tbuckley/cabot-search huggingface dataset:
THE NUCLEAR HORMONE RECEPTOR GENE SUPERFAMILY
Authors: Ralff C. J. Ribeiro, M.D, Peter J. Kushner, Ph.D, John D. Baxter, M.D
Journal: Annual Review of Medicine (1995)

▪ Abstract The nuclear hormone receptor gene superfamily encodes structurally related proteins that regulate transcription of target genes. These macromolecules include receptors for steroid and thyroid hormones, vitamins, and other proteins for which no ligands have been found. These receptors have modular domains. The DNA-binding domain directs the receptors to bind specific DNA sequences as monomers, homodimers, or heterodimers. The ligand-binding domain responds to binding of the cognate hormone; this domain and the amino terminal domain interact with other transcription factors. Nuclear receptor-specific actions are derived from a combination of diverse elements, including availability of ligand, receptors, and nonreceptor factors; target-site structure; interactions with other proteins, such as the general transcription factors; and influences of other signaling pathways. These interactions result in ligand-regulated and ligand-independent effects on initiation of transcription of the target genes. Understanding the mechanisms of nuclear receptor action will enhance our knowledge of transcription and hormone influences on disease and facilitate the design of drugs with greater therapeutic value.
Primary human herpesvirus 8 infection generates a broadly specific CD8+ T-cell response to viral lytic cycle proteins
Authors: Qiong J. Wang, Frank J. Jenkins, Lisa P. Jacobson, Lawrence A. Kingsley, Richard D. Day, Zhi-Wei Zhang, Yuan-Xiang Meng, Philip E. Pellet, Konstantin G. Kousoulas, Abolghasem Baghian, Charles R. Rinaldo
Journal: Blood (2001)
Mechanisms behind hypocholesterolaemia in hairy cell leukaemia
Authors: G. Juliusson, S. Vitols, J. Liliemark
Journal: BMJ (1995)

be informed of the risks to these patients and the need for prompt referral to hospital.Patients may be given a supply of penicillin (or amoxycillin) to be kept at home and taken when symptoms of sepsis develop.However, patients must also be advised to obtain urgent medical attention.Ciprofloxacin has variable activity against pneumo- coccus and therefore should not be used as first line treatment unless later sensitivities indicate otherwise.4The drug was ineffective before admission in two of our patients (cases 1 and 6).Lymphoproliferative malignancies are associated with hypogammaglobulinaemia.Prophylactic intra- venous immunoglobulin is beneficial, especially in those who have low concentrations of functional IgG and are susceptible to recurrent bacterial infections.5Immunisation with pneumococcal vaccine is asso- ciated with an impaired response in immunocompro- mised patients.If such patients are to be immunised those that do not show a rise in antibody titre could be considered for prophylactic intravenous immuno- globulin.We thank Dr E McKay-Ferguson for providing the data on positive blood cultures, Dr J E Chandler for allowing us to report on two patients under his care, and Miss Alison Hammond for typing the manuscript.
Phase I and Pharmacokinetic Studies of CYT-6091, a Novel PEGylated Colloidal Gold-rhTNF Nanomedicine
Authors: Steven K. Libutti, Giulio F. Paciotti, Adriana A. Byrnes, H. Richard Alexander, William E. Gannon, Melissa Walker, Geoffrey D. Seidel, Nargiza Yuldasheva, Lawrence Tamarkin
Journal: Clinical Cancer Research (2010)

