tbuckley/cabot-search huggingface dataset:
Connexins in leukocytes: shuttling messages?
Authors: C Wong
Journal: Cardiovascular Research (2004)

Gap junctions, formed by the connexin (Cx) protein family, are intercellular channels that permit the cytoplasmic exchange of ions and small metabolites between neighboring cells, a process called gap junction intercellular communication (GJIC). These channels possess unique properties, including distinctive permeabilities for various signaling molecules, which depend on the connexin member(s) that form them. Importantly, GJIC must be properly controlled as its misregulation might contribute to diseases. Morphological and functional studies have revealed 'gap junction-like' structures and cell-to-cell communication involving cells of the immune system. The connexins involved in such contacts have been partially identified in recent years. This review focuses on the potential physiological roles of gap junctions in the development and recruitment of leukocytes as well as in the regulation of the immune response. Furthermore, the importance of GJIC in immuno-inflammatory pathologies is illustrated in atherosclerosis.
The aggressive peripheral T‐cell lymphomas: 2013
Authors: James O. Armitage
Journal: American Journal of Hematology (2013)

Background T‐cell lymphomas make up approximately 10–15% of lymphoid malignancies. The frequency of these lymphomas varies geographically, with the highest incidence in parts of Asia. Diagnosis The diagnosis of aggressive peripheral T‐cell lymphoma (PTCL) is usually made using the WHO classification. The ability of hematopathologists to reproducibly diagnosis aggressive PTCL is lower than for aggressive B‐cell lymphomas, with a range of 72–97% for the aggressive PTCLs. Risk Stratification Patients with aggressive PTCL are staged using the Ann Arbor Classification. Although somewhat controversial, PET scans appear to be useful as they are in aggressive B‐cell lymphomas. The most commonly used prognostic index is the International Prognostic Index. The specific subtype of aggressive PTCL is an important risk factor, with the best survival seen in anaplastic large cell lymphoma—particularly young patients with the anaplastic lymphoma kinase positive subtype. Risk Adapted Therapy Anaplastic large cell lymphoma is the only subgroup to have a good response to a CHOP‐like regimen. Angioimmunoblastic T‐cell lymphoma has a prolonged disease‐free survival in only ∼20% of patients, but younger patients who have an autotransplant in remission seem to do better. PTCL‐NOS (not otherwise specified) is not one disease. Anthracycline containing regimens have disappointing results and a new approach is needed. NK/T‐cell lymphoma localized to the nose and nasal sinuses seems to be best treated with radiotherapy containing regimens. Enteropathy associated PTCL and hepatosplenic PTCL are rare disorders with a generally poor response to therapy, although selected patients with enteropathy associated PTCL seem to benefit from intensive therapy. Am. J. Hematol. 88:911–918, 2013. © 2013 Wiley Periodicals, Inc.
Cost Effectiveness of Molecular Profiling for Adjuvant Decision Making in Patients With Node-Negative Breast Cancer
Authors: Julia Bonastre, Sophie Marguet, Beranger Lueza, Stefan Michiels, Suzette Delaloge, Mahasti Saghatchian
Journal: Journal of Clinical Oncology (2014)

To conduct an economic evaluation of the 70-gene signature used to guide adjuvant chemotherapy decision making both in patients with node-negative breast cancer (NNBC) and in the subgroup of estrogen receptor (ER) -positive patients.We used a mixed approach combining patient-level data from a multicenter validation study of the 70-gene signature (untreated patients) and secondary sources for chemotherapy efficacy, unit costs, and utility values. Three strategies on which to base the decision to administer adjuvant chemotherapy were compared: the 70-gene signature, Adjuvant! Online, and chemotherapy in all patients. In the base-case analysis, costs from the French National Insurance Scheme, life-years (LYs), and quality-adjusted life-years (QALYs) were computed for the three strategies over a 10-year period. Cost-effectiveness acceptability curves using the net monetary benefit were computed, combining bootstrap and probabilistic sensitivity analyses.The mean differences in LYs and QALYs were similar between the three strategies. The 70-gene signature strategy was associated with a higher cost, with a mean difference of €2,037 (range, €1,472 to €2,515) compared with Adjuvant! Online and of €657 (95% CI, -€642 to €3,130) compared with systematic chemotherapy. For a €50,000 per QALY willingness-to-pay threshold, the probability of being the most cost-effective strategy was 92% (76% in ER-positive patients) for the Adjuvant! Online strategy, 6% (4% in ER-positive patients) for the systematic chemotherapy strategy, and 2% (20% in ER-positive patients) for the 70-gene strategy.Optimizing adjuvant chemotherapy decision making based on the 70-gene signature is unlikely to be cost effective in patients with NNBC.
Clinical Trial Evidence Supporting FDA Approval of Novel Therapeutic Agents, 2005-2012
Authors: Nicholas S. Downing, Jenerius A. Aminawung, Nilay D. Shah, Harlan M. Krumholz, Joseph S. Ross
Journal: JAMA (2014)

