tbuckley/cabot-search huggingface dataset:
On the adaptation in potassium excretion associated with nephron reduction in the dog
Authors: Raymond G. Schultze, Dennis D. Taggart, Howard Shapiro, J. Phillip Pennell, Sali Caglar, Neal S. Bricker
Journal: Journal of Clinical Investigation (1971)

An effort to examine certain aspects of the adaptation in potassium excretion associated with nephron reduction was made in dogs with unilateral remnant kidneys. A constant intake of potassium was maintained by tube feeding and studies were performed before and after removal of the intact control kidney. The removal of the intact kidney created the need for the remaining nephrons of the remnant kidney to increase their rate of potassium excretion markedly. Sodium intake was held constant either at a normal or a low level. Mineralocorticoid hormone activity was maintained either at a high level by the administration of 0.2 mg 9-alpha-fluorohydrocortisone daily or at a low level by performing bilateral adrenalectomy and administering a minimal maintenance dose of deoxycorticosterone acetate (DOCA) and cortisol. Potassium excretion per nephron increased strikingly within 18 hr of contralateral nephrectomy and by 7 days, excretion rates were 600% of control values for the remnant kidney. More potassium was excreted in the first 5 hr after administration of a test dose of potassium by the remnant kidney alone in the postnephrectomy state than by both the remnant and intact kidneys in the prenephrectomy state. 24 hr excretion of potassium by the remnant kidney postnephrectomy averaged 92% of the administered load of potassium. The adaptation in potassium excretion was independent of the concurrent rate of sodium excretion and of mineralocorticoid hormone activity and persisted during constriction of the renal artery, a stimulus which presumably decreased distal delivery of sodium. The adaptation and the continued modulation of potassium excretion could not be explained adequately by an increase in impermeant anion excretion per nephron. Finally, known changes in hydrogen ion excretion per nephron associated with nephron reduction are in a direction opposite to those which would explain the acquired kaliuresis per nephron.
Transcriptome-wide characterization of the eIF4A signature highlights plasticity in translation regulation
Authors: Claudia A Rubio, Benjamin Weisburd, Matthew Holderfield, Carolina Arias, Eric Fang, Joseph L DeRisi, Abdallah Fanidi
Journal: Genome biology (2014)

Abstract Background Protein synthesis is tightly regulated and alterations to translation are characteristic of many cancers. Translation regulation is largely exerted at initiation through the eukaryotic translation initiation factor 4 F (eIF4F). eIF4F is pivotal for oncogenic signaling as it integrates mitogenic signals to amplify production of pro-growth and pro-survival factors. Convergence of these signals on eIF4F positions this factor as a gatekeeper of malignant fate. While the oncogenic properties of eIF4F have been characterized, genome-wide evaluation of eIF4F translational output is incomplete yet critical for developing novel translation-targeted therapies. Results To understand the impact of eIF4F on malignancy, we utilized a genome-wide ribosome profiling approach to identify eIF4F-driven mRNAs in MDA-MB-231 breast cancer cells. Using Silvestrol, a selective eIF4A inhibitor, we identify 284 genes that rely on eIF4A for efficient translation. Our screen confirmed several known eIF4F-dependent genes and identified many unrecognized targets of translation regulation. We show that 5’UTR complexity determines Silvestrol-sensitivity and altering 5’UTR structure modifies translational output. We highlight physiological implications of eIF4A inhibition, providing mechanistic insight into eIF4F pro-oncogenic activity. Conclusions Here we describe the transcriptome-wide consequence of eIF4A inhibition in malignant cells, define mRNA features that confer eIF4A dependence, and provide genetic support for Silvestrol’s anti-oncogenic properties. Importantly, our results show that eIF4A inhibition alters translation of an mRNA subset distinct from those affected by mTOR-mediated eIF4E inhibition. These results have significant implications for therapeutically targeting translation and underscore a dynamic role for eIF4F in remodeling the proteome toward malignancy.
Overcoming CYP1A1/1A2 Mediated Induction of Metabolism by Escalating Erlotinib Dose in Current Smokers
Authors: Andrew N. Hughes, Mary E.R. O'Brien, W. Jeffrey Petty, Jonathan B. Chick, Elaine Rankin, Penella J. Woll, David Dunlop, Marianne Nicolson, Ramesh Boinpally, Julie Wolf, Allan Price
Journal: Journal of Clinical Oncology (2009)