Abstract Purpose: A novel nanomedicine, CYT-6091, constructed by simultaneously binding recombinant human tumor necrosis factor alpha (rhTNF) and thiolyated polyethylene glycol to the surface of 27-nm colloidal gold particles, was tested in a phase I dose escalation clinical trial in advanced stage cancer patients. Experimental Design: CYT-6091, whose dosing was based on the amount of rhTNF in the nanomedicine, was injected intravenously, and 1 cycle of treatment consisted of 2 treatments administered 14 days apart. Results: Doses from 50 μg/m2 to 600 μg/m2 were well tolerated, and no maximum tolerated dose (MTD) was reached, as the highest dose exceeded the target dosage of 1-mg rhTNF per treatment, exceeding the previous MTD for native rhTNF by 3-fold. The first 2 patients on the study, each receiving 50 μg/m2, did not receive any prophylactic antipyretics or H2 blockade. A predicted, yet controllable fever occurred in these patients, so all subsequently treated patients received prophylactic antipyretics and H2 blockers. However, even at the highest dose rhTNF's dose-limiting toxic effect of hypotension was not seen. Using electron microscopy to visualize nanoparticles of gold in patient biopsies of tumor and healthy tissue showed that patient biopsies taken 24 hours after treatment had nanoparticles of gold in tumor tissue. Conclusions: These data indicate that rhTNF formulated as CYT-6091 may be administered systemically at doses of rhTNF that were previously shown to be toxic and that CYT-6091 may target to tumors. Future clinical studies will focus on combining CYT-6091 with approved chemotherapies for the systemic treatment of nonresectable cancers. Clin Cancer Res; 16(24); 6139–49. ©2010 AACR.
Skin Tumors Induced by Sorafenib; Paradoxic RAS–RAF Pathway Activation and Oncogenic Mutations of <i>HRAS</i>, <i>TP53</i>, and <i>TGFBR1</i>
Authors: Jean Philippe Arnault, Christine Mateus, Bernard Escudier, Gorana Tomasic, Janine Wechsler, Emilie Hollville, Jean-Charles Soria, David Malka, Alain Sarasin, Magalie Larcher, Jocelyne André, Nyam Kamsu-Kom, Lise Boussemart, Ludovic Lacroix, Alain Spatz, Alexander M. Eggermont, Sabine Druillennec, Stephan Vagner, Alain Eychène, Nicolas Dumaz, Caroline Robert
Journal: Clinical Cancer Research (2011)

Abstract Purpose: The emergence of skin tumors in patients treated with sorafenib or with more recent BRAF inhibitors is an intriguing and potentially serious event. We carried out a clinical, pathologic, and molecular study of skin lesions occurring in patients receiving sorafenib. Experimental Design: Thirty-one skin lesions from patients receiving sorafenib were characterized clinically and pathologically. DNA extracted from the lesions was screened for mutation hot spots of HRAS, NRAS, KiRAS, TP53, EGFR, BRAF, AKT1, PI3KCA, TGFBR1, and PTEN. Biological effect of sorafenib was studied in vivo in normal skin specimen and in vitro on cultured keratinocytes. Results: We observed a continuous spectrum of lesions: from benign to more inflammatory and proliferative lesions, all seemingly initiated in the hair follicles. Eight oncogenic HRAS, TGFBR1, and TP53 mutations were found in 2 benign lesions, 3 keratoacanthomas (KA) and 3 KA-like squamous cell carcinoma (SCC). Six of them correspond to the typical UV signature. Treatment with sorafenib led to an increased keratinocyte proliferation and a tendency toward increased mitogen-activated protein kinase (MAPK) pathway activation in normal skin. Sorafenib induced BRAF–CRAF dimerization in cultured keratinocytes and activated CRAF with a dose-dependent effect on MAP-kinase pathway activation and on keratinocyte proliferation. Conclusion: Sorafenib induces keratinocyte proliferation in vivo and a time- and dose-dependent activation of the MAP kinase pathway in vitro. It is associated with a spectrum of lesions ranging from benign follicular cystic lesions to KA-like SCC. Additional and potentially preexisting somatic genetic events, like UV-induced mutations, might influence the evolution of benign lesions to more proliferative and malignant tumors. Clin Cancer Res; 18(1); 263–72. ©2011 AACR.
Rationale and strategies for implementing community-based transfer protocols for primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction
Authors: Richard E Waters, Kanwar P Singh, Matthew T Roe, Mat Lotfi, Michael H Sketch, Kenneth W Mahaffey, L.Kristin Newby, John H Alexander, Robert A Harrington, Robert M Califf, Christopher B Granger
Journal: Journal of the American College of Cardiology (2004)
Anal Cancer Incidence: Genital Warts, Anal Fissure or Fistula, Hemorrhoids, and Smoking
Authors: E. A. Holly, A. S. Whittemore, D. A. Aston, D. K. Ahn, B. J. Nickoloff, J. J. Kristiansen
Journal: JNCI Journal of the National Cancer Institute (1989)

