tbuckley/cabot-search huggingface dataset:
The Origin and Function of the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)/Glucagon Superfamily*
Authors: Nancy M. Sherwood, Sandra L. Krueckl, John E. McRory
Journal: Endocrine Reviews (2000)

The pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily includes nine hormones in humans that are related by structure, distribution (especially the brain and gut), function (often by activation of cAMP), and receptors (a subset of seven-transmembrane receptors). The nine hormones include glucagon, glucagon-like peptide-1 (GLP-1), GLP-2, glucose-dependent insulinotropic polypeptide (GIP), GH-releasing hormone (GRF), peptide histidine-methionine (PHM), PACAP, secretin, and vasoactive intestinal polypeptide (VIP). The origin of the ancestral superfamily members is at least as old as the invertebrates; the most ancient and tightly conserved members are PACAP and glucagon. Evidence to date suggests the superfamily began with a gene or exon duplication and then continued to diverge with some gene duplications in vertebrates. The function of PACAP is considered in detail because it is newly (1989) discovered; it is tightly conserved (96% over 700 million years); and it is probably the ancestral molecule. The diverse functions of PACAP include regulation of proliferation, differentiation, and apoptosis in some cell populations. In addition, PACAP regulates metabolism and the cardiovascular, endocrine, and immune systems, although the physiological event(s) that coordinates PACAP responses remains to be identified.
Safe and efficient transduction of synovial tissue after local injection of AAV5.hIFNβ in non-human primates with collagen-induced arthritis
Authors: L Bevaart, N Broeksta, K de Cortie, M A van Geldorp, M P M Vierboom, J F Wright, P P Tak, M J Vervoordeldonk
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Backgroundand objectives</h3> Recombinant AAV5.NFkB.hIFN-β (ART-I02) is an adeno-associated type 5 (rAAV5) vector expressing the human interferon β (hIFN-β) under development for local treatment of rheumatoid arthritis (RA). The authors investigated biodistribution and safety after intra-articular (ia) injection of the gene construct in rhesus monkeys with CIA. <h3>Materials and methods</h3> Arthritis was induced in 15 monkeys (13 male and 2 female) with chicken type II collagen (ChCII, 4 mg). All monkeys were naïve or showed limited (1:10–1:31,6) neutralising antibody (Nab) titers to AAV5 at the start of the study. All animals (N=5 per group) were treated with a single dose of ART-I02 (1.10<sup>13</sup> vg/ml or 1,4.10<sup>12</sup> vg/ml) or placebo in the first involved PIP joint (0,1 ml) and in the ipsilateral knee (1 ml) and ankle joint (0,5 ml). Clinical signs and symptoms were monitored for a maximum of 4 weeks until the human end-point in the study was reached. Serum, joints and organs were collected for histological analysis. Serum was analysed for acute phase response (CRP, IL-6 levels), ChCII antibodies and Nab. Presence of ART-I02 vector genomes in 16 tissues was analysed using qPCR. Expression of hIFNβ was analysed in knee synovial tissue (ST) samples by ELISA. Histological evaluation by an experienced pathologist was performed on all organs collected to evaluate toxicity induced by the vector. <h3>Results</h3> No adverse events were observed after ia injection of ART-I02. All animals experienced an acute phase response (CRP&gt;50 mg/L-752 mg/L) with simultaneous rising of IL-6 levels and the production of anti-ChCII IgG antibodies associated with the development of arthritis. High titers of Nab to rAAV5 were observed (between 1:3.160 and 1:100.000) at the end of the study. Vector DNA was detected in ST of the injected knee joint and the popliteal (draining) lymph node (injected side) at the highest copy numbers. No vector DNA was detected in ovaries (2/2). In four out of eight animals testes was positive for vector DNA (100 copies/ug DNA). In animals which had a longer follow up after injection (&gt;14 days) the testes were negative for vector DNA, indicating this could be a transient effect. In knee ST samples a varied level of expression of hIFNβ was observed. No abnormalities were observed after histological evaluation of all organs. <h3>Conclusions</h3> Intra-articular injection of ART-I02 at high doses is well-tolerated and does not induce adverse events in the monkey CIA model of RA. This study represents an important step towards a phase I clinical trial in RA patients.
364 High fat diet induces severe hepatic fibrosis in inducible nitric oxide gene-knockout mice
Authors: Y CHEN
Journal: Hepatology (2003)

