tbuckley/cabot-search huggingface dataset:
Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice
Authors: Raul Lazaro, Raymond Wu, Sunyoung Lee, Nian‐Ling Zhu, Chia‐Lin Chen, Samuel W. French, Jun Xu, Keigo Machida, Hidekazu Tsukamoto
Journal: Hepatology (2014)

Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (polymorphonuclear; PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat and the rest from intragastric feeding of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericellular fibrosis to AH in 57% (15 of 26) of mice, accompanied by inductions of chemokines ( Spp1 , Cxcl1 , and interleukin [ Il ] ‐17a ), progenitor genes ( Cd133 , Cd24 , Nanog , and epithelial cell adhesion molecule), PMN infiltration, and clinical features of AH, such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce AH incidence and inductions of progenitor and fibrogenic genes, but rather enhances the Il‐17a induction and PMN infiltration in some mice. Furthermore, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. Conclusion : These results suggest that SPP1 has a protective, rather than causal, role for experimental AH reproduced in our model. (H epatology 2015;61:129–140)
Abstract 3595: Inverse Association of Adiponectin with Insulin Resistance is Attenuated with the Escalation of Insulin Resistance: a Possible Finding of Adiponectin Resistance
Authors: Kunihiro Matsushita, Hiroshi Yatsuya, Koji Tamakoshi, Takashi Muramatsu, Hirotsugu Mitsuhashi, Rei Shibata, Takahisa Kondo, Toyoaki Murohara, Hideaki Toyoshima
Journal: Circulation (2007)

Introduction: Adiponectin has been known to play an important role in the glucose and lipid metabolism, and thereby may be considered as a potential treatment target for diabetes mellitus or atherosclerotic diseases. Recently, some basic studies showed that adiponectin might not function in an insulin-resistant condition, a concept called “adiponectin resistance.” However, this concept has not been confirmed in human. Therefore, we assessed the hypothesis that the well-known inverse association between adiponectin and insulin resistance is weakened in the insulin-resistant state. Methods: We studied 2,316 middle-aged Japanese men without a medical history of cancer, cardiovascular disease, diabetes, hypertension, or dyslipidemia to determine whether or not the association between serum adiponectin levels and the insulin resistance index (HOMA-IR) differed according to insulin resistant states. Results: Mean age and body mass index of study subjects were 48±7 and 23±3, respectively. A multiple linear regression analysis revealed that log-adiponectin was inversely associated with log-HOMA-IR independently of covariates (β= − 0.235, P &lt;0.001). Subsequently, we re-analyzed after dividing study subjects according to the tertile of HOMA-IR. As shown in the Table , the inverse association between adiponectin and HOMA-IR was considerably weakened with the escalation of insulin resistance. Specifically, adiponectin was almost positively associated with HOMA-IR in insulin-resistant subjects (β= 0.114, P =0.059). Interestingly, statistically significant associations of adiponectin with triglyceride and HDL-C were uniformly observed in all tertiles. Conclusion: The inverse association of adiponectin with insulin resistance weakened with the escalation of insulin resistance, suggesting the existence of “adiponectin resistance” in insulin-resistant individuals. This adiponectin resistance may be restricted in glucose metabolism. Table. Coefficients of adiponectin in multiple linear regression analyses with independent variables
Abstract P221: Effects of Immediate Antihypertensive Treatment in Men and Women with Acute Ischemic Stroke: The CATIS Study
Authors: Qi Zhao, Yonghong Zhang, Jing Chen, Tan Xu, Chung-Shiuan Chen, Weijun Tong, Lydia A Bazzano, Jiang He
Journal: Circulation (2014)