We conducted a study of 126 patients with anal and rectal squamous cell carcinoma and 372 randomly selected control subjects in the San Francisco Bay Area (CA) to test the hypothesis that these tumors are related to a history of anal intercourse, the presence of sexually transmitted diseases and other conditions of the anal area, treatment of these diseases or conditions, and history of use of cigarettes or other substances. The relative risk (RR) of cancer was elevated for men with a history of homosexual activity (RR = 12.4, P less than .001). However, after adjustment for other risk factors, this risk was reduced to 2.7 (P = .28). Risk was elevated for homosexual male patients who reported a history of genital warts (RR = 12.6, P = .03), anal fissure or fistula (RR = 9.1, P = .05), and cigarette smoking (RR = 1.9 for 20 pack-yr, P less than .001; RR = 5.2 for 50 pack-yr, P less than .001). (Pack-year is a unit of cigarette use equal to 365 packs.) There was also elevated risk for heterosexual male and female patients who reported a history of genital warts (RR = 4.4, P = .003), anal fissure or fistula (RR = 2.4, P = .03), and more than 12 episodes of hemorrhoids (RR = 2.6, P less than .001). These findings suggest that anal cancer risk is etiologically related to human papillomaviruses that cause genital warts. In addition, constant irritation, chronic inflammatory changes, and repeated epithelial regeneration that accompany noninfectious conditions may be related to risk of anal cancer. The higher risk among homosexual men is related to the higher prevalence of anal cancer risk factors for this group.
Angiocrine Factors Modulate Tumor Proliferation and Motility through EphA2 Repression of Slit2 Tumor Suppressor Function in Endothelium
Authors: Dana M. Brantley-Sieders, Charlene M. Dunaway, Meghana Rao, Sarah Short, Yoonha Hwang, Yandong Gao, Deyu Li, Aixiang Jiang, Yu Shyr, Jane Y. Wu, Jin Chen
Journal: Cancer Research (2010)

It is well known that tumor-derived proangiogenic factors induce neovascularization to facilitate tumor growth and malignant progression. However, the concept of "angiocrine" signaling, in which signals produced by endothelial cells elicit tumor cell responses distinct from vessel function, has been proposed, yet remains underinvestigated. Here, we report that angiocrine factors secreted from endothelium regulate tumor growth and motility. We found that Slit2, which is negatively regulated by endothelial EphA2 receptor, is one such tumor suppressive angiocrine factor. Slit2 activity is elevated in EphA2-deficient endothelium. Blocking Slit activity restored angiocrine-induced tumor growth/motility, whereas elevated Slit2 impaired growth/motility. To translate our findings to human cancer, we analyzed EphA2 and Slit2 expression in human cancer. EphA2 expression inversely correlated with Slit2 in the vasculature of invasive human ductal carcinoma samples. Moreover, analysis of large breast tumor data sets revealed that Slit2 correlated positively with overall and recurrence-free survival, providing clinical validation for the tumor suppressor function for Slit2 in human breast cancer. Together, these data support a novel, clinically relevant mechanism through which EphA2 represses Slit2 expression in endothelium to facilitate angiocrine-mediated tumor growth and motility by blocking a tumor suppressive signal.
Approval of FDA commissioner held up by emergency contraception issue
Authors: Janice Hopkins Tanne
Journal: BMJ (2005)

Three US senators last week tried to push the administration into making emergency contraception available over the counter by blocking the appointment of a government nominee to a senior administrative post.

Immediately after a divided Senate committee approved the nomination of the acting commissioner of the Food and Drug Administration, Lester Crawford, to become the permanent commissioner, the three senators said they would block necessary approval by the full Senate.

The senators said they would put a “hold” on his nomination—a Senate tradition that prevents a nomination moving forward. It is used to draw attention to an issue, to force negotiation, or to end an issue. It can be overridden by a vote of 60 of the …
Use of Epstein-Barr virus-transformed B cell lines for the generation of immunoglobulin-producing human B cell hybridomas.
Authors: N Chiorazzi, R L Wasserman, H G Kunkel
Journal: The Journal of Experimental Medicine (1982)

HGPRTase-deficient EBV-transformed B cell lines were shown to be effective fusion partners with mitogen-activated human B cells for the construction of Ig-producing human B cell hybridomas. In a series of experiments using these lines and B cells from several tissue sources, approximatley 20% of the cultures plated were consistently positive for growth after hypoxanthine-aminopterin-thymidine selection and approximatley 30% of these synthesized significant new Ig. A marked increase in Ig secretion was observed after hybridization, which was due to new Ig; Ig from the parental lime was shown to disappear in several instances. Special analyses were carried out on a human hybridoma secreting antibody specific for tetanus toxoid and tetanus toxin and stable subclones were derived. These studies suggest that EBV-transformed lines will prove useful in human hybridization studies, thus making a large library of B cell lines available for the generation of human monoclonal antibodies.
Readaptation of the Peritoneum Following Extended Pelvic Lymphadenectomy and Cystectomy Has a Significant Beneficial Impact on Early Postoperative Recovery and Complications: Results of a Prospective Randomized Trial
Authors: Beat Roth, Frédéric D. Birkhäuser, Pascal Zehnder, Fiona C. Burkhard, George N. Thalmann, Urs E. Studer
Journal: European Urology (2010)
Obstetric Management in Gestational Diabetes
Authors: Deborah L. Conway
Journal: Diabetes Care (2007)