<h3>Importance</h3> Many patients and physicians assume that the safety and effectiveness of newly approved therapeutic agents is well understood; however, the strength of the clinical trial evidence supporting approval decisions by the US Food and Drug Administration (FDA) has not been evaluated. <h3>Objectives</h3> To characterize pivotal efficacy trials (clinical trials that serve as the basis of FDA approval) for newly approved novel therapeutic agents. <h3>Design and Setting</h3> Cross-sectional analysis using publicly available FDA documents for all novel therapeutic agents approved between 2005 and 2012. <h3>Main Outcomes and Measures</h3> Pivotal efficacy trials were classified according to the following design features: randomization, blinding, comparator, and trial end point. Surrogate outcomes were defined as any end point using a biomarker expected to predict clinical benefit. The number of patients, trial duration, and trial completion rates were also determined. <h3>Results</h3> Between 2005 and 2012, the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. The median number of pivotal trials per indication was 2 (interquartile range, 1-2.5), although 74 indications (36.8%) were approved on the basis of a single pivotal trial. Nearly all trials were randomized (89.3% [95% CI, 86.4%-92.2%]), double-blinded (79.5% [95% CI, 75.7%-83.2%]), and used either an active or placebo comparator (87.1% [95% CI, 83.9%-90.2%]). The median number of patients enrolled per indication among all pivotal trials was 760 (interquartile range, 270-1550). At least 1 pivotal trial with a duration of 6 months or greater supported the approval of 68 indications (33.8% [95% CI, 27.2%-40.4%]). Pivotal trials using surrogate end points as their primary outcome formed the exclusive basis of approval for 91 indications (45.3% [95% CI, 38.3%-52.2%]), clinical outcomes for 67 (33.3% [95% CI, 26.8%-39.9%]), and clinical scales for 36 (17.9% [95% CI, 12.6%-23.3%]). Trial features differed by therapeutic and indication characteristics, such as therapeutic area, expected length of treatment, orphan status, and accelerated approval. <h3>Conclusions and Relevance</h3> The quality of clinical trial evidence used by the FDA as the basis for recent approvals of novel therapeutic agents varied widely across indications. This variation has important implications for patients and physicians as they make decisions about the use of newly approved therapeutic agents.
The Case for Increased Funding for Research in Pulmonary and Critical Care
Authors: Marc Peters-Golden, James R. Klinger, Shannon S. Carson
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

The current economic and political climate places future funding of the National Institutes of Health (NIH) and other federal biomedical research programs in jeopardy. This Pulmonary Perspective seeks to arm the diverse membership of the American Thoracic Society with the information necessary to understand and articulate the value of biomedical research in their respective communities. We provide a historical overview of NIH funding in general and of allocations directed at respiratory-related research in particular. We argue that this is in fact an opportune time to expand investments in biomedical research and that doing so makes sense from the perspectives of improving health, curtailing health care expenditures, and job creation and economic growth. We further argue that current levels of allocation toward respiratory research are incommensurate with the medical, economic, and societal burden of respiratory disease in the United States. Respiratory disease currently is the only leading cause of death that has risen, rather than fallen, in recent decades. Declines in the burden of cardiovascular disease and cancer followed substantial increases in research funding, and slowing the rising burden of respiratory disease will likewise require a greatly expanded investment in pulmonary, critical care, and sleep research.
Prognostic Factors in Human Herpesvirus 8–Related Lymphoproliferative Disorders Associated With HIV Infection
Authors: Cecilia Simonelli, Rosamaria Tedeschi, Annunziata Gloghini, Michele Spina, Renato Talamini, Paolo De Paoli, Umberto Tirelli, Antonino Carbone
Journal: Journal of Clinical Oncology (2005)
CDK4 deficiency promotes genomic instability and enhances Myc-driven lymphomagenesis
Authors: Yuanzhi Lu, Yongsheng Wu, Xiaoling Feng, Rulong Shen, Jing H. Wang, Mohammad Fallahi, Weimin Li, Chunying Yang, William Hankey, Weiqiang Zhao, Ramesh K. Ganju, Ming O. Li, John L. Cleveland, Xianghong Zou
Journal: Journal of Clinical Investigation (2014)

