tbuckley/cabot-search huggingface dataset:
Human Xeno-Autoantibodies against a Non-Human Sialic Acid Serve as Novel Serum Biomarkers and Immunotherapeutics in Cancer
Authors: Vered Padler-Karavani, Nancy Hurtado-Ziola, Minya Pu, Hai Yu, Shengshu Huang, Saddam Muthana, Harshal A. Chokhawala, Hongzhi Cao, Patrick Secrest, Dinorah Friedmann-Morvinski, Oded Singer, Darius Ghaderi, Inder M. Verma, Yu-Tsueng Liu, Karen Messer, Xi Chen, Ajit Varki, Richard Schwab
Journal: Cancer Research (2011)

Abstract Human carcinomas can metabolically incorporate and present the dietary non-human sialic acid Neu5Gc, which differs from the human sialic acid N-acetylneuraminic acid (Neu5Ac) by 1 oxygen atom. Tumor-associated Neu5Gc can interact with low levels of circulating anti-Neu5Gc antibodies, thereby facilitating tumor progression via chronic inflammation in a human-like Neu5Gc-deficient mouse model. Here we show that human anti-Neu5Gc antibodies can be affinity-purified in substantial amounts from clinically approved intravenous IgG (IVIG) and used at higher concentrations to suppress growth of the same Neu5Gc-expressing tumors. Hypothesizing that this polyclonal spectrum of human anti-Neu5Gc antibodies also includes potential cancer biomarkers, we then characterize them in cancer and noncancer patients' sera, using a novel sialoglycan microarray presenting multiple Neu5Gc-glycans and control Neu5Ac-glycans. Antibodies against Neu5Gcα2−6GalNAcα1-O-Ser/Thr (GcSTn) were found to be more prominent in patients with carcinomas than with other diseases. This unusual epitope arises from dietary Neu5Gc incorporation into the carcinoma marker Sialyl-Tn, and is the first example of such a novel mechanism for biomarker generation. Finally, human serum or purified antibodies rich in anti-GcSTn-reactivity kill GcSTn-expressing human tumors via complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity. Such xeno-autoantibodies and xeno-autoantigens have potential for novel diagnostics, prognostics, and therapeutics in human carcinomas. Cancer Res; 71(9); 3352–63. ©2011 AACR.
Phase I/II Trial of Weekly Intravenous 130-nm Albumin-Bound Paclitaxel As Initial Chemotherapy in Patients With Stage IV Non–Small-Cell Lung Cancer
Authors: Naiyer A. Rizvi, Gregory J. Riely, Christopher G. Azzoli, Vincent A. Miller, Kenneth K. Ng, John Fiore, Gloria Chia, Martin Brower, Robert Heelan, Michael J. Hawkins, Mark G. Kris
Journal: Journal of Clinical Oncology (2008)

Nanoparticle albumin-bound paclitaxel (NAB-paclitaxel) is an albumin-bound formulation of paclitaxel that has demonstrated improved efficacy compared with paclitaxel in the treatment of metastatic breast cancer. We undertook this trial to determine the maximum-tolerated dose (MTD) and single-agent activity of NAB-paclitaxel administered on a weekly basis to patients with stage IV non-small-cell lung cancer (NSCLC).This was an open-label, single-arm, phase I/II study. Patients were treated with NAB-paclitaxel intravenously during 30 minutes without corticosteroid or antihistamine premedications on days 1, 8, and 15 of a 28-day cycle. Radiologic tumor assessment was performed every 8 weeks.Dose levels of 100 and 125 mg/m(2) were tolerated without dose-limiting toxicities (DLTs). At 150 mg/m(2) the MTD was exceeded; two of three patients experienced a DLT (grade 3 sensory neuropathy and febrile neutropenia). The 125 mg/m(2) dose level was expanded and determined to be the MTD. A total of 40 patients were treated at 125 mg/m(2). The objective response rate was 30% (12 of 40 patients; 95% CI, 16% to 44%), median time to progression was 5 months (95% CI, 3 to 8 months), and median overall survival was 11 months (95% CI, 7 months to not reached). The 1-year survival was 41%.NAB-paclitaxel 125 mg/m(2) administered on days 1, 8, and 15 of a 28-day cycle was well tolerated and demonstrated encouraging single-agent activity. No corticosteroid premedication was administered and no hypersensitivity reactions were seen. Additional studies of single-agent NAB-paclitaxel as well as platinum-based combinations are warranted.
The Association Between Hospital Care Intensity and Surgical Outcomes in Medicare Patients
Authors: Kyle H. Sheetz, Justin B. Dimick, Amir A. Ghaferi
Journal: JAMA Surgery (2014)

