tbuckley/cabot-search huggingface dataset:
Hostile takeovers: viral appropriation of the NF-kB pathway
Authors: John Hiscott, Hakju Kwon, Pierre Génin
Journal: Journal of Clinical Investigation (2001)

Transcriptional regulators of the NF-kB/IkB family promote the expression of well over 100 target genes, the majority of which participate in the host immune response (1). These proteins include a multitude of cytokines and chemokines, receptors required for immune recognition, proteins involved in antigen presentation, and adhesion receptors involved in transmigration across blood vessels walls. Because of this extensive role in immune action, NF-kB has been termed the central mediator of the immune response. Gene knockout and other studies establish roles for NF-kB in the ontogeny of the immune system but also demonstrate that NF-kB participates at multiple steps during oncogenesis (2) and the regulation of programmed cell death (3).

For several reasons, the NF-kB pathway provides an attractive target to viral pathogens. Activation of NF-kB is a rapid, immediate early (IE) event that occurs within minutes after exposure to a relevant inducer, does not require de novo protein synthesis, and results in a strong transcriptional stimulation of several early viral as well as cellular genes. In this review, we will describe strategies that viruses have evolved to modulate the NF-kB pathway, to enhance viral replication, host cell survival, and evasion of immune responses. Activation of NF-kB constitutes an obvious target because many of its target genes — growth factors, cytokines and their receptors, and proto-oncogenes — profoundly influence the host cell cycle. In addition, some viruses exploit the antiapoptotic properties of NF-kB to evade the host defense mechanisms that limit replication by killing infected cells, or conversely to trigger apoptosis as a mechanism to increase virus spread.

Perhaps not surprisingly, the persistent activation of the NF-kB pathway maintained by certain viruses contributes to oncogenic transformation (2). In addition to the classic studies with the avian REV-T retrovirus which contains the v-Rel oncoprotein and induces a rapid and fatal B-cell lymphoma in young birds (4), several lines of evidence demonstrate that NF-kB family members contribute to human oncogenesis. Localization of NF-kB–encoding genes at sites of chromosomal translocations and genomic rearrangements in cancer, high levels of NF-kB activity in many breast cancer cells, and constitutive nuclear NF-kB complexes in Hodgkin’s lymphoma cells all support this view (2). Furthermore, as discussed below, viral oncogene products, including human T-cell leukemia virus type 1 (HTLV-1) Tax protein and Epstein-Barr virus latent infection membrane protein 1 (EBV LMP1), each act by unique mechanisms to disrupt NF-kB regulation and initiate viral transformation.
PERIPHERAL BLOOD STEM CELLS FOR AUTOGRAFTING
Authors: Elizabeth J. Shpall, MD, Pablo J. Cagnoni, MD, Scott I. Bearman, MD, Maureen Ross, MD, PhD, Roy B. Jones, PhD, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract High-dose therapy with autologous hematopoietic progenitor cell support is effective treatment for patients with a variety of high-risk malignancies. Accelerating of marrow recovery from near-lethal or lethal toxicity with hematopoietic cell support improves the safety and cost effectiveness of the high-dose regimens. Peripheral blood progenitor cells will soon replace marrow as the major source of hematopoietic support. This chapter reviews the techniques of peripheral blood progenitor cell collection, mobilization, purification (for tumor removal), and ex vivo expansion.
Drainage of esophageal leakage using endoscopic vacuum therapy: a prospective pilot study
Authors: M. Ahrens, T. Schulte, J. Egberts, C. Schafmayer, J. Hampe, A. Fritscher-Ravens, D. Broering, B. Schniewind
Journal: Endoscopy (2010)