Temporal lobe epilepsy (TLE) is a chronic neurological disease characterized by recurrent spontaneous seizures. MicroRNAs are dysregulated in various pathological conditions including epilepsy. Therefore, we hypothesized that the dysregulation of these microRNAs might also be associated with the pathogenesis of TLE. In this study, we found that a microRNA, hsa-miR-155-5p, was upregulated in patients with TLE post-surgery, and hence associated with clinical and pathological manifestations and seizure outcomes. We then used a rat model of experimental epilepsy induced by pilocarpine and revealed that the rat homologue was upregulated as well. Importantly, injection of an antagomiR of rno-miR-155-5p in vivo resulted in a reduction of the pathophysiological features associated with the status epilepticus, which was accompanied by decrease of apoptosis in the hippocampus. This effect was correlated with an increase in rat Sestrin-3 expression, which was a gene known to counteract oxidative stress. This rescue was also observed after injection of a lentivirus carrying the small interfering RNA of rat Sestrin-3 gene in the hippocampus. In addition, rno-miR-155-5p as well as rat Sestrin-3 mRNA and protein expression were partly dependent on oxidative stress induced by H2O2 in PC12 cells. Taken together, our data suggest that rno-miR-155-5p is a potent post-transcriptional regulator of rat Sestrin-3 and it may be one of the molecular links between brain damage and increased risk for seizures during damage by oxidative stress.
Prostate Cancer Progression Correlates with Increased Humoral Immune Response to a Human Endogenous Retrovirus GAG Protein
Authors: Bernardo Sgarbi Reis, Achim A. Jungbluth, Denise Frosina, Megan Holz, Erika Ritter, Eiichi Nakayama, Toshiaki Ishida, Yuichi Obata, Brett Carver, Howard Scher, Peter T. Scardino, Susan Slovin, Sumit K. Subudhi, Victor E. Reuter, Caroline Savage, James P. Allison, Jonathan Melamed, Elke Jäger, Gerd Ritter, Lloyd J. Old, Sacha Gnjatic
Journal: Clinical Cancer Research (2013)

Human endogenous retroviruses (HERV) encode 8% of the human genome. While HERVs may play a role in autoimmune and neoplastic disease, no mechanistic association has yet been established. We studied the expression and immunogenicity of a HERV-K GAG protein encoded on chromosome 22q11.23 in relation to the clinical course of prostate cancer.In vitro expression of GAG-HERV-K was analyzed in panels of normal and malignant tissues, microarrays, and cell lines, and effects of demethylation and androgen stimulation were evaluated. Patient sera were analyzed for seroreactivity to GAG-HERV-K and other self-antigens by ELISA and seromics (protein array profiling).GAG-HERV-K expression was most frequent in prostate tissues and regulated both by demethylation of the promoter region and by androgen stimulation. Serum screening revealed that antibodies to GAG-HERV-K are found in a subset of patients with prostate cancer (33 of 483, 6.8%) but rarely in male healthy donors (1 of 55, 1.8%). Autoantibodies to GAG-HERV-K occurred more frequently in patients with advanced prostate cancer (29 of 191 in stage III-IV, 21.0%) than in early prostate cancer (4 of 292 in stages I-II, 1.4%). Presence of GAG-HERV-K serum antibody was correlated with worse survival of patients with prostate cancer, with a trend for faster biochemical recurrence in patients with antibodies to GAG-HERV-K.Preferential expression of GAG-HERV-K ch22q11.23 in prostate cancer tissue and increased frequency of autoantibodies observed in patients with advanced prostate cancer make this protein one of the first bona fide retroviral cancer antigens in humans, with potential as a biomarker for progression and biochemical recurrence rate of prostate cancer. Clin Cancer Res; 19(22); 6112-25. ©2013 AACR.
Hypomorphic Rag mutations can cause destructive midline granulomatous disease
Authors: Suk See De Ravin, Edward W. Cowen, Kol A. Zarember, Narda L. Whiting-Theobald, Douglas B. Kuhns, Netanya G. Sandler, Daniel C. Douek, Stefania Pittaluga, Pietro L. Poliani, Yu Nee Lee, Luigi D. Notarangelo, Lei Wang, Frederick W. Alt, Elizabeth M. Kang, Joshua D. Milner, Julie E. Niemela, Mary Fontana-Penn, Sara H. Sinal, Harry L. Malech
Journal: Blood (2010)
Viral pathogenesis of hepatocellular carcinoma in the United States
Authors: T. Jake Liang, Lennox J. Jeffers, K. Rajender Reddy, Maria De Medina, I. Talley Parker, Hugo Cheinquer, Victor Idrovo, Alfredo Rabassa, Eugene R. Schiff
Journal: Hepatology (1993)

