tbuckley/cabot-search huggingface dataset:
Analysis of nucleotide substitutions of mitochondrial DNAs in Drosophila melanogaster and its sibling species.
Authors: Y Satta, H Ishiwa, S I Chigusa
Journal: Molecular Biology and Evolution (1987)

To study the rate and pattern of nucleotide substitution in mitochondrial DNA (mtDNA), we cloned and sequenced a 975-bp segment of mtDNA from Drosophila melanogaster, D. simulans, and D. mauritiana containing the genes for three transfer RNAs and parts of two protein-coding genes, ND2 and COI. Statistical analysis of synonymous substitutions revealed a predominance of transitions over transversions among the three species, a finding differing from previous results obtained from a comparison of D. melanogaster and D. yakuba. The number of transitions observed was nearly the same for each species comparison, including D. yakuba, despite the differences in divergence times. However, transversions seemed to increase steadily with increasing divergence time. By contrast, nonsynonymous substitutions in the ND2 gene showed a predominance of transversions over transitions. Most transversions were between A and T and seemed to be due to some kind of mutational bias to which the A + T-rich mtDNA of Drosophila species may be subject. The overall rate of nucleotide substitution in Drosophila mtDNA appears to be slightly faster (approximately 1.4 times) than that of the Adh gene. This contrasts with the result obtained for mammals, in which the mtDNA evolves approximately 10 times faster than single-copy nuclear DNA. We have also shown that the start codon of the COI gene is GTGA in D. simulans and GTAA in D. mauritiana. These codons are different from that of D. melanogaster (ATAA).
Improving the Recognition of Hereditary Interstitial Kidney Disease
Authors: Anthony J. Bleyer
Journal: Journal of the American Society of Nephrology (2008)

Autosomal dominant tubulointerstitial kidney disease is characterized by the poorly recognized inheritance of slowly progressive renal failure leading to ESRD in later life. Patients with this condition have bland urinary sediment, and renal ultrasound typically reveals normal to small kidneys, with occasional individuals having small medullary cysts. Diagnosis relies on the clinical acumen of the nephrologist. Obtaining a thorough family history and records of affected family members is especially helpful. Kidney biopsy is frequently unhelpful, whereas genetic linkage studies or mutations in the UMOD gene may identify the problem.
Bile acids in the diarrhoea of ileal resection
Authors: W. D. Mitchell, J. M. Findlay, R. J. Prescott, M. A. Eastwood, D. B. Horn
Journal: Gut (1973)

Twenty individual diarrhoeal stools from three patients with ileal resection were centrifuged at 14 000 <i>g</i> for one hour at 10°C to separate the stool into pellet and supernatant. Bile acids and electrolytes were measured in each phase. Relationships were examined between chenodeoxycholic acid and cholic acid in each phase and <i>in toto</i> to electrolyte and water loss. Chenodeoxycholic acid was associated with electrolyte and water loss whether present in solid or liquid phase. The association varied between individuals. The cholic acid content of the stool showed no association with electrolyte and water loss. It would appear that it is the total amount of chenodeoxycholic acid entering the colon, irrespective of its physical state, that is important in the diarrhoea of ileal dysfunction.
Novel mechanism of antibodies to hepatitis B virus in blocking viral particle release from cells
Authors: Avidan U. Neumann, Sandra Phillips, Idit Levine, Samreen Ijaz, Harel Dahari, Rachel Eren, Shlomo Dagan, Nikolai V. Naoumov
Journal: Hepatology (2010)

