tbuckley/cabot-search huggingface dataset:
Effects of HIV Protease Inhibitor Ritonavir on Akt-Regulated Cell Proliferation in Breast Cancer
Authors: Anjaiah Srirangam, Ranjana Mitra, Mu Wang, J. Christopher Gorski, Sunil Badve, LeeAnn Baldridge, Justin Hamilton, Hiromitsu Kishimoto, John Hawes, Lang Li, Christie M. Orschell, Edward F. Srour, Janice S. Blum, David Donner, George W. Sledge, Harikrishna Nakshatri, David A. Potter
Journal: Clinical Cancer Research (2006)

Abstract Purpose: These studies were designed to determine whether ritonavir inhibits breast cancer in vitro and in vivo and, if so, how. Experimental Design: Ritonavir effects on breast cancer cell growth were studied in the estrogen receptor (ER)–positive lines MCF7 and T47D and in the ER-negative lines MDA-MB-436 and MDA-MB-231. Effects of ritonavir on Rb-regulated and Akt-mediated cell proliferation were studied. Ritonavir was tested for inhibition of a mammary carcinoma xenograft. Results: ER-positive estradiol-dependent lines (IC50, 12-24 μmol/L) and ER-negative (IC50, 45 μmol/L) lines exhibit ritonavir sensitivity. Ritonavir depletes ER-α levels notably in ER-positive lines. Ritonavir causes G1 arrest, depletes cyclin-dependent kinases 2, 4, and 6 and cyclin D1 but not cyclin E, and depletes phosphorylated Rb and Ser473 Akt. Ritonavir induces apoptosis independent of G1 arrest, inhibiting growth of cells that have passed the G1 checkpoint. Myristoyl-Akt, but not activated K-Ras, rescues ritonavir inhibition. Ritonavir inhibited a MDA-MB-231 xenograft and intratumoral Akt activity at a clinically attainable serum Cmax of 22 ± 8 μmol/L. Because heat shock protein 90 (Hsp90) substrates are depleted by ritonavir, ritonavir effects on Hsp90 were tested. Ritonavir binds Hsp90 (KD, 7.8 μmol/L) and partially inhibits its chaperone function. Ritonavir blocks association of Hsp90 with Akt and, with sustained exposure, notably depletes Hsp90. Stably expressed Hsp90α short hairpin RNA also depletes Hsp90, inhibiting proliferation and sensitizing breast cancer cells to low ritonavir concentrations. Conclusions: Ritonavir inhibits breast cancer growth in part by inhibiting Hsp90 substrates, including Akt. Ritonavir may be of interest for breast cancer therapeutics and its efficacy may be increased by sustained exposure or Hsp90 RNA interference.
Gene Turnover in the Avian Globin Gene Families and Evolutionary Changes in Hemoglobin Isoform Expression
Authors: Juan C. Opazo, Federico G. Hoffmann, Chandrasekhar Natarajan, Christopher C. Witt, Michael Berenbrink, Jay F. Storz
Journal: Molecular Biology and Evolution (2014)