Reviewing the areas of controversy related to the obstetric management of women with GDM, we are unfortunately unable to provide significant refinement of the recommendations agreed upon after the Fourth International Workshop-Conference due to the lack of properly controlled and powered clinical studies in this area since 1997. In the area of the need for antenatal fetal surveillance in women with milder degrees of GDM, we may be able to draw indirect conclusions from ongoing cohort studies that will include large numbers of women. In the area of optimal timing and mode of delivery to avoid fetal injury, large well-controlled prospective studies do not currently exist and are urgently needed. In addition, refinement of fetal and pelvic imaging techniques to more accurately identify the maternal-fetal pairs most likely to benefit from avoiding vaginal delivery, and the more widespread availability of these technologies, may also prove to be of benefit in the obstetric management of women with GDM.
The Bacillus subtilis Quorum-Sensing Molecule CSF Contributes to Intestinal Homeostasis via OCTN2, a Host Cell Membrane Transporter
Authors: Mikihiro Fujiya, Mark W. Musch, Yasushi Nakagawa, Shien Hu, John Alverdy, Yutaka Kohgo, Olaf Schneewind, Bana Jabri, Eugene B. Chang
Journal: Cell Host & Microbe (2007)
A natural model of immunologic tolerance. Tolerance to murine C5 is mediated by T cells, and antigen is required to maintain unresponsiveness.
Authors: D E Harris, L Cairns, F S Rosen, Y Borel
Journal: The Journal of Experimental Medicine (1982)

A unique experimental model is described, where natural immunologic tolerance to a well-defined soluble native antigen (murine C5) is examined in congenic strains of mice that differ only by the presence or the absence of C5. A highly sensitive hemolytic assay was developed to detect nanogram amounts of C5 as well as an assay of anti-C5 inhibition of C5 hemolytic activity. The latter was more sensitive than immunodiffusion. Two reciprocal approaches were used to study the cellular basis of tolerance in irradiated hosts of either strain. In the first, lymphoid cells from either strain were transferred to irradiated B10.D2OSN hosts that were lacking C5 and so would not hinder detection of anti-C5 antibody upon challenge with murine C5. Second, lymphoid cells from either strain were transferred to irradiated B10.D2NSN hosts, whose native C5 provided the antigenic stimulus. The immune response of whole nonadherent spleen cell suspension as well as mixtures of T and B cells (separated on the basis of surface immunoglobulin) from either strain were studied. In addition, the duration of tolerance and the antigen requirement to maintain it in irradiated C5-deficient hosts repopulated with C5-sufficient spleen cells was examined. The positive control of irradiated C5-deficient hosts repopulated with syngeneic spleen cells showed a primary and secondary response to immunization. In contrast, C5-sufficient spleen cells failed to respond both in the primary and the secondary response. Because the unresponsiveness was not caused by antigen carryover and was not antigen specific, it represents central tolerance. In C5-sufficient irradiated hosts (where immunization was not required and antigen was present in natural form and physiological concentration), transfer of C5-deficient cells mediated a drop in C5 levels to 10-20% of that noted in unreconstituted controls. T and B cell mixing experiments from the two strains into deficient or sufficient hosts demonstrated that tolerance is T cell dependent and that C5-sufficient or -deficient B cells could cooperate with nontolerant C5-sufficient T cells to produce significant anti-C5 antibody or mediate a significant drop in C5 levels. In addition, the presence of antigen was necessary to maintain tolerance. In conclusion, these results show that (a) natural tolerance to C5 is an active process that is T cell dependent and requires the presence of antigen; (b) in this natural model, clonal abortion does not seem to occur; and (c) both tolerant and nontolerant B cells retain the capacity to produce autoantibody.
Percutaneous Left Atrial Appendage Closure vs Warfarin for Atrial Fibrillation
Authors: Vivek Y. Reddy, Horst Sievert, Jonathan Halperin, Shephal K. Doshi, Maurice Buchbinder, Petr Neuzil, Kenneth Huber, Brian Whisenant, Saibal Kar, Vijay Swarup, Nicole Gordon, David Holmes
Journal: JAMA (2014)

