tbuckley/cabot-search huggingface dataset:
Haptoglobin Genotype Is a Regulator of Reverse Cholesterol Transport in Diabetes In Vitro and In Vivo
Authors: Rabea Asleh, Rachael Miller-Lotan, Michael Aviram, Tony Hayek, Michael Yulish, Joanne E. Levy, Benjamin Miller, Shany Blum, Uzi Milman, Chen Shapira, Andrew P. Levy
Journal: Circulation Research (2006)

Two common alleles exist at the haptoglobin (Hp) locus, and the Hp2 allele is associated with an increased incidence of cardiovascular disease, specifically in diabetes mellitus (DM). Oxidative stress is increased in Hp2 mice and humans with DM. Oxidative modification of the apolipoprotein A-I inhibits reverse cholesterol transport. We sought to test the hypothesis that reverse cholesterol transport is impaired in Hp2 DM mice and humans. In vitro, using serum from non-DM and DM individuals, we measured cholesterol efflux from 3 H-cholesterol–labeled macrophages. In vivo, we injected 3 H-cholesterol–loaded macrophages intraperitoneally into non-DM and DM mice with the Hp1-1 or Hp2-2 genotype and monitored 3 H-tracer levels in plasma, liver, and feces. In vitro, in DM individuals only, we observed significantly decreased cholesterol efflux from macrophages incubated with serum from Hp2-1 or Hp2-2 as compared with Hp1-1 individuals ( P &lt;0.01). The interaction between Hp type and DM was recapitulated using purified Hp and glycated Hb. In vivo, DM mice loaded with 3 H-cholesterol–labeled macrophages had a 40% reduction in 3 H-cholesterol in plasma, liver, and feces as compared with non-DM mice ( P &lt;0.01). The reduction in reverse cholesterol transport associated with DM was significantly greater in Hp2-2 mice as compared with Hp1-1 mice (54% versus 25% in plasma; 52% versus 27% in liver; 57% versus 32% in feces; P &lt;0.03). reverse cholesterol transport is decreased in Hp2-2 DM. This may explain in part the increased atherosclerotic burden found in Hp2-2 DM individuals.
Antibody-Dependent Cell Cytotoxicity Synapses Form in Mice during Tumor-Specific Antibody Immunotherapy
Authors: Pascale Hubert, Adèle Heitzmann, Sophie Viel, André Nicolas, Xavier Sastre-Garau, Pablo Oppezzo, Otto Pritsch, Eduardo Osinaga, Sebastian Amigorena
Journal: Cancer Research (2011)

Antibody-dependent cell cytotoxicity (ADCC) plays a critical role in monoclonal antibody (mAb)-mediated cancer therapy. ADCC, however, has not been directly shown in vivo but inferred from the requirement for IgG Fc receptors (FcγR) in tumor rejection in mice. Here, we investigated the mechanism of action of a Tn antigen-specific chimeric mAb (Chi-Tn), which binds selectively to a wide variety of carcinomas, but not to normal tissues, in both humans and mice. Chi-Tn mAb showed no direct toxicity against carcinomas cell lines in vitro but induced the rejection of a murine breast tumor in 80% to 100% of immunocompetent mice, when associated with cyclophosphamide. Tumor rejection was abolished in Fc receptors-associated γ chain (FcR-γ)-deficient mice, suggesting a role for ADCC. Indeed, tumor cells formed stable conjugates in vivo with FcR-γ chain-expressing macrophages and neutrophils in Chi-Tn mAb-treated but not in control mAb-treated mice. The contact zone between tumor cells and ADCC effectors accumulated actin, FcγR and phospho-tyrosines. The in vivo formed ADCC synapses were organized in multifocal supra-molecular activation clusters. These results show that in vivo ADCC mediated by macrophages and neutrophils during tumor rejection by Chi-Tn mAb involves a novel type of multifocal immune synapse between effectors of innate immunity and tumor cells.
<i>BRAF</i>Wild-Type Melanoma in Situ Arising In a<i>BRAF</i>V600E Mutant Dysplastic Nevus
Authors: Jean-Marie Tan, Lynlee L. Lin, Duncan Lambie, Ross Flewell-Smith, Kasturee Jagirdar, Helmut Schaider, Richard A. Sturm, Tarl W. Prow, H. Peter Soyer
Journal: JAMA Dermatology (2015)