Abstract Antibodies are thought to exert antiviral activities by blocking viral entry into cells and/or accelerating viral clearance from circulation. In particular, antibodies to hepatitis B virus (HBV) surface antigen (HBsAg) confer protection, by binding circulating virus. Here, we used mathematical modeling to gain information about viral dynamics during and after single or multiple infusions of a combination of two human monoclonal anti-HBs (HepeX-B) antibodies in patients with chronic hepatitis B. The antibody HBV-17 recognizes a conformational epitope, whereas antibody HBV-19 recognizes a linear epitope on the HBsAg. The kinetic profiles of the decline of serum HBV DNA and HBsAg revealed partial blocking of virion release from infected cells as a new antiviral mechanism, in addition to acceleration of HBV clearance from the circulation. We then replicated this approach in vitro , using cells secreting HBsAg, and compared the prediction of the mathematical modeling obtained from the in vivo kinetics. In vitro , HepeX-B treatment of HBsAg-producing cells showed cellular uptake of antibodies, resulting in intracellular accumulation of viral particles. Blocking of HBsAg secretion also continued after HepeX-B was removed from the cell culture supernatants. Conclusion: These results identify a novel antiviral mechanism of antibodies to HBsAg (anti-HBs) involving prolonged blocking of the HBV and HBsAg subviral particles release from infected cells. This may have implications in designing new therapies for patients with chronic HBV infection and may also be relevant in other viral infections.
Treatment with a CO-releasing molecule (CORM-3) reduces joint inflammation and erosion in murine collagen-induced arthritis
Authors: M L Ferrandiz, N Maicas, I Garcia-Arnandis, M C Terencio, R Motterlini, I Devesa, L A B Joosten, W B van den Berg, M J Alcaraz
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> CO-releasing molecules (CO-RMs) are a novel class of anti-inflammatory agents. We have examined the possible therapeutic effects of CORM-3 in collagen-induced arthritis (CIA). <h3>Methods:</h3> Arthritis was induced in DBA-1/J mice by type II collagen. Animals were treated with CORM-3 (5 and 10 mg/kg/day, intraperitoneally) or the inactive compound iCORM-3 (10 mg/kg/day, intraperitoneally) unable to release CO, from days 22 to 31. Production of anti-type II collagen antibodies, cytokines and cartilage olimeric matrix protein (COMP) was evaluated by enzyme-linked immunosorbent assay, and prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) by radioimmunoassay. Localisation of cyclooxygenase-2 (COX-2), haem oxygenase-1 (HO-1), intercellular adhesion molecule-1 (ICAM-1) and receptor activator of nuclear factor κB ligand (RANKL) was examined by immunohistochemistry. <h3>Results:</h3> Therapeutic administration of CORM-3 suppressed clinical and histopathological manifestations of disease. The levels of PGE<sub>2</sub>, interleukin (IL)1β, IL2, IL6, IL10 and tumour necrosis factor (TNF)α in joint tissues were inhibited by CORM-3. By contrast, CORM-3 augmented IL4. Anti-type II collagen antibodies and COMP levels in serum were reduced by CORM-3. Treatment with CORM-3 decreased cellular infiltration, joint inflammation and destruction, as well as the expression of COX-2, ICAM-1 and RANKL, whereas HO-1 increased. These beneficial effects were due to CO release, as iCORM-3 was ineffective. <h3>Conclusion:</h3> This study reveals the antiarthritic properties of CORM-3 in the CIA model and supports the notion that CO-RMs could be developed as a novel strategy for the treatment of inflammatory and arthritic conditions.
Etanercept therapy in rheumatoid arthritis and the risk of malignancies: a systematic review and individual patient data meta-analysis of randomised controlled trials
Authors: T Bongartz, F C Warren, D Mines, E L Matteson, K R Abrams, A J Sutton
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Purpose:</h3> Tumour necrosis factor (TNF) plays an important role in inflammation and may affect tumour growth control. To assess the risk of malignancy with etanercept, a fusion protein that inhibits TNF action, a meta-analysis was performed using individual patient data from randomised controlled trials (RCT) in patients with rheumatoid arthritis (RA). <h3>Methods:</h3> A search was conducted of bibliographic databases, abstracts from annual meetings and any unpublished studies on file with manufacturers of etanercept to December 2006. Only RCT of etanercept used for 12 weeks or more in patients with RA were included. Nine trials met the inclusion criteria. To adjudicate endpoints, the case narratives of potential cases were reviewed. Patient-level data were extracted from the clinical trials databases. <h3>Results:</h3> The nine trials included 3316 patients, 2244 who received etanercept (contributing 2484 person-years of follow-up) and 1072 who received control therapy (1051 person-years). Malignancies were diagnosed in 26 patients in the etanercept group (incidence rate (IR) 10.47/1000 person-years) and seven patients in the control group (IR 6.66/1000 person-years). A Cox's proportional hazards, fixed-effect model stratified by trial yielded a hazard ratio of 1.84 (95% CI 0.79 to 4.28) for the etanercept group compared with the control group. <h3>Conclusions:</h3> In this analysis, the point estimate of malignancy risk was higher in etanercept-treated patients, although the results were not statistically significant. The approach of obtaining individual patient data of RCT in cooperation with trial sponsors allowed important insights into the methodological advantages and challenges of sparse adverse event data meta-analysis.
Phosphoinositide 3-Kinase Mediates Enhanced Spontaneous and Agonist-Induced Contraction in Aorta of Deoxycorticosterone Acetate-Salt Hypertensive Rats
Authors: Carrie A. Northcott, Matthew N. Poy, Sonia M. Najjar, Stephanie W. Watts
Journal: Circulation Research (2002)