The G1 kinase CDK4 is amplified or overexpressed in some human tumors and promotes tumorigenesis by inhibiting known tumor suppressors. Here, we report that CDK4 deficiency markedly accelerated lymphoma development in the Eμ-Myc transgenic mouse model of B lymphoma and that silencing or loss of CDK4 augmented the tumorigenic potential of Myc-driven mouse and human B cell lymphoma in transplant models. Accelerated disease in CDK4-deficient Eμ-Myc transgenic mice was associated with rampant genomic instability that was provoked by dysregulation of a FOXO1/RAG1/RAG2 pathway. Specifically, CDK4 phosphorylated and inactivated FOXO1, which prevented FOXO1-dependent induction of Rag1 and Rag2 transcription. CDK4-deficient Eμ-Myc B cells had high levels of the active form of FOXO1 and elevated RAG1 and RAG2. Furthermore, overexpression of RAG1 and RAG2 accelerated lymphoma development in a transplant model, with RAG1/2-expressing tumors exhibiting hallmarks of genomic instability. Evaluation of human tumor samples revealed that CDK4 expression was markedly suppressed, while FOXO1 expression was elevated, in several subtypes of human non-Hodgkin B cell lymphoma. Collectively, these findings establish a context-specific tumor suppressor function for CDK4 that prevents genomic instability, which contributes to B cell lymphoma. Furthermore, our data suggest that targeting CDK4 may increase the risk for the development and/or progression of lymphoma.
Serum concentrations of 7?-hydroxy-4-cholesten-3-one reflect bile acid synthesis in humans
Authors: G Sauter, F Berr, U Beuers, S Fischer, G Paumgartner
Journal: Hepatology (1996)

Serum concentrations of 7alpha-hydroxy-4-cholesten-3-one (alpha-HC) have recently been shown to reflect the activity of cholesterol 7 alpha-hydroxylase in humans. To evaluate the relationship between alpha-HC in serum and bile acid synthesis, serum concentrations of alpha-HC, and rates of bile acid synthesis, as measured by the isotope dilution technique using gas chromatography-mass spectrometry, were determined simultaneously. Regression analysis revealed a positive linear correlation of serum alpha-Hc with synthesis of cholic acid (CA) (r = .59, P = .02), chenodeoxycholic acid (CDCA) (r = .75, P = .001), and total synthesis of both primary bile acids (r = .83, P < .001) in patients with gallstones and normal liver function (n = 15). alpha-HC was also correlated to input rates of deoxycholic acid (DCA) (r = .53, P <.05). Addition of patients with chronic cholestatic liver disease (n = 5) improved the correlation between serum alpha-HC and synthesis of CA (r = .75, P < .001), CDCA (r = .77, P < .001), and both primary bile acid combined (r = .87), P < .001). Our data are in agreement with the concept that synthesis of bile acids is regulated by cholesterol 7 alpha-hydroxylase activity and that alpha-HC in serum may serve as a convenient marker for the semiquantitative assessment of bile acid synthesis in humans.
Prognostic Significance of Histopathologic Subsets in Idiopathic Pulmonary Fibrosis
Authors: JULIE A. BJORAKER, JAY H. RYU, MARK K. EDWIN, JEFFREY L. MYERS, HENRY D. TAZELAAR, DARRELL R. SCHROEDER, KENNETH P. OFFORD
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Idiopathic pulmonary fibrosis (IPF) is a generally fatal disorder with a reported median survival of 3 to 6 yr. This has been based on relatively few studies with diagnoses inconsistently confirmed by adequate lung biopsy. Retrospective analysis of 104 patients with IPF who had open lung biopsy (OLB) at Mayo Medical Center from 1976 to 1985 was performed to establish the overall survival rate, the spectrum of histopathological subgroups and their associated prognostic significance. The study group consisted of 54 men and 50 women with a median age of 63 yr. Median survival was 3.8 yr after diagnosis by OLB with an estimated 10 yr survival of 27%. Current histopathologic review showed a heterogeneous group including usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), nonspecific interstitial pneumonia/fibrosis (NSIP), acute interstitial pneumonia (AIP), bronchiolitis, bronchiolitis obliterans organizing pneumonia (BOOP), and others. Median survival of the UIP group was 2.8 yr which is significantly worse (p < 0.001) than for other subgroups of chronic interstitial pneumonias. IPF includes several histopathologic subgroups with significantly different survival rates. Patients with UIP have worse survival than patients with other types of idiopathic chronic interstitial pneumonias including NSIP. Accurate histopathologic classification is essential for prognostication in patients with IPF.
Selection of a new generation of orally active α‐ketohydroxypyridine iron chelators intended for use in the treatment of iron overload
Authors: G. J. Kontoghiorghes, J. Barr, P. Nortey, L. Sheppard
Journal: American Journal of Hematology (1993)