Major leakage from an esophageal anastomosis is a life-threatening surgical complication. Endoscopically guided endoluminal vacuum therapy using polyurethane sponges is a new method for treating such leakage.Between June 2007 and June 2009, five patients (mean age 68 years) who developed anastomotic leakage after esophageal surgery were prospectively evaluated. After endoscopic diagnosis of a major leakage, polyurethane sponges were endoscopically positioned in the wound cavity of the anastomosis. Continuous suction was applied via drainage tubes fixed to the sponges. Initially sponges were endoscopically changed three times per week.In all five patients treatment was successful. Median time to reduce levels of inflammation markers by 50 % was 10 days for white blood cell (WBC) count and 7 days for C-reactive protein (CRP). The smallest initial wound cavity size was 42 cm (3) and the largest was 157 cm (3). The median duration of drainage was 28 days, with a median of 9 sponge changes and a median time to total cavity closure of 42 days. Two patients needed anastomotic dilation by Savary-Miller bougienage due to stenosis found on further follow-up. One of these patients died of acute severe hemorrhage from an aortoanastomotic fistula after the dilation procedure.Endoscopically assisted vacuum therapy is a well-tolerated and effective therapeutic option for treatment of major esophageal leaks after surgery. Additional surgery was avoided in all cases. However, the occurrence of a delayed aortoesophageal fistula calls for careful further investigation of this new technique.
Hidden Complexities in Assessment of Glycemic Outcomes
Authors: Leonard M. Pogach, Mangala Rajan, Miriam Maney, Chin-Lin Tseng, David C. Aron
Journal: Diabetes Care (2010)

OBJECTIVE To evaluate facility rankings in achieving &amp;lt;7% A1C levels based on the complexity of glycemic treatment regimens using threshold and continuous measures. RESEARCH DESIGN AND METHODS We conducted a retrospective administrative data analysis of Veterans Health Administration Medical Centers in 2003–2004. Eligible patients were identified using National Committee for Quality Assurance (NCQA) measure specifications. A complex glycemic regimen (CGR) was defined as receipt of insulin or three oral agents. Facilities were ranked using five ordinal categories based up both z score distribution and statistical significance (P &amp;lt; 0.05). Rankings using the NCQA definition were compared with a subset receiving CGRs using both a &amp;lt;7% threshold and a continuous measure awarding proportional credit for values between 7.9 and &amp;lt;7.0%. Ranking correlation was assessed using the Spearman correlation coefficient. RESULTS A total of 203,302 patients (mean age 55.2 years) were identified from 127 facilities (range 480–5,411, mean 1,601); 26.7% (17.9–35.2%) were receiving CGRs, including 22.0% receiving insulin. Mean A1C and percent achieving A1C &amp;lt;7% were 7.48 and 48% overall and 8.32 and 24.8% for those receiving CGRs using the threshold measure; proportion achieved was 60.1 and 37.2%, respectively, using the continuous measure. Rank correlation between the overall and CGR subset was 0.61; 8 of 24 of the highest or lowest ranked facilities changed to nonsignificance status; an additional five sites changed rankings. CONCLUSIONS Facility rankings in achieving the NCQA &amp;lt;7% measure as specified differ markedly from rankings using the CGR subset. Measurement for public reporting or payment should stratify rankings by CGR. A continuous measure may better align incentives with treatment intensity.
Angiotensin (1–7) counteracts the negative effect of angiotensin II on insulin signalling in HUVECs
Authors: Eliezer Joseph Tassone, Angela Sciacqua, Francesco Andreozzi, Ivan Presta, Maria Perticone, Daniela Carnevale, Manuel Casaburo, Marta Letizia Hribal, Giorgio Sesti, Francesco Perticone
Journal: Cardiovascular Research (2013)

Angiotensin II participates to the regulation of cardiovascular physiology and it is involved in molecular mechanisms of insulin resistance. Angiotensin (1-7), derived from angiotensin II metabolism, is able to counteract many of the haemodynamic and non-haemodynamic actions of angiotensin II. In this study, we investigated in human umbilical vein endothelial cells (HUVECs) the possible action of angiotensin (1-7) on the insulin signalling pathway.We stimulated HUVECs with insulin, angiotensin II and angiotensin (1-7), testing the effects on endothelial nitric oxide synthase (eNOS) enzyme activation and on insulin receptor substrate-1 (IRS1) phosphorylation. Moreover, we analysed the involvement of angiotensin type1, type2, and Mas receptors in these actions. Finally, we measured the nitric oxide (NO) production, the intracellular cGMP and the PKG-related activity in HUVECs, and the subsequent functional vasoactive effect of angiotensin (1-7) in mesenteric arteries of mice. Angiotensin II inhibits the insulin-induced Akt and eNOS phosphorylation, reducing the NO production. On the other hand, angiotensin (1-7) counteracts the inhibitory effect of angiotensin II, being able to restore the insulin-induced Akt/eNOS activation and the NO production. This effect is mediated by the Mas receptor. The inhibitory effects of angiotensin II on insulin signalling are, at least in part, mediated by an increased serine phosphorylation of IRS₁. Angiotensin (1-7) inhibits the serine phosphorylation of IRS1 induced by angiotensin II.In endothelial cells angiotensin (1-7) counteracts the negative effects of angiotensin II on insulin signalling and NO production. The balance between angiotensin II and angiotensin (1-7) could represent a key mechanism in the pathophysiological processes leading to endothelial dysfunction and insulin-resistance.
Characterization and isolation of stem cell-enriched human hair follicle bulge cells
Authors: M. Ohyama
Journal: Journal of Clinical Investigation (2005)

