tbuckley/cabot-search huggingface dataset:
Steroid hormone receptors: an update
Authors: M Beato, J Klug
Journal: Human Reproduction Update (2000)

Steroid hormones (SHs) arelipophilic molecules derived from cholesterol and synthesized in the adrenal cortex (glucocorticoids, mineralocorticoids, and adrenal androgens), the testes (testicular androgens, oestrogen), and the ovary and placenta (oestrogens and progestagens or progestins). SHs reach their target cells via the blood, where they are bound to carrier proteins, and because of their lipophilic nature pass the cell membrane by simple diffusion. Within the target cells SHs bind to steroid hormone receptors (SHRs), the key mediators of SH action, which are complexed to chaperones, e.g. heat shock protein 90 (Hsp90), that help other proteins to fold and prevent aggregation. SHRs are intracellular transcription factors that can be activated, among other possibilities, by the specific and high affinity binding of ligand to exert positive or negative effects on the expression of target genes. Binding of agonistic or antagonistic ligands leads to different allosteric changes of SHRs making them competent to exert positive or negative effects on the expression of target genes by different mechanisms. (i) After dissociation of chaperones the liganded SHR–complexes can bind to chromatin organized DNA sequences in the vicinity of target genes, termed hormone response elements (HREs). The HRE-recruited hormone-receptor-complexes are then able to initiate chromatin remodelling and to relay activating or repressing signals to the target genes transcription machinery; (ii) through protein–protein interactions with other sequence-specific transcription factors, SHRs can also regulate the activity of many genes that are switched on, for instance, during stress or an inflammatory response; (iii) the SH response can also be integrated in the intracellular signalling network via cross-talk of SHRs with signal transduction pathways that transmit extracellular signals via membrane receptors and activation of protein kinase cascades to nuclear transcription factors that activate various target genes. By all these different mechanisms SHRs modulate numerous and specific responses in a large variety of cells, whereby their particular effect depends on the physiological, cellular and genetic context.
A comparison of rhTPO and rhIL-11 following ifosfamide (I), carboplatin (C) and etoposide (E) (ICE) in pediatric patients with recurrent solid tumors or lymphoma
Authors: A. L. Angiolillo, M. Krailo, J. Laver, S. C. Goldman, O. Bessmertny, C. Van de Ven, V. Davenport, G. Reaman, M. S. Cairo
Journal: Journal of Clinical Oncology (2004)

8535 Background: Thrombocytopenia remains the dose limiting toxicity (DLT) for dose intensification of ICE chemotherapy. In an attempt to reduce the incidence of grade IV thrombocytopenia and enhance platelet (plt) reconstitution, we investigated rhTPO (CCG-09717) and rhIL-11 + G-SCF (C9305) after ICE chemotherapy in children with recurrent/refractory solid tumors. Methods: Patients (pts) received I 1800mg/m2 on days (d) 0–4, C 400mg/m2 on d 0–1 and E 100 mg/m2 on d 0–4. In CCG-09717, pts received rhTPO (1.2, 2.4 or 3.6 μg/kg/d) on d +4, +6, +8, +10 and +12. In C9305, rhIL-11 was given at doses of 25, 50, 75, 100 or 125 μg/kg/d beginning d +6. All pts received G-CSF (5 μg/kg/d) on d +6. Results: The median d to ANC ≥1000/mm3 for rhTPO (1.2, 2.4 and 3.6 μg/kg/d) was 20 to 19.5 d, respectively, and rhIL-11, 23 d (25 μg/kg) to 16.5 d (100 μg/kg) for ANC ≥500/mm3. The median d to plt ≥100k/mm3 for rhTPO at 1.2, 2.4 and 3.6 μg/kg/d was 24 to 22 d, respectively (median plt tx d 2 [0–7d]) and for rhIL-11 was 24.5 to 20 d, respectively (median plt tx d 3 [25 μg/kg] to 2 [100 μg/kg]). A dose dependent increase in AUC0-∞ was 2350±630 and 3066±846 ng.hr/mL with mean Cmax (63.3 ± 9.7 and 89.3 ± 15.7 ng/ml) and mean T1/2 (47 ± 13 and 64 ± 42 hr) after the 2.4 and 3.6 μg/kg/d doses of rhTPO, respectively. For rhIL-11, a dose dependent increase in mean Cmax was 7.6–25.5 ng/mL and AUC0-∞ 56.7–208.6 ng.hr/mL at doses of 25–100 μg/kg with mean Tmax 2.4 to 3.1 hr and mean T1/2 4 to 8 hr. There was a significant increase of peripheral blood CFU-megs with rhTPO compared to baseline (0±0 vs 287±97 CFU-meg, p<0.001) vs (0.0 vs 0.0 p=NS) for IL-11. There was no evidence of DLT or antibody formation attributable to rhTPO and no MTD. Papilledema was a DLT of rhIL-11 at doses above 50 μg/kg/d. Periosteal bone changes were seen especially at the 100μg/kg rhIL-11 dose level. 3.7% developed an antibody to rhIL-11. The MTD of rhIL-11 was 50 μg/kg/d. Conclusion: RhTPO vs rhIL-11 in children was associated with a larger T1/2, increased AUC0-∞, less toxicity but similar time to plt recovery and median number of plt tx following ICE. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Wyeth Oncology
Interventions for Female Pattern Hair Loss
Authors: Esther J. van Zuuren, Zbys Fedorowicz
Journal: JAMA Dermatology (2017)