Gender difference in the risk and prognosis of ischemic stroke has been reported. We examined the effects of immediate antihypertensive treatment on clinical outcomes among acute ischemic stroke by gender in the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS). CATIS was a randomized, single-blind, and blinded end-point trial conducted in 4,071 acute ischemic stroke patients (2,604 men and 1,467 women). Eligible stroke patients with elevated systolic blood pressure (SBP) were randomly assigned to receive antihypertensive treatment (lowering SBP by 10-25% within the first 24 hours after randomization and BP &lt; 140/90 mm Hg within 7 days) or control (discontinuing all antihypertensive medications). The primary outcome was a combination of death and major disability (defined by a modified Rankin score ≥ 3) at day 14 (or at discharge if earlier than 14 days) and 3-month post-treatment follow-up. The primary outcome was not significantly different between the treatment and control groups in either men or women. The primary outcome event rates for the two comparison groups were 31.6% and 32.1% in men ( P = 0.79) and 37.3% and 36.1% in women ( P = 0.65) at day 14; and were 23.6% and 24.5% in men ( P = 0.60) and 28.0% and 26.6% in women ( P = 0.56) at 3-month follow-up. The secondary outcomes were not different between treatment and control groups among men and women at 14 days or hospital discharge and at 3 months. The median modified Rankin scores (interquartile range) for the comparison groups were 2.0 (1.0-3.0) and 2.0 (1.0-3.0) in both men and women at day 14 or hospital discharge. The modified Rankin score, recurrent stroke, vascular event, and all-cause mortality at 3-month follow-up were similar between the treatment and control groups for both men and women. For example, the vascular event rates for the comparison groups were 2.4% and 3.0% in men ( P = 0.34) and 2.4% and 2.9% in women ( P = 0.58). There were no significant treatment and sex interactions for any of the primary and secondary outcomes. In conclusion, these data suggest that immediate antihypertensive treatment within the first 48 hours after stroke onset has no gender-specific effect on short-term outcomes of patients with acute ischemic stroke.
Cross-reactivity among some metals in a murine metal allergy model
Authors: M. Kinbara, Y. Nagai, T. Takano-Yamamoto, S. Sugawara, Y. Endo
Journal: British Journal of Dermatology (2011)

Information concerning cross-reactivity among metal allergens is scarce. We previously devised a murine metal allergy model using lipopolysaccharide (LPS) as an adjuvant. LPS reduces the minimum allergy-inducing concentration (MAIC) of metals at both the sensitization and the elicitation steps.Here, we examined allergic cross-reactivity among some metals in this murine model, and compared the effects of ultrapure (99·99% or more) and low purity (93-99%) metal salts.A mixture of a metal salt and Escherichia coli LPS was injected intraperitoneally into BALB/c mice (0·25 mL per mouse). Ten days later, metal salts (with or without LPS) were challenged to ear pinnas (20 μL per ear), and ear swelling was measured.Among the ultrapure metals tested (Ni, Pd, Co, Cr, Cu and Au), only Ni and Pd cross-reacted. In this cross-reaction, their MAICs were at the same level. Combined challenge with Ni and Pd at sub-MAICs (but not at higher concentrations) produced an additive effect. Surprisingly, mice sensitized with low purity Ni reacted to all the tested low purity metals (Ni, Pd, Co and Cr), and the low purity metals were shown to contain contaminant metals.In our model: (i) Ni and Pd (members of the same group in the periodic table of elements) cross-react with each other, (ii) this cross-reaction may depend on true and false antigens forming metal-protein complexes with similar spatial geometries, (iii) Co, Cr, Cu and Au do not cross-react with each other, (iv) in low purity materials, trace contaminant metals may be sufficient to evoke allergy, and thus (v) high purity metal salts should be considered for use in clinical patch testing.
Abstract 628: Pro-Apoptotic Bnip3 Functions as a Mitochondrial Sensor of Oxidative Stress in Myocardial Ischemia/Reperfusion
Authors: Dieter A Kubli, Melissa N Quinsay, Asa B Gustafsson
Journal: Circulation (2007)