The apparent stasis in the evolution of avian chromosomes suggests that birds may have experienced relatively low rates of gene gain and loss in multigene families. To investigate this possibility and to explore the phenotypic consequences of variation in gene copy number, we examined evolutionary changes in the families of genes that encode the α- and β-type subunits of hemoglobin (Hb), the tetrameric α2β2 protein responsible for blood-O2 transport. A comparative genomic analysis of 52 bird species revealed that the size and membership composition of the α- and β-globin gene families have remained remarkably constant during approximately 100 My of avian evolution. Most interspecific variation in gene content is attributable to multiple independent inactivations of the αD-globin gene, which encodes the α-chain subunit of a functionally distinct Hb isoform (HbD) that is expressed in both embryonic and definitive erythrocytes. Due to consistent differences in O2-binding properties between HbD and the major adult-expressed Hb isoform, HbA (which incorporates products of the αA-globin gene), recurrent losses of αD-globin contribute to among-species variation in blood-O2 affinity. Analysis of HbA/HbD expression levels in the red blood cells of 122 bird species revealed high variability among lineages and strong phylogenetic signal. In comparison with the homologous gene clusters in mammals, the low retention rate for lineage-specific gene duplicates in the avian globin gene clusters suggests that the developmental regulation of Hb synthesis in birds may be more highly conserved, with orthologous genes having similar stage-specific expression profiles and similar functional properties in disparate taxa.
Depression and Self-Reported Functional Status in Older Primary Care Patients
Authors: Paula A. Sinclair, Jeffrey M. Lyness, Deborah A. King, Christopher Cox, Eric D. Caine
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors' goal was to examine whether depression is associated with overreporting of functional disability. METHOD: The subjects were 304 patients 60 years old or older who were recruited from primary care settings. Measures included examiner ratings of depression diagnosis and medical burden and self-reported and examiner-rated functional assessments. Multiple regression techniques were used to determine the independent association of depression with self-reported function after examiner-rated function was added to the analysis as a covariate. RESULTS: Depression diagnosis was associated with poorer self-reported role functioning, whether the patient attributed the disability to physical or emotional causes. Depression was not independently associated with poorer self-reported physical functioning. CONCLUSIONS: Clinicians and researchers should recognize that depression can confound the self-reporting and attribution of functional disability.
Effect of Periodontal Treatment on Glycemic Control of Diabetic Patients
Authors: Wijnand J. Teeuw, Victor E.A. Gerdes, Bruno G. Loos
Journal: Diabetes Care (2010)

OBJECTIVE There is growing evidence that periodontitis may affect general health. This study was assigned to explore the robustness of observations that periodontal therapy leads to the improvement of glycemic control in diabetic patients. RESEARCH DESIGN AND METHODS A literature search (until March 2009) was carried out using two databases (MEDLINE and the Cochrane Library) with language restriction to English. Selection of publications was based on 1) original investigations, 2) controlled periodontal intervention studies where the diabetic control group received no periodontal treatment, and 3) study duration of ≥3 months. RESULTS Screening of the initial 639 identified studies and reference checking resulted in five suitable articles. A total of 371 patients were included in this analysis with periodontitis as predictor and the actual absolute change in A1C (ΔA1C) as the outcome. The duration of follow-up was 3–9 months. All studies described a research population of type 2 diabetic patients in whom glycemic control improved after periodontal therapy compared with the control group (range ΔA1C: Δ−1.17 up to Δ−0.05%). The studies in a meta-analysis demonstrated a weighted mean difference of ΔA1C before and after therapy of −0.40% (95% CI −0.77 to −0.04%, P = 0.03) favoring periodontal intervention in type 2 diabetic patients. Nevertheless, this improvement in %A1C must be interpreted with care due to limited robustness as evidenced by heterogeneity among studies (59.5%, P = 0.04). CONCLUSIONS The present meta-analysis suggests that periodontal treatment leads to an improvement of glycemic control in type 2 diabetic patients for at least 3 months.
The endocytosis and intracellular fate of nanomedicines: Implication for rational design
Authors: Longfa Kou, Jin Sun, Yinglei Zhai, Zhonggui He
Journal: Asian Journal of Pharmaceutical Sciences (2013)

Nanomedicines employ multiple endocytic pathways to enter cells. Their following fate is interesting, but it is not sufficient understood currently. This review introduces the endocytic pathways, presents new technologies to confirm the specific endocytic pathways and discusses factors for pathway selection. In addition, some intriguing implication about nanomedicine design based on endocytosis will also be discussed at the end. This review may provide new thoughts for the design of novel multifunctional nanomedicines.
Phenotypic Alteration of Vascular Smooth Muscle Cells Precedes Elastolysis in a Mouse Model of Marfan Syndrome
Authors: Tracie E. Bunton, Nancy Jensen Biery, Loretha Myers, Barbara Gayraud, Francesco Ramirez, Harry C. Dietz
Journal: Circulation Research (2001)