Which interventions are effective and safe for treating female pattern hair loss (FPHL)?There was low- to moderate-quality evidence that topical minoxidil (2% and 5%) was associated with improvements in FPHL. There was low-quality evidence that finasteride was no more effective than placebo. There were inconsistent results from studies that laser devices were effective, but total hair count increased compared with baseline (moderate- to low-quality evidence). Most treatments were not associated with higher adverse event rates than placebo.
FEMALE GENDER IS ASSOCIATED WITH MAJOR ADVERSE CARDIOVASCULAR EVENTS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY
Authors: Susie N. Hong-Zohlman, Raymond Chan, Barry Maron, iacopo olivotto, Gabriele E. Assenza, John Lesser, Tammy Haas, Christiane Gruner, Andrew Crean, Harry Rakowski, James Udelson, Ethan Rowin, Benedetta Tomberli, Paolo Spirito, Francesco Formisano, Elena Biagini, Claudio Rapezzi, Carlo Nicola De Cecco, Camillo Autore, E. Francis Cook, Thomas Hauser, C. Michael Gibson, Warren Manning, Evan Appelbaum, Martin Maron
Journal: Journal of the American College of Cardiology (2012)
Cholinergic Mechanisms in the Sinus Node
Authors: THOMAS N. JAMES
Journal: Circulation Research (1966)

Acetylcholine is directly perfused into the canine sinus node in vivo through its cannulated nutrient artery. After atropinization, the chronotropic action from intranodal administration of acetylcholine was identical to that of control injections of Ringer's solution alone. Eserine produced only a negative chronotropic action before, and no significant action after, atropinization. Direct perfusion of the sinus node with hemicholinium (1 mg/ml) completely blocked the response to vagal stimulation but had no effect on the response to stimulation of the stellate ganglion. The evidence is interpreted as indicating that acetylcholine has only a negative chronotropic action in the canine sinus node and that it neither releases significant amounts of local nodal norepinephrine nor is necessary to the normal response of the sinus node to stellate ganglion stimulation.
Impaired Differentiation of Osteoclasts in TREM-2–deficient Individuals
Authors: Marina Cella, Cecilia Buonsanti, Carey Strader, Takayuki Kondo, Andrea Salmaggi, Marco Colonna
Journal: The Journal of Experimental Medicine (2003)