Hospitals' care intensity varies widely across the United States. Payers and policy makers have become focused on promoting quality, low-cost, efficient health care.To evaluate whether increased hospital care intensity (HCI) is associated with improved outcomes following major surgery.Using national Medicare data in this retrospective cohort study, we identified 706,520 patients at 2544 hospitals who underwent 1 of 7 major cardiovascular, orthopedic, or general surgical operations.The HCI Index, which is validated and publicly available through the Dartmouth Atlas of Healthcare.Risk- and reliability-adjusted mortality, major complication, and failure-to-rescue rates.Hospital care intensity varied 10-fold. High-HCI hospitals had greater rates of major complications when compared with low-HCI centers (risk ratio, 1.04; 95% CI, 1.03-1.05). There was a decrease in failure to rescue at high compared with low-HCI hospitals (risk ratio, 0.95; 95% CI, 0.94-0.97). Using multilevel-models, HCI reduced the variation in failure-to-rescue rates between hospitals by 2.7% after accounting for patient comorbidities and hospital resources. Patients treated at high-HCI hospitals had longer hospitalizations, more inpatient deaths, and lower hospice use during the last 2 years of life.Failure-to-rescue rates were lower at high-care intensity hospitals. Conversely, care intensity explains a very small proportion of variation in failure-to-rescue rates across hospitals.
E-selectin ligands mediate tumor necrosis factor-induced neutrophil sequestration and pulmonary edema in guinea pig lungs.
Authors: S K Lo, B Bevilacqua, A B Malik
Journal: Circulation Research (1994)

We have previously shown in perfused guinea pig lungs that tumor necrosis factor-alpha (TNF-alpha) pretreatment of lungs enhanced neutrophil sequestration as reflected by a 2.4-fold increase in lung myeloperoxidase (MPO) activity. Subsequent perfusion of phorbol 12-myristate 13-acetate (PMA) to activate the sequestered neutrophils produced an approximately threefold increase in the pulmonary capillary hydrostatic pressure and fulminant pulmonary edema. Using this ex vivo model of lung injury, we studied the role of three putative E-selectin ligands, sialyl-Lewis X, Lewis X, and dimeric sialyl-Lewis X, in mediating neutrophil sequestration and pulmonary edema. We pretreated neutrophils with monoclonal antibodies (mAbs) directed against these E-selectin ligands. Pretreatment of neutrophils with mAbs to sialyl-Lewis X and Lewis X reduced the neutrophil sequestration, as evidenced by 45% and 27% reductions in MPO activity from control levels, respectively. This occurred in parallel with inhibition of neutrophil adhesion to the TNF-alpha-activated endothelial cells in vitro. The mAbs to dimeric sialyl-Lewis X and an isotype-matched control mAb against lactosamines present on neutrophils had no effect on lung MPO activity and neutrophil adhesion. All mAbs to sialyl-Lewis X, Lewis X, and dimeric sialyl-Lewis X reduced the increases in the pulmonary capillary hydrostatic pressure after challenge of the sequestered neutrophils with PMA and also reduced lung weight gain by 71%, 45% and 38%, respectively. The control mAb to the lactosamines had no effect on the pulmonary capillary hydrostatic pressure and lung weight gain.(ABSTRACT TRUNCATED AT 250 WORDS)
Human autoantibody to RNA polymerase I transcription factor hUBF. Molecular identity of nucleolus organizer region autoantigen NOR-90 and ribosomal RNA transcription upstream binding factor.
Authors: E K Chan, H Imai, J C Hamel, E M Tan
Journal: The Journal of Experimental Medicine (1991)