Chronic hepatitis B virus infection is closely associated with the development of hepatocellular carcinoma, which is a major cause of cancer death worldwide. Recent studies have implicated hepatitis C virus infection as a major pathogenic agent of HBsAg-negative hepatocellular carcinoma. The significance of hepatitis C virus and hepatitis B virus infections in the occurrence of HBsAg-negative hepatocellular carcinoma has not been well established in the United States. We studied 91 HBsAg-negative American patients with hepatocellular carcinoma for evidence of hepatitis C virus or hepatitis B virus infection. These patients had no other predisposing factors to hepatocellular carcinoma. A sensitive polymerase chain reaction was employed to detect hepatitis C virus RNA and hepatitis B virus DNA in serum and liver. Three sets of hepatitis C virus and hepatitis B virus primers were used to optimize the detection of viral genomes. Hepatitis C virus antibodies were measured with second-generation immunoassays. Twenty-six (29%) of these patients carried low levels of hepatitis B virus DNA in either serum, liver/tumor tissue or both. On the basis of the results from serological and polymerase chain reaction analyses of serum and liver, we found that 53 of 91 patients (58%) exhibited evidence of hepatitis C virus infection. When data were combined, 14 patients (15%) had evidence of hepatitis B virus/hepatitis C virus coinfection, whereas 12 (13%) were infected with hepatitis B virus alone and 39 (43%) had hepatitis C virus only. Twenty-six (29%) had no markers of hepatitis B virus or hepatitis C virus infection.(ABSTRACT TRUNCATED AT 250 WORDS)
Suppression of the JNK Pathway by Induction of a Metabolic Stress Response Prevents Vascular Injury and Dysfunction
Authors: Eberhard Schulz, Jörn Dopheide, Swenja Schuhmacher, Shane R. Thomas, Kai Chen, Andreas Daiber, Philip Wenzel, Thomas Münzel, John F. Keaney
Journal: Circulation (2008)

Background— Oxidative injury and dysfunction of the vascular endothelium are early and causal features of many vascular diseases. Single antioxidant strategies to prevent vascular injury have met with mixed results. Methods and Results— Here, we report that induction of a metabolic stress response with adenosine monophosphate kinase (AMPK) prevents oxidative endothelial cell injury. This response is characterized by stabilization of the mitochondrion and increased mitochondrial biogenesis, resulting in attenuation of oxidative c-Jun N-terminal kinase (JNK) activation. We report that peroxisome proliferator coactivator 1α is a key downstream target of AMPK that is both necessary and sufficient for the metabolic stress response and JNK attenuation. Moreover, induction of the metabolic stress response in vivo attenuates reactive oxygen species–mediated JNK activation and endothelial dysfunction in response to angiotensin II in wild-type mice but not in animals lacking either the endothelial isoform of AMPK or peroxisome proliferator coactivator 1α. Conclusion— These data highlight AMPK and peroxisome proliferator coactivator 1α as potential therapeutic targets for the amelioration of endothelial dysfunction and, as a consequence, vascular disease.
A randomized phase II study of 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy compared with bevacizumab plus 5-fluorouracil, hydroxyurea, and twice-daily radiotherapy for intermediate-stage and T4N0-1 head and neck cancers
Authors: J.K. Salama, D.J. Haraf, K.M. Stenson, E.A. Blair, M.E. Witt, R. Williams, R. Kunnavakkam, E.E.W. Cohen, T. Seiwert, E.E. Vokes
Journal: Annals of Oncology (2011)
Downregulation of Pdcd4 by mir-21 facilitates glioblastoma proliferation in vivo
Authors: A. B. Gaur, S. L. Holbeck, N. H. Colburn, M. A. Israel
Journal: Neuro-Oncology (2011)

MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in developmental and physiological processes and are implicated in the pathogenesis of several human diseases, including cancer. They function by regulating target gene expression post-transcriptionally. In this study, we examined the role of oncogenic mir-21 in the pathogenesis of glioblastoma, the most aggressive form of primary brain tumor. We have previously reported that mir-21 is expressed at higher levels in primary glioblastoma-tissue and glioblastoma-derived cell lines than in normal brain tissue. We demonstrate that downregulation of mir-21 in glioblastoma-derived cell lines results in increased expression of its target, programmed cell death 4 (Pdcd4), a known tumor-suppressor gene. In addition, our data indicate that either downregulation of mir-21 or overexpression of its target, Pdcd4, in glioblastoma-derived cell lines leads to decreased proliferation, increased apoptosis, and decreased colony formation in soft agar. Using a glioblastoma xenograft model in immune-deficient nude mice, we observe that glioblastomaderived cell lines in which mir-21 levels are downregulated or Pdcd4 is over-expressed exhibit decreased tumor formation and growth. Significantly, tumors grow when the glioblastoma-derived cell lines are transfected with anti-mir-21 and siRNA to Pdcd4, confirming that the tumor growth is specifically regulated by Pdcd4. These critical in vivo findings demonstrate an important functional linkage between mir-21 and Pdcd4 and further elucidate the molecular mechanisms by which the known high level of mir-21 expression in glioblastoma can attribute to tumorigenesis—namely, inhibition of Pdcd4 and its tumor-suppressive functions.
Serum Proteomic Profiling by Matrix-Assisted Laser Desorption-Ionization Time-of-Flight Mass Spectrometry for Cancer Diagnosis: Next Steps
Authors: Eleftherios P. Diamandis
Journal: Cancer Research (2006)

Approximately 4 years ago, Petricoin et al. published a new approach for diagnosing ovarian cancer by using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF-MS; ref. [1][1]). The principle of this method is relatively straightforward. It has been hypothesized
Type 2 Diabetes in Asians: Prevalence, Risk Factors, and Effectiveness of Behavioral Intervention at Individual and Population Levels
Authors: Mary Beth Weber, Reena Oza-Frank, Lisa R. Staimez, Mohammed K. Ali, K.M. Venkat Narayan
Journal: Annual Review of Nutrition (2012)

This review summarizes the current data on diabetes risk factors, prevalence, and prevention efforts in Asia and Asian migrant populations. Studies indicate that type 2 diabetes mellitus is a large and growing threat to public health in Asian populations. Furthermore, Asian subgroups (e.g., South Asians/Asian Indians, Chinese) have unique risk factor profiles for developing diabetes, which differ from other populations and between Asian ethnic groups. Lifestyle intervention programs are effective in preventing diabetes in Asians, as with other ethnicities. The strength of these findings is lessened by the lack of systematically collected data using objective measurements. Large epidemiologic studies of diabetes prevalence and risk factor profiles and translational trials identifying sustainable and culturally acceptable lifestyle programs for Asian subgroups are needed.
Community case management of severe pneumonia with oral amoxicillin in children aged 2–59 months in Haripur district, Pakistan: a cluster randomised trial
Authors: Abdul Bari, Salim Sadruddin, Attaullah Khan, Ibad ul Haque Khan, Amanullah Khan, Iqbal A Lehri, William B Macleod, Matthew P Fox, Donald M Thea, Shamim A Qazi
Journal: The Lancet (2011)
Diversity and pattern of inheritance of autoantibodies in families with multiple cases of systemic lupus erythematosus.
Authors: Y Shoenfeld, H Slor, S Shafrir, I Krause, J Granados, G M Villarreal, D Alarcon-Segovia
Journal: Annals of the Rheumatic Diseases (1992)

The pattern of inheritance of autoantibodies in eight families chosen from a pool of 110 families of patients with systemic lupus erythematosus (SLE) is described. In all the eight families at least two members were already affected by SLE. In total, 19 patients and 43 first degree relatives were examined. The inheritance of a large set of antinuclear antibodies (for example, DNA, Sm, RNP, Ro, La, histones) and 16/6 idiotype seemed to be related to some unknown genetic factors but not related to HLA. The presence of numerous antinuclear autoantibodies in the serum of a subject was not necessarily associated with overt disease. The incidence of the 16/6 idiotype among patients and their relatives was low. It is not yet clear whether the 9autoantibody burden9 is greater in families with multiple cases of SLE than in families with single cases.
Monitoring Cholesterol Levels: Measurement Error or True Change?
Authors: Paul P. Glasziou, Les Irwig, Stephane Heritier, R. John Simes, Andrew Tonkin
Journal: Annals of Internal Medicine (2008)