Abstract The prospect of selecting oral α‐ketohydroxypyridine chelators intended for clinical use in iron overload has been examined using several animal models of efficacy and toxicity. Studies using iron dextran‐loaded mice labelled with 59 Fe have shown that only the 1‐substituted methyl, ethyl, (n)propyl, allyl, cyclopropyl, 2′‐methoxyethyl, 3′‐ethoxypropyl, or 2‐methyl‐ or 2‐ethyl‐ 3‐hydroxypyrid‐4‐one chelators were orally effective in increasing iron ( 59 Fe) excretion by comparison to intraperitoneally administered desferrioxamine at the same dose (250 mg/kg). In contrast, chelators containing ‐H, mono‐ or dihydroxyalkyl and diethoxyethyl 1‐substituents caused very little or no increase in iron ( 59 Fe) excretion by the oral or intraperitoneal routes. In vitro studies using ferritin and haemosiderin have shown that equivalent iron release took place with both groups of chelators irrespective of their in vivo effects. In most cases there was no correlation between the n‐octanol/water partition coefficient (K par ) and iron removal efficacy but positive correlation between the lipophilicity and acute or subacute toxicity of these chelators in rats. The most toxic chelator in the chronic toxicity studies in rats was the lipophilic 1, 2‐diethyl‐3‐hydroxypyrid‐4‐one (EL1NEt). The most effective chelator in increasing iron excretion in mice and rabbits was 1‐allyl‐2‐methyl‐3‐hydroxypyrid‐4‐one (L1NAll), and the chelator with the highest safety margin in mice and rats was 1, 2‐dimethyl‐3‐hydroxypyrid‐4‐one (L1). Overall the oral effectiveness in increasing iron excretion by these chelators in animals does not appear to be related to their lipophilicity or their ability to mobilise polynuclear iron in vitro but rather to other properties possibly related to their rate of biotransformation and excretion. © 1993 Wiley‐Liss, Inc.
SCFβ-TRCP suppresses angiogenesis and thyroid cancer cell migration by promoting ubiquitination and destruction of VEGF receptor 2
Authors: Shavali Shaik, Carmelo Nucera, Hiroyuki Inuzuka, Daming Gao, Maija Garnaas, Gregory Frechette, Lauren Harris, Lixin Wan, Hidefumi Fukushima, Amjad Husain, Vania Nose, Guido Fadda, Peter M. Sadow, Wolfram Goessling, Trista North, Jack Lawler, Wenyi Wei
Journal: The Journal of Experimental Medicine (2012)

The incidence of human papillary thyroid cancer (PTC) is increasing and an aggressive subtype of this disease is resistant to treatment with vascular endothelial growth factor receptor 2 (VEGFR2) inhibitor. VEGFR2 promotes angiogenesis by triggering endothelial cell proliferation and migration. However, the molecular mechanisms governing VEGFR2 stability in vivo remain unknown. Additionally, whether VEGFR2 influences PTC cell migration is not clear. We show that the ubiquitin E3 ligase SCFβ-TRCP promotes ubiquitination and destruction of VEGFR2 in a casein kinase I (CKI)–dependent manner. β-TRCP knockdown or CKI inhibition causes accumulation of VEGFR2, resulting in increased activity of signaling pathways downstream of VEGFR2. β-TRCP–depleted endothelial cells exhibit enhanced migration and angiogenesis in vitro. Furthermore, β-TRCP knockdown increased angiogenesis and vessel branching in zebrafish. Importantly, we found an inverse correlation between β-TRCP protein levels and angiogenesis in PTC. We also show that β-TRCP inhibits cell migration and decreases sensitivity to the VEGFR2 inhibitor sorafenib in poorly differentiated PTC cells. These results provide a new biomarker that may aid a rational use of tyrosine kinase inhibitors to treat refractory PTC.
Functional Cloning of Src-like Adapter Protein-2 (SLAP-2), a Novel Inhibitor of Antigen Receptor Signaling
Authors: Sacha J. Holland, X. Charlene Liao, Marcy K. Mendenhall, Xiulan Zhou, Jorge Pardo, Peter Chu, Collin Spencer, Alan Fu, Ning Sheng, Peiwen Yu, Erlina Pali, Anup Nagin, Mary Shen, Simon Yu, Eva Chan, Xian Wu, Connie Li, Max Woisetschlager, Gregorio Aversa, Frank Kolbinger, Mark K. Bennett, Susan Molineaux, Ying Luo, Donald G. Payan, Helena S.Y. Mancebo, Jun Wu
Journal: The Journal of Experimental Medicine (2001)