The human hair follicle bulge is an important niche for keratinocyte stem cells (KSCs). Elucidation of human bulge cell biology could be facilitated by analysis of global gene expression profiles and identification of unique cell-surface markers. The lack of distinctive bulge morphology in human hair follicles has hampered studies of bulge cells and KSCs. In this study, we determined the distribution of label-retaining cells to define the human anagen bulge. Using navigated laser capture microdissection, bulge cells and outer root sheath cells from other follicle regions were obtained and analyzed with cDNA microarrays. Gene transcripts encoding inhibitors of WNT and activin/bone morphogenic protein signaling were overrepresented in the bulge, while genes responsible for cell proliferation were underrepresented, consistent with the existence of quiescent noncycling KSCs in anagen follicles. Positive markers for bulge cells included CD200, PHLDA1, follistatin, and frizzled homolog 1, while CD24, CD34, CD71, and CD146 were preferentially expressed by non-bulge keratinocytes. Importantly, CD200+ cells (CD200hiCD24loCD34loCD71loCD146lo) obtained from hair follicle suspensions demonstrated high colony-forming efficiency in clonogenic assays, indicating successful enrichment of living human bulge stem cells. The stem cell behavior of enriched bulge cells and their utility for gene therapy and hair regeneration will need to be assessed in in vivo assays.
Antigen-pulsed dendritic cells expressing macrophage-derived chemokine elicit Th2 responses and promote specific humoral immunity
Authors: Toshiaki Kikuchi, Ronald G. Crystal
Journal: Journal of Clinical Investigation (2001)

Macrophage-derived chemokine (MDC) is a potent chemoattractant for antigen-specific T lymphocytes. We hypothesized that Adenovirus- (Ad-) transduced dendritic cells (DCs) overexpressing MDC would enhance the T cell-mediated humoral immune response specific for antigens presented by the DC. We challenged two strains of mice with lethal Pseudomonas aeruginosa infection 3 weeks after immunization with AdMDC-modified DCs pulsed with heat-killed P. aeruginosa. MDC-expressing DCs specifically attracted T lymphocytes and preserved typical DC surface phenotypes without growth factors in vitro. Mice immunized with AdMDC/Pseudomonas/DCs developed high levels of serum anti-Pseudomonas Ab's and were protected from a lethal respiratory challenge with Pseudomonas. The in vivo protective immunity required CD4(+) T cells, B cells, and IL-4, but not CD8(+) T cells and IL-12. AdMDC/DCs pulsed with Pseudomonas yielded significant but not absolute cross-protection against different strains of P. aeruginosa. Pseudomonas-pulsed AdMDC/DCs protected mice from Pseudomonas but not Escherichia coli and vice versa; this microbe-specific protection correlated with microbe-specific induction of CD4(+) T cell proliferation and IL-4 secretion. Based on these observations, AdMDC-modified DCs pulsed with a killed bacteria may be a useful approach to vaccination against infectious disorders.
THE PERMEABILITY OF RAT TRANSITIONAL EPITHELIUM: THE RELATIONSHIP BETWEEN STRUCTURE AND FUNCTION
Authors: R. M. HICKS
Journal: British Journal of Dermatology (1969)

SUMMARY.— Both the transitional epithelium of the mammalian urinary bladder and the epidermis of skin are specialized to prevent loss of endogenous water. Under abnormal circumstances, the bladder epithelium may differentiate into a stratified, cornified epithelium which closely resembles normal epidermis. It thus has the capacity to produce some of the same subcellular components, including proteins, as skin and may indeed do so normally. The water barrier in the bladder, like that in skin, depends on the integrity of a thick proline‐rich cell membrane, but whereas this membrane is water permeable in the skin, the evidence suggests it to be impermeable to water in the bladder. Some of the similarities and differences between the barriers to loss of endogenous water in skin and bladder, and their possible mechanisms of action are discussed.
Mutations of the BCR-ABL-kinase domain occur in a minority of patients with stable complete cytogenetic response to imatinib
Authors: D W Sherbenou, M J Wong, A Humayun, L S McGreevey, P Harrell, R Yang, M Mauro, M C Heinrich, R D Press, B J Druker, M W Deininger
Journal: Leukemia (2007)
An investigation of circulating and in situ lymphocyte subsets and Langerhans cells in the skin and cervix of patients with chronic renal failure
Authors: K.J. McKERROW, R.J. HAWTHORN, W. THOMPSON
Journal: British Journal of Dermatology (1989)

