tbuckley/cabot-search huggingface dataset:
Epigenetic Repression of <i>microRNA-129-2</i> Leads to Overexpression of <i>SOX4</i> Oncogene in Endometrial Cancer
Authors: Yi-Wen Huang, Joseph C. Liu, Daniel E. Deatherage, Jingqin Luo, David G. Mutch, Paul J. Goodfellow, David S. Miller, Tim H-M. Huang
Journal: Cancer Research (2009)

Abstract Genetic amplification, mutation, and translocation are known to play a causal role in the upregulation of an oncogene in cancer cells. Here, we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high mobility group box family, was found to be overexpressed (P &amp;lt; 0.005) in endometrial tumors (n = 74) compared with uninvolved controls (n = 20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared with the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P &amp;lt; 0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n = 6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacologic induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P &amp;lt; 0.001) and poor overall survival (P &amp;lt; 0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may upregulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA derepresses its oncogenic target in cancer cells. [Cancer Res 2009;69(23):9038–46]
Characterization of a novel Long QT syndrome mutation G52R-KCNE1 in a Chinese family
Authors: L Ma
Journal: Cardiovascular Research (2003)

Objectives: To identify the underlying genetic basis of a Chinese pedigree with Long QT syndrome, the causally related genes were screened in a family and the functional consequence of the identified gene mutation was evaluated in vitro. Methods: Mutations in the five defined Long QT syndrome related genes were screened with polymerase chain reaction and single-strand conformation polymorphism methods and direct sequencing. The electrophysiological properties of the identified mutation were characterized in the Xenopus oocyte heterologous expression system. Results: A novel missense mutation, G to A at position 154 in the KCNE1 gene was identified in a Chinese Long QT syndrome family, which leads to an amino acid substitution of arginine (R) for glycine (G) at position 52 (G52R-KCNE1). Of 26 family members (one DNA was not available), seven were mutation carriers and two of them with normal electrocardiogram. Compared with wild-type KCNE1/KCNQ1 channels, coexpression of G52R-KCNE1 with KCNQ1 in Xenopus oocytes did not amplify the KCNQ1 current amplitudes and slightly changed the activation kinetics of the KCNQ1 channels. Coexpression of KCNQ1 together with wild type KCNE1 and G52R-KCNE1 reduced the wild-type Iks current amplitude by 50%, whereas other biophysical properties of the Iks were not altered. Conclusions: Our findings indicate that glycine52 in the transmembrane domain is critical for KCNE1 function. The mutant G52R-KCNE1 has a dominant negative effect on Iks current, which reduces the Iks current amplitude and leads to a prolongation of the cardiac action potential. This could underlie the molecular mechanism of ventricular arrhythmias and sudden death in those patients.
Neonatal Estradiol Stimulation Prevents Epilepsy in Arx Model of X-Linked Infantile Spasms Syndrome
Authors: Pedro R. Olivetti, Atul Maheshwari, Jeffrey L. Noebels
Journal: Science Translational Medicine (2014)

Estradiol treatment of a mouse model of X-linked infantile spasms syndrome during the neonatal period prevents epilepsy in adulthood, restores interneurons, and alters mRNA levels of Arx targets.
STUDIES ON BACTERIEMIA
Authors: David E. Rogers, Marian Ann Melly
Journal: The Journal of Experimental Medicine (1958)

Rabbits given an intravenous injection of an 18 to 24 hour broth culture of E. coli commonly died within 28 hours. The injection of a 4 hour broth culture of the same strain of E. coli containing equal numbers of living bacilli produced only an occasional death. Initial clearance rates and subsequent bacteriemias were similar in animals receiving either culture. Study of changes in circulating leukocytes or the temperature response to washed bacterial cells or culture filtrates failed to reveal obvious differences in host response to young or old cultures. It was found that both living bacterial cells and some substance or substances present in culture filtrates were required to produce subsequent death. The injection of whole old cultures containing both these factors produced hypothermia instead of the endotoxin type fever response which followed the injection of whole young cultures. Subsequent experiments revealed that this hypothermia appeared to be secondary to a period of transient but profound shock which occurred soon after the injection in rabbits receiving old cultures. No significant alterations in arterial pressure accompanied injections of young cultures. Evidence is presented which suggests that this period of hypotension rendered animals more likely to die with a persisting bacteriemia tolerated without event by non-shocked animals. The mechanisms which operate to increase mortality during the post shock period are as yet unclarified.
Genotype–Phenotype Correlations in Non-Finnish Congenital Nephrotic Syndrome
Authors: Eduardo Machuca, Geneviève Benoit, Fabien Nevo, Marie-Josèphe Tête, Olivier Gribouval, Audrey Pawtowski, Per Brandström, Chantal Loirat, Patrick Niaudet, Marie-Claire Gubler, Corinne Antignac
Journal: Journal of the American Society of Nephrology (2010)

