tbuckley/cabot-search huggingface dataset:
Clinical and cost effectiveness of paclitaxel, docetaxel, gemcitabine, and vinorelbine in non-small cell lung cancer: a systematic review
Authors: A Clegg
Journal: Thorax (2002)

Background: Lung cancer remains a devastating disease with few effective treatment options. Recent developments in chemotherapy have led to cautious optimism. This paper reviews the evidence on the clinical and cost effectiveness of four of the new generation drugs for patients with lung cancer. Methods: A systematic review of randomised controlled trials (RCTs) identified from 11 electronic databases (including Medline, Cochrane library and Embase), reference lists and contact with experts and industry was performed to assess clinical effectiveness of paclitaxel, docetaxel, gemcitabine and vinorelbine. Clinical effectiveness was assessed using the outcomes of patient survival, quality of life, and adverse effects. Cost effectiveness was assessed by development of a costing model and presented as incremental cost per life year saved (LYS) compared with best supportive care (BSC). Results: Of the 33 RCTs included, five were judged to be of good quality, 10 of adequate quality, and 18 of poor quality. Gemcitabine, paclitaxel, and vinorelbine as first line treatment and docetaxel as second line treatment appear to be more beneficial for non-small cell lung cancer than BSC and older chemotherapy agents, increasing patient survival by 2–4 months against BSC and some comparator regimes. These gains in survival do not appear to be at the expense of quality of life. Survival gains were delivered at reasonable levels of incremental cost effectiveness for vinorelbine, vinorelbine with cisplatin, gemcitabine, gemcitabine with cisplatin, and paclitaxel with cisplatin regimens compared with BSC. Conclusion: Although the clinical benefits of the new drugs appear relatively small, their benefit to patients with lung cancer appears to be worthwhile and cost effective.
Molecular cloning and functional expression of human connexin37, an endothelial cell gap junction protein.
Authors: K E Reed, E M Westphale, D M Larson, H Z Wang, R D Veenstra, E C Beyer
Journal: Journal of Clinical Investigation (1993)

Gap junctions allow direct intercellular coupling between many cells including those in the blood vessel wall. They are formed by a group of related proteins called connexins, containing conserved transmembrane and extracellular domains, but unique cytoplasmic regions that may confer connexin-specific physiological properties. We used polymerase chain reaction amplification and cDNA library screening to clone DNA encoding a human gap junction protein, connexin37 (Cx37). The derived human Cx37 polypeptide contains 333 amino acids, with a predicted molecular mass of 37,238 D. RNA blots demonstrate that Cx37 is expressed in multiple organs and tissues (including heart, uterus, ovary, and blood vessel endothelium) and in primary cultures of vascular endothelial cells. Cx37 mRNA is coexpressed with connexin43 at similar levels in some endothelial cells, but at much lower levels in others. To demonstrate that Cx37 could form functional channels, we stably transfected communication-deficient Neuro2A cells with the Cx37 cDNA. The induced intercellular channels were studied by the double whole cell patch clamp technique. These channels were reversibly inhibited by the uncoupling agent, heptanol (2 mM). The expressed Cx37 channels exhibited multiple conductance levels and showed a pronounced voltage dependence. These electrophysiological characteristics are similar to, but distinct from, those of previously characterized connexins.
Macrophage inflammatory protein 3α transgene attracts dendritic cells to established murine tumors and suppresses tumor growth
Authors: Toshiaki Fushimi, Akira Kojima, Malcolm A.S. Moore, Ronald G. Crystal
Journal: Journal of Clinical Investigation (2000)