In dividing eukaryotic cells, nucleoli disperse before mitosis and reform in daughter cells at sites of ribosomal RNA (rRNA) gene clusters that are at the secondary constrictions of chromosomes, called nucleolus organizer regions (NORs). In this study, cDNA clones for a NOR autoantigen (NOR-90) were selected using a specific human autoantibody probe and were subsequently identified to encode an alternative form of the reported human upstream binding factor (hUBF). Results from immunoprecipitation showed that anti-NOR-90 antibodies recognized both forms of hUBF/NOR-90. Our data therefore showed that UBF, a critical factor in the regulation of rRNA transcription, was tightly bound to NOR during mitosis even when rRNA synthesis was thought to be minimal. Furthermore, we identified a nucleolar transcription factor as a novel target for human autoimmune response.
Risk of bleeding and arterial thromboembolism in patients with non-valvular atrial fibrillation either maintained on a vitamin K antagonist or switched to a non-vitamin K-antagonist oral anticoagulant: a retrospective, matched-cohort study
Authors: Kim Bouillon, Marion Bertrand, Géric Maura, Pierre-Olivier Blotière, Philippe Ricordeau, Mahmoud Zureik
Journal: The Lancet Haematology (2015)
Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition
Authors: Nicolas Charette, Christine De Saeger, Valérie Lannoy, Yves Horsmans, Isabelle Leclercq, Peter Stärkel
Journal: Molecular Cancer (2010)

Abstract Background Dysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Salirasib is an S-prenyl-cysteine analog that has been shown to block ras and/or mTOR activation in several non hepatic tumor cell lines. We investigated in vitro the effect of salirasib on cell growth as well as its mechanism of action in human hepatoma cell lines (HepG2, Huh7, and Hep3B) and its in vivo effect in a subcutaneous xenograft model with HepG2 cells. Results Salirasib induced a time and dose dependent growth inhibition in hepatocarcinoma cells through inhibition of proliferation and partially through induction of apoptosis. A 50 percent reduction in cell growth was obtained in all three cell lines at a dose of 150 μM when they were cultured with serum. By contrast, salirasib was more potent at reducing cell growth after stimulation with EGF or IGF2 under serum-free conditions, with an IC 50 ranging from 60 μM to 85 μM. The drug-induced anti-proliferative effect was associated with downregulation of cyclin A and to a lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction was related to a global pro-apoptotic balance with caspase 3 activation, cytochrome c release, death receptor upregulation, and a reduced mRNA expression of the apoptosis inhibitors cFLIP and survivin. These effects were associated with ras downregulation and mTOR inhibition, without reduction of ERK and Akt activation. In vivo , salirasib reduced tumour growth from day 5 onwards. After 12 days of treatment, mean tumor weight was diminished by 56 percent in the treated animals. Conclusions Our results show for the first time that salirasib inhibits the growth of human hepatoma cell lines through inhibition of proliferation and induction of apoptosis, which is associated with ras and mTOR inhibition. The therapeutic potential of salirasib in human HCC was further confirmed in a subcutaneous xenograft model.
Visceral hypersensitivity: facts, speculations, and challenges
Authors: M CAMILLERI
Journal: Gut (2001)

Visceral hypersensitivity is currently the holy grail....it is widely regarded as the reason for the development of functional gastrointestinal diseases, including functional dyspepsia and irritable bowel syndrome.1 Although the field has advanced considerably in the past decade, it is necessary to take stock and realistically appraise our current understanding. Identifying issues of controversy will help address the directions or priorities to advance this field in the future. Thus our objectives are to review the current understanding of the neuroanatomy and physiology of gut sensation, briefly review examples of the relationship between symptoms and sensorimotor dysfunction, and discuss controversies and speculations requiring more thorough study. In pursuing this discussion, we have drawn on experience and data from several regions of the gut as work in a single region does not provide the comprehensive or broad perspectives necessary.

Enteroendocrine cells in the lining of the gut serve as chemical and mechanical transducers for local reflexes (for example, peristalsis) or initiation of afferent projections to the central nervous system.1 2 As with somatic sensation, gut afferent signals reach conscious perception through a three neurone chain.2 The first order neurone, whose cell body is in the dorsal root ganglion, terminates in the dorsal column laminae of the spinal cord (fig 1). En passant fibres project to noradrenergic neurones in prevertebral ganglia, and this reflex centre results in modulation of viscus functions, including motility. Somatic and visceral afferents converge on dorsal horn neurones and result in viscerosomatic projection or referred pain. Descending modulatory fibres (serotonergic, adrenergic, and possibly others) from brain stem centres such as the periaqueductal grey alter the sensitivity of the dorsal horn neurones and thus serve to centrally control the intensity of perception during visceral stimulation (fig1).1



Figure 1 
Three order neurone chain resulting in visceral perception; note …
Associations of Visceral and Subcutaneous Fat Areas With the Prevalence of Metabolic Risk Factor Clustering in 6,292 Japanese Individuals
Authors: Yumi Matsushita, Toru Nakagawa, Shuichiro Yamamoto, Yoshihiko Takahashi, Tetsuji Yokoyama, Mitsuhiko Noda, Tetsuya Mizoue
Journal: Diabetes Care (2010)