Purpose Cigarette smoking induces CYP1A1/1A2 and is hypothesized to alter erlotinib pharmacokinetics. This study aimed to determine the maximum tolerated dose (MTD) of erlotinib in advanced non–small-cell lung cancer (NSCLC) patients who smoke and compare the pharmacokinetics of erlotinib at the MTD in current smokers with 150 mg. Patients and Methods Cohorts of NSCLC patients currently smoking ≥ 10 cigarettes per day for ≥ 1 year received escalating doses of erlotinib for 14 days until dose-limiting toxicity (DLT). A separate cohort of patients was then randomly assigned to erlotinib at either MTD or 150 mg daily with pharmacokinetics assessed at day 14. Erlotinib was continued until progression or intolerable toxicity. Results Four dose levels were evaluated in 22 patients: 200, 250, 300, and 350 mg. DLT was observed in one of six patients at 300 mg (rash) and two of five patients at 350 mg (acneiform dermatitis and fatigue/decreased Eastern Cooperative Oncology Group performance status). Thirty-five patients were randomly assigned to 150 mg or 300 mg. Common adverse events (all grades) were: skin toxicity (150 mg, 29%; 300 mg, 67%), diarrhea (150 mg, 18%; 300 mg, 50%), and fatigue (150 mg, 12%; 300 mg, 17%). Erlotinib exposure was dose-proportional within dose range tested. Median steady-state trough erlotinib plasma concentrations were 0.375 and 1.22 μg/mL for 150 mg and 300 mg, respectively. Conclusion The MTD of erlotinib in NSCLC patients who smoke was 300 mg. Steady-state trough plasma concentrations and incidence of rash and diarrhea in smokers at 300 mg were similar to those in former or never smokers receiving 150 mg in previous studies. The potential benefit of higher erlotinib doses in current smokers warrants further evaluation.
Risk of Second Malignancies in Survivors of Retinoblastoma: More Than 40 Years of Follow-up
Authors: Tamara Marees, Annette C. Moll, Saskia M. Imhof, Michiel R. de Boer, Peter J. Ringens, Flora E. van Leeuwen
Journal: JNCI Journal of the National Cancer Institute (2008)

Survivors of hereditary retinoblastoma have an elevated risk of developing second malignancies, but data on the risk in middle-aged retinoblastoma survivors (ie, those with more than 40 years of follow-up) are scarce.Data from the Dutch retinoblastoma registry were used to analyze risks of second malignancies in 668 retinoblastoma survivors, diagnosed from 1945 to 2005 (median age = 24.9 years) and classified as having had hereditary or nonhereditary disease based on the presence of family history, bilateral disease, or a germline RB1 mutation. Standardized incidence ratios (SIRs) and absolute excess risks (AERs) of subsequent cancers in patients with hereditary and nonhereditary disease were estimated by comparison with Dutch sex-, age-, and calendar year-specific rates. Multivariable Cox regression and competing risk analyses were used to determine associations of treatment with risks of second malignancies. All statistical tests were two-sided.After a median follow-up of 21.9 years, the risk of second malignancies in survivors of hereditary retinoblastoma (SIR = 20.4, 95% confidence interval [CI] = 15.6 to 26.1) far exceeded the risk of survivors of nonhereditary retinoblastoma (SIR = 1.86, 95% CI = 0.96 to 3.24). Among patients with hereditary disease, treatment with radiotherapy was associated with a further increase in the risk of a subsequent cancer (hazard ratio = 2.81, 95% CI = 1.28 to 6.19). After 30 years of follow-up, elevated risks of epithelial cancers (lung, bladder, and breast) were observed among survivors of hereditary retinoblastoma. After 40 years of follow-up, the AER of a second malignancy among survivors of hereditary retinoblastoma had increased to 26.1 excess cases per 1000 person-years. The cumulative incidence of any second malignancy 40 years after retinoblastoma diagnosis was 28.0% (95% CI = 21.0% to 35.0%) for patients with hereditary disease.Our analysis of middle-aged hereditary retinoblastoma survivors suggests that these individuals have an excess risk of epithelial cancer. Lifelong follow-up studies are needed to evaluate the full spectrum of subsequent cancer risk in hereditary retinoblastoma survivors.
Impact of chemotherapy on the nutritional status and quality of life during treatment for breast cancer
Authors: S. Antoun, E. Tournay, A. Rey, C. Widakowich, F. André, G. Nitenberg, B. Raynard, S. Delaloge, R. Bahleda
Journal: Journal of Clinical Oncology (2008)