Dendritic cells (DCs) are powerful antigen-presenting cells that function as the principal activators of T cells. Since the human CC chemokine, macrophage inflammatory protein 3α (MIP-3α), is chemotactic for DCs in vitro, we hypothesized that adenovirus-mediated gene transfer of MIP-3α (ΑdMIP-3α) to tumors might induce local accumulation of DCs and inhibit growth of preexisting tumors. AdMIP-3α directed expression of mRNA and protein in vitro, and the supernatant of A549 cells infected with AdMIP-3α was chemotactic for DCs. In vivo, injection of AdMIP-3α into subcutaneous tumors resulted in local expression of the MIP-3α cDNA and in the local accumulation of DCs. In four syngeneic tumor models, growth of established tumors was significantly inhibited compared with untreated tumors or tumors injected with control vector, and in all but the poorly immunogenic LLC carcinoma model, this treatment increased survival advantage of the preexisting tumors. In all four tumor models, intratumoral injection of AdMIP-3α induced the local accumulation of CD8b.2+ cells and elicited tumor-specific cytotoxic T-lymphocyte activity, and adoptive transfer of splenocytes of animals receiving this treatment protected against a subsequent challenge with the identical tumor cells. In wild-type but not in CD8-deficient mice, AdMIP-3α inhibited the growth of tumors. Finally, AdMIP-3α also inhibited the growth of distant tumors. This strategy may be useful for enlisting the help of DCs to boost anti-tumor immunity against local and metastatic tumors without the necessity of ex vivo isolation and manipulation of DCs.
The serology of chronic hepatitis B infection revisited.
Authors: T Maruyama, A McLachlan, S Iino, K Koike, K Kurokawa, D R Milich
Journal: Journal of Clinical Investigation (1993)

The serology of chronic hepatitis B infection has been established through the use of commercial immunoassays to measure the structural antigens of the hepatitis B virus and their respective antibodies in serum. However, the commercial assays have not been designed to detect serum antibodies in the presence of an excess of circulating antigens. A series of serum samples from 200 HBeAg-positive, chronically infected hepatitis B patients with varying degrees of liver disease were analyzed using novel immunoassays designed to detect antibodies in the presence of circulating viral antigens. All patients, regardless of their liver disease, were seronegative for antibodies specific for the envelope antigens or the secreted nucleoprotein antigen (HBeAg) when the commercial assays were used. In contrast, virtually all chronically infected patients with liver disease and approximately 50% of patients without liver disease demonstrated anti-HBe and anti-envelope antibodies when sera were tested in the more sensitive immunoassays. Furthermore, asymptomatic patients could be serologically distinguished from symptomatic patients based on antibody fine specificity, titer, and IgG subclass. This study revealed that the majority of chronically infected hepatitis B patients produce a variety of antibodies for many years, and are not immunologically unresponsive, as suggested by the current assays.
MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis
Authors: Désirée van der Heijde, Pedro Machado, Jürgen Braun, Kay-Geert A Hermann, Xenofon Baraliakos, Benjamin Hsu, Daniel Baker, Robert Landewé
Journal: Annals of the Rheumatic Diseases (2011)

Objective To investigate the relationship between MRI inflammation at the vertebral unit and the formation and growth of syndesmophytes at the same vertebral unit. Methods An 80% random sample of the ASSERT database was analysed. MRI were scored using the ankylosing spondylitis (AS) spinal MRI activity score (at baseline, 24 and 102 weeks) and spinal x-rays were scored using the modified Stoke AS spine score (at baseline and 102 weeks). Data were analysed at the patient level and the vertebral unit level using a multilevel approach to adjust for within-patient correlation. Results There was a slightly increased probability of developing syndesmophytes in vertebral units with MRI activity, which was maintained after adjustment for within-patient correlation (per vertebral unit level) and treatment, and after further adjustment for potential confounders, resulting in significant OR ranging from 1.51 to 2.26. Growth of existing syndesmophytes at the vertebral unit level was not associated with MRI activity. At the patient level only a trend for an association was observed. Conclusion MRI inflammation in a vertebral unit slightly increases the propensity to form a new syndesmophyte in the same vertebral unit, but does not predict the growth of already existing syndesmophytes. Despite this association, the large majority of new syndesmophytes developed in vertebral units without inflammation. The subtle association at the vertebral unit level did not translate into an association at the patient level.
Management of Metabolic Effects Associated With Anticancer Agents Targeting the PI3K-Akt-mTOR Pathway
Authors: Naifa L. Busaidy, Azeez Farooki, Afshin Dowlati, John P. Perentesis, Janet E. Dancey, Laurence A. Doyle, Joanna M. Brell, Lillian L. Siu
Journal: Journal of Clinical Oncology (2012)