Bnip3 is a member of the BH3-only subfamily of pro-apoptotic Bcl-2 proteins and is associated with mitochondrial dysfunction and cell death in the myocardium. We previously found that Bnip3 contributes to ischemia/reperfusion (I/R) injury, but it is not known how I/R causes activation of Bnip3. We have investigated potential mechanism(s) by which Bnip3 activity is regulated. Western blot analysis of heart lysates revealed that Bnip3 forms a ∼48 kDa complex after I/R that is sensitive to reduction by DTT. Complex formation was reduced when hearts were perfused with the reactive oxygen species (ROS) scavenger N-acetyl cysteine prior to I/R. The complex also increased in isolated myocytes treated with hydrogen peroxide, suggesting that the DTT-sensitive complex is formed by increased oxidative stress. To further investigate the function of this complex, we overexpressed Bnip3 in HL-1 myocytes and found that most of Bnip3 existed in the 48-kDa complex which correlated with increased cell death. In contrast, endogenous Bnip3 in the heart exists mainly as a monomer under normal conditions. Scanning of the Bnip3 protein sequence revealed a single conserved Cys residue at position 64, which may be susceptible to oxidation. Mutation of the Cys to an Ala or deletion of the N-term (aa 1–64) resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes. Separation of purified Bnip3 on SDS-PAGE showed the presence of the same DTT sensitive complex, suggesting that the complex is a Bnip3 homodimer. The transmembrane (TM) domain of Bnip3 has previously been identified to be important for homodimerization, and contains a His residue at position 173 that is essential for homodimerization. Mutation of the His to an Ala also resulted in reduced cell death activity of Bnip3 compared to wild type when overexpressed in HL-1 myocytes, suggesting that homodimerization is important for cell death activity of Bnip3. A consequence of I/R is the production of ROS and oxidation of proteins, which promotes formation of Cys disulfide bonds between proteins. Thus, these studies suggest that Bnip3 functions as a redox sensor in cells where increased oxidative stress induces homodimerization of Bnip3 via N-terminal Cys residue and the C-terminal TM domain.
Genome-wide microarray analysis of the Ionizing-radiation induced TGF-β signaling pathway in pancreatic carcinoma cells
Authors: Mohammed M. Shareef, Marianna Zagurovskaya-Sultanov, Anna E. Reeves, Swati Girdhani, Mansoor M. Ahmed
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4390 

In response to transforming growth factor beta (TGF-beta), Smad4 forms complexes with activated Smad2 and Smad3, which facilitates the translocation into the nucleus, where they bind to the SMAD Binding Element (SBE) and both positively and negatively regulate TGF-beta target genes. Mutation or deletion of Smad4 is found in about 50% of pancreatic tumors leading to the abrogation of the SMAD signaling pathway. Ionizing radiation (IR), an important therapeutic modality, induces the expression of TGF-β1 via the induction of early growth response 1 (EGR-1) gene. Previous studies have analyzed the TGF-β mediated expression of several genes. However, the interplay between the TGF-β signaling and other IR-induced signaling pathways are likely to have a bearing on the outcome of the radiotherapy. Therefore, it is imperative to understand the modulation of these pathways for better therapeutic designs. Capan1 cells, which harbor p53 mutations and have intact TGF-β signaling pathway, were either untreated or treated with 7Gy IR or with 7Gy IR with neutralizing antibody to TGF-β. The total RNA extracts were subjected to microarray analysis using human U133 plus 2.0 array (47000 genes) from affymetrix. Genes that showed significant changes in expression (1389) with IR were categorized as upregulated (892) or downregulated (497). The gene expression profile was analyzed for abrogation of upregulation or downregulation by anti-TGF-β plus IR exposure suggestive of these genes being regulated by IR-induced TGF-β signaling. We currently have complete list of SBE harboring genes (554 genes) that was mined using in-silico approach (developed by our group). Correlating the genes identified as targets of IR-induced TGF-β signaling with the genes harboring SBE sites in their promoters will help in the identification of direct targets of the SMADs. This analyses will be useful in designing customized microarrays. The mRNA and protein levels of TGF-β signaling machinery and the it’s downstream effector genes regulating carcinogenesis, growth inhibition/apoptosis and metastasis in treated tumor tissue specimens will predict the overall prognosis and response rate to radiotherapy in pancreatic tumors. Validation of several of these genes is currently being carried out by real time RT-PCR analysis. Thus, the present study identified IR-induced TGF-β responsive genes in the pancreatic carcinoma cells.
Abstract 20355: Cardiac Magnetic Resonance Assessment of Absolute Myocardial Blood Flow and Myocardial Perfusion Reserve Compared With FFR in Patients With Coronary Artery Disease
Authors: Yoshihisa Kanaji, Tetsumin Lee, Tadashi Murai, Asami Suzuki, Junji Matsuda, Makoto Araki, Tsunekazu Kakuta
Journal: Circulation (2014)