Arteries from deoxycorticosterone acetate (DOCA)-salt and N ω -nitro- l -arginine (L-NNA) hypertensive but not normotensive rats develop spontaneous tone. LY294002 and wortmannin, phosphoinositide 3-kinase (PI3-kinase) inhibitors, eliminate spontaneous tone. We hypothesized that PI3-kinase protein and/or activity was increased in hypertension and contributed to the observed enhanced contractility. PI3-kinase activity assays revealed 2-fold higher activity in thoracic aorta from DOCA-salt [systolic blood pressure (SBP)=184±5 mm Hg] compared with sham rats (SBP=111±2 mm Hg). Western analyses of aortic homogenates revealed the presence of p85α, p110α, p110β, and p110δ but not p110γ PI3-kinase subunits; p110δ protein was elevated in aorta of hypertensive rats as compared with sham. Aortic homogenates from L-NNA rats also had elevated p110β protein density, but neither L-NNA nor DOCA-salt had differences in p85α and p110α. Total Akt density was unaltered, but pAkt was significantly lower in homogenates from DOCA-salt rats. LY294002 (20 μmol/L) and nifedipine (50 nmol/L) abolished Ca 2+ -induced spontaneous tone in aorta from DOCA-salt rats. However, LY294002 did not alter BayK8644-induced contraction, indicating that LY294002 does not inhibit L-type Ca 2+ channels directly. PTEN (phosphatase and tensin homolog) and pPTEN were expressed but not different in aorta from DOCA-salt and sham rats. LY294002 corrected the enhanced contraction to KCl and norepinephrine in aorta from DOCA-salt rats. These data support an increase in PI3-kinase activity and p110δ density in aorta from L-NNA and DOCA-salt rats. Importantly, this increase contributes to the enhanced contractility observed in two models of hypertension.
TNF- downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents
Authors: A. Valerio
Journal: Journal of Clinical Investigation (2006)

Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-α. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-α downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the reduction of mitochondrial biogenesis observed with TNF-α. Our findings demonstrate that TNF-α impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
Histopathological modifications in haemophilic synovial tissue
Authors: L Ibba-Manneschi, D Melchiorre, A F Milia, M Manetti, G Benelli, E Romano, S Guiducci, S Linari, M Morfini, M Innocenti, M Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2010)

Haemophilia is characterised by spontaneous bleeding, mainly in the larger joints. Repeated bleeding episodes lead to synovitis and then to haemophilic arthropathy (HA) with synovial changes, cartilage damage and bone remodelling which result in disability. The pathogenesis of this blood-induced cartilage damage is very little known, but it has been suggested that the recurrent presence of blood induces synoviocyte hypertrophy and hyperplasia with intense neovascularisation and inflammation of the synovial membrane. This results in the production of catabolic enzymes and cytokines by inflammatory cells which induce and exacerbate the pathological process.

To …
A Phase I Study of a Tropism-Modified Conditionally Replicative Adenovirus for Recurrent Malignant Gynecologic Diseases
Authors: Kristopher J. Kimball, Meredith A. Preuss, Mack N. Barnes, Minghui Wang, Gene P. Siegal, Wen Wan, Huichien Kuo, Souheil Saddekni, Cecil R. Stockard, William E. Grizzle, Raymond D. Harris, Rosemarie Aurigemma, David T. Curiel, Ronald D. Alvarez
Journal: Clinical Cancer Research (2010)

