tbuckley/cabot-search huggingface dataset:
Sp1-Mediated TRAIL Induction in Chemosensitization
Authors: Jing Xu, Jun-Ying Zhou, Wei-Zen Wei, Sjaak Philipsen, Gen Sheng Wu
Journal: Cancer Research (2008)

Abstract The regulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) in cancer chemotherapy is not fully understood. Here, we show that the histone deacetylase (HDAC) inhibitors induce TRAIL in human breast cancer cells. Induction of TRAIL by the HDAC inhibitor MS275 can be enhanced by Adriamycin. Using different reporter constructs in conjunction with transcription activity assays and chromatin immunoprecipitation assays, we provide evidence that the transcription factor Sp1 is responsible for TRAIL induction by MS275 alone or in combination with Adriamycin. Further, we show that the combined treatment of breast cancer cells with MS275 and Adriamycin significantly increases apoptotic cell death via the activation of both death receptor and mitochondrial apoptotic pathways. Down-regulation of TRAIL by small interfering RNA silencing decreased MS275-mediated Adriamycin-induced caspase activation and apoptosis, thus conferring Adriamycin resistance. More importantly, breast cancer T47D cells in which Sp1 was knocked down or Sp1-knockout mouse embryonic stem cells were resistant to the combined treatments. Taken together, our results indicate that induction of TRAIL by the combined treatments with MS275 and Adriamycin is mediated by Sp1 and suggest that transcription factor Sp1 is an important target for the development of novel anticancer agents. [Cancer Res 2008;68(16):6718–26]
Proteogenomic Analysis Reveals Unanticipated Adaptations of Colorectal Tumor Cells to Deficiencies in DNA Mismatch Repair
Authors: Patrick J. Halvey, Xiaojing Wang, Jing Wang, Ajaz A. Bhat, Punita Dhawan, Ming Li, Bing Zhang, Daniel C. Liebler, Robbert J.C. Slebos
Journal: Cancer Research (2013)

A growing body of genomic data on human cancers poses the critical question of how genomic variations translate to cancer phenotypes. We used standardized shotgun proteomics and targeted protein quantitation platforms to analyze a panel of 10 colon cancer cell lines differing by mutations in DNA mismatch repair (MMR) genes. In addition, we performed transcriptome sequencing (RNA-seq) to enable detection of protein sequence variants from the proteomic data. Biologic replicate cultures yielded highly consistent proteomic inventories with a cumulative total of 6,513 protein groups with a protein false discovery rate of 3.17% across all cell lines. Networks of coexpressed proteins with differential expression based on MMR status revealed impact on protein folding, turnover and transport, on cellular metabolism and on DNA and RNA synthesis and repair. Analysis of variant amino acid sequences suggested higher stability of proteins affected by naturally occurring germline polymorphisms than of proteins affected by somatic protein sequence changes. The data provide evidence for multisystem adaptation to MMR deficiency with a stress response that targets misfolded proteins for degradation through the ubiquitin-dependent proteasome pathway. Enrichment analysis suggested epithelial-to-mesenchymal transition in RKO cells, as evidenced by increased mobility and invasion properties compared with SW480. The observed proteomic profiles demonstrate previously unknown consequences of altered DNA repair and provide an expanded basis for mechanistic interpretation of MMR phenotypes.
Lessons to be learnt from unsuccessful clinical trials
Authors: R. L. Smyth
Journal: Thorax (2011)

In Thorax , Lenney and colleagues have described their trials and tribulations with the MASCOT study, which compared three different treatment options in children with asthma whose condition was not adequately controlled on low-dose inhaled corticosteroids (ICS).1 The study, which aimed to initially recruit 900 children and enter 450 into a randomised comparison, recently had to close because it had fallen considerably short of its recruitment targets and funding was not extended (by the NIHR Health Technology Assessment Programme). The MASCOT trial was coordinated by the NIHR Medicines for Children Research Network (MCRN) Clinical Trials Unit and supported by the NIHR MCRN and Primary Care Research Networks, which provided an infrastructure of research nurses and other staff to support recruitment of children both in the community and from hospital outpatient clinics. The trial addressed a very important clinical question, but despite a great deal of effort by researchers, clinical trial methodologists and support staff, it failed. Why was this and what lessons can be learnt for the future?