Abstract —Marfan syndrome is associated with early death due to aortic aneurysm. The condition is caused by mutations in the gene (FBN1) encoding fibrillin-1, a major constituent of extracellular microfibrils. Prior observations suggested that a deficiency of microfibrils causes failure of elastic fiber assembly during late fetal development. Mice homozygous for a targeted hypomorphic allele (mgR) of Fbn1 revealed a predictable sequence of abnormalities in the vessel wall including elastic fiber calcification, excessive deposition of matrix elements, elastolysis, and intimal hyperplasia. Here we describe previously unrecognized concordant findings in elastic vessels from patients with Marfan syndrome. Furthermore, ultrastructural analysis of mgR mice revealed cellular events that initiate destructive changes. The first detectable abnormality was an unusually smooth surface of elastic laminae, manifesting the loss of cell attachments that are normally mediated by fibrillin-1. Adjacent cells adopted alteration in their expression profile accompanied by morphological changes but retained expression of vascular smooth muscle cell markers. The abnormal synthetic repertoire of these morphologically abnormal smooth muscle cells in early vascular lesions included elastin, among other matrix elements, and matrix metalloproteinase 9, a known mediator of elastolysis. Ultimately, cell processes associated with zones of elastic fiber thinning and fragmentation. These data suggest that the loss of cell attachments signals a nonproductive program to synthesize and remodel an elastic matrix. This refined understanding of the pathogenesis of vascular disease in Marfan syndrome will facilitate the development of therapeutic strategies.
[118] EXTRACELLULAR SUPEROXIDE DISMUTASE GENE TRANSFER REDUCES PORTAL PRESSURE AND IMPROVES INTRAHEPATIC ENDOTHELIAL DYSFUNCTION IN CIRRHOTIC RAT LIVERS BY DIMINISHING SUPEROXIDE AND INCREASING NITRIC OXIDE BIOAVAILABILITY
Authors: B. Lavina, J. Gracia-Sancho, A. Rodriguez-Vilarrupla, Y. Chu, D.D. Heistad, J. Bosch, J.C. Garcia-Pagan
Journal: Journal of Hepatology (2007)
Single-Cell Cloning of Human, Donor-Derived Antileukemia T-Cell Lines for <i>In vitro</i> Separation of Graft-versus-Leukemia Effect from Graft-versus-Host Reaction
Authors: Daniela Montagna, Liane Daudt, Franco Locatelli, Enrica Montini, Ilaria Turin, Daniela Lisini, Giovanna Giorgiani, Maria Ester Bernardo, Rita Maccario
Journal: Cancer Research (2006)

Abstract In previous studies, we showed the possibility of expanding in vitro polyclonal CTL lines directed against patient leukemia cells using effector cells derived from both HLA-matched and HLA-mismatched hematopoietic stem cell donors. Some CTL lines, especially those derived from an HLA-disparate donor, displayed residual alloreactivity against patient nonmalignant cells. In this study, we evaluated the possibility of separating in vitro CTLs with selective graft-versus-leukemia (GVL) activity from those potentially involved in the development of graft-versus-host disease (GVHD) through single T-cell cloning of antileukemia polyclonal CTL lines. We showed that CTLs that were expanded from a single T-cell clone (TCC), able to selectively kill leukemia blasts and devoid of alloreactivity towards nonmalignant cells, can be obtained from antileukemia alloreactive polyclonal CTL lines. TCCs expressed a wide repertoire of different T-cell receptor (TCR)-Vβ families, mainly produced IFNγ and interleukin 2, irrespective of CD8 or CD4 phenotype, and could be extensively expanded in vitro without losing their peculiar functional features. The feasibility of our approach for in vitro separation of GVL from GVH reaction opens perspectives for using TCCs, which are selectively reactive towards leukemia blasts, for antileukemia adoptive immune therapy approaches after hematopoietic stem cell transplantation, in particular from HLA-mismatched donors. (Cancer Res 2006; 66(14): 7310-6)
Inhibition by β-blockade of the ST segment elevation after acute myocardial infarction in man
Authors: J Shillingford
Journal: Cardiovascular Research (2000)

The changes in height and extent of the ST segment elevation after the administration of the β-blocking drug practolol to nine patients with acute myocardial infarction have been studied. In all the patients there was a reduction in the area of ST segment elevation recorded over the surface of the chest and in eight of the nine there was a reduction in the total height (ΣST) and mean height (ST) of the ST segment elevation. These findings are discussed in relation to (1) quantitating the extent and severity of the ischaemic lesion in man, and (2) the reduction in the extent and severity of the ischaemia by β-blockade.
Role of Hedgehog Signaling in Malignant Pleural Mesothelioma
Authors: Yandong Shi, Ubiratan Moura, Isabelle Opitz, Alex Soltermann, Hubert Rehrauer, Svenja Thies, Walter Weder, Rolf A. Stahel, Emanuela Felley-Bosco
Journal: Clinical Cancer Research (2012)