Mutations in <i>NPHS1</i>, which encodes nephrin, are the main causes of congenital nephrotic syndrome (CNS) in Finnish patients, whereas mutations in <i>NPHS2</i>, which encodes podocin, are typically responsible for childhood-onset steroid-resistant nephrotic syndrome in European populations. Genotype–phenotype correlations are not well understood in non-Finnish patients. We evaluated the clinical presentation, kidney histology, and disease progression in non-Finnish CNS cases by mutational screening in 107 families (117 cases) by sequencing the entire coding regions of <i>NPHS1</i>, <i>NPHS2</i>, <i>PLCE1</i>, <i>WT1</i>, <i>LAMB2</i>, <i>PDSS2</i>, <i>COQ2</i>, and <i>NEPH1</i>. We found that CNS describes a heterogeneous group of disorders in non-Finnish populations. We identified nephrin and podocin mutations in most families and only rarely found mutations in genes implicated in other hereditary forms of NS. In approximately 20% of cases, we could not identify the underlying genetic cause. Consistent with the major role of nephrin at the slit diaphragm, <i>NPHS1</i> mutations associated with an earlier onset of disease and worse renal outcomes than <i>NPHS2</i> mutations. Milder cases resulting from mutant <i>NPHS1</i> had either two mutations in the cytoplasmic tail or two missense mutations in the extracellular domain, including at least one that preserved structure and function. In addition, we extend the spectrum of known <i>NPHS1</i> mutations by describing long <i>NPHS1</i> deletions. In summary, these data demonstrate that CNS is not a distinct clinical entity in non-Finnish populations but rather a clinically and genetically heterogeneous group of disorders.
Regulation of CD4+NKG2D+ Th1 Cells in Patients with Metastatic Melanoma Treated with Sorafenib: Role of IL-15Rα and NKG2D Triggering
Authors: Ana I. Romero, Nathalie Chaput, Vichnou Poirier-Colame, Sylvie Rusakiewicz, Nicolas Jacquelot, Kariman Chaba, Erwan Mortier, Yannick Jacques, Sophie Caillat-Zucman, Caroline Flament, Anne Caignard, Meriem Messaoudene, Anne Aupérin, Philippe Vielh, Philippe Dessen, Camillo Porta, Christine Mateus, Maha Ayyoub, Danila Valmori, Alexander Eggermont, Caroline Robert, Laurence Zitvogel
Journal: Cancer Research (2013)

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4(+)NKG2D(+) T cells. Hence, the increase of blood CD4(+)NKG2D(+) T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint-blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4(+)NKG2D(+) subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D(+) Th1 cells.
The White Adipose Tissue Used in Lipotransfer Procedures Is a Rich Reservoir of CD34+ Progenitors Able to Promote Cancer Progression
Authors: Ines Martin-Padura, Giuliana Gregato, Paola Marighetti, Patrizia Mancuso, Angelica Calleri, Chiara Corsini, Giancarlo Pruneri, Michela Manzotti, Visnu Lohsiriwat, Mario Rietjens, Jean-Yves Petit, Francesco Bertolini
Journal: Cancer Research (2011)