The first series of tribulations that the investigators ran into related to the preparation, packaging and supply of the investigational medicinal products (IMPs) and placebos. To design the trial as a double-blind comparison, among three treatment arms, each child had to take three preparations: ICS plus montelukast and long-acting beta-agonist (LABA) placebo, or ICS plus LABA and montelukast placebo, or ICS plus LABA placebo and montelukast placebo. The investigators depended on two pharmaceutical companies for the supply of these active drugs and placebo. In their section entitled ‘Study progress’, they chronicle a series of problems, which together delayed study initiation by at least 18 months. To maintain the double-blind design, the investigators were critically dependent on …
Cochrane reviews compared with industry supported meta-analyses and other meta-analyses of the same drugs: systematic review
Authors: Anders W Jørgensen, Jørgen Hilden, Peter C Gøtzsche
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To compare the methodological quality and conclusions in Cochrane reviews with those in industry supported meta-analyses and other meta-analyses of the same drugs. <b>Design</b> Systematic review comparing pairs of meta-analyses that studied the same two drugs in the same disease and were published within two years of each other. <b>Data sources</b> Cochrane Database of Systematic Reviews (2003, issue 1), PubMed, and Embase. <b>Data extraction</b> Two observers independently extracted data and used a validated scale to judge the methodological quality of the reviews. <b>Results</b> 175 of 1596 Cochrane reviews had a meta-analysis that compared two drugs. Twenty four meta-analyses that matched the Cochrane reviews were found: eight were industry supported, nine had undeclared support, and seven had no support or were supported by non-industry sources. On a 0-7 scale, the median quality score was 7 for Cochrane reviews and 3 for other reviews (P &lt; 0.01). Compared with industry supported reviews and reviews with undeclared support, Cochrane reviews had more often considered the potential for bias in the review—for example, by describing the method of concealment of allocation and describing excluded patients or studies. The seven industry supported reviews that had conclusions recommended the experimental drug without reservations, compared with none of the Cochrane reviews (P = 0.02), although the estimated treatment effect was similar on average (z = 0.46, P = 0.64). Reviews with undeclared support and reviews with not for profit support or no support had conclusions that were similar in cautiousness to the Cochrane reviews. <b>Conclusions</b> Industry supported reviews of drugs should be read with caution as they were less transparent, had few reservations about methodological limitations of the included trials, and had more favourable conclusions than the corresponding Cochrane reviews.
Acute inhalation of cigarette smoke increases lower respiratory tract nitric oxide concentrations
Authors: D C Chambers, W S Tunnicliffe, J G Ayres
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Cigarette smoking is associated with a number of common pulmonary diseases including chronic airflow limitation and bronchial carcinoma. Lower respiratory tract (LRT) nitric oxide (NO) concentrations are reduced in habitual cigarette smokers between cigarettes, and although this finding has been implicated in the pathogenesis of smoking related disease, the underlying mechanisms are unclear. A study was undertaken to determine the nature and time course for changes in LRT NO concentrations following acute inhalation of cigarette smoke. <h3>METHODS</h3> Twenty four healthy habitual smokers were studied. The concentration of LRT NO in exhaled breath before, one and ten minutes after smoking a single cigarette was measured using chemiluminescence. <h3>RESULTS</h3> LRT NO concentrations increased in all subjects from a mean (SE) of 2.6 (0.27) to 4.8 (0.26) ppb (p&lt;0.0001) at one minute, and at 10 minutes remained significantly raised above the baseline level at 3.2 (0.25) ppb (p = 0.003). The mean (95% CI) increases in NO concentrations were 2.2 (1.7 to 2.7) and 0.6 (0.2 to 1.0) ppb, respectively. <h3>CONCLUSIONS</h3> These findings were unexpected in both their direction and time course. They suggest a novel mechanism for the handling of NO in the human lung. We hypothesise that NO is trapped in the epithelial lining fluid (ELF) of the normal human respiratory tract in bioequivalent forms such as S-nitrosothiols or peroxynitrite and that this trapping mechanism is sensitive to the redox state of the ELF. LRT NO concentrations will thus increase with oxidant exposure and decline as pulmonary antioxidant defence mechanisms take effect. These findings may have implications for the pathogenesis and diagnosis of oxidant mediated pulmonary disease.
Homosexuality: III. Psychiatric Disorders and Disability in the Male Homosexual
Authors: MARCEL T. SAGHIR, ELI ROBINS, BONNIE WALBRAN, KATHYE A. GENTRY
Journal: American Journal of Psychiatry (1970)