Background: The diagnostic value of absolute myocardial blood flow (AMBF) obtained by cardiac magnetic resonance (CMR) quantitative measurement remains uncertain. We evaluated the subendocardial, epicardial, transmural AMBF, and myocardial perfusion reserve (MPR) derived from AMBF determined by perfusion CMR. We also assessed the relationship between CMR-derived AMBF and fractional flow reserve (FFR) in patients with coronary artery disease (CAD). Methods and Results: We investigated 38 CAD patients (mean age, 67±10 years; male, 89%, 46 vessels territories) who underwent perfusion CMR both at stress and rest, and invasive coronary angiography. FFR was measured in all vessels with stenosis more than 40% by QCA. FFR&lt;0.8 was considered hemodynamically significant stenosis. Patients with previous revascularization and/or myocardial infarction, and with renal dysfunction were excluded. We perform quantitative analysis of the transmural, subendocardial and epicardial AMBF, and MPR at mid-ventricular level. AMBF distributed in the wide range both subendocardium and subepicardium. At stress, AMBF was significantly increased in all of the subendocardial, epicardial, and transmural layers of the ischemic segment at adenosine-induced hyperemia from rest AMBF. (At rest: subendocardial 245±122 ml/100g/min, epicardial 124 [75-233] ml/100g/min, transmural 172 [102-261] ml/100mg/min. At stress: subendocardial 380 [156-517] ml/100g/min, epicardial 275 [158-502] ml/100g/mintransmural 287 [152-456] ml/100g/min.) There was a significant relationship between transmural AMBF and FFR, transmural MPR and FFR values, with r = 0.33 (p = 0.028), r=0.39 (p=0.007). The transmural MPR&lt;2.47 threshold yielded a sensitivity of 0.92 (95% confidence interval: 0.77 to 0.99) and a specificity of 0.71 (0.44-0.90) to detect coronary ischemia with a FFR &lt;0.8, and an area under the ROC curve (AUC) of 0.77 (0.62 to 0.88) for vessel-based analysis. Subendocardial AMBF and MPR gradually decreased with decreasing FFR at ischemic segment, but it was not significant. Conclusions: The quantitative analysis of transmural AMBF and myocardial MPR on perfusion cardiac magnetic resonance may predicts hemodynamically significant CAD as defined by FFR.
Upregulated TCRζ improves cytokine secretion in T cells from patients with AML
Authors: Shaohua Chen, Xianfeng Zha, Li Shi, Lingling Zhou, Lijian Yang, Bo Li, Xiuli Wu, Jun Zhong, Tao Zhang, Yuhong Lu, Kanger Zhu, Yangqiu Li
Journal: Journal of Hematology & Oncology (2015)

Previous studies indicated that upregulating TCRζ partially recovers T cell function in patients with leukemia. In this study, we characterized the cytokine profile of TCRζ-transfected T cells from acute myeloid leukemia (AML) patients by Quantibody®Array Glass Chip. Firstly, the significantly lower expression of TCRζ in CD3+/TCRζ+ cells from AML patients was found. Increased secretion of IL-2, IL-8, IL-10, IL-13, IFN-γ, TNF-α, GM-CSF, growth-regulated oncogene (GRO), MIP-1b, and regulated on activation, normal T cell expressed and secreted (RANTES) could be detected in T cells from AML patients after TCRζ upregulating. We concluded that upregulating TCRζ in T cells from AML can alter the secretion profile of cytokines and chemokine which are involved in T cell proliferation and activation.
Evidence for loss of heterozygosity in human psoriatic lesions
Authors: None Zachos, None Koumantaki, None Vareltzidis, None Spandidos
Journal: British Journal of Dermatology (1998)