Abstract Purpose: The aim of this study was to assess the activity of hedgehog signaling pathway in malignant pleural mesothelioma (MPM). Experimental Design: The expression of hedgehog signaling components was assessed by quantitative PCR and in situ hybridization in 45 clinical samples. Primary MPM cultures were developed in serum-free condition in 3% oxygen and were used to investigate the effects of smoothened (SMO) inhibitors or GLI1 silencing on cell growth and hedgehog signaling. In vivo effects of SMO antagonists were determined in an MPM xenograft growing in nude mice. Results: A significant increase in GLI1, sonic hedgehog, and human hedgehog interacting protein gene expression was observed in MPM tumors compared with nontumoral pleural tissue. SMO antagonists inhibited GLI1 expression and cell growth in sensitive primary cultures. This effect was mimicked by GLI1 silencing. Reduced survivin and YAP protein levels were also observed. Survivin protein levels were rescued by overexpression of GLI1 or constitutively active YAP1. Treatment of tumor-bearing mice with the SMO inhibitor HhAntag led to a significant inhibition of tumor growth in vivo accompanied by decreased Ki-67 and nuclear YAP immunostaining and a significant difference in selected gene expression profile in tumors. Conclusions: An aberrant hedgehog signaling is present in MPM, and inhibition of hedgehog signaling decreases tumor growth indicating potential new therapeutic approach. Clin Cancer Res; 18(17); 4646–56. ©2012 AACR.
Global Lung Oncology Branch trial 3 (GLOB3): final results of a randomised multinational phase III study alternating oral and i.v. vinorelbine plus cisplatin versus docetaxel plus cisplatin as first-line treatment of advanced non-small-cell lung cancer
Authors: E.H. Tan, J. Rolski, T. Grodzki, C.P. Schneider, U. Gatzemeier, P. Zatloukal, E. Aitini, G. Carteni, H. Riska, Y.H. Tsai, R. Abratt
Journal: Annals of Oncology (2009)
Comparison of Penetrating Keratoplasty and Deep Lamellar Keratoplasty for Macular Corneal Dystrophy and Risk Factors of Recurrence
Authors: Jun Cheng, Xiaolin Qi, Jing Zhao, Hualei Zhai, Lixin Xie
Journal: Ophthalmology (2012)

To compare the therapeutic effects of penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) on patients with macular corneal dystrophy (MCD) and to analyze the risk factors of postoperative recurrence.Retrospective, interventional, comparative case series.Fifty-one patients (78 eyes) with MCD treated by PK or DALK at Shandong Eye Institute between January 1992 and December 2010.The medical records of the patients were reviewed retrospectively.Best-corrected visual acuity, corneal endothelial density, complications, recurrence, graft survival, and risk factors for recurrence.Penetrating keratoplasty was performed in 57 eyes, and DALK was performed in 21 eyes. The mean follow-up time was 5.1±4.1 years (range, 1.0-18.0 years). The best-corrected visual acuity of the PK group was much better than that of the DALK group at 1, 2, 3, and 5 years. The corneal endothelial density was reduced to 1000 cells/mm2 or less within 5 years in 21.6% (11/51) of eyes treated by PK and in none of the eyes treated by DALK. The 1-year incidence rate of complications was 21.1% in the PK group, higher than the 4.8% rate in the DALK group. At the last visit, the rate of graft clarity was 87.7% and 85.7% in the 2 groups, respectively. Ten eyes (17.5%) treated by PK had recurrent MCD, with a rate of 0.8%, 7.7%, and 40% at 1, 5, and 10 years, respectively, whereas 9 eyes (42.9%) treated by DALK demonstrated recurrence, with a rate of 14.3% and 49.5% at 1 and 5 years, respectively. The recurrence risk was higher in patients whose age was 18 years or younger at onset or younger than 30 years at surgery. The recurrence risk after DALK was 5.066 times higher than that after PK.Penetrating keratoplasty more often immediately improves the visual acuity of patients with MCD, but many complications seem to be inevitable, especially continuous loss of corneal endothelium. Despite poor visual acuity and recurrence after surgery, DALK may produce fewer complications overall and more durable stability of the ocular surface compared with PK. The selection of PK or DALK for MCD should depend on the actual need and situation of certain patients.The author(s) have no proprietary or commercial interest in any materials discussed in this article.
Transplantable Tumor Lines Generated in Clonal Zebrafish
Authors: Igor V. Mizgireuv, Sergei Y. Revskoy
Journal: Cancer Research (2006)

