tbuckley/cabot-search huggingface dataset:
Speed of onset of action of Tilarin
Authors: ARLENE DONNELLY, DAVID . BERNSTELN, STANLEY GOLDSTEIN, JAY GROSSMAN, HOWARD J. SCHWAM, THOMAS B. CASALE
Journal: Allergy (1996)

Donnelly A., Bernstein D. I., Goldstein S., Grossman J., Schwartz H. J., Casale T. B. Speed of onset of action of Tilarin. Two studies have been carried out specifically to examine the speed of onset of action of intranasal nedocromil sodium 1% (Tilarin®) for the relief of symptoms due to ragweed allergic rhinitis. One, a multicentre placebo-controlled comparative study using a QID regimen, 1 spray per nostril, was designed to assess the speed of onset of action of nedocromil sodium during the first week of treatment in patients with rhinitis symptoms, and to evaluate the efficacy and safety of nedocromil sodium during 6 weeks of treatment (1). A 1-week baseline, the start of which was timed to coincide with the start of the ragweed season, was followed by 6 weeks double-blind trial treatment; only patients (n = 166) who were symptomatic at the end of baseline were included in the double-bhd phase. Non-parametric analyses of all variables including a summary score (stuffy nose, runny nose, itchy nose and sneezing) showed that the onset of action of nedocromil sodium occurred on the first day of treatment. Further, patients using nedocromil sodium had less symptoms during the 10 days of peak pollen, at which time physician assessment showed reduced mucosal oedema and nasal discharge, and both patient and clinician opinions favoured nedocromil sodium. No significant adverse events were reported during as 6-week study. In the second study (2), 104 patients were randomly allocated to receive either nedocromil sodium or placebo, QID. They then spent 10 hours per day for 2 consecutive days in Iowa City Park during the peak of the ragweed season. Only patients showing significant symptoms of seasonal allergic rhinitis (SAR) during 3 hourly baseline assessments were included. Over the 2-day period, symptom scores for stuffy nose, runny nose, itchy nose and sneezing, and global symptom summary scores, were recorded at 19 hourly time points. At home in the evening, patients recorded symptom scores for the post-exposure period. In comparison with placebo, nedocromil sodium significantly improved rhinitis symptoms within 2 hours, and this reduction in SAR symptoms was maintained throughout the 2-day exposure period. Post exposure symptom summary scores were also significantly lower in patients treated with nedocromil sodium than in those patients treated with placebo. Overall, very few adverse events were reported, none of them serious. In conclusion, nedocromil sodium 1% nasal spray acts rapidly, within 2 hours on the first day of treatment, to reduce ongoing symptoms of SAR. Relief of rhinitis symptoms is maintained throughout the peak pollen period with nedocromil sodium QID, which appears to be a safe and well tolerated treatment for ragweed SAR.
Fanconi anemia (FA)–associated 3q gains in leukemic transformation consistently target EVI1, but do not affect low TERC expression in FA
Authors: Stefan Meyer, Claire Bristow, Mark Wappett, Stuart Pepper, Anthony D. Whetton, Helmut Hanenberg, Heidemarie Neitzel, Marcin W. Wlodarski, Wolfram Ebell, Holger Tönnies
Journal: Blood (2011)
Likelihood-Based Clustering (LiBaC) for Codon Models, a Method for Grouping Sites according to Similarities in the Underlying Process of Evolution
Authors: Le Bao, Hong Gu, Katherine A. Dunn, Joseph P. Bielawski
Journal: Molecular Biology and Evolution (2008)

Models of codon evolution are useful for investigating the strength and direction of natural selection via a parameter for the nonsynonymous/synonymous rate ratio (omega = d(N)/d(S)). Different codon models are available to account for diversity of the evolutionary patterns among sites. Codon models that specify data partitions as fixed effects allow the most evolutionary diversity among sites but require that site partitions are a priori identifiable. Models that use a parametric distribution to express the variability in the omega ratio across site do not require a priori partitioning of sites, but they permit less among-site diversity in the evolutionary process. Simulation studies presented in this paper indicate that differences among sites in estimates of omega under an overly simplistic analytical model can reflect more than just natural selection pressure. We also find that the classic likelihood ratio tests for positive selection have a high false-positive rate in some situations. In this paper, we developed a new method for assigning codon sites into groups where each group has a different model, and the likelihood over all sites is maximized. The method, called likelihood-based clustering (LiBaC), can be viewed as a generalization of the family of model-based clustering approaches to models of codon evolution. We report the performance of several LiBaC-based methods, and selected alternative methods, over a wide variety of scenarios. We find that LiBaC, under an appropriate model, can provide reliable parameter estimates when the process of evolution is very heterogeneous among groups of sites. Certain types of proteins, such as transmembrane proteins, are expected to exhibit such heterogeneity. A survey of genes encoding transmembrane proteins suggests that overly simplistic models could be leading to false signal for positive selection among such genes. In these cases, LiBaC-based methods offer an important addition to a "toolbox" of methods thereby helping to uncover robust evidence for the action of positive selection.
Femtosecond Laser–Assisted Sutureless Anterior Lamellar Keratoplasty
Authors: Sonia H. Yoo, George D. Kymionis, Aaleya Koreishi, Takeshi Ide, David Goldman, Carol L. Karp, Terrence P. O'Brien, William W. Culbertson, Eduardo C. Alfonso
Journal: Ophthalmology (2008)
Curing Mice with Large Tumors by Locally Delivering Combinations of Immunomodulatory Antibodies
Authors: Min Dai, Yuen Yee Yip, Ingegerd Hellstrom, Karl Erik Hellstrom
Journal: Clinical Cancer Research (2014)