OBJECTIVE We examined the relationships of visceral fat area (VFA), subcutaneous fat area, and waist circumference, determined using computed tomography (CT), and BMI with metabolic risk factors in a large Japanese population. RESEARCH DESIGN AND METHODS Study subjects comprised 6,292 men and women who participated in the Hitachi Health Study and received CT examinations in 2007 and 2008. RESULTS Regarding the clustering of metabolic risk factors, the odds ratios (ORs) for the VFA quintiles were 1.0 (ref.), 2.4, 3.4, 5.0, and 9.7 for men and 1.0 (ref.), 1.5, 2.6, 4.6, and 10.0 for women (P &amp;lt; 0.001 for trends in both sexes). For the highest quintiles, the OR for VFA was 1.5 to 2 times higher than those of the other anthropometric indexes in both sexes. CONCLUSIONS We demonstrated a superior performance of VFA to predict the clustering of metabolic risk factors compared with other anthropometric indexes.
The use of shear stress for targeted drug delivery
Authors: Till Saxer, Andreas Zumbuehl, Bert Müller
Journal: Cardiovascular Research (2013)

Stenosed segments of arteries significantly alter the blood flow known from healthy vessels. In particular, the wall shear stress at critically stenosed arteries is at least an order of magnitude higher than in healthy situations. This alteration represents a change in physical force and might be used as a trigger signal for drug delivery. Mechano-sensitive drug delivery systems that preferentially release their payload under increased shear stress are discussed. Therefore, besides biological or chemical markers, physical triggers are a further principle approach for targeted drug delivery. We hypothesize that such a physical trigger is much more powerful to release drugs for vasodilation, plaque stabilization, or clot lysis at stenosed arteries than any known biological or chemical ones.
The Synthetic Triterpenoid CDDO-Imidazolide Suppresses STAT Phosphorylation and Induces Apoptosis in Myeloma and Lung Cancer Cells
Authors: Karen Liby, Nga Voong, Charlotte R. Williams, Renee Risingsong, Darlene B. Royce, Tadashi Honda, Gordon W. Gribble, Michael B. Sporn, John J. Letterio
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Excessive activity of the transcription factors known as signal transducers and activators of transcription (STAT) contributes to the development and progression of malignancy in many organs. It is, therefore, important to develop new drugs to control the STATs, particularly their phosphorylation state, which is required for their transcriptional activity. Experimental Design: Myeloma and lung cancer cells were treated with the new synthetic triterpenoid CDDO-Imidazolide, and STAT phosphorylation and apoptosis were evaluated by immunoblotting and fluorescence-activated cell sorting analysis. Results: We now report that CDDO-Imidazolide, previously shown to be a potent agent for control of inflammation, cell proliferation, and apoptosis, rapidly (within 30-60 minutes) and potently (at nanomolar levels) suppresses either constitutive or interleukin-6-induced STAT3 and STAT5 phosphorylation in human myeloma and lung cancer cells. Furthermore, in these cells, CDDO-Imidazolide also up-regulates critical inhibitors of STATs, such as suppressor of cytokine signaling-1 and SH2-containing phosphatase-1 (a tyrosine phosphatase). Moreover, gene array studies reported here show that CDDO-Imidazolide potently regulates the transcription of important genes that are targets of the STATs. Conclusions: Our new data thus show that CDDO-Imidazolide is a potent suppressor of STAT signaling and provide a further mechanistic basis for future clinical use of this agent to control inflammation or cell proliferation.
Extracts of lung cancer cells reveal antitumour antibodies in sera of patients with lung cancer
Authors: A.V. Bazhin, M.S. Savchenko, O.N. Shifrina, S.Y. Chikina, M.A. Goncharskaia, G. Jaques, A.G. Chuchalin, P.P. Philippov
Journal: European Respiratory Journal (2003)