Agents inhibiting the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.
Gene Transfer of Matrix Metalloproteinase-9 Induces Tumor Regression of Breast Cancer<i>In vivo</i>
Authors: Christina Bendrik, Jennifer Robertson, Jack Gauldie, Charlotta Dabrosin
Journal: Cancer Research (2008)

Abstract Matrix metalloproteinases (MMP) are important regulators of angiogenesis and tumor progression by degradation of extracellular matrix. Clinical trials using MMP inhibitors have failed and recent studies suggest that MMPs may in contrast suppress tumor growth. It is not known, however, if MMPs or their inhibitors, tissue inhibitor of metalloproteinases (TIMP), can be used as therapy of established cancer. Here, adenovirus vectors carrying the human genes for MMP-9, TIMP-1, or empty controls were injected intratumorally in breast cancers established in mice supplemented with estradiol and treated with tamoxifen. Microdialysis was used to quantify MMP activity and sampling of endostatin and vascular endothelial growth factor (VEGF) in situ. We show that AdMMP-9 increased MMP activity in vivo, decreased tumor growth rate, and decreased microvessel area significantly. AdMMP-9 therapy resulted in significantly increased levels of endostatin in vivo, whereas VEGF levels were unaffected. As previously shown, tamoxifen exposure by itself increased MMP activity in all treatment groups. Moreover, the combined therapy with AdMMP-9 and tamoxifen further reduced tumor growth and increased the endostatin levels compared with either treatment alone. Gene transfer of TIMP-1 had no effects on tumor progression and counteracted the therapeutic effect of tamoxifen in our breast cancer model. This is the first report showing that overexpression of MMP-9 results in increased generation of antiangiogenic fragments, decreased angiogenesis, and therapeutic effects of established breast cancer. [Cancer Res 2008;68(9):3405–12]
Epicutaneous sensitization results in IgE-dependent intestinal mast cell expansion and food-induced anaphylaxis
Authors: Lisa M. Bartnikas, Michael F. Gurish, Oliver T. Burton, Sabine Leisten, Erin Janssen, Hans C. Oettgen, Jacqueline Beaupré, Christopher N. Lewis, K. Frank Austen, Stephanie Schulte, Jason L. Hornick, Raif S. Geha, Michiko K. Oyoshi
Journal: Journal of Allergy and Clinical Immunology (2013)
GreenLight HPS 120-W Laser Vaporization Versus Transurethral Resection of the Prostate for Treatment of Benign Prostatic Hyperplasia: A Randomized Clinical Trial with Midterm Follow-up
Authors: Abdulla Al-Ansari, Nagy Younes, Venkataramana Pai Sampige, Khalid Al-Rumaihi, Ardalan Ghafouri, Tawiz Gul, Ahmed A. Shokeir
Journal: European Urology (2010)
Prevalence, Clinicopathologic Associations, and Molecular Spectrum of <i>ERBB2</i> (<i>HER2</i>) Tyrosine Kinase Mutations in Lung Adenocarcinomas
Authors: Maria E. Arcila, Jamie E. Chaft, Khedoudja Nafa, Sinchita Roy-Chowdhuri, Christopher Lau, Michael Zaidinski, Paul K. Paik, Maureen F. Zakowski, Mark G. Kris, Marc Ladanyi
Journal: Clinical Cancer Research (2012)