20674 Background: Chemotherapy (CT) is often incriminated in malnutrition and quality of life (QOL) deterioration during cancer, either because of its own role or due to CT-induced toxicities, notably digestive adverse effects. The aim of this study was to analyze the consequences of adjuvant CT on the nutritional status and QOL during breast cancer. Methods: A prospective study of 40 patients treated for breast cancer (BK) by adjuvant CT. Standard CT regimens were used according to nodal status (FEC 100 alone or FEC 100 and docetaxel). The following parameters were collected after each CT course: weight (WT), body mass index (BMI), albuminemia (ALB), transthyretin (TTR), body components evaluated by impedancemetry (Bodystat Quadscan 4000), and QOL parameters assessed using the QLQ-C30 questionnaire. Results: The study has enrolled 40 female patients, median age 52 years (range 28–71), median initial BMI 24.1 kg/m2 (range 17.7–41.8). No changes in nutritional clinical (WT, BMI) or biological (ALB, TTR) parameters were observed over time nor after a more sensitive analysis of body components. Lean body mass (LBM) and fat mass (FM) values remained stable. Grade 2–3 toxicities following CT were observed in 37%, 13%, 11% and 3% of patients for nausea, mucositis, vomiting and diarrhea respectively. Appetite disturbances (p=0.02), increased fatigue (p=0.0004) and a decreased QOL score (0.0001) were observed during CT courses. Adjustment of the analysis as a function of time showed no significant statistical correlation between QOL deterioration and nutritional parameters. Conclusions: Despite the presence of anorexia and nausea during adjuvant CT for BK, no changes in the nutritional status were observed even when sensitive measures such as LBM and FM were used. QOL deterioration and fatigue are not associated with a decline in muscle mass. No significant financial relationships to disclose.
Rb Depletion Results in Deregulation of E-Cadherin and Induction of Cellular Phenotypic Changes that Are Characteristic of the Epithelial-to-Mesenchymal Transition
Authors: Yoshimi Arima, Yasumichi Inoue, Tatsuhiro Shibata, Hidemi Hayashi, Osamu Nagano, Hideyuki Saya, Yoichi Taya
Journal: Cancer Research (2008)