The BRAF V600E mutation accounts for the majority of BRAF mutations found in cutaneous melanoma and is also commonly found in nevi. We used dermoscopy-targeted sampling and a microbiopsy device coupled with DNA sequence analysis to highlight BRAF V600E heterogeneity within a multicomponent melanocytic proliferation. This sampling technique demonstrates the prospect of in vivo application in a clinical setting.A man in his 50s with Fitzpatrick skin type II presented with an irregularly pigmented melanocytic lesion on his back that met melanoma-specific dermoscopic criteria, and diagnostic shave excision of the lesion was performed. Histopathologic analysis revealed a melanoma in situ arising in a dysplastic nevus. Dermoscopy-targeted microbiopsy specimens were taken across the lesion, and genotyping was carried out on extracted DNA samples for BRAF and NRAS mutations. The melanoma in situ showed only BRAF wild-type results, while the dysplastic nevus showed both BRAF wild-type and BRAF V600E mutations. Sequencing in all DNA samples revealed NRAS wild-type genotype.Dermoscopy-targeted sampling and genotyping of a melanoma in situ arising in a dysplastic nevus revealed a phenotype-genotype paradox that confounds the exclusive significance of BRAF and NRAS mutations in melanoma pathogenesis. Further studies are required to investigate the importance of other candidate genes linked to melanomagenesis.
Fish Consumption and Incidence of Diabetes
Authors: Pengcheng Xun, Ka He
Journal: Diabetes Care (2012)

OBJECTIVE —Ecological data suggest an inverse correlation between fish consumption and diabetes prevalence. However, epidemiological data on fish intake and diabetes incidence are controversial and inconclusive. Therefore, we aimed to assess the literature and determine the association between fish consumption and diabetes risk quantitatively. RESEARCH DESIGN AND METHODS —Prospective cohort studies published through August 2011 in peer-reviewed journals indexed in PubMed were selected. Additional information was retrieved through Google or a hand search of the references from relevant articles. The weighted relative risk (RR) and corresponding 95% CI for incident diabetes was estimated using random-effects models. RESULTS —A database was derived from nine eligible studies (12 independent cohorts), including 438,214 individuals with an average 11.4-year follow-up. Compared with those who never consumed fish or ate fish less than once per month, the pooled RR of incident diabetes was 0.99 (95% CI 0.85–1.16) for individuals who ate fish five or more times per week (Ptrend = 0.80). Similar results were found for long-chain n-3 polyunsaturated fatty acid intake. Study location was an effect modifier. An inverse association between fish intake and diabetes incidence was found by combining studies conducted in Eastern but not Western countries. CONCLUSIONS —Accumulated evidence generated from this meta-analysis does not support an overall inverse association of fish or fish oil intake with incidence of diabetes. The null association was modified by study location (Eastern vs. Western countries), which may reflect the possible difference between Eastern and Western dietary patterns. Further studies are warranted.
Characterization of the function of intercellular adhesion molecule (ICAM)-3 and comparison with ICAM-1 and ICAM-2 in immune responses.
Authors: A R de Fougerolles, X Qin, T A Springer
Journal: The Journal of Experimental Medicine (1994)