Activating mutations in the tyrosine kinase domain of HER2 (ERBB2) have been described in a subset of lung adenocarcinomas (ADCs) and are mutually exclusive with EGFR and KRAS mutations. The prevalence, clinicopathologic characteristics, prognostic implications, and molecular heterogeneity of HER2-mutated lung ADCs are not well established in U.S. patients.Lung ADC samples (N = 1,478) were first screened for mutations in EGFR (exons 19 and 21) and KRAS (exon 2), and negative cases were then assessed for HER2 mutations (exons 19-20) using a sizing assay and mass spectrometry. Testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1, and AKT was conducted by mass spectrometry. ALK rearrangements and HER2 amplification were assessed by FISH.We identified 25 cases with HER2 mutations, representing 6% of EGFR/KRAS/ALK-negative specimens. Small insertions in exon 20 accounted for 96% (24/25) of the cases. Compared with insertions in EGFR exon 20, there was less variability, with 83% (20/24) being a 12 bp insertion causing duplication of amino acids YVMA at codon 775. Morphologically, 92% (23/25) were moderately or poorly differentiated ADC. HER2 mutation was not associated with concurrent HER2 amplification in 11 cases tested for both. HER2 mutations were more frequent among never-smokers (P < 0.0001) but there were no associations with sex, race, or stage.HER2 mutations identify a distinct subset of lung ADCs. Given the high prevalence of lung cancer worldwide and the availability of standard and investigational therapies targeting HER2, routine clinical genotyping of lung ADC should include HER2.
Thymidine Selectively Enhances Growth Suppressive Effects of Camptothecin/Irinotecan in MSI+ Cells and Tumors Containing a Mutation of <i>MRE11</i>
Authors: Rene Rodriguez, Lasse Tengbjerg Hansen, Geraldine Phear, Jennifer Scorah, Mogens Spang-Thomsen, Angela Cox, Thomas Helleday, Mark Meuth
Journal: Clinical Cancer Research (2008)

Abstract Purpose: DNA synthesis inhibitors and damaging agents are widely used in cancer therapy; however, sensitivity of tumors to such agents is highly variable. The response of tumor cells in culture to these agents is strongly influenced by the status of DNA damage response pathways. Here, we attempt to exploit the altered response of mismatch repair (MMR)-deficient colon cancer cells and tumors to camptothecin or irinotecan and thymidine by combining them to improve therapeutic response. Experimental Design: A panel of colon cancer cell lines was assayed for response to camptothecin-thymidine combinations by measuring colony formation, cell cycle distribution, and senescence. Cell strains defective in p53, p21, or Mre11 were used in these assays to investigate the role of these cell cycle regulators. The in vivo antitumor response of xenografts to irinotecan and thymidine combinations was assessed in nude mice. Results: Camptothecin-thymidine combinations suppress colony formation of MMR-deficient tumor cells 10- to 3,000-fold relative to that obtained with camptothecin alone and significantly reduce the concentrations of the agents required to induce late S/G2 arrest and senescence. Sensitivity is not a direct result of MMR, p53, or p21 status. However MMR-deficient cell lines containing an intronic frameshift mutation of MRE11 show greatest sensitivity to these agents. Increased sensitivity to this combination is also evident in vivo as thymidine enhances irinotecan-induced growth suppression of MMR-deficient tumors carrying the MRE11 mutation in mouse xenografts. Conclusion: Irinotecan-thymidine combinations may be particularly effective when targeted to MSI+ tumors containing this readily detectable MRE11 mutation.
Hostility and Depression Associated with Suicide Attempts
Authors: MYRNA WEISSMAN, KAREN FOX, GERALD L. KLERMAN
Journal: American Journal of Psychiatry (1973)

Hostility and depression are important factors associated with suicide attempts. Efforts to determine their respective importance, however, have been hindered because they are correlated to some extent with each other and with age and sex. The authors compared 29 acutely depressed women and 29 matched suicide attempters. Manifest hostility emerged as an important distinguishing characteristic of the suicide attempters, who had pervasive and overtly hostile relationships, a poor long-term work history, antisocial behavior, and were demanding and hostile during psychiatric interview. This contrasted with the depressives, who were compliant at interview. The theoretical and clinical implications of these findings are discussed.
Trends in Pregnancy-Related Smoking Rates in the United States, 1987-1996
Authors: Shahul H. Ebrahim
Journal: JAMA (2000)