Psoriasis, a disease of human skin, is characterized by abnormal differentiation and hyperproliferation of keratinocytes; it has a genetic background. Using 11 highly polymorphic microsatellite markers on eight chromosome arms, we performed an allelotype analysis in 14 psoriatic plaques, in order to reveal any chromosome deletions involved in the development of the disease. We detected loss of heterozygosity (LOH) on at least one microsatellite marker in nine of 14 (64%) cases. We also observed particular genetic loci altered with LOH, on chromosomes 3p, 7p/q and 8p. Our results suggest that LOH is an important phenomenon in the development of psoriatic plaques, providing evidence for deletion of regulatory genes.
Endogenously Expressed Multimeric Self-Cleaving Hammerhead Ribozymes Ablate Mutant Collagen in Cellulo
Authors: Belinda E. Peace, Jane B. Florer, David Witte, Yoel Smicun, Iva Toudjarska, George Wu, Michael W. Kilpatrick, Petros Tsipouras, Richard J. Wenstrup
Journal: Molecular Therapy (2005)

Hammerhead ribozymes are small catalytic RNA molecules that can be targeted to any RNA molecule containing a putative cleavage site. We developed a vector (pCOLZ) that uses the COL1A1 promoter to drive expression of a self-cleaving multimeric ribozyme (M8Rz547) and its monomeric counterpart (Rz547). The ribozymes were stably coexpressed in MC3T3-E1 osteoblasts expressing a truncated COL1A1 target transcript. The multimeric ribozyme exhibited self-cleavage to derivative fragments, including monomers. Increased expression of ribozymes was found in cells expressing the multimeric ribozyme. A modest reduction of truncated target transcript and protein was seen in cells expressing the ribozyme monomer, while nearly complete ablation of target transcript and protein occurred in cells expressing the ribozyme multimer. A reversion to a more normal collagen phenotype, measured as an increase in fibril diameter and restored fibrillar architecture, and a decreased rate of collagen turnover were seen in cells expressing the ribozyme multimer.
Abstract 3648: Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics
Authors: Rajkumar Noubade, Holbrook Kohrt, Lisa Marshall, Idit Sagiv-Barfi, Jonathan Hebb, Cariad Chester, Amanda Rajapaksa, Erin Waller, Steve Young, Jay Powers, Juan Jaen
Journal: Cancer Research (2014)

Abstract Objective: Inhibition of indoleamine-2,3-dioxygenase-1 (IDO-1), indoleamine-2,3- dioxygenase-2 (IDO-2), and/or tryptophan-2,3-dioxygenase (TDO) represent novel opportunities for reversing the immunosuppressed microenvironment found in cancer patients. However, little is known about the relative expression of these enzymes in tumors and associated lymph nodes of mouse tumor models, including those previously utilized in the preclinical characterization of tool compounds or even clinical candidates that inhibit one of these enzymes. This report describes the systematic characterization of expression of these enzymes in several of the most commonly used mouse tumor models. Study Design: Tumor models evaluated included B16F10 melanoma, B16-GMCSF melanoma and PAN02 pancreatic in C57BL/6 mice, and 4T1 breast and CT26 colon in Balb/c mice. Cells were injected s.c. into the flanks of 8-week old female mice. In each model, tumors and draining lymph nodes were collected from separate cohorts of mice when the mean tumor volumes reached 100 and 1,000 mm3, respectively. Expression of the 3 enzymes of interest was assessed using a variety of techniques, including qRT-PCR, Western blot and FACS. Results: A highly complex picture arises from our study. Expression levels of each of the enzymes studied here were highly dependent on the choice of tumor cell, the tissue analyzed (tumor vs. lymph node), as well as the stage of growth of the tumor. In general, the most commonly expressed of the 3 enzymes was IDO-1, primarily on tumor cells and dendritic cells in the lymph nodes. Conclusion: It is critically important, in the preclinical evaluation of potential new drugs, to select mouse models that recapitulate specific and well-characterized elements of the signaling pathway targeted by those drugs. The results presented in this communication should be of particular interest to those investigators pursuing a therapeutic strategy of immunosuppression reversal. Citation Format: Rajkumar Noubade, Holbrook Kohrt, Lisa Marshall, Idit Sagiv-Barfi, Jonathan Hebb, Cariad Chester, Amanda Rajapaksa, Erin Waller, Steve Young, Jay Powers, Juan Jaen. Expression of tolerogenic enzymes IDO-1, IDO-2 and TDO in commonly used mouse tumor models and impact on model selection for evaluation of immunosuppression reversal by novel therapeutics. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3648. doi:10.1158/1538-7445.AM2014-3648