Abstract Purpose: To determine the maximum tolerated dose (MTD), toxicity spectrum, clinical activity, and biological effects of the tropism-modified, infectivity-enhanced conditionally replicative adenovirus (CRAd), Ad5–Δ24–Arg-Gly-Asp (RGD), in patients with malignant gynecologic diseases. Experimental Design: Cohorts of eligible patients were treated daily for 3 days through an i.p. catheter. Vector doses ranged from 1 × 109 to 1 × 1012 viral particles per day. Toxicity was evaluated using CTCv3.0. CA-125 and Response Evaluation Criteria in Solid Tumors (RECIST) criteria were used to determine clinical efficacy. Corollary biological studies included assessment of CRAd replication, wild-type virus generation, viral shedding, and neutralizing antibody response. Results: Twenty-one patients were treated. Adverse clinical effects were limited to grade 1/2 fever, fatigue, or abdominal pain. No vector-related grade 3/4 toxicities were noted. No clinically significant laboratory abnormalities were noted. The maximum tolerated dose was not reached. Over a 1 month follow-up, 15 (71%) patients had stable disease and six (29%) had progressive disease. No partial or complete responses were noted. Seven patients had a decrease in CA-125; four had a &amp;gt;20% drop. RGD-specific PCR showed the presence of study vector in ascites of 16 patients. Seven revealed an increase in virus after day 3, suggesting replication of Ad5-Δ24-RGD. Minimal wild-type virus generation was detected. Viral shedding studies showed insignificant shedding in the serum, saliva, and urine. Anti-adenoviral neutralizing antibody effects were prevalent. Conclusions: This study, the first to evaluate an infectivity-enhanced CRAd in human cancer, shows the feasibility, safety, potential antitumor response, and biological activity of this approach in ovarian cancer. Further evaluation of infectivity enhanced virotherapy approaches for malignant gynecologic diseases is warranted. Clin Cancer Res; 16(21); 5277–87. ©2010 AACR.
Preformed Membrane-Associated Stores of Interleukin (Il)-12 Are a Previously Unrecognized Source of Bioactive IL-12 That Is Mobilized within Minutes of Contact with an Intracellular Parasite
Authors: Marlon Quinones, Sunil K. Ahuja, Peter C. Melby, Lyle Pate, Robert L. Reddick, Seema S. Ahuja
Journal: The Journal of Experimental Medicine (2000)

The prevailing paradigm is that production of the interleukin (IL)-12 p70 heterodimer, a critical T helper cell type 1 (Th1)–inducing cytokine, depends on the induced transcription of the p40 subunit. Concordant with this paradigm, we found that dendritic cells (DCs) produced IL-12 p70 only after at least 2–4 h of stimulation with lipopolysaccharide plus interferon γ. However, using several complementary experimental approaches, including electron and confocal microscopy, we now show that resting murine and human myeloid cells, including macrophages/DCs and DC-rich tissues, contain a novel source of bioactive IL-12 that is preformed and membrane associated. These preformed, membrane-associated IL-12 p70 stores are released within minutes after in vitro or in vivo contact with Leishmania donovani, an intracellular pathogen. Our findings highlight a novel source of bioactive IL-12 that is readily available for the rapid initiation of Th1 host responses to pathogens such as Leishmania species.
Combination Mammalian Target of Rapamycin Inhibitor Rapamycin and HSP90 Inhibitor 17-Allylamino-17-Demethoxygeldanamycin Has Synergistic Activity in Multiple Myeloma
Authors: Lanie K. Francis, Yazan Alsayed, Xavier Leleu, Xiaoying Jia, Ujjal K. Singha, Judith Anderson, Michael Timm, Hai Ngo, Ganwei Lu, Alissa Huston, Lori A. Ehrlich, Elizabeth Dimmock, Suzanne Lentzsch, Teru Hideshima, G. David Roodman, Kenneth C. Anderson, Irene M. Ghobrial
Journal: Clinical Cancer Research (2006)

Abstract Purpose: The phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway and the heat shock protein family are up-regulated in multiple myeloma and are both regulators of the cyclin D/retinoblastoma pathway, a critical pathway in multiple myeloma. Inhibitors of mTOR and HSP90 protein have showed in vitro and in vivo single-agent activity in multiple myeloma. Our objective was to determine the effects of the mTOR inhibitor rapamycin and the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on multiple myeloma cells. Experimental Design: Multiple myeloma cell lines were incubated with rapamycin (0.1-100 nmol/L) and 17-AAG (100-600 nmol/L) alone and in combination. Results: In this study, we showed that the combination of rapamycin and 17-AAG synergistically inhibited proliferation, induced apoptosis and cell cycle arrest, induced cleavage of poly(ADP-ribose) polymerase and caspase-8/caspase-9, and dysregulated signaling in the phosphatidylinositol 3-kinase/AKT/mTOR and cyclin D1/retinoblastoma pathways. In addition, we showed that both 17-AAG and rapamycin inhibited angiogenesis and osteoclast formation, indicating that these agents target not only multiple myeloma cells but also the bone marrow microenvironment. Conclusions: These studies provide the basis for potential clinical evaluation of this combination for multiple myeloma patients.
A Mouse Mammary Tumor Virus-Like Long Terminal Repeat Superantigen in Human Breast Cancer
Authors: Yue Wang, Jian-Dong Jiang, Dongping Xu, Yan Li, Chunfeng Qu, James F. Holland, Beatriz G-T. Pogo
Journal: Cancer Research (2004)