TREM-2 is an immunoglobulin-like cell surface receptor associated with DAP12/KARAP that activates monocyte-derived dendritic cells (DCs) in vitro. Recently, it has been shown that genetic defects of human DAP12/KARAP and TREM-2 result in a rare syndrome characterized by bone cysts and presenile dementia called Nasu-Hakola disease. This observation suggests that TREM-2 may function in myeloid cells other than DCs, most probably osteoclasts (OCs) and microglial cells, which are involved in bone modeling and brain function. Consistent with this prediction, here we show that OC differentiation is dramatically arrested in TREM-2-deficient patients, resulting in large aggregates of immature OCs that exhibit impaired bone resorptive activity. These results demonstrate a critical role for TREM-2 in the differentiation of mononuclear myeloid precursors into functional multinucleated OCs.
Molecular Detection of Tumor Cells in Regional Lymph Nodes Is Associated With Disease Recurrence and Poor Survival in Node-Negative Colorectal Cancer: A Systematic Review and Meta-Analysis
Authors: Nuh N. Rahbari, Ulrich Bork, Edith Motschall, Kristian Thorlund, Markus W. Büchler, Moritz Koch, Jürgen Weitz
Journal: Journal of Clinical Oncology (2011)

Up to 25% of patients with node-negative colorectal cancer (CRC) on conventional histopathologic analysis ultimately die of recurrent disease. We performed a systematic review with meta-analyses to clarify whether molecular detection of isolated tumor cells or micrometastases in regional lymph nodes indicates high risk of disease recurrence and poor survival in node-negative CRC.The following databases were searched in August 2011 to identify studies on the prognostic significance of molecular tumor-cell detection in regional lymph nodes of node-negative CRC: MEDLINE, BIOSIS, Science Citation Index, EMBASE, CCMed, and publisher databases. We extracted hazard ratios (HRs) and associated 95% CIs from the identified studies and performed random-effects model meta-analyses on overall survival, disease-specific survival, and disease-free survival.A total of 39 studies with a cumulative sample size of 4,087 patients were included. Immunohistochemistry, reverse transcriptase polymerase chain reaction, and both techniques were applied in 30, seven, and two studies, respectively. Thirteen studies were graded with low risk of bias. Meta-analyses revealed that molecular tumor-cell detection in regional lymph nodes was associated with poor overall survival (HR, 2.20; 95% CI, 1.43 to 3.40), disease-specific survival (HR, 3.37; 95% CI, 2.31 to 4.93), and disease-free survival (HR, 2.24; 95% CI, 1.57-3.20). Subgroup analyses showed the prognostic significance of molecular tumor-cell detection of being independent of the applied detection method, molecular target, and number of retrieved lymph nodes.Molecular detection of occult disease in regional lymph nodes is associated with an increased risk of disease recurrence and poor survival in patients with node-negative CRC.
Comparative Efficacy of a Once-Daily Controlled-Release Formulation of Glipizide and Immediate-Release Glipizide in Patients With NIDDM
Authors: Michael Berelowitz, Christine Fischette, William Cefalu, David S Schade, Tamara Sutfin, Ione A Kourides
Journal: Diabetes Care (1994)

OBJECTIVE To compare the efficacy and safety of controlled-release glipizide (glipizide-GITS [gastrointestinal therapeutic system]) and immediate-release glipizide in patients with non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS In a multicenter, open-label, randomized, two-way crossover study, 132 patients with NIDDM received daily doses of 5, 20, or 40 mg of either glipizide-GITS or immediate-release glipizide for 8 weeks followed by 8 weeks of the alternate formulation. Plasma glucose, serum insulin, C-peptide, and plasma glipizide levels were measured at fasting and post-Sustacal challenge at the end of 1 and 8 weeks of each treatment phase. HbA1c was measured at the end of weeks 7 and 8 of each treatment phase. RESULTS Both formulations of glipizide yielded similar mean HbA1c values. However, mean fasting plasma glucose (FPG) levels were significantly lower with glipizide-GITS treatment than with immediate-release glipizide at the end of week 1 (11.0 vs. 11.6 mmol/l; P &amp;lt; 0.01) and at the end of the 8-week treatment phase (10.9 vs. 11.7 mmol/l; P &amp;lt; 0.001). Fasting insulin and C-peptide levels were lower after 5 mg glipizide-GITS vs. immediate-release glipizide. Glucose responses to Sustacal were similar after both formulations of glipizide; however, serum insulin (P &amp;lt; 0.01) and C-peptide responses (P &amp;lt; 0.05) were lower with glipizide-GITS than with immediate-release glipizide treatment at the end of the 8-week treatment phase. Mean plasma glipizide concentrations were stable by the end of week 1, and the concentrations increased proportionately with dose. Once-daily Glipizide-GITS provided effective mean glipizide concentrations (&amp;gt; 50 ng/ml) 24 h after dosing, even at the lowest (5 mg) dose level. Both formulations were well tolerated. CONCLUSIONS Glipizide-GITS was significantly more effective than immediate-release glipizide in reducing FPG levels. Both formulations reduced postprandial plasma glucose levels equally; however, glipizide-GITS exerted its control in the presence of lower plasma glipizide concentrations in addition to significantly lower insulin and C-peptide levels. This suggests that glipizide-GITS improves insulin sensitivity.
Impact of an Asthma Educational Program on Children at an Asthma Camp
Authors: A.T. Vu, M.C. Glaum, E.G. Naik, M. Grandstaff, M.N. Shah, P. Panagos, R. Franck, J.T. Ramey, R.F. Lockey
Journal: Journal of Allergy and Clinical Immunology (2006)
Internet-based surveillance systems for monitoring emerging infectious diseases
Authors: Gabriel J Milinovich, Gail M Williams, Archie C A Clements, Wenbiao Hu
Journal: The Lancet Infectious Diseases (2013)