Abstract Purpose: Immunomodulatory mAbs can treat cancer, but cures are rare except for small tumors. Our objective was to explore whether the therapeutic window increases by combining mAbs with different modes of action and injecting them into tumors. Experimental Design: Combinations of mAbs to CD137/PD-1/CTLA-4 or CD137/PD-1/CTLA-4/CD19 were administrated intratumorally to mice with syngeneic tumors (B16 and SW1 melanoma, TC1 lung carcinoma), including tumors with a mean surface of approximately 80 mm2. Survival and tumor growth were assessed. Immunologic responses were evaluated using flow cytometry and qRT-PCR. Results: More than 50% of tumor-bearing mice had complete regression and long-term survival after tumor injection with mAbs recognizing CD137/PD-1/CTLA-4/CD19 with similar responses in three models. Intratumoral injection was more efficacious than intraperitoneal injection in causing rejection also of untreated tumors in the same mice. The three-mAb combination could also induce regression, but was less efficacious. There were few side effects, and therapy-resistant tumors were not observed. Transplanted tumor cells rapidly caused a Th2 response with increased CD19 cells. Successful therapy shifted this response to the Th1 phenotype with decreased CD19 cells and increased numbers of long-term memory CD8 effector cells and T cells making IFNγ and TNFα. Conclusions: Intratumoral injection of mAbs recognizing CD137/PD-1/CTLA-4/CD19 can eradicate established tumors and reverse a Th2 response with tumor-associated CD19 cells to Th1 immunity, whereas a combination lacking anti-CD19 is less effective. There are several human cancers for which a similar approach may provide clinical benefit. Clin Cancer Res; 21(5); 1127–38. ©2014 AACR. See related commentary by Dronca and Dong, p. 944
Vibration Perception Threshold as a Measure of Distal Symmetrical Peripheral Neuropathy in Type 1 Diabetes
Authors: Catherine L. Martin, Barbara H. Waberski, Rodica Pop-Busui, Patricia A. Cleary, Sarah Catton, James W. Albers, Eva L. Feldman, William H. Herman
Journal: Diabetes Care (2010)

To describe the sensitivity, specificity, positive predictive value, and negative predictive value of vibration perception threshold (VPT) testing in subjects with type 1 diabetes relative to gold standard assessments of peripheral neuropathy.VPT was determined in 1,177 adults with type 1 diabetes 13-14 years after participating in a study of intensive (INT) versus conventional (CONV) diabetes treatment. Abnormal VPT was defined by values exceeding 2.5 SD above age-specific normal values. Signs and symptoms of peripheral neuropathy were assessed and electrodiagnostic studies were performed to establish definite clinical neuropathy, abnormal nerve conduction, and confirmed clinical neuropathy (the presence of both definite clinical neuropathy and abnormal nerve conduction).Thirty-seven percent of subjects had definite clinical neuropathy, 61% had abnormal nerve conduction, and 30% had confirmed clinical neuropathy. Abnormal VPT was more common among former CONV than among INT subjects (64 vs. 57%, P < 0.05) and was associated with older age. VPT was a sensitive measure of confirmed clinical neuropathy (87%) and of definite clinical neuropathy (80%) and a specific measure of abnormal nerve conduction (62%). Higher VPT cut points improved test sensitivity and lower cut points improved specificity. Areas under the receiver operating characteristic curves ranged from 0.71-0.83 and were higher for older than for younger subjects and highest for those with confirmed clinical neuropathy.VPT was a sensitive measure of peripheral neuropathy. Future researchers may choose to select VPT cut points for defining abnormality based on the population studied and clinical outcome of interest.
Heterogeneity of DNA fragments associated with the sickle-globin gene.
Authors: J Feldenzer, J G Mears, A L Burns, C Natta, A Bank
Journal: Journal of Clinical Investigation (1979)