Abstract The retinoblastoma tumor suppressor protein (Rb) is mutated or expressed at very low levels in several tumor types, including retinoblastoma and osteosarcoma, as well as small cell lung, colon, prostate, bladder, and breast carcinomas. Loss or reduction of Rb expression is seen most commonly in high-grade breast adenocarcinomas, suggesting that a relationship may exist between loss of Rb function and a less-differentiated state, increased proliferation, and high metastatic potential. In this study, we found that knockdown of Rb by small interfering RNA in MCF7 breast cancer cells disrupts cell-cell adhesion and induces a mesenchymal-like phenotype. The epithelial-to-mesenchymal transition (EMT), a key event in embryonic morphogenesis, is implicated in the metastasis of primary tumors. Additionally, Rb is decreased during growth factor– and cytokine-induced EMT and overexpression of Rb inhibits the EMT in MCF10A human mammary epithelial cells. Ectopic expression and knockdown of Rb resulted in increased or reduced expression of E-cadherin, which is specifically involved in epithelial cell-cell adhesion. Other EMT-related transcriptional factors, including Slug and Zeb-1, are also induced by Rb depletion. Furthermore, we confirmed that Rb binds to an E-cadherin promoter sequence in association with the transcription factor activator protein-2α. Finally, in breast cancer specimens, we observed a concurrent down-regulation of Rb and E-cadherin expression in mesenchymal-like invasive cancers. These findings suggest that Rb inactivation contributes to tumor progression due to not only loss of cell proliferation control but also conversion to an invasive phenotype and that the inhibition of EMT is a novel tumor suppressor function of Rb. [Cancer Res 2008;68(13):5104–12]
Nabel speaks up about directing the NHLBI
Authors: Stacie Bloom
Journal: Journal of Clinical Investigation (2005)

The National Heart, Lung, and Blood Institute (NHLBI) covers extensive ground, exploring causes, prevention, therapy, and diagnosis of diseases involving the heart, blood, blood vessels, and lung. The NHLBI also researches sleep disorders and coordinates the NIH Woman’s Health Initiative. Elizabeth Nabel, formerly the scientific director of clinical research in the NHLBI intramural program and a board-certified cardiologist, is now at its helm.
Concurrent application of tretinoin (retinoic acid) partially protects against corticosteroid-induced epidermal atrophy
Authors: A.J. MCMICHAEL, C.E.M. GRIFFITHS, H.S. TALWAR, L.J. FINKEL, E.S. RAFAL, T.A. HAMILTON, J.J. VOORHEES
Journal: British Journal of Dermatology (1996)

Cutaneous atrophy arising from prolonged use of potent topical corticosteroids has long been a concern. Thus, it would be advantageous to find an agent which protects against atrophy produced by corticosteroids but at the same time does not impair their anti‐inflammatory effects. Recent work shows that topical all‐trans retinoic acid (tretinoin) prevents skin atrophy in mice treated with topical corticosteroids, but such studies have not been performed in humans. We performed an 8‐week clinical, histological and biochemical study to test the ability of tretinoin to enhance efficacy and inhibit atrophogenicity of topical corticosteroids, when used in the treatment of psoriasis. In each of 20 psoriasis patients, one plaque, and its perilesional skin, was treated once daily with betamethasone dipropionate and tretinoin 0·1%, and one plaque, and its perilesional skin, treated with once daily betamethasone dipropionate and tretinoin vehicle. There was no difference in the speed or degree of improvement in plaques treated with either the topical corticosteroid/tretinoin combination or with corticosteroid alone. Light microscopy revealed a 19% reduction in epidermal thickness, in corticosteroid‐treated perilesional skin, as compared with a slight (1%) increase in corticosteroid/ tretinoin‐treated perilesional areas (P= 0.067). Western blot analysis showed a 55% reduction in procollagen I aminopropeptide in perilesional skin treated with corticosteroid alone, as compared with a 45% reduction in corticosteroid/tretinoin‐treated perilesional skin. These data indicate that the addition of tretinoin does not impair the efficacy of a topical corticosteroid, in the treatment of psoriasis, and partially ameliorates epidermal atrophy produced by the topical corticosteroid.
Enhanced Hematopoiesis by Hematopoietic Progenitor Cells Lacking Intracellular Adaptor Protein, Lnk
Authors: Satoshi Takaki, Hatsue Morita, Yoshinari Tezuka, Kiyoshi Takatsu
Journal: The Journal of Experimental Medicine (2002)