The objective of the present study was to reveal antitumour antibodies in sera of patients with small cell lung cancer (SCLC). The antibodies in sera of patients with SCLC and other tumours were detected by immunoblotting with whole extracts of SCLC cells as the antigen source. Sera of patients with various pulmonological disorders, irradiated during the liquidation of consequences of the Chernobyl nuclear power plant incident (a high-risk group in lung cancer), were also analysed. The present authors' found that SCLC sera contain a set (pattern) of antitumour antibodies which are rarely detected in sera of patients with cancers different from SCLC and very rarely, if ever, present in sera of healthy individuals. The sensitivity and the specificity of the pattern are equal to 80% and 91%, correspondingly. In the high-risk group in lung cancer, the frequencies of the antibodies are somewhat lower than the corresponding values in SCLC sera, but significantly larger than those in healthy sera. The findings of the present study create a basis for clinical application of the antitumour antibodies described.
Systematic review and meta-analysis of proton pump inhibitor therapy in peptic ulcer bleeding
Authors: Grigoris I Leontiadis, Virender K Sharma, Colin W Howden
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To review randomised controlled trials of treatment with a proton pump inhibitor in patients with ulcer bleeding and determine the impact on mortality, rebleeding, and surgical intervention. <b>Design</b> Systematic review and meta-analysis. <b>Data sources</b> Cochrane Collaboration9s trials register, Medline, and Embase, handsearched abstracts, and pharmaceutical companies. <b>Review methods</b> Included randomised controlled trials compared proton pump inhibitor with placebo or H<sub>2</sub> receptor antagonist in endoscopically proved bleeding ulcer and reported at least one of mortality, rebleeding, or surgical intervention. Trials were graded for methodological quality. Two assessors independently reviewed each trial, and disagreements were resolved by consensus. <b>Results</b> We included 21 randomised controlled trials comprising 2915 patients. Proton pump inhibitor treatment had no significant effect on mortality (odds ratio 1.11, 95% confidence interval 0.79 to 1.57; number needed to treat (NNT) incalculable) but reduced rebleeding (0.46, 0.33 to 0.64; NNT 12) and surgery (0.59, 0.46 to 0.76; NNT 20). Results were similar when the meta-analysis was restricted to the 10 trials with the highest methodological quality: 0.96, 0.46 to 2.01, for mortality; 0.41, 0.25 to 0.68, NNT 10, for rebleeding; 0.62, 0.46 to 0.83, NNT 25, for surgery. <b>Conclusions</b> Treatment with a proton pump inhibitor reduces the risk of rebleeding and the requirement for surgery after ulcer bleeding but has no benefit on overall mortality.
The influence of anti-TNF therapy upon incidence of keratinocyte skin cancer in patients with rheumatoid arthritis: longitudinal results from the British Society for Rheumatology Biologics Register
Authors: Louise K Mercer, Adele C Green, James B Galloway, Rebecca Davies, Mark Lunt, William G Dixon, Kath D Watson, Deborah PM Symmons, Kimme L Hyrich
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> To compare the risk of keratinoctye skin cancer (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) in patients treated for rheumatoid arthritis (RA) compared with the general population, and to determine whether anti-tumour necrosis factor (TNF) therapy exacerbates this risk. <h3>Methods</h3> Patients with RA enrolled in the British Society for Rheumatology Biologics Register, a prospective national cohort established in 2001 to monitor the safety of anti-TNF, were followed until 2008. 11 881 patients treated with anti-TNF were compared with 3629 patients receiving non-biological disease-modifying antirheumatic drugs (nbDMARD). Standardised incidence ratios (SIR) were calculated for each cohort and rates between cohorts were compared using Cox proportional HR, adjusted using inverse probability of treatment weighting. <h3>Results</h3> SIR for skin cancer was increased in both cohorts compared with the English population: SIR 1.72 (95% CI 1.43 to 2.04) anti-TNF; 1.83 (95% CI 1.30 to 2.50) nbDMARD only. In patients without previous skin cancer, BCC incidence per 100 000 patient-years was 342 (95% CI 290 to 402) after anti-TNF and 407 (95% CI 288 to 558) after nbDMARD. HR after anti-TNF adjusted for treatment weighting was 0.95 (95% CI 0.53 to 1.71). SCC incidence per 100 000 patient-years: anti-TNF 53 (95% CI 33 to 79); nbDMARD 43 (95% CI 12 to 110); adjusted HR 1.16 (95% CI 0.35 to 3.84). <h3>Conclusions</h3> Skin cancers were increased among treated patients with RA. No evidence was found that anti-TNF therapy exacerbates the risk of BCC or SCC but this cannot be excluded. Patients with RA should use sun protection and be monitored for skin cancer.
Poly(N-vinylpyrrolidone)-block-poly(d,l-lactide) as a new polymeric solubilizer for hydrophobic anticancer drugs: in vitro and in vivo evaluation
Authors: D. Le Garrec, S. Gori, L. Luo, D. Lessard, D.C. Smith, M.-A. Yessine, M. Ranger, J.-C. Leroux
Journal: Journal of Controlled Release (2004)