We previously reported a 660-bp mouse mammary tumor virus (MMTV)-like env gene sequence in approximately 38% of human breast cancer DNA, but not in normal breasts or other tumors. This MMTV-like env gene sequence was expressed in 66% of the env gene-positive human breast cancers. An entire proviral structure was identified in human breast cancer DNA with high homology to MMTV and low homology to known human endogenous retrovirus. MMTV-like long terminal repeat (LTR) sequences were also detected in 41.5% of human breast cancers. They contain hormone-responsive elements, TEF-1 family elements, and the open reading frame for the superantigen (SAg). We have now amplified and sequenced MMTV-like sag sequences from 10 human breast cancers, and we found that they are highly homologous to those of MMTV. However, deletions and insertions at the COOH-terminal of sag were observed. The immune function of the human MMTV-like LTR SAg was also investigated. The sag gene was cloned and expressed in a human B-cell line (Ramos). T-cell proliferation and cytokine releasing assays were performed after cocultivation of T cells with irradiated Ramos SAg-expressing cells. The results indicate that expression of the human SAg stimulates T-cell activation in vitro, as the mouse SAg does. Because the T-cell responses in vitro are considered similar to those in vivo, these results suggest that the human LTR SAg might also play a role in human breast carcinogenesis.
Degranulation patterns of eosinophil granulocytes as determinants of eosinophil driven disease
Authors: J S Erjefalt
Journal: Thorax (2001)

<h3>Background</h3> Injury to the spinal cord can result in loss of sympathetic innervation causing a drop in BP and HR, this condition is known as neurogenic shock. There is debate among the literature on how and when neurogenic shock presents and what values of HR and BP should be used to define it. Previous studies do not take into account multiple prehospital and emergency department recordings. <h3>Objective</h3> To improve understanding of how neurogenic shock presents in humans, allowing better identification and treatment. <h3>Methods</h3> The Trauma Audit and Research Network database for an adult major trauma centre was used to isolate patients with a spinal cord injury. Qualifying patients had all available BPs and HRs collated into a database. Patients with neurogenic shock were isolated, allowing data analysis. <h3>Results</h3> Out of 3069 trauma patients, 33 met the inclusion criteria, of which 15 experienced neurogenic shock. 87% of the patients who had neurogenic shock experienced it within 2 hours of injury. Neurogenic shock below the T6 level was less common (p=0.009); however, there were still four cases in the cohort. More patients with complete spinal cord injury had neurogenic shock (p=0.039). <h3>Conclusions</h3> Neurogenic shock is variable and unpredictable. It can present in the prehospital environment and without warning in a patient with previously normal vital signs. The medical team should be aware of it in all patients with spinal cord injury regardless of injury level.
Chemotherapy of experimental streptococcal endocarditis. IV. Further observations on prophylaxis.
Authors: L L Pelletier, D T Durack, R G Petersdorf
Journal: Journal of Clinical Investigation (1975)

The ability of antibiotics to prevent Streptococcus sanguis endocarditis was tested in rabbits. Only vancomycin or a combination of penicillin G plus streptomycin always prevented infection when administered as a single dose. A loading dose of 30 mg/kg of phenoxymethyl penicillin (penicillin V) followed by additional 7.5 mg/kg doses for 48 h proved to be the only successful prophylactic program that could be given orally to man. Cefazolin alone or with streptomycin in multiple doses was also an effective alternative to penicillin or penicillin derivatives. Erythromycin uniformly failed to protect animals from bacterial endocarditis but showed greater prophylactic efficacy when a low inoculum of streptococci was used.