There was little difference demonstrated in the prevalence of psychopathology between a group of 89 male homosexuals and a control group of 35 unmarried men. There was, however, slightly more disability and more clinically significant change in the lives of the homosexual men. Despite the slight increase in disability and the changes in their lives, the homosexual men functioned well.
Celecoxib Versus Placebo for Men With Prostate Cancer and a Rising Serum Prostate-Specific Antigen After Radical Prostatectomy and/or Radiation Therapy
Authors: Matthew R. Smith, Judith Manola, Donald S. Kaufman, William K. Oh, Glenn J. Bubley, Philip W. Kantoff
Journal: Journal of Clinical Oncology (2006)

Purpose To assess the biologic activity of celecoxib, a selective cyclooxygenase-2 inhibitor, in men with recurrent prostate cancer using change in prostate-specific antigen (PSA) doubling time (PSADT) as the primary outcome variable. Patients and Methods Participants had histologically confirmed prostate cancer, no recent hormone therapy, rising serum PSA after radical prostatectomy and/or radiation therapy, and no radiographic evidence of metastases. Patients were randomly assigned to celecoxib (400 mg by mouth twice daily) or placebo. Treatment continued until disease progression or until adverse effects stopped treatment. A positive outcome was defined as post-treatment PSADT of more than 200% baseline PSADT with no new metastases. Results The study was terminated early after information about the cardiovascular safety of celecoxib prompted review of ongoing clinical studies. Before discontinuation of the study, 78 men were assigned randomly to either celecoxib or placebo. Eight (20%) of 40 men in the placebo group and 15 (40%) of 38 men in the celecoxib group had post-treatment PSADT of more than 200% of baseline PSADT with no new metastases (P = .08). Mean PSA velocity increased by 3.0% for the placebo group and decreased by 3.4% for the celecoxib group (P = .02). Conclusion Although the primary efficacy objective was not met, this study provides some evidence for biologic activity of celecoxib in prostate cancer. Compared with placebo, celecoxib significantly decreased mean PSA velocity and tended to increase the proportion of men who doubled their PSADT.
Tendon healing: can it be optimised?
Authors: N Maffulli, H D Moller, C H Evans
Journal: British Journal of Sports Medicine (2002)

Growth factors may be useful in tendon healing, possibly introduced using gene therapy

Tendon disorders are a major problem in sports and occupational medicine. Tendons have the highest tensile strength of all connective tissue because of a high proportion of collagen in the fibres and their closely packed parallel arrangement in the direction of force. The individual collagen fibrils are arranged into fascicles which contain blood vessels and nerve fibres. Specialised fibroblasts, tenocytes, lie within these fascicles and exhibit high structural organisation.1 Histologically, they appear as star shaped cells in cross sections. In longitudinal sections, they are arranged in rows following the direction of the tendon fibres. This specialised arrangement is related to their function, as tenocytes synthesise both fibrillar and non-fibrillar components of the extracellular matrix, and are able to reabsorb collagen fibrils.2 The fascicles themselves are enclosed by epitenon. This is surrounded by the paratenon, and the potential space between them is filled by a thin, lubricating film of fluid which allows gliding of the tendon during motion.