We have characterized the immunobiology of the interaction of intercellular adhesion molecule 3 (ICAM-3; CD50) with its counter-receptor, leukocyte function-associated antigen 1 (LFA-1; CD11a/CD18). Purified ICAM-3 supported LFA-1-dependent adhesion in a temperature- and cation-dependent manner. Activation of cells bearing LFA-1 increased adhesiveness for ICAM-3 in parallel to adhesiveness for ICAM-1. Although CBR-IC3/1 monoclonal antibody (mAb) blocked adhesion of cells to purified LFA-1, when tested alone, neither CBR-IC3/1 nor five novel ICAM-3 mAbs characterized here blocked adhesion of cells to purified ICAM-3 or homotypic adhesion. Two ICAM-3 mAbs, CBR-IC3/1 and CBR-IC3/2, were required to block LFA-1-dependent adhesion to purified ICAM-3- or LFA-1-dependent, ICAM-1-, ICAM-2-independent homotypic adhesion of lymphoid cell lines. Two ICAM-3 mAbs, CBR-IC3/1 and CBR-IC3/6, induced LFA-1-independent aggregation that was temperature and divalent cation dependent and was completely inhibited by ICAM-3 mAb, CBR-IC3/2, recognizing a distinct epitope. Purified ICAM-3 provided a costimulatory signal for proliferation of resting T lymphocytes. mAb to ICAM-3, together with mAbs to ICAM-1 and ICAM-2, inhibited peripheral blood lymphocyte proliferation in response to phytohemagglutinin, allogeneic stimulator cells, and specific antigen. Inhibition was almost complete and to the same level as with mAb to LFA-1, suggesting the most functionally important, and possibly all, of the ligands for LFA-1 have been defined.
Adaptation to Environmental Temperature Is a Major Determinant of Molecular Evolutionary Rates in Archaea
Authors: M. Groussin, M. Gouy
Journal: Molecular Biology and Evolution (2011)

Methods to infer the ancestral conditions of life are commonly based on geological and paleontological analyses. Recently, several studies used genome sequences to gain information about past ecological conditions taking advantage of the property that the G+C and amino acid contents of bacterial and archaeal ribosomal DNA genes and proteins, respectively, are strongly influenced by the environmental temperature. The adaptation to optimal growth temperature (OGT) since the Last Universal Common Ancestor (LUCA) over the universal tree of life was examined, and it was concluded that LUCA was likely to have been a mesophilic organism and that a parallel adaptation to high temperature occurred independently along the two lineages leading to the ancestors of Bacteria on one side and of Archaea and Eukarya on the other side. Here, we focus on Archaea to gain a precise view of the adaptation to OGT over time in this domain. It has been often proposed on the basis of indirect evidence that the last archaeal common ancestor was a hyperthermophilic organism. Moreover, many results showed the influence of environmental temperature on the evolutionary dynamics of archaeal genomes: Thermophilic organisms generally display lower evolutionary rates than mesophiles. However, to our knowledge, no study tried to explain the differences of evolutionary rates for the entire archaeal domain and to investigate the evolution of substitution rates over time. A comprehensive archaeal phylogeny and a non homogeneous model of the molecular evolutionary process allowed us to estimate ancestral base and amino acid compositions and OGTs at each internal node of the archaeal phylogenetic tree. The last archaeal common ancestor is predicted to have been hyperthermophilic and adaptations to cooler environments can be observed for extant mesophilic species. Furthermore, mesophilic species present both long branches and high variation of nucleotide and amino acid compositions since the last archaeal common ancestor. The increase of substitution rates observed in mesophilic lineages along all their branches can be interpreted as an ongoing adaptation to colder temperatures and to new metabolisms. We conclude that environmental temperature is a major factor that governs evolutionary rates in Archaea.
Toll-like Receptors Induce a Phagocytic Gene Program through p38
Authors: Sean E. Doyle, Ryan M. O'Connell, Gustavo A. Miranda, Sagar A. Vaidya, Edward K. Chow, Philip T. Liu, Shinobu Suzuki, Nobutaka Suzuki, Robert L. Modlin, Wen-Chen Yeh, Timothy F. Lane, Genhong Cheng
Journal: The Journal of Experimental Medicine (2003)