Cholesterol level monitoring is a common clinical activity, but the optimal monitoring interval is unknown and practice varies.To estimate, in patients receiving cholesterol-lowering medication, the variation in initial response to treatment, the long-term drift from initial response, and the detectability of long-term changes in on-treatment cholesterol level ("signal") given short-term, within-person variation ("noise").Analysis of cholesterol measurement data in the LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) study.Randomized, placebo-controlled trial in Australia and New Zealand (June 1990 to May 1997).9014 patients with past coronary heart disease who were randomly assigned to receive pravastatin or placebo.Serial cholesterol concentrations at randomization, 6 months, and 12 months, and then annually to 5 years.Both the placebo and pravastatin groups showed small increases in within-person variability over time. The estimated within-person SD increased from 0.40 mmol/L (15 mg/dL) (coefficient of variation, 7%) to 0.60 mmol/L (23 mg/dL) (coefficient of variation, 11%), but it took almost 4 years for the long-term variation to exceed the short-term variation. This slow increase in variation and the modest increase in mean cholesterol level, about 2% per year, suggest that most of the variation in the study is due to short-term biological and analytic variability. Our calculations suggest that, for patients with levels that are 0.5 mmol/L or more (> or =19 mg/dL) under target, monitoring is likely to detect many more false-positive results than true-positive results for at least the first 3 years after treatment has commenced.Patients may respond differently to agents other than pravastatin. Future values for nonadherent patients were imputed.The signal-noise ratio in cholesterol level monitoring is weak. The signal of a small increase in cholesterol level is difficult to detect against the background of a short-term variability of 7%. In annual rechecks in adherent patients, many apparent increases in cholesterol level may be false positive. Independent of the office visit schedule, the interval for monitoring patients who are receiving stable cholesterol-lowering treatment could be lengthened.
Cathepsin cysteine proteases are effectors of invasive growth and angiogenesis during multistage tumorigenesis
Authors: Johanna A Joyce, Amos Baruch, Kareem Chehade, Nicole Meyer-Morse, Enrico Giraudo, Fong-Ying Tsai, Doron C Greenbaum, Jeffrey H Hager, Matthew Bogyo, Douglas Hanahan
Journal: Cancer Cell (2004)
Extensive DNA methylation in normal colorectal mucosa in hyperplastic polyposis
Authors: P Minoo
Journal: Gut (2006)

Hyperplastic polyposis of the colorectum is a precancerous condition that has been linked with DNA methylation. The polyps in this condition have been distinguished from typical small hyperplastic polyps and renamed sessile serrated adenomas. Sessile serrated adenomas also occur sporadically and appear to be indistinguishable from their counterparts in hyperplastic polyposis.The existence of distinguishing molecular features was explored in a series of serrated polyps and matched normal mucosa from patients with and without hyperplastic polyposis by assessing mutation of BRAF, DNA methylation in 14 markers (MINTs 1, 2 and 31, p16, MGMT, MLH1, RASSF1, RASSF2, NORE1 (RASSF5), RKIP, MST1, DAPK, FAS, and CHFR), and immunoexpression of MLH1.There was more extensive methylation in sessile serrated adenomas from subjects with hyperplastic polyposis (p<0.0001). A more clearcut difference in patients with hyperplastic polyposis was the finding of extensive DNA methylation in normal mucosa from the proximal colon.A genetic predisposition may underlie at least some forms of hyperplastic polyposis in which the earliest manifestation may be hypermethylation of multiple gene promoters in normal colorectal mucosa. Additionally, some of the heterogeneity within hyperplastic polyposis may be explained by different propensities for MLH1 inactivation within polyps.
Traffic-related air pollution: an avoidable exposure to improve respiratory health
Authors: Peter D Sly
Journal: Thorax (2014)

Respiratory disease taken as a whole is a major global burden contributing significantly to morbidity and mortality at all stages of life. According to WHO estimates, asthma is the most prevalent respiratory condition with over 300 million people affected globally and an additional 100 million diagnoses forecast by 2025. The second most prevalent condition is COPD, with an estimated 210 million suffering globally. Pneumonia and acute lower respiratory illnesses are the leading causes of death in children under 5 years of age, responsible for an estimated 1.4 million deaths annually. It is currently understood that low lung function is a major risk factor linking all these entities, increasing susceptibility to these global health problems.

Lung function is known to track throughout childhood,1 ,2 so to a very real extent the lung function one is born with is a major determinant of future respiratory health.3–5 However, lung function may grow better6 or less well7–9 than anticipated depending on environmental exposures, especially those occurring in early life. Airway branching pattern develops during the first 16–18 weeks of fetal development, with alveolar development beginning later and continuing in early postnatal life. Thus, the respiratory system is vulnerable to adverse environmental exposures in both prenatal and postnatal life. The most compelling data for prenatal exposures influencing lung function at birth10 and beyond11 …