Abstract Previous studies have suggested a “catalytic role” in neoplastic angiogenesis and cancer progression for bone marrow–derived endothelial progenitor cells (EPC). However, preclinical and clinical studies have shown that the quantitative role of marrow-derived EPCs in cancer vascularization is extremely variable. We have found that human and murine white adipose tissue (WAT) is a very rich reservoir of CD45-CD34+ EPCs with endothelial differentiation potential, containing a mean of 263 times more CD45-CD34+ cells/mL than bone marrow. Compared with marrow-derived CD34+ cells mobilized in blood by granulocyte colony–stimulating factor, purified WAT-CD34+ cells expressed similar levels of stemness-related genes, significantly increased levels of angiogenesis-related genes, and increased levels of FAP-α, a crucial suppressor of antitumor immunity. In vitro, WAT-CD34+ cells generated mature endothelial cells and capillary tubes as efficiently as mature mesenchymal cells. The coinjection of human WAT-CD34+ cells from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient mice. Endothelial cells derived from human WAT-CD34+ cells lined the lumen of cancer vessels. These data indicate that CD34+ WAT cells can promote cancer progression and metastases. Our results highlight the importance of gaining a better understanding of the role of different WAT-derived cells used in lipotransfer for breast reconstruction in patients with breast cancer. Cancer Res; 72(1); 325–34. ©2011 AACR.
Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans
Authors: Elin Jaensson, Heli Uronen-Hansson, Oliver Pabst, Bertus Eksteen, Jiong Tian, Janine L. Coombes, Pia-Lena Berg, Thomas Davidsson, Fiona Powrie, Bengt Johansson-Lindbom, William W. Agace
Journal: The Journal of Experimental Medicine (2008)

A functionally distinct subset of CD103(+) dendritic cells (DCs) has recently been identified in murine mesenteric lymph nodes (MLN) that induces enhanced FoxP3(+) T cell differentiation, retinoic acid receptor signaling, and gut-homing receptor (CCR9 and alpha4beta7) expression in responding T cells. We show that this function is specific to small intestinal lamina propria (SI-LP) and MLN CD103(+) DCs. CD103(+) SI-LP DCs appeared to derive from circulating DC precursors that continually seed the SI-LP. BrdU pulse-chase experiments suggested that most CD103(+) DCs do not derive from a CD103(-) SI-LP DC intermediate. The majority of CD103(+) MLN DCs appear to represent a tissue-derived migratory population that plays a central role in presenting orally derived soluble antigen to CD8(+) and CD4(+) T cells. In contrast, most CD103(-) MLN DCs appear to derive from blood precursors, and these cells could proliferate within the MLN and present systemic soluble antigen. Critically, CD103(+) DCs with similar phenotype and functional properties were present in human MLN, and their selective ability to induce CCR9 was maintained by CD103(+) MLN DCs isolated from SB Crohn's patients. Thus, small intestinal CD103(+) DCs represent a potential novel target for regulating human intestinal inflammatory responses.
The inhibition of epithelial repair by mast cell chymase
Authors: P. Gordins, J.R. Purkiss, P.M. Lackie, E.C. Adam, A.R. McEuen, A.F. Walls
Journal: Journal of Allergy and Clinical Immunology (2005)

RATIONALE: As an increased secretion of mast cell proteases and a damaged airway epithelium are features of bronchial asthma, we have investigated the actions of mast cell chymase on processes of epithelial repair.
Differences in immunochemical characteristics of cryoglobulins in rheumatoid arthritis and systemic lupus erythematosus and their complement binding properties.
Authors: C.C Erhardt, P Mumford, R.N Maini
Journal: Annals of the Rheumatic Diseases (1984)

Cryoglobulins isolated from sera of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) were analysed for their immunoglobulin, antibody, and complement components. In both disease categories the cryoglobulins contained predominantly IgG with lesser amounts of IgM and IgA, but relative to serum more IgM was concentrated in the cryoglobulins. IgM rheumatoid factor was found in 65% of RA cryoglobulins but in only 17% of SLE cryoglobulins (p less than 0.02), whereas SLE cryoglobulins contained more DNA binding activity than RA cryoglobulins (p less than 0.01). C1q binding activity was detectable in the majority of SLE and RA sera and SLE cryoglobulins. Paradoxically only two out of 34 RA cryoglobulins bound C1q, although rheumatoid factor activity was present in both cryoglobulins and sera. When isolated from serum the rheumatoid factor fraction strongly bound C1q. Both RA and SLE cryoglobulins contained similar small amounts of C3 and C4. Differences in antibody composition and complement binding activity of cryoglobulins from RA and SLE sera may reflect properties of immune complexes which affect their tissue localisation and pathogenicity.
The Promise of Cell-Based Therapies for Diabetic Complications
Authors: Yagna P.R. Jarajapu, Maria B. Grant
Journal: Circulation Research (2010)