Hematopoietic stem cells (HSCs) give rise to variety of hematopoietic cells via pluripotential progenitors and lineage-committed progenitors and are responsible for blood production throughout adult life. Amplification of HSCs or progenitors represents a potentially powerful approach to the treatment of various blood disorders and to applying gene therapy by bone marrow transplantation. Lnk is an adaptor protein regulating the production of B cells. Here we show that Lnk is also expressed in hematopoietic progenitors in bone marrow, and that in the absence of Lnk, the number and the hematopoietic ability of progenitors are significantly increased. Augmented growth signals through c-Kit partly contributed to the enhanced hematopoiesis by lnk−/− cells. Lnk was phosphorylated by and associated with c-Kit, and selectively inhibited c-Kit–mediated proliferation by attenuating phosphorylation of Gab2 and activation of mitogen-activated protein kinase cascade. These observations indicate that Lnk plays critical roles in the expansion and function of early hematopoietic progenitors, and provide useful clues for the amplification of hematopoietic progenitor cells.
Hypoxia-Inducible Transcription Factor-1α Triggers an Autocrine Survival Pathway During Embryonic Cardiac Outflow Tract Remodeling
Authors: Hongbin Liu, Steven A. Fisher
Journal: Circulation Research (2008)

The cardiac outflow tract (OFT) of birds and mammals undergoes complex remodeling in the transition to a dual circulation. We have previously suggested a role of myocardial hypoxia and hypoxia inducible factor (HIF)-1 in the apoptosis-dependent remodeling of the OFT. In the present study, we transduced recombinant adenovirus-mediated HIF-1α in embryonic chick OFT myocardium to test its role in OFT remodeling. HIF-1α reduced the prevalence of apoptosis in OFT cardiomyocytes at stages 25 and 30, as determined by lysosome accumulation and caspase-3 activity. Associated conotruncal defects included malrotation of the aorta and excessive infundibular myocardium. HIF-1 targets induced in these gain-of-function experiments included vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, and stromal cell–derived factor-1. To test the role of VEGF in this context, an adenovirus expressing secreted Flk1 (VEGF receptor 2) that binds and blocks VEGF signaling was targeted to the OFT myocardium. This caused increased cell death in the OFT myocardium at stages 25 and 30. Associated conotruncal heart defects included malrotation of the aorta, defects in the subpulmonic infundibulum associated with a small right ventricle, and increased OFT mesenchyme with failure of semilunar valve formation. We conclude that hypoxia signaling through HIF-1 and VEGF provides an autocrine survival signal in the developing cardiac OFT and that perturbation in this pathway causes OFT defects that model congenital human conotruncal heart defects.
The Molecular Basis of Lmo2-Induced T-Cell Acute Lymphoblastic Leukemia
Authors: David J. Curtis, Matthew P. McCormack
Journal: Clinical Cancer Research (2010)

T-cell acute lymphoblastic leukemia (T-ALL) is commonly caused by the overexpression of oncogenic transcription factors in developing T cells. In a mouse model of one such oncogene, LMO2, the cellular effect is to induce self-renewal of committed T cells in the thymus, which persist long-term while acquiring additional mutations and eventually giving rise to leukemia. These precancerous stem cells (pre-CSC) are intrinsically resistant to radiotherapy, implying that they may be refractory to conventional cancer therapies. However, they depend on an aberrantly expressed stem cell-like self-renewal program for their maintenance, in addition to a specialized thymic microenvironmental niche. Here, we discuss potential approaches for targeting pre-CSCs in T-ALL by using therapies directed at oncogenic transcription factors themselves, downstream self-renewal pathways, and the supportive cell niche.
Corrigendum to “Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis” [J Hepatol 2014; 60: 955–961]
Authors: Ezequiel Rodríguez, Chiara Elia, Elsa Solà, Rogelio Barreto, Isabel Graupera, Alida Andrealli, Gustavo Pereira, Maria Poca, Jordi Sánchez, Mónica Guevara, Germán Soriano, Carlo Alessandria, Javier Fernández, Vicente Arroyo, Pere Ginès
Journal: Journal of Hepatology (2014)
Prognostic Value of Radionuclide Angiography in Patients With Right Ventricular Arrhythmias
Authors: Dominique Le Guludec, Hélène Gauthier, Raphael Porcher, Robert Frank, Doumit Daou, Salah Benelhadj, Antoine Leenhardt, Thomas Lavergne, Marc Faraggi, Michel S. Slama
Journal: Circulation (2001)