Emerging infectious diseases present a complex challenge to public health officials and governments; these challenges have been compounded by rapidly shifting patterns of human behaviour and globalisation. The increase in emerging infectious diseases has led to calls for new technologies and approaches for detection, tracking, reporting, and response. Internet-based surveillance systems offer a novel and developing means of monitoring conditions of public health concern, including emerging infectious diseases. We review studies that have exploited internet use and search trends to monitor two such diseases: influenza and dengue. Internet-based surveillance systems have good congruence with traditional surveillance approaches. Additionally, internet-based approaches are logistically and economically appealing. However, they do not have the capacity to replace traditional surveillance systems; they should not be viewed as an alternative, but rather an extension. Future research should focus on using data generated through internet-based surveillance and response systems to bolster the capacity of traditional surveillance systems for emerging infectious diseases.
Combining the Power of Stories and the Power of Numbers: Mixed Methods Research and Mixed Studies Reviews
Authors: Pierre Pluye, Quan Nha Hong
Journal: Annual Review of Public Health (2013)

This article provides an overview of mixed methods research and mixed studies reviews. These two approaches are used to combine the strengths of quantitative and qualitative methods and to compensate for their respective limitations. This article is structured in three main parts. First, the epistemological background for mixed methods will be presented. Afterward, we present the main types of mixed methods research designs and techniques as well as guidance for planning, conducting, and appraising mixed methods research. In the last part, we describe the main types of mixed studies reviews and provide a tool kit and examples. Future research needs to offer guidance for assessing mixed methods research and reporting mixed studies reviews, among other challenges.
Molecular evolution of voltage-sensitive ion channel genes: on the origins of electrical excitability.
Authors: M Strong, K G Chandy, G A Gutman
Journal: Molecular Biology and Evolution (1993)

We have analyzed nucleic acid and amino acid sequence alignments of a variety of voltage-sensitive ion channels, using several methods for phylogenetic tree reconstruction. Ancient duplications within this family gave rise to three distantly related groups, one consisting of the Na+ and Ca++ channels, another the K+ channels, and a third including the cyclic nucleotide-binding channels. A series of gene duplications produced at least seven mammalian homologues of the Drosophila Shaker K+ channel; clones of only three of these genes are available from all three mammalian species examined (mouse, rat, and human), pointing to specific genes that have yet to be recovered in one or another of these species. The Shaw-related K+ channels and the Na+ channel family have also undergone considerable expansion in mammals, relative to flies. These expansions presumably reflect the needs of the high degree of physiological and neuronal complexity of mammals. Analysis of the separate domains of the four-domain channels (Ca++ and Na+) supports their having evolved by two sequential gene duplications and implies the historical existence of a functional two-domain channel.
Antigens Varying in Affinity for the B Cell Receptor Induce Differential B Lymphocyte Responses
Authors: Valerie Kouskoff, Sara Famiglietti, Georges Lacaud, Paul Lang, James E. Rider, Brian K. Kay, John C. Cambier, David Nemazee
Journal: The Journal of Experimental Medicine (1998)