Abstract : The discovery of endothelial progenitor cells (EPCs) in human peripheral blood advanced the field of cell-based therapeutics for many pathological conditions. Despite the lack of agreement about the existence and characteristics of EPCs, autologous EPC populations represent a novel treatment option for complications requiring therapeutic revascularization and vascular repair. Patients with diabetic complications represent a population of patients that may benefit from cellular therapy yet their broadly dysfunctional cells may limit the feasibility of this approach. Diabetic EPCs have decreased migratory prowess and reduced proliferative capacity and an altered cytokine/growth factor secretory profile that can accelerate deleterious repair mechanisms rather than support proper vascular repair. Furthermore, the diabetic environment poses additional challenges for the autologous transplantation of cells. The present review is focused on correcting diabetic EPC dysfunction and the challenges involved in the application of cell-based therapies for treatment of diabetic vascular complications. In addition, ex vivo and in vivo functional manipulation(s) of EPCs to overcome these hurdles are discussed.
gp120 modulates the biology of human hepatic stellate cells: a link between HIV infection and liver fibrogenesis
Authors: R. Bruno, S. Galastri, P. Sacchi, S. Cima, A. Caligiuri, R. DeFranco, S. Milani, S. Gessani, L. Fantuzzi, F. Liotta, F. Frosali, G. Antonucci, M. Pinzani, F. Marra
Journal: Gut (2009)

<h3>Objective</h3> In patients with hepatitis C virus (HCV)/HIV co-infection, a faster progression of liver fibrosis to cirrhosis has been reported. In this study, an investigation was carried out to determine whether gp120, an HIV envelope protein, modulates the biology of human hepatic stellate cells (HSCs), key cell types in the pathogenesis of fibrosis. <h3>Methods</h3> Myofibroblastic HSCs were isolated from normal human liver tissue. Gene expression was measured by real-time PCR. Cell migration was assessed in Boyden chambers. Intracellular signalling pathways were evaluated using phosphorylation-specific antibodies or by transfection of a reporter plasmid. <h3>Results</h3> Transcripts for the chemokine receptors CCR5 and CXCR4, which bind gp120, were detectable in human HSCs. Upon exposure to M-tropic recombinant gp120, which binds CCR5, a significant increase in HSC chemotaxis was observed (1.6±0.3-fold, p=0.03). The effects of gp120 were prevented by protein inactivation. gp120 also resulted in a significant increase in secretion (1.5±0.3-fold, p=0.03) and gene expression (1.47±0.13-fold, p=0.02) of the proinflammatory chemokine monocyte chemoattractant protein-1, and in increased gene expression of tissue inhibitor of metalloprotease-1 and interleukin-6 (2.03±0.57-fold, p=0.02). gp120-induced migration required Akt activation. gp120 also induced activation of nuclear factor-κB (NF-κB) and p38<sup>MAPK</sup>. Preincubation of HSCs with TAK779, a CCR5 receptor antagonist, prevented gp120-mediated chemotaxis and monocyte chemoattractant protein-1 secretion. Expression of CCR5 was detectable in areas of inflammation and fibrogenesis in liver biopsies of patients with HCV/HIV co-infection. <h3>Conclusions</h3> This study shows that HIV gp120 modulates different aspects of HSC biology, including directional cell movement and expression of proinflammatory cytokines. These results identify a direct pathway possibly linking HIV infection with liver fibrogenesis via envelope proteins.
Detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in nongenital seborrhoeic keratosis
Authors: Y-H. Li, G. Chen, X-P. Dong, H-D. Chen
Journal: British Journal of Dermatology (2004)