Rates of smoking are increasing among adolescents and young adults, but trends in smoking among pregnant women have not been studied.To assess pregnancy-related variations in smoking behaviors and their determinants among women of childbearing age in the United States.Analysis of data collected between 1987-1996 from the Behavioral Risk Factor Surveillance System survey.A total of 187302 (178499 nonpregnant and 8803 pregnant) noninstitutionalized women aged 18 to 44 years from 33 states.Prevalence rates of smoking initiation and current smoking, median number of cigarettes smoked, and adjusted odds ratios for smoking stratified by pregnancy status; prevalence rate ratio for current smoking comparing pregnant with nonpregnant women.The overall percentage of women who had ever initiated smoking decreased significantly from 44.1% in 1987 to 38.2% in 1996. During that 10-year period, the prevalence of current smoking also decreased significantly among both pregnant women (16.3% to 11.8%) and nonpregnant women (26.7% to 23.6%). Overall, pregnant women were about half (54%) as likely as nonpregnant women to be current smokers during 1987-1996. Over time, the median number of cigarettes smoked per day by pregnant smokers remained at 10, whereas among nonpregnant smokers it decreased from 19 to 15 (P<.05 for trend). In the same period, among young women (aged 18-20 years), prevalence rates of smoking initiation and current smoking increased slightly. Sociodemographic subgroups of women at increased risk for current smoking were the same for pregnant and nonpregnant women (ie, those with a completed high school education or less, whites, and those who were unmarried).In this analysis, the decline in smoking over time among pregnant women was primarily due to the overall decline in smoking initiation rates among women of childbearing age, not to an increased rate of smoking cessation related to pregnancy. To foster effective perinatal tobacco control, efforts are needed to further reduce the number of young women who begin smoking. Clinicians should query all pregnant women and women of childbearing age about smoking and provide cessation and relapse interventions to each smoker.
Tandem repeats modify the structure of human genes hosted in segmental duplications
Authors: Anna De Grassi, Francesca D Ciccarelli
Journal: Genome biology (2009)

Abstract Background Recently duplicated genes are often subject to genomic rearrangements that can lead to the development of novel gene structures. Here we specifically investigated the effect of variations in internal tandem repeats (ITRs) on the gene structure of human paralogs located in segmental duplications. Results We found that around 7% of the primate-specific genes located within duplicated regions of the genome contain variable tandem repeats. These genes are members of large groups of recently duplicated paralogs that are often polymorphic in the human population. Half of the identified ITRs occur within coding exons and may be either kept or spliced out from the mature transcript. When ITRs reside within exons, they encode variable amino acid repeats. When located at exon-intron boundaries, ITRs can generate alternative splicing patterns through the formation of novel introns. Conclusions Our study shows that variation in the number of ITRs impacts on recently duplicated genes by modifying their coding sequence, splicing pattern, and tissue expression. The resulting effect is the production of a variety of primate-specific proteins, which mostly differ in number and sequence of amino acid repeats.
Answering the Burning Question of How Transient Receptor Potential Vanilloid-1 Channel Antagonists Cause Unwanted Hyperthermia
Authors: Samir S. Ayoub, John C. Hunter, Daniel L. Simmons
Journal: Pharmacological Reviews (2009)

The treatment of chronic pain with new therapies that lack the side effects of existing analgesics is one of medicine9s great unmet needs. Toward this goal, antagonists of the transient receptor potential vanilloid-1 (TRPV1) channel have shown some promise. However, the development of these compounds has been hindered by an unpleasant on-target hyperthermic side effect. With compelling evidence, the accompanying critical review by Romanovsky et al. (p. 228) regarding TRPV1 takes a position on the sites of action of TRPV1 agonists and antagonists on the thermoregulatory system that controls this side effect. From this comes insight on potential ways to overcome the unwanted hyperthermic action of TRPV1 antagonists.
Letter: Bile acids and post-vagotomy diarrhoea.
Authors: J G Allan, V P Gerskowitch, R I Russell
Journal: BMJ (1973)

Lung Cancer and Smoking SIR,-It seems that cigarette smokers adjust the number of cigarettes smokzd to obtain a predetermined dose of nicotine (Dr.M. A. H. Russell and others, 1 December, p. 512).Would it not be much safer (no tar), and much cleaner for non-smokers in the vicinity, to market nicotine inhalers, similar to those used by asthmatics?The price of these could be adjusted so that the Govern- ment need not lose revenue.The nicotine addicts would presumably not be at risk from bronchogenic carcinoma and chronic bronchitis, and there would be no carbon monoxide to contribute to atheroma forma- tion.-Iam, etc.,