The B cell receptor (BCR) triggers a variety of biological responses that differ depending upon the properties of the antigen. A panel of M13 phage-displayed peptide ligands with varying affinity for the 3-83 antibody was generated to explore the role of antigen-BCR affinity in cell activation studies using primary 3-83 transgenic mouse B cells. Multiple parameters of activation were measured. T cell–independent B cell proliferation, antibody secretion, induction of germline immunoglobulin γ1 transcripts, and B cell production of interleukin (IL) 2 and interferon γ responses were better correlated with antigen-BCR affinity than with receptor occupancy. In contrast, other responses, such as upregulation of major histocompatibility complex class II and B7.2 (CD86), secretion of IL-6, and B cell proliferation in the context of CD40 signaling were only weakly dependent on antigen affinity. Biochemical analysis revealed that at saturating ligand concentrations the ability of phage to stimulate some early signaling responses, such as Ca++ mobilization and tyrosine phosphorylation of syk or Igα, was highly affinity dependent, whereas the ability to stimulate Lyn phosphorylation was less so. These data suggest that the BCR is capable of differential signaling. The possibility that differential BCR signaling by antigen determines whether an antibody response will be T independent or dependent is discussed.
Reactivation of ERK Signaling Causes Resistance to EGFR Kinase Inhibitors
Authors: Dalia Ercan, Chunxiao Xu, Masahiko Yanagita, Calixte S. Monast, Christine A. Pratilas, Joan Montero, Mohit Butaney, Takeshi Shimamura, Lynette Sholl, Elena V. Ivanova, Madhavi Tadi, Andrew Rogers, Claire Repellin, Marzia Capelletti, Ophélia Maertens, Eva M. Goetz, Anthony Letai, Levi A. Garraway, Matthew J. Lazzara, Neal Rosen, Nathanael S. Gray, Kwok-Kin Wong, Pasi A. Jänne
Journal: Cancer Discovery (2012)

Abstract The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here, we show, in multiple complementary models, that resistance to WZ4002 develops through aberrant activation of extracellular signal-regulated kinase (ERK) signaling caused by either an amplification of mitogen-activated protein kinase 1 (MAPK1) or by downregulation of negative regulators of ERK signaling. Inhibition of MAP–ERK kinase (MEK) or ERK restores sensitivity to WZ4002 and prevents the emergence of drug resistance. We further identify MAPK1 amplification in an erlotinib-resistant EGFR-mutant non–small cell lung carcinoma patient. In addition, the WZ4002-resistant MAPK1-amplified cells also show an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Significance: Our study identifies activated ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. Cancer Discov; 2(10); 934–47. ©2012 AACR. Read the Commentary on this article by Blakely and Bivona, p. 872. This article is highlighted in the In This Issue feature, p. 857.
Significance of tumour mass on T-lymphocyte levels in patients with gastrointestinal cancer.
Authors: H S Shukla, R H Whitehead, L E Hughes
Journal: Gut (1979)

The relationship between tumour load and immunity in gastrointestinal cancer has been studied by sequential comparison in patients whose tumour has been removed and those whose tumour was found to be inoperable. Total lymphocyte count, absolute and percentage T- and B-lymphocyte counts, effect of papain on E-rosetting cell levels, and inhibitory effect of cancer sera on E-rosette formation by normal lymphocytes have been studied in 30 patients with stomach or colorectal cancer, and 10 control patients with benign gastrointestinal disease. The examination was done on each patient before and at regular intervals after operation up to 24 weeks. Operable cases, with removal of tumour load, showed a temporary fall in total lymphocyte count and T cell counts, which returned to normal by four weeks postoperatively. Inoperable cases (15 patients) showed a progressive fall in total lymphocyte count and a relatively greater depression of T cell counts, in parallel with increasing tumour mass. E-receptor blocking factor was demonstrated in the sera of cancer patients. This factor was related to tumour mass and presumably was of tumour origin, as it persisted in the inoperable group but disappeared by 12 weeks after tumour removal. The factor explained the excess depresion of T cells over total lymphocytes, but does not explain the continuing depression of total lymphocyte count in the cancer patients.