Toll-like receptor (TLR) signaling and phagocytosis are hallmarks of macrophage-mediated innate immune responses to bacterial infection. However, the relationship between these two processes is not well established. Our data indicate that TLR ligands specifically promote bacterial phagocytosis, in both murine and human cells, through induction of a phagocytic gene program. Importantly, TLR-induced phagocytosis of bacteria was found to be reliant on myeloid differentiation factor 88–dependent signaling through interleukin-1 receptor–associated kinase-4 and p38 leading to the up-regulation of scavenger receptors. Interestingly, individual TLRs promote phagocytosis to varying degrees with TLR9 being the strongest and TLR3 being the weakest inducer of this process. We also demonstrate that TLR ligands not only amplify the percentage of phagocytes uptaking Escherichia coli, but also increase the number of bacteria phagocytosed by individual macrophages. Taken together, our data describe an evolutionarily conserved mechanism by which TLRs can specifically promote phagocytic clearance of bacteria during infection.
Intensive Versus Intermediate Glucose Control in Surgical Intensive Care Unit Patients
Authors: Takehiro Okabayashi, Yasuo Shima, Tatsuaki Sumiyoshi, Akihito Kozuki, Teppei Tokumaru, Tasuo Iiyama, Takeki Sugimoto, Michiya Kobayashi, Masataka Yokoyama, Kazuhiro Hanazaki
Journal: Diabetes Care (2014)

The optimal perioperative blood glucose range to improve surgical site infection (SSI) in surgical intensive care unit (ICU) patients remains unclear. We sought to determine whether the incidence of SSI is reduced by perioperative intensive insulin therapy (IT).Patients were randomly assigned to receive perioperative intensive IT, with a target blood glucose range of 4.4-6.1 mmol/L, or intermediate IT, with a target blood glucose range of 7.7-10.0 mmol/L in the surgical ICU. We defined the primary end point as the incidence of SSI.Study participants were randomly assigned to glucose control with one of two target ranges: for 225 patients in the intermediate IT group or for 222 patients in the intensive IT group, respectively. No patients in either group became hypoglycemic (<4.4 mmol/L) during their stay in the surgical ICU. In our series, the rate of SSI after hepato-biliary-pancreatic surgery was 6.7%. Patients in the intensive IT group, compared with the intermediate IT group, had fewer postoperative SSIs (9.8% vs. 4.1%, P = 0.028) and a lower incidence of postoperative pancreatic fistula after pancreatic resection (P = 0.040). The length of hospitalization required for patients in the intensive IT group was significantly shorter than that in the intermediate IT group (P = 0.017).We found that intensive IT decreased the incidence of SSI among patients who underwent hepato-biliary-pancreatic surgery: a blood glucose target of 4.4 to 6.1 mmol/L resulted in lower rate of SSI than did a target of 7.7-10.0 mmol/L.
Apoptosis of the Thick Ascending Limb Results in Acute Kidney Injury
Authors: Manakan B. Srichai, Chuanming Hao, Linda Davis, Anastasia Golovin, Min Zhao, Gilbert Moeckel, Steve Dunn, Nada Bulus, Raymond C. Harris, Roy Zent, Matthew D. Breyer
Journal: Journal of the American Society of Nephrology (2008)

Ischemia- or toxin-induced acute kidney injury is generally thought to affect the cells of the proximal tubule, but it has been difficult to define the involvement of other tubular segments because of the widespread damage caused by ischemia/reperfusion or toxin-induced injury in experimental models. For evaluation of whether thick ascending limb (TAL)-specific epithelial injury results in acute kidney injury, a novel transgenic mouse model that expresses the herpes simplex virus 1 thymidine kinase gene under the direction of the TAL-specific Tamm-Horsfall protein promoter was generated. After administration of gancyclovir, these mice demonstrated apoptosis only in TAL cells, with little evidence of neutrophil infiltration. Compared with control mice, blood urea nitrogen and creatinine levels were at least five-fold higher in the transgenic mice, which also developed oliguria and impaired urinary concentrating ability. These findings suggest that acute injury targeted only to the TAL is sufficient to cause severe acute kidney injury in mice with features similar to those observed in humans.
Possible Role of Calponin h1 as a Tumor Suppressor in Human Uterine Leiomyosarcoma
Authors: A. Horiuchi, T. Nikaido, S. Taniguchi, S. Fujii
Journal: JNCI Journal of the National Cancer Institute (1999)