We have examined the genetic polymorphism previously reported to be associated with the sickle-cell (beta s) gene. The polymorphism involves an alteration of the DNA sequence 3' to the beta-globin gene as detected with the restriction endonuclease, Hpa I. In normal individuals, the beta-globin gene is contained within a DNA fragment of 7.6 kilobases (kb), whereas 87% of individuals with sickle-cell anemia have been reported to have the beta s-gene associated with a 13.0-kb Hpa I fragment. We have studied this polymorphism in 31 New York Black individuals homozygous for sickle-cell anemia to ascertain its genetic and biochemical significance and to evaluate its potential use in the prenatal diagnosis of sickle-cell disease. Our results show only a 58% association of the beta s-gene and the 13.0-kb Hpa I fragment, as well as the presence of additional variants involving the Hpa I site. In addition, the 13.0-kb fragment is also found associated with the beta c- and beta A-genes. Thus, the Hpa I polymorphism probably represents a change in DNA not specifically associated with the beta s-gene, and appears to antedate the beta s-and beta c-mutations.
Vascular Endothelial Growth Factor Receptor-1 Contributes to Resistance to Anti–Epidermal Growth Factor Receptor Drugs in Human Cancer Cells
Authors: Roberto Bianco, Roberta Rosa, Vincenzo Damiano, Gennaro Daniele, Teresa Gelardi, Sonia Garofalo, Valeria Tarallo, Sandro De Falco, Davide Melisi, Roberto Benelli, Adriana Albini, Anderson Ryan, Fortunato Ciardiello, Giampaolo Tortora
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The resistance to selective EGFR inhibitors involves the activation of alternative signaling pathways, and Akt activation and VEGF induction have been described in EGFR inhibitor–resistant tumors. Combined inhibition of EGFR and other signaling proteins has become a successful therapeutic approach, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. Experimental Design: We established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and EGFR-independent pathways. Results: Multitargeted inhibitor vandetanib (ZD6474) inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both wild-type and EGFR inhibitor–resistant human colon, prostate, and breast cancer cells. We found that the resistant cell lines exhibit, as common feature, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor, and augmented migration capabilities and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGF receptor (VEGFR)-2, RET, and EGFR, vandetanib efficiently inhibits also VEGFR-1. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, whereas exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. Conclusions: This study shows that VEGFR-1 contributes to anti-EGFR drug resistance in different human cancer cells. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation, and migration, suggesting its potential utility in patients resistant to EGFR inhibitors.
Biochemical markers of cerebrovascular injury in sleep apnoea syndrome
Authors: W. Jordan, J. Hagedohm, J. Wiltfang, G. Laier-Groeneveld, H. Tumani, A. Rodenbeck, E. Rüther, G. Hajak
Journal: European Respiratory Journal (2002)

Sleep apnoea syndrome (SAS) is a known risk factor for vascular diseases and stroke. Structural brain damage, manifesting as an overt neurological deficit or more subtly as cognitive dysfunction, is a frequent symptom in SAS. The presence of a biochemical marker of cerebral injury would be of great benefit in SAS to screen for even small brain damage and to monitor efficiacy of therapy. Therefore, in 10 patients with mild SAS (age 50.8±9.9 yrs, respiratory disturbance index (RDI) 18±3.6, lowest arterial oxygen saturation (min S a,O 2 ) 80.5±4.06%) and nine patients with severe SAS (age 50.3±11.5 yrs, RDI 75.4±21.7, min S a,O 2 56.56±14.58%), serum concentrations of neuron-specific enolase (NSE), S‐100β protein, and β‐trace were measured just before and after sleep using commercially available assays. Only serum levels in the normal range could be found, independent of when the blood was taken or the degree of SAS. Structural cerebral injury caused by sleep apnoea syndrome in patients without neurological symptoms or previous cerebrovascular events may be too small to produce a measurable increase in S‐100β, neuron‐specific enolase and β‐trace serum concentrations or subclinical cerebral damage may be outside the lower detection limits of the analytical methods which were used. There is a need for biochemical markers and more sensitive methods for detecting small cerebral injury in sleep apnoea syndrome.
Paracrine Transfer of Mouse Mammary Tumor Virus Superantigen
Authors: Marc Delcourt, Jacques Thibodeau, Francois Denis, Rafick-Pierre Sekaly
Journal: The Journal of Experimental Medicine (1997)

