Herranz, G. Canto, M. Blanca, R. Rodríguez, M. Villalba, O. Palomares
Journal: Allergy (2014)

Act d 12 (11S globulin) and Act d 13 (2S albumin) are two novel relevant allergens from kiwi seeds that might be useful to improve the diagnostic sensitivity and the management of kiwifruit-allergic patients.To perform a comprehensive structural and immunological characterization of purified Act d 12 and Act d 13 from kiwi seeds.Sera from 55 well-defined kiwifruit-allergic patients were used. Act d 12 and Act d 13 were purified by chromatographic procedures. Circular dichroism, mass spectrometry, concanavalin A detection, immunoblotting, enzyme-linked immunosorbent assays, basophil activation tests, and IgE-inhibition experiments were used.Act d 12 and Act d 13 were purified from kiwi seeds to homogeneity by combining size-exclusion, ion-exchange, and RP-HPLC chromatographies. Both purified allergens preserve the structural integrity and display typical features of their homologous counterparts from the 11S globulin and 2S albumin protein families, respectively. These allergens are released from kiwi seeds after oral and gastric digestion of whole kiwifruit, demonstrating their bioavailability after ingestion. The allergens retain the capacity to bind serum IgE from kiwifruit-allergic patients, induce IgE cross-linking in effector-circulating basophils, and display in vitro IgE cross-reactivity with homologous counterparts from peanut and tree nuts.Purified Act d 12 and Act d 13 from kiwi seeds are well-defined molecules involved in in vitro IgE cross-reactivity with peanut and tree nuts. Their inclusion in component-resolved diagnosis of kiwifruit allergy might well contribute to improve the diagnostic sensitivity and the management of kiwifruit-allergic patients.
Actionable Diagnosis of Neuroleptospirosis by Next-Generation Sequencing
Authors: Michael R. Wilson, Samia N. Naccache, Erik Samayoa, Mark Biagtan, Hiba Bashir, Guixia Yu, Shahriar M. Salamat, Sneha Somasekar, Scot Federman, Steve Miller, Robert Sokolic, Elizabeth Garabedian, Fabio Candotti, Rebecca H. Buckley, Kurt D. Reed, Teresa L. Meyer, Christine M. Seroogy, Renee Galloway, Sheryl L. Henderson, James E. Gern, Joseph L. DeRisi, Charles Y. Chiu
Journal: New England Journal of Medicine (2014)

A 14-year-old boy with severe combined immunodeficiency presented three times to a medical facility over a period of 4 months with fever and headache that progressed to hydrocephalus and status epilepticus necessitating a medically induced coma. Diagnostic workup including brain biopsy was unrevealing. Unbiased next-generation sequencing of the cerebrospinal fluid identified 475 of 3,063,784 sequence reads (0.016%) corresponding to leptospira infection. Clinical assays for leptospirosis were negative. Targeted antimicrobial agents were administered, and the patient was discharged home 32 days later with a status close to his premorbid condition. Polymerase-chain-reaction (PCR) and serologic testing at the Centers for Disease Control and Prevention (CDC) subsequently confirmed evidence of Leptospira santarosai infection.
G Protein Polymorphisms in Hypertension, Atherosclerosis, and Diabetes
Authors: Winfried Siffert
Journal: Annual Review of Medicine (2004)

A common C825T polymorphism in the gene GNB3, which encodes the β3 subunit of heterotrimeric G proteins, was identified in cell lines from patients with hypertension. The 825T allele is associated with increased intracellular signal transduction. Many population-based and case-control studies in different ethnicities have investigated an association between this polymorphism and hypertension, obesity, and atherosclerosis. A critical assessment of published studies suggests that 825T allele carriers have an increased risk for hypertension combined with features of the metabolic syndrome, such as dyslipidemia, hypercholesterolemia, insulin resistance, and obesity. It is anticipated that this polymorphism will be used in clinical practice to better characterize hypertension and for individualized treatment regimens.