Tendon healing is classically considered to occur through extrinsic and intrinsic healing. The intrinsic model produces obliteration of the tendon and its tendon sheath. Healing of the defect involves an exudative and a formative phase which, on the whole, are very similar to those associated with wound healing.3 Extrinsic healing occurs through the chemotaxis of the specialised fibroblasts into the defect from the ends of the tendon sheath.4 The process can be divided into three phases: inflammation, repair, and organisation or remodelling. In the inflammatory phase, occurring three to seven days after the injury, cells migrate from the extrinsic peritendinous tissue such as the tendon sheath, periosteum, subcutaneous tissue, and fascicles, as well as from the epitenon and endotenon.5 Initially, the extrinsic response far …
Remarks on SOME FORMS OF SPASM IN CHILDHOOD: THEIR CAUSE AND TREATMENT
Authors: A. D. Fordyce
Journal: BMJ (1931)

It has been said' that " a child is the sum total of his movements or tendencies to move."Movement follows on muscular contraction resulting from nervous stimula- tion, and spasm in ordinary medical parlance is a term used to mean involuntary sustained muscular contraction occurring as an abnormal manifestation.Such spasm may be usefully considered as it discloses itself to the clinician at different sites and in different bodily con- ditions.An abnormal condition of neuro-muscular apparatusfor example, spasm-may be produced by a local peripheral cause, or result from a primiiary lesion or abnormality of the central nervous system interfering with its function of nervous control.It is not possible, however, to dissociate the mental functions and the functions of nervous control in the central nervous system, and spasm may occur from disturbance of the mental functions, with no detectable abnormality in local neuro-muscular apparatus or in the central seat bf nervous control.Thus emotional disturbance may be the primary exciting cause.Careful attention must also be given to the degree of development of the intellectual powers in childhood.If, then, we have to take into account such varying factors in etiology, we must go further and consider important influences affecting the functions of the central nervous system.Such, in this connexion, are the influence on bodily processes of endocrine secretion, calciu-m meta- bolism, and the phenomena of anaphylaxis; the results of training and education; and the development of inhibition.The symptom of spasm may be considered in four groups.
Mycoplasma pneumoniae infection is associated with subacute cough
Authors: X. Yuan, Y. Liu, C. Bai, Y. Luo, R. Wang, R. Wang, Y. Cai, X. Zhao
Journal: European Respiratory Journal (2013)

Mycoplasma pneumoniae infection is associated with subacute coughTo the Editor:Cough, one of the most common reasons patients seek medical attention [1], is categorised according to duration.Acute cough lasts ,3 weeks, subacute cough lasts 3-8 weeks and chronic cough .8weeks [2,3].Acute cough is usually due to viral infection; it is transient and self-limiting [4].Chronic cough has a variety of causes that can be established in 88-100% of patients using a diagnostic algorithm [3].In contrast, the aetiology of subacute cough remains poorly defined, although post-infectious cough, sinusitis, post-nasal drip and bronchial asthma are listed as possible causes [2,3,5,6].As subacute cough is often refractory to recommended therapies, a better understanding of its aetiology is needed.The present work examined a possible role for Mycoplasma pneumoniae infection in subacute cough.Between July 2010 and June 2011, patients who visited the Dept of Respiration at the Affiliated Hospital of Academy of Military and Medical Sciences (AHAMMS, Beijing, China) on their own initiative were screened and enrolled if they met the following criteria: cough was the only major complaint; cough was not associated with haemoptysis; cough had lasted for 3-8 weeks (determined by patient recall); chest radiography was normal; and age o15 years.Exclusion criteria included inpatient status, a prior history of lung or other systemic disease that could account for cough, current or past smoking, taking angiotensinconverting enzyme inhibitors, known immunodeficiency or pregnancy.Control subjects were enrolled from healthy medical staff in the department, their family members and relatives of patients who accompanied the patients.Control subjects had no cough for o1 month and were subject to the same exclusion criteria as patients.Efforts were made to match controls with patients by age, sex and time of enrolment.The study was approved by the ethics committee of AHAMMS (protocol #2010-08-99-1).
Age-related changes in lung structure and function in the senescence-accelerated mouse (SAM): SAM-P/1 as a new murine model of senile hyperinflation of lung.
Authors: M Kurozumi, T Matsushita, M Hosokawa, T Takeda
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