In an effort to identify novel therapeutic targets for autoimmunity and transplant rejection, we developed and performed a large-scale retroviral-based functional screen to select for proteins that inhibit antigen receptor-mediated activation of lymphocytes. In addition to known regulators of antigen receptor signaling, we identified a novel adaptor protein, SLAP-2 which shares 36% sequence similarity with the known Src-like adaptor protein, SLAP. Similar to SLAP, SLAP-2 is predominantly expressed in hematopoietic cells. Overexpression of SLAP-2 in B and T cell lines specifically impaired antigen receptor-mediated signaling events, including CD69 surface marker upregulation, nuclear factor of activated T cells (NFAT) promoter activation and calcium influx. Signaling induced by phorbol myristate acetate (PMA) and ionomycin was not significantly reduced, suggesting SLAP-2 functions proximally in the antigen receptor signaling cascade. The SLAP-2 protein contains an NH2-terminal myristoylation consensus sequence and SH3 and SH2 Src homology domains, but lacks a tyrosine kinase domain. In antigen receptor–stimulated cells, SLAP-2 associated with several tyrosine phosphorylated proteins, including the ubiquitin ligase Cbl. Deletion of the COOH terminus of SLAP-2 blocked function and abrogated its association with Cbl. Mutation of the putative myristoylation site of SLAP-2 compromised its inhibitory activity and impaired its localization to the membrane compartment. Our identification of the negative regulator SLAP-2 demonstrates that a retroviral-based screening strategy may be an efficient way to identify and characterize the function of key components of many signal transduction systems.
Characterization of the role of CaMKI-like kinase (CKLiK) in human granulocyte function
Authors: Sandra Verploegen, Laurien Ulfman, Hanneke W. M. van Deutekom, Corneli van Aalst, Henk Honing, Jan-Willem J. Lammers, Leo Koenderman, Paul J. Coffer
Journal: Blood (2005)
Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors
Authors: R Issa
Journal: Gut (2001)

<i>Background</i>—Virtual colonoscopy is a potentially powerful tool for non-invasive colorectal evaluation. In vitro studies have established its accuracy in simulated polyp detection but little data exist regarding its use in clinical practice. <i>Aims</i>—To evaluate the ability of virtual colonoscopy to detect colorectal cancers and polyps in patients with endoscopically proven colorectal neoplasms and to correlate the findings of virtual colonoscopy with those of conventional colonoscopy, surgery, and histopathology. <i>Patients</i>—Thirty eight patients with endoscopic findings suggestive of colorectal carcinoma. <i>Methods</i>—Virtual colonoscopy was performed using thin section helical computed tomography (CT) of the abdomen and pelvis after rectal insufflation of room air. Commercially available software was used to generate endoscopic “fly through” examinations of the colon from the CT data. Results were correlated with the findings of conventional colonoscopy and with the surgical and histopathological outcome in each case. <i>Results</i>—Thirty eight pathologically proven colorectal cancers and 23 adenomatous polyps were present. On virtual colonoscopy, all cancers and all polyps measuring greater than 6 mm in size were identified; there were two false positive reports of polyps. On conventional colonoscopy, there was one false positive report of a malignant sigmoid stricture; four subcentimetre polyps were overlooked. Virtual colonoscopy enabled visualisation of the entire colon in 35 patients; conventional colonoscopy was incomplete in 14 patients. Virtual colonoscopy correctly localised all 38 cancers, compared with 32 using conventional colonoscopy. <i>Conclusion</i>—Virtual colonoscopy is a feasible method for evaluating the colon; it may have role in diagnosis of colorectal cancer and polyps.
JAUNDICE IN MICE DUE TO ANOMALIES OF THE BILIARY TRACT
Authors: Alwin M. Pappenheimer, F. S. Cheever, Herman Salk
Journal: The Journal of Experimental Medicine (1955)

There has been described a previously unrecognized disease of mice, characterized by progressive jaundice, first appearing during the nursing period. This has been shown to be due to congenital absence of the terminal segment of the common bile duct, or to the absence of intrahepatic ducts. In the former case, there is distension of the cystic and hepatic ducts, and of the gall bladder, with mucoid material. Biliary cirrhosis and infarct-like areas of necrosis are commonly found in the liver. The cause of the necroses has not been positively determined, but it is suggested that they result from defective arteriolization of the hepatic parenchyma. Inflammatory lesions of the biliary passages, when present, are attributed to secondary bacterial infection. Protozoan-like parasites were present in the gastric epithelium of all mice examined. Their relationship to the biliary and hepatic lesions is as yet undetermined.