Calponin h1, a basic actin-binding protein capable of inhibiting smooth muscle contraction, is a constitutive element of smooth muscle cells. However, in leiomyosarcoma (a type of smooth muscle neoplasm of the uterus), reduced expression of calponin h1 is observed, as we have reported previously. In this study, we sought to assess the effects (in vitro and in vivo) of increasing calponin h1 expression in leiomyosarcoma cells.A plasmid containing a human calponin h1 complementary DNA and a bacterial neomycin-resistance gene was transfected into the human leiomyosarcoma cell lines SKN and SK-LMS-1 by electroporation. Southern blotting, reverse transcription-polymerase chain reaction analysis, western blotting, and immunohistochemistry were used to confirm DNA transfer and expression of the calponin h1 protein in neomycin-resistant clones. We characterized the morphology of calponin h1-transfected cells, and we evaluated their proliferative activity and tumorigenicity by use of a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide assay, an anchorage-independent growth assay, and a nude mouse tumorigenicity assay.The morphology of calponin h1-transfected cells in culture resembled that of cultured normal myometrial smooth muscle cells. With SK-LMS-1 cells, proliferation of calponin h1-transfection cells was reduced to 69% of control; with SKN cells, calponin h1 transfection reduced proliferation to 70% of control. In assays of anchorage-independent growth and in vivo tumorigenicity, both growth and tumorigenicity were statistically significantly reduced in calponin h1-transfected leiomyosarcoma cells.Calponin h1 may function as a tumor suppressor in leiomyosarcoma. Clinically, transfer of a calponin h1 complementary DNA into poorly differentiated leiomyosarcoma cells may be of potential therapeutic value through induction of a normal, differentiated cellular phenotype.
Phase I Evaluation of CDP791, a PEGylated Di-Fab′ Conjugate that Binds Vascular Endothelial Growth Factor Receptor 2
Authors: N.C. Ton, G.J.M. Parker, A. Jackson, S. Mullamitha, G.A. Buonaccorsi, C. Roberts, Y. Watson, K. Davies, S. Cheung, L. Hope, F. Power, J. Lawrance, J. Valle, M. Saunders, R. Felix, J.A. Soranson, L. Rolfe, K. Zinkewich-Peotti, G.C. Jayson
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Specific blocking of vascular endothelial growth factor receptor 2 (VEGFR-2) is a novel therapeutic approach. Here, we report the first phase I clinical trial evaluation of CDP791, a PEGylated di-Fab′ conjugate that binds VEGFR-2. Experimental Design: Cohorts of patients received CDP791 at doses between 0.3 and 30 mg/kg every 3 weeks for the initial two doses. Results: The compound was well tolerated with no dose-limiting toxicity. Dose-related hypertension was observed in patients receiving CDP791 10 mg/kg or more and several patients on the higher doses developed infusion-related cutaneous hemangiomata arising 28 to 106 days after the first drug administration and resolving 3 weeks after cessation. Biopsy and histologic evaluation showed that CDP791-bound VEGFR-2 is non-phosphorylated, suggesting that the drug is biologically active. Concentrations of CDP791 considered biologically relevant were sustained for 3 weeks when doses of 10 mg/kg or more were administered. Although no reductions in vascular permeability were recorded using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), there was a significant dose level–related reduction in tumor growth. While challenging the recent dogma that active VEGF inhibitors should modulate DCE-MRI measurements of vascular permeability, this highlights the potential of serial three-dimensional tumor measurements to detect tumor growth arrest. Twelve patients received drug for more than two treatments, although no partial or complete responses were seen. Conclusion: The data show that CDP791 is biologically active and well tolerated, achieving appropriate plasma concentrations when administered at 10 mg/kg or more every 3 weeks.
Alcohol Intake Between Menarche and First Pregnancy: A Prospective Study of Breast Cancer Risk
Authors: Y. Liu, G. A. Colditz, B. Rosner, C. S. Berkey, L. C. Collins, S. J. Schnitt, J. L. Connolly, W. Y. Chen, W. C. Willett, R. M. Tamimi
Journal: JNCI Journal of the National Cancer Institute (2013)