Background DNA of epidermodysplasia verruciformis (EV)-associated human papillomaviruses (HPVs) has been widely detected in lesions of malignant skin tumours, benign tumours and other proliferative diseases of epithelial origin. Objectives To investigate the presence of EV-associated HPV DNA in nongenital seborrhoeic keratosis (SK) and to elucidate the prevalence of distinct HPV genotypes. Methods We investigated HPV DNA in 55 nongenital SK biopsies, which were compared with 48 normal skin biopsies (healthy controls) using a nested polymerase chain reaction (PCR) using consensus primers CP65/CP70 and CP66/CP69. The positive PCR products were retracted and used to prepare recombination clones with T-vector. Distinct clones were analysed with endonucleases, and HPV genotypes were identified by direct sequencing. Results EV-associated HPV DNA was detected in 42 of 55 (76%) nongenital SK biopsies vs. only 13 of 48 (27%) healthy controls (χ2 = 22·087; P < 0·005). The prevalence was higher in patients with more than five lesions than in those with only one lesion (P < 0·05). Ten distinct HPV genotypes were detected in the nongenital SK biopsies: HPV 20, 23, 5, renal transplant recipient (RTR) X7, HPV 17, 37, 17b, RTRX4, RTRX4b and strain SK3. HPV 20 was found in 26 of 42 (62%) positive specimens, followed by HPV 23 (11 of 42, 26%) and HPV 5 (six of 42, 14%). Existence of multiple HPV genotypes was observed in 12 of 42 (29%) positive specimens. In healthy controls, five genotypes of EV-associated HPV (HPV 20, 23, 5, 17 and RTRX4) were detected, with the same predominant genotype of HPV 20 (five of 13, 38%). Several distinct HPV genotypes were found to coexist in four of 13 (31%) positive specimens. Conclusions This study provides some evidence that EV-associated HPVs might play a part in the pathogenesis of nongenital SK.
Phase I and Pharmacokinetic Study of LY293111, an Orally Bioavailable LTB<sub>4</sub> Receptor Antagonist, in Patients With Advanced Solid Tumors
Authors: Gary K. Schwartz, Aaron Weitzman, Eileen O'Reilly, Les Brail, Dinesh P. de Alwis, Ann Cleverly, Barbara Barile-Thiem, Vincent Vinciguerra, Daniel R. Budman
Journal: Journal of Clinical Oncology (2005)

Purpose LY293111, a novel diaryl ether carboxylic acid derivative, is a potent and selective inhibitor of the lipoxygenase pathway either directly through 5′-lipoxygenase or via antagonism of the leukotriene B 4 (LTB 4 ) receptor. More recently it has been determined to have peroxisome proliferator activated receptor-gamma agonist (PPARγ) activity. LY293111 has antineoplastic activity in a variety of preclinical models. The tolerability and pharmacokinetics of LY293111 administered continuously, by mouth, BID for repeat cycles of 21 days was evaluated. Patients and Methods Thirty-eight patients with advanced solid tumors were treated at five dose levels (200 to 800 mg BID) for a total of 102 cycles. Results The most common toxicity was diarrhea (76%). One patient at 600 mg BID (n = 11) and two at 800 mg BID (n = 8), experienced dose-limiting grade 3 diarrhea. Dose reductions and/or delays were infrequent. Increases in steady-state maximum plasma concentration (C max,ss ) and area under the steady-state plasma concentration time curve 0 to 12 hours (AUC τ,ss ) on day 8 could be considered to be dose-proportional over the four-fold-dose range. Interpatient variability in C max,ss and AUC τ,ss was estimated to be 65% and 71% respectively. There was a small increase in AUC (1.37; 90% CI, 0.85 to 2.21) between single and multiple doses. Two patients with progressive chondrosarcoma and melanoma had stable disease lasting approximately 336 and 168 days, respectively. Conclusion LY293111 can be administered safely by continuous oral therapy with mild toxicities. Diarrhea is dose-limiting. The recommended phase II dose will be 600 mg BID. The steady-state concentrations in humans exceed relevant levels observed in preclinical models.