Transplantable zebrafish tumors are a novel and very promising model in cancer research. However, further progress in this field has been contained by a lack of true inbred lines in zebrafish. To overcome this problem, we generated two lines of homozygous diploid clonal zebrafish lines (i.e., CB1 and CW1), which allowed us to carry out transplantation of any tissue, including tumors, from one fish to another within a line without rejection of the graft. The primary tumors in CB1 fish were induced by N-nitrosodiethylamine (DEN). The histologic analysis of these tumors revealed different types of hepatocellular carcinomas, hepatoblastomas, hepatoma, cholangiocarcinoma, and pancreatic carcinoma. Four spontaneous acinar cell carcinomas of pancreas were also found in 10- to 18-month-old CB1 fish. Small pieces of tissue or cell suspensions of either DEN-induced or spontaneous tumors were serially transplanted into the peritoneal cavity of syngeneic fish at different stages of development from 5-day-old larvae to adult fish. The development of grossly visible tumors occurred from 2 weeks to 3 months after tumor grafting and grew either as solitary smooth nodules or as an amorphous jelly-like mass infiltrating abdominal organs. The majority of tumors were also successfully transplanted to isogeneic (F1 generation from crossing CB1 x CW1) fish. At the present time, 19 transplantable zebrafish tumor lines have been generated and maintained for as long as 3 to 25 passages. This model provides a novel tool for studying experimental tumor biology and therapy and will become a cost effective system for high throughput screening of anticancer drugs.
Defective TNF-α–mediated hepatocellular apoptosis and liver damage in acidic sphingomyelinase knockout mice
Authors: Carmen García-Ruiz, Anna Colell, Montserrat Marí, Albert Morales, María Calvo, Carlos Enrich, José C. Fernández-Checa
Journal: Journal of Clinical Investigation (2003)

This study addressed the contribution of acidic sphingomyelinase (ASMase) in TNF-α–mediated hepatocellular apoptosis. Cultured hepatocytes depleted of mitochondrial glutathione (mGSH) became sensitive to TNF-α, undergoing a time-dependent apoptotic cell death preceded by mitochondrial membrane depolarization, cytochrome c release, and caspase activation. Cyclosporin A treatment rescued mGSH-depleted hepatocytes from TNF-α–induced cell death. In contrast, mGSH-depleted hepatocytes deficient in ASMase were resistant to TNF-α–mediated cell death but sensitive to exogenous ASMase. Furthermore, although in vivo administration of TNF-α or LPS to galactosamine-pretreated ASMase+/+ mice caused liver damage, ASMase–/– mice exhibited minimal hepatocellular injury. To analyze the requirement of ASMase, we assessed the effect of glucosylceramide synthetase inhibition on TNF-α–mediated apoptosis. This approach, which blunted glycosphingolipid generation by TNF-α, protected mGSH-depleted ASMase+/+ hepatocytes from TNF-α despite enhancement of TNF-α–stimulated ceramide formation. To further test the involvement of glycosphingolipids, we focused on ganglioside GD3 (GD3) because of its emerging role in apoptosis through interaction with mitochondria. Analysis of the cellular redistribution of GD3 by laser scanning confocal microscopy revealed the targeting of GD3 to mitochondria in ASMase+/+ but not in ASMase–/– hepatocytes. However, treatment of ASMase–/– hepatocytes with exogenous ASMase induced the colocalization of GD3 and mitochondria. Thus, ASMase contributes to TNF-α–induced hepatocellular apoptosis by promoting the mitochondrial targeting of glycosphingolipids.
Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph+CD34+CD38neg) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy
Authors: S Mustjoki, P Rohon, K Rapakko, S Jalkanen, P Koskenvesa, T Lundán, K Porkka
Journal: Leukemia (2009)