Adult alcohol consumption during the previous year is related to breast cancer risk. Breast tissue is particularly susceptible to carcinogens between menarche and first full-term pregnancy. No study has characterized the contribution of alcohol consumption during this interval to risks of proliferative benign breast disease (BBD) and breast cancer.We used data from 91,005 parous women in the Nurses' Health Study II who had no cancer history, completed questions on early alcohol consumption in 1989, and were followed through June 30, 2009, to analyze breast cancer risk. A subset of 60,093 women who had no history of BBD or cancer in 1991 and were followed through June 30, 2001, were included in the analysis of proliferative BBD. Relative risks (RRs) were estimated using Cox proportional hazard regression.We identified 1609 breast cancer cases and 970 proliferative BBD cases confirmed by central histology review. Alcohol consumption between menarche and first pregnancy, adjusted for drinking after first pregnancy, was associated with risks of breast cancer (RR = 1.11 per 10 g/day intake; 95% confidence interval [CI] = 1.00 to 1.23) and proliferative BBD (RR = 1.16 per 10 g/day intake; 95% CI = 1.02 to 1.32). Drinking after first pregnancy had a similar risk for breast cancer (RR = 1.09 per 10 g/day intake; 95% CI = 0.96 to 1.23) but not for BBD. The association between drinking before first pregnancy and breast neoplasia appeared to be stronger with longer menarche to first pregnancy intervals.Alcohol consumption before first pregnancy was consistently associated with increased risks of proliferative BBD and breast cancer.
ISCHEMIC PRECONDITIONING AND INHIBITION OF THE MALATE-ASPARTATE SHUTTLE PRESERVES MITOCHONDRIAL RESPIRATION AND DECREASES ROS PRODUCTION IN THE ISOLATED RAT HEART
Authors: Nichlas Riise Jespersen, Takashi Yokota, Kim Nielsen, Nicolaj B. Støttrup, Jonas Povlsen, Flemming Dela, Hans Erik Bøtker
Journal: Journal of the American College of Cardiology (2013)
Second-line chemotherapy in advanced pancreatic carcinoma: a multicenter survey of the Gruppo Oncologico Italia Meridionale on the activity and safety of the FOLFOX4 regimen in clinical practice
Authors: V. Gebbia, E. Maiello, F. Giuliani, N. Borsellino, M. Caruso, G. Di Maggio, F. Ferraù, R. Bordonaro, F. Verderame, P. Tralongo, L. Di Cristina, R. Agueli, P. Russo, G. Colucci
Journal: Annals of Oncology (2007)
Cardiorespiratory Fitness and the Incidence of Type 2 Diabetes
Authors: Susumu S. Sawada, I-Min Lee, Takashi Muto, Kazuko Matuszaki, Steven N. Blair
Journal: Diabetes Care (2003)

OBJECTIVE—To investigate the association between cardiorespiratory fitness and the incidence of type 2 diabetes among Japanese men. RESEARCH DESIGN AND METHODS—This prospective cohort study was conducted in 4,747 nondiabetic Japanese men, aged 20–40 years at baseline, enrolled in 1985 with follow-up to June 1999. Cardiorespiratory fitness was measured using a cycle ergometer test, and Vo2max was estimated. During a 14-year follow-up, 280 men developed type 2 diabetes. RESULTS—The age-adjusted relative risks of developing type 2 diabetes across quartiles of cardiorespiratory fitness (lowest to highest) were 1.0 (referent), 0.56 (95% CI 0.42–0.75), 0.35 (0.25–0.50), and 0.25 (0.17–0.37) (for trend, P &amp;lt; 0.001). After further adjustment for BMI, systolic blood pressure, family history of diabetes, smoking status, and alcohol intake, the association between type 2 diabetes risk and cardiorespiratory fitness was attenuated but remained significant (1.0, 0.78, 0.63, and 0.56, respectively; for trend, P = 0.001). CONCLUSIONS—These results indicate that a low cardiorespiratory fitness level is an important risk factor for incidence of type 2 diabetes among Japanese men.