Transfer of vSAG7, the endogenous superantigen encoded in the Mtv7 locus, from MHC class II− to MHC class II+ cells has been suggested to occur both in vivo and in vitro. This transfer usually leads to the activation and deletion of T cells expressing responsive Vβs. However, there is no direct molecular evidence for such a transfer. We have developed an in vitro system which confirms this property of vSAGs. vSAG7 was transfected into a class II− murine fibroblastic line. Coculture of these cells with class II+ cells and murine T cell hybridomas expressing the specific Vβs led to high levels of IL-2 production which was specifically inhibited by vSAG7- and MHC class II–specific mAbs. Moreover, injection of vSAG7+ class II− cells in mice led to expansion of Vβ6+ CD4+ cells. We show that this transfer activity is paracrine but does not require cell-to-cell contact. Indeed, vSAG7 was transferred across semi-permeable membranes. Transfer can occur both from class II− and class II+ cells, indicating that MHC class II does not sequester vSAG7. Finally, competition experiments using bacterial toxins with well defined binding sites showed that the transferred vSAG7 fragment binds to the α1 domain of HLA-DR.
Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells
Authors: Konrad Steinestel, Silke Brüderlein, Jochen K Lennerz, Julie Steinestel, Klaus Kraft, Christian Pröpper, Viktor Meineke, Peter Möller
Journal: Molecular Cancer (2014)

The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer. In 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix. Our data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.
Definitive Surgical Treatment of Enterocutaneous Fistula
Authors: Rachel M. Owen, Timothy P. Love, Sebastian D. Perez, Jahnavi K. Srinivasan, Jyotirmay Sharma, Jonathan D. Pollock, Carla I. Haack, John F. Sweeney, John R. Galloway
Journal: JAMA Surgery (2012)

To analyze postoperative outcomes, morbidity, and mortality following enterocutaneous fistula (ECF) takedown.Retrospective review of the complete medical records of patients who presented to a single tertiary care referral center from December 24, 1987, to June 18, 2010, and subsequently underwent definitive surgical treatment for ECF originating from the stomach, small bowel, colon, or rectum.Postoperative fistula recurrence and mortality.A total of 153 patients received operative intervention for ECF. Most ECFs were referred to us from outside institutions (75.2%), high output (52.3%), originating from the small bowel (88.2%), and iatrogenic in cause (66.7%). Successful ECF closure was ultimately achieved in 128 patients (83.7%). Six patients (3.9%) died within 30 days of surgery, and overall 1-year mortality was 15.0%. Postoperative complications occurred in 134 patients, for an overall morbidity rate of 87.6%. Significant risk factors for fistula recurrence were numerous, but postoperative ventilation for longer than 48 hours, organ space surgical site infection, and blood transfusion within 72 hours of surgery carried the most considerable impact (relative risks, 4.87, 4.07, and 3.91, respectively; P < .05). Risk of 1-year mortality was also associated with multiple risk factors, the most substantial of which were postoperative pulmonary and infectious complications. Closure of abdominal fascia was protective against both recurrent ECF and mortality (relative risks, 0.47 and 0.38, respectively; P < .05).Understanding risk factors both associated with and protective against ECF recurrence and postoperative morbidity and mortality is imperative for appropriate ECF management. Closure of abdominal fascia is of utmost importance, and preventing postoperative complications must be prioritized to optimize patient outcomes.
Intravascular Ultrasound Findings in the Multicenter, Randomized, Double-Blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) Trial
Authors: Patrick W. Serruys, Muzaffer Degertekin, Kengo Tanabe, Alexandre Abizaid, J. Edouardo Sousa, Antonio Colombo, Giulio Guagliumi, William Wijns, Wietze K. Lindeboom, Jurgen Ligthart, Pim J. de Feyter, Marie-Claude Morice
Journal: Circulation (2002)

The goal of this intravascular ultrasound investigation was to provide a more detailed morphological analysis of the local biological effects of the implantation of a sirolimus-eluting stent compared with an uncoated stent.In the RAVEL trial, 238 patients with single de novo lesions were randomized to receive either an 18-mm sirolimus-eluting stent (Bx VELOCITY stent, Cordis) or an uncoated stent (Bx VELOCITY stent). In a subset of 95 patients (sirolimus-eluting stent=48, uncoated stent=47), motorized intravascular ultrasound pullback (0.5 mm/s) was performed at a 6-month follow-up. Stent volumes, total vessel volumes, and plaque-behind-stent volumes were comparable. However, the difference in neointimal hyperplasia (2+/-5 versus 37+/-28 mm3) and percent of volume obstruction (1+/-3% versus 29+/-20%) at 6 months between the 2 groups was highly significant (P<0.001), emphasizing the nearly complete abolition of the proliferative process inside the drug-eluting stent. Analysis of the proximal and distal edge volumes showed no significant difference between the 2 groups in external elastic membrane or lumen and plaque volume at the proximal and distal edges. There was also no evidence of intrastent thrombosis or persisting dissection at the stent edges. Although there was a higher incidence of incomplete stent apposition in the sirolimus group compared with the uncoated stent group (P<0.05), it was not associated with any adverse clinical events at 1 year.Sirolimus-eluting stents are effective in preventing neointimal hyperplasia without creating edge effect and without affecting the plaque burden behind the struts.