While effective in preventing stroke in patients with atrial fibrillation (AF), warfarin is limited by a narrow therapeutic profile, a need for lifelong coagulation monitoring, and multiple drug and diet interactions.To determine whether a local strategy of mechanical left atrial appendage (LAA) closure was noninferior to warfarin.PROTECT AF was a multicenter, randomized (2:1), unblinded, Bayesian-designed study conducted at 59 hospitals of 707 patients with nonvalvular AF and at least 1 additional stroke risk factor (CHADS2 score ≥1). Enrollment occurred between February 2005 and June 2008 and included 4-year follow-up through October 2012. Noninferiority required a posterior probability greater than 97.5% and superiority a probability of 95% or greater; the noninferiority margin was a rate ratio of 2.0 comparing event rates between treatment groups.Left atrial appendage closure with the device (n = 463) or warfarin (n = 244; target international normalized ratio, 2-3).A composite efficacy end point including stroke, systemic embolism, and cardiovascular/unexplained death, analyzed by intention-to-treat.At a mean (SD) follow-up of 3.8 (1.7) years (2621 patient-years), there were 39 events among 463 patients (8.4%) in the device group for a primary event rate of 2.3 events per 100 patient-years, compared with 34 events among 244 patients (13.9%) for a primary event rate of 3.8 events per 100 patient-years with warfarin (rate ratio, 0.60; 95% credible interval, 0.41-1.05), meeting prespecified criteria for both noninferiority (posterior probability, >99.9%) and superiority (posterior probability, 96.0%). Patients in the device group demonstrated lower rates of both cardiovascular mortality (1.0 events per 100 patient-years for the device group [17/463 patients, 3.7%] vs 2.4 events per 100 patient-years with warfarin [22/244 patients, 9.0%]; hazard ratio [HR], 0.40; 95% CI, 0.21-0.75; P = .005) and all-cause mortality (3.2 events per 100 patient-years for the device group [57/466 patients, 12.3%] vs 4.8 events per 100 patient-years with warfarin [44/244 patients, 18.0%]; HR, 0.66; 95% CI, 0.45-0.98; P = .04).After 3.8 years of follow-up among patients with nonvalvular AF at elevated risk for stroke, percutaneous LAA closure met criteria for both noninferiority and superiority, compared with warfarin, for preventing the combined outcome of stroke, systemic embolism, and cardiovascular death, as well as superiority for cardiovascular and all-cause mortality.clinicaltrials.gov Identifier: NCT00129545.
Physiological and Clinical Consequences of Relief of Right Ventricular Outflow Tract Obstruction Late After Repair of Congenital Heart Defects
Authors: Louise Coats, Sachin Khambadkone, Graham Derrick, Shankar Sridharan, Silvia Schievano, Bryan Mist, Rod Jones, John E. Deanfield, Denis Pellerin, Philipp Bonhoeffer, Andrew M. Taylor
Journal: Circulation (2006)

Background— Right ventricular outflow tract obstruction (RVOTO) is a common problem after repair of congenital heart disease. Percutaneous pulmonary valve implantation (PPVI) can treat this condition without consequent pulmonary regurgitation or cardiopulmonary bypass. Our aim was to investigate the clinical and physiological response to relieving RVOTO. Methods and Results— We studied 18 patients who underwent PPVI for RVOTO (72% male, median age 20 years) from a total of 93 who had this procedure for various indications. All had a right ventricular outflow tract (RVOT) gradient &gt;50 mm Hg on echocardiography without important pulmonary regurgitation (less than mild or regurgitant fraction &lt;10% on magnetic resonance imaging [MRI]). Cardiopulmonary exercise testing, tissue Doppler echocardiography, and MRI were performed before and within 50 days of PPVI. PPVI reduced RVOT gradient (51.4 to 21.7 mm Hg, P &lt;0.001) and right ventricular systolic pressure (72.8 to 47.3 mm Hg, P &lt;0.001) at catheterization. Symptoms and aerobic (25.7 to 28.9 mL · kg −1 · min −1 , P =0.002) and anaerobic (14.4 to 16.2 mL · kg −1 · min −1 , P =0.002) exercise capacity improved. Myocardial systolic velocity improved acutely (tricuspid 4.8 to 5.3 cm/s, P =0.05; mitral 4.7 to 5.5 cm/s, P =0.01), whereas isovolumic acceleration was unchanged. The tricuspid annular velocity was not maintained on intermediate follow-up. Right ventricular end-diastolic volume (99.9 to 89.7 mL/m 2 , P &lt;0.001) fell, whereas effective stroke volume (43.7 to 48.3 mL/m 2 , P =0.06) and ejection fraction (48.0% to 56.8%, P =0.01) increased. Left ventricular end-diastolic volume (72.5 to 77.4 mL/m 2 , P =0.145), stroke volume (45.3 to 50.6 mL/m 2 , P =0.02), and ejection fraction (62.6% to 65.8%, P =0.03) increased. Conclusions— PPVI relieves RVOTO, which leads to an early improvement in biventricular performance. Furthermore, it reduces symptoms and improves exercise tolerance. These findings have important implications for the management of this increasingly common condition.