This study was designed to detect possible changes in the immunocytology of the human immune system in the skin, cervix and peripheral blood of patients with chronic renal failure (CRF) treated by conservative methods, haemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). In the skin, Langerhans cell numbers were reduced in CRF, CAPD and HD patients but in the cervix, Langerhans cells were reduced only in the CRF patients. There was a preponderance of T suppressor lymphocytes compared with T helper lymphocytes in the epidermis in the CRF and the CAPD groups. The presence of natural killer cells in the epidermis of the renal groups compared to controls was significant in the CRF and HD patients while the presence of T suppressor lymphocytes in the epidermis compared to controls was significant only in the CAPD patients. In the dermis, there was a mixed cellular infiltrate of T helper and T suppressor lymphocytes but with no subset attaining significance. The dermal infiltrate of T helper lymphocytes in all three groups of renal patients was significantly reduced compared to controls. In CRF patients, peripheral blood pan T cells, T helper and T suppressor lymphocytes and B lymphocytes were reduced, while T suppressor lymphocytes were reduced in both HD and CAPD patients, compared to controls. Though the results confirm alteration of the immunocytology of the skin, cervix and peripheral blood, we could not relate them to a clinical finding.
Hepatocyte nuclear factor 4α is implicated in endoplasmic reticulum stress-induced acute phase response by regulating expression of cyclic adenosine monophosphate responsive element binding protein H
Authors: Jennifer Luebke‐Wheeler, Kezhong Zhang, Michele Battle, Karim Si‐Tayeb, Wendy Garrison, Sodhi Chhinder, Jixuan Li, Randal J. Kaufman, Stephen A. Duncan
Journal: Hepatology (2008)

Loss of the nuclear hormone receptor hepatocyte nuclear factor 4α (HNF4α) in hepatocytes results in a complex pleiotropic phenotype that includes a block in hepatocyte differentiation and a severe disruption to liver function. Recent analyses have shown that hepatic gene expression is severely affected by the absence of HNF4α, with expression of 567 genes reduced by ≥2.5-fold (P ≤ 0.05) in Hnf4α−/− fetal livers. Although many of these genes are direct targets, HNF4α has also been shown to regulate expression of other liver transcription factors, and this raises the possibility that the dependence on HNF4α for normal expression of some genes may be indirect. We postulated that the identification of transcription factors whose expression is regulated by HNF4α might reveal roles for HNF4α in controlling hepatic functions that were not previously appreciated. Here we identify cyclic adenosine monophosphate responsive element binding protein H (CrebH) as a transcription factor whose messenger RNA can be identified in both the embryonic mouse liver and adult mouse liver and whose expression is dependent on HNF4α. Analyses of genomic DNA revealed an HNF4α binding site upstream of the CrebH coding sequence that was occupied by HNF4α in fetal livers and facilitated transcriptional activation of a reporter gene in transient transfection analyses. Although CrebH is highly expressed during hepatogenesis, CrebH−/− mice were viable and healthy and displayed no overt defects in liver formation. However, upon treatment with tunicamycin, which induces an endoplasmic reticulum (ER)–stress response, CrebH−/− mice displayed reduced expression of acute phase response proteins. Conclusion: These data implicate HNF4α in having a role in controlling the acute phase response of the liver induced by ER stress by regulating expression of CrebH. (HEPATOLOGY 2008.)
Tiling Path Genomic Profiling of Grade 3 Invasive Ductal Breast Cancers
Authors: Rachael Natrajan, Maryou B. Lambros, Socorro María Rodríguez-Pinilla, Gema Moreno-Bueno, David S.P. Tan, Caterina Marchió, Radost Vatcheva, Sydonia Rayter, Betania Mahler-Araujo, Laura G. Fulford, Daniela Hungermann, Alan Mackay, Anita Grigoriadis, Kerry Fenwick, Narinder Tamber, David Hardisson, Andrew Tutt, Jose Palacios, Christopher J. Lord, Horst Buerger, Alan Ashworth, Jorge S. Reis-Filho
Journal: Clinical Cancer Research (2009)