Background —The prognosis of patients with right ventricular (RV) arrhythmias remains uncertain. This study prospectively evaluated the prognostic value of RV and left ventricular (LV) involvement assessed by radionuclide angiography (RNA) as predictors for sudden death. Methods and Results —Patients (n=188) with severe arrhythmias originating from the RV were followed up for a mean of 45±34 months. Data on clinical presentation, resting and stress ECG, signal-averaged ECG, 24-hour Holter monitoring, and programmed stimulation were collected along with RNA. Patients were classified as group I (n=82) with normal RNA or group II (n=106) with an abnormal RV suggestive of arrhythmogenic RV cardiomyopathy, classified as diffuse or localized disease, with or without associated LV abnormalities. During follow-up, 14 patients died suddenly, all in group II. None of the clinical and electrical data were predictive of death. An abnormal RNA study was a highly predictive factor for death ( P &lt;0.005), as well as the presence of LV abnormalities ( P &lt;0.01). Conclusions —The present study confirms that arrhythmogenic RV cardiomyopathy is a severe disease with a high risk for cardiac death. Evidence of RV abnormalities in patients presenting with RV arrhythmias is highly predictive for sudden death, as is its association with LV involvement.
Evidence for modulation of human epidermal differentiation and remodelling by CD40
Authors: M. Concha, M.A. Vidal, I. Moreno, C. Salem, C.D. Figueroa, D. Schmitt, J. PEguet-Navarro
Journal: British Journal of Dermatology (2003)

Summary Background It is widely accepted that CD40 plays a critical role in the regulation of immune response. However, the significance of CD40 expression on normal human keratinocytes is only partially known.
Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus
Authors: Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Wataru Yano, Ryo Suzuki, Kohjiro Ueki, Iseki Takamoto, Hidemi Satoh, Toshiyuki Maki, Tetsuya Kubota, Masao Moroi, Miki Okada-Iwabu, Osamu Ezaki, Ryozo Nagai, Yoichi Ueta, Takashi Kadowaki, Tetsuo Noda
Journal: Journal of Clinical Investigation (2004)

We previously demonstrated that insulin receptor substrate 2 (Irs2) KO mice develop diabetes associated with hepatic insulin resistance, lack of compensatory beta cell hyperplasia, and leptin resistance. To more precisely determine the roles of Irs2 in beta cells and the hypothalamus, we generated beta cell-specific Irs2 KO and hypothalamus-specific Irs2 knockdown (betaHT-IRS2) mice. Expression of Irs2 mRNA was reduced by approximately 90% in pancreatic islets and was markedly reduced in the arcuate nucleus of the hypothalamus. By contrast, Irs2 expression in liver, muscle, and adipose tissue of betaHT-IRS2 mice was indistinguishable from that of control mice. The betaHT-IRS2 mice displayed obesity and leptin resistance. At 4 weeks of age, the betaHT-IRS2 mice showed normal insulin sensitivity, but at 8 and 12 weeks, they were insulin resistant with progressive obesity. Despite their normal insulin sensitivity at 8 weeks with caloric restriction, the betaHT-IRS2 mice exhibited glucose intolerance and impaired glucose-induced insulin secretion. beta Cell mass and beta cell proliferation in the betaHT-IRS2 mice were reduced significantly at 8 and 12 weeks but not at 10 days. Insulin secretion, normalized by cell number per islet, was significantly increased at high glucose concentrations in the betaHT-IRS2 mice. We conclude that, in beta cells and the hypothalamus, Irs2 is crucially involved in the regulation of beta cell mass and leptin sensitivity.