To characterize the molecular genetic profiles of grade 3 invasive ductal carcinomas of no special type using high-resolution microarray-based comparative genomic hybridization (aCGH) and to identify recurrent amplicons harboring putative therapeutic targets associated with luminal, HER-2, and basal-like tumor phenotypes.Ninety-five grade 3 invasive ductal carcinomas of no special type were classified into luminal, HER-2, and basal-like subgroups using a previously validated immunohistochemical panel. Tumor samples were microdissected and subjected to aCGH using a tiling path 32K BAC array platform. Selected regions of recurrent amplification were validated by means of in situ hybridization. Expression of genes pertaining to selected amplicons was investigated using quantitative real-time PCR and gene silencing was done using previously validated short hairpin RNA constructs.We show that basal-like and HER-2 tumors are characterized by "sawtooth" and "firestorm" genetic patterns, respectively, whereas luminal cancers were more heterogeneous. Apart from confirming known amplifications associated with basal-like (1q21, 10p, and 12p), luminal (8p12, 11q13, and 11q14), and HER-2 (17q12) cancers, we identified previously unreported recurrent amplifications associated with each molecular subgroup: 19q12 in basal-like, 1q32.1 in luminal, and 14q12 in HER-2 cancers. PPM1D gene amplification (17q23.2) was found in 20% and 8% of HER-2 and luminal cancers, respectively. Silencing of PPM1D by short hairpin RNA resulted in selective loss of viability in tumor cell lines harboring the 17q23.2 amplification.Our results show the power of aCGH analysis in unraveling the genetic profiles of specific subgroups of cancer and for the identification of novel therapeutic targets.
Primary Immunodeficiency Diseases: Definition, Diagnosis, and Management
Authors: A. D. B. Webster
Journal: JAMA (2009)

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Strength and Weakness of the Genetic Approach to the Development of the Nervous System
Authors: G S Stent
Journal: Annual Review of Neuroscience (1981)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Comparison of the Framingham and Reynolds Risk Scores for Global Cardiovascular Risk Prediction in the Multiethnic Women's Health Initiative
Authors: Nancy R. Cook, Nina P. Paynter, Charles B. Eaton, JoAnn E. Manson, Lisa W. Martin, Jennifer G. Robinson, Jacques E. Rossouw, Sylvia Wassertheil-Smoller, Paul M Ridker
Journal: Circulation (2012)

Framingham-based and Reynolds Risk scores for cardiovascular disease (CVD) prediction have not been directly compared in an independent validation cohort. We selected a case-cohort sample of the multiethnic Women's Health Initiative Observational Cohort, comprising 1722 cases of major CVD (752 myocardial infarctions, 754 ischemic strokes, and 216 other CVD deaths) and a random subcohort of 1994 women without prior CVD. We estimated risk using the Adult Treatment Panel III (ATP-III) score, the Reynolds Risk Score, and the Framingham CVD model, reweighting to reflect cohort frequencies. Predicted 10-year risk varied widely between models, with ≥10% risk in 6%, 10%, and 41% of women with the ATP-III, Reynolds, and Framingham CVD models, respectively. Calibration was adequate for the Reynolds model, but the ATP-III and Framingham CVD models overestimated risk for coronary heart disease and major CVD, respectively. After recalibration, the Reynolds model demonstrated improved discrimination over the ATP-III model through a higher c statistic (0.765 versus 0.757; P=0.03), positive net reclassification improvement (NRI; 4.9%; P=0.02), and positive integrated discrimination improvement (4.1%; P<0.0001) overall, excluding diabetics (NRI=4.2%; P=0.01), and in white (NRI=4.3%; P=0.04) and black (NRI=11.4%; P=0.13) women. The Reynolds (NRI=12.9%; P<0.0001) and ATP-III (NRI=5.9%; P=0.0001) models demonstrated better discrimination than the Framingham CVD model. The Reynolds Risk Score was better calibrated than the Framingham-based models in this large external validation cohort. The Reynolds score also showed improved discrimination overall and in black and white women. Large differences in risk estimates exist between models, with clinical implications for statin therapy.