Age-related changes in lung structure and function were investigated in murine models of accelerated senescence (SAM-P/1) and of normal aging (SAM-R/1). In morphometric studies, most of the parameters examined, including lung volume, mean linear intercept, total alveolar duct air volume, and total alveolar air volume, began to increase and the internal surface area per unit lung volume and total elastic fiber length per unit lung volume began to decrease from 2 months of age, and these changes continued to progress up to 10 months of age in SAM-P/1. In SAM-R/1, there were no significant changes in these parameters from 2 to 6 months of age, thereafter slight but steady changes were observed up to 25 months of age. Thus, significant differences in these parameters between SAM-P/1 and SAM-R/1 became evident in mice 6 to 17 months of age. Internal surface area and total elastic fiber length showed no age-related changes after 2 months of age, and total alveolar air volume showed no age-related changes after 6 months of age in either strain. All morphometric parameters examined showed similar levels at 17 months of age in SAM-P/1 and 25 months of age in SAM-R/1. Histologic observations revealed no evidence of destruction of the alveolar wall or elastic fibers in the lung.(ABSTRACT TRUNCATED AT 250 WORDS)
A Calmodulin-Binding Site on Cyclin E Mediates Ca <sup>2+</sup> -Sensitive G <sub>1</sub> /S Transitions in Vascular Smooth Muscle Cells
Authors: Jaehyun Choi, Andrew Chiang, Nicolas Taulier, Robert Gros, Asif Pirani, Mansoor Husain
Journal: Circulation Research (2006)

Calcium transients are known to control several transition points in the eukaryotic cell cycle. For example, we have previously shown that a coordinate elevation in the intracellular free calcium ion concentration is required for G1- to S-phase cell cycle progression in vascular smooth muscle cells (VSMC). However, the molecular basis for this Ca2+ sensitivity was not known. Using buffers with differing [Ca2+], we found that the kinase activity of mouse and human cyclin E/CDK2, but not other G1/S-associated cell cycle complexes, was responsive to physiological changes in [Ca2+]. We next determined that this Ca2+-responsive kinase activity was dependent on a direct interaction between calmodulin (CaM), one of the major Ca2+-signal transducers of eukaryotic cells, and cyclin E. Pharmacological inhibition of CaM abrogated the Ca2+ sensitivity of cyclin E/CDK2 and retarded mouse VSMC proliferation by causing G1 arrest. We next defined the presence of a highly conserved 22 amino acid N-terminal CaM-binding motif in mammalian cyclin E genes (dissociation constant, 1.5+/-0.1 micromol/L) and showed its essential role in mediating Ca2+-sensitive kinase activity of cyclin E/CDK2. Mutant human cyclin E protein, lacking this CaM-binding motif, was incapable of binding CaM or responding to [Ca2+]. Taken together, these findings reveal CaM-dependent cyclin E/CDK2 activity as a mediator of the known Ca2+ sensitivity of the G1/S transition of VSMC.
Response of Automatic Continuous Positive Airway Pressure Devices to Different Sleep Breathing Patterns
Authors: Ramon Farré, Josep M. Montserrat, Jordi Rigau, Xavier Trepat, Paula Pinto, Daniel Navajas
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Evaluating the usefulness of automatic continuous positive airway pressure (CPAP) in treating the sleep apnea–hypopnea syndrome (SAHS) is not easy because the algorithms for automatic CPAP implemented in the devices available are not well known and are probably dependent on the device. In addition, at present it is not possible to test the behavior of automatic CPAP devices in response to well-defined breathing patterns. Our aim was to implement a bench test to characterize the responses of automatic CPAP devices by subjecting them to breathing patterns of patients with SAHS. To this end, a variety of typical breathing patterns (normal, apneas, hypopneas, flow limitation, snoring) previously recorded in patients with SAHS during sleep were reproduced by a breathing waveform generator. Five commercially available automatic CPAP devices were tested. The responses of the devices to apneas, hypopneas, flow limitation, and snoring were considerably different. In some devices, the response was modified by air leaks similar to the ones found in patients. Consequently, the effectiveness of automatic CPAP assessed in clinical tests performed by using particular devices has no general validity. Testing automatic CPAP devices in a bench study is a useful first step in evaluating the performance of this new type of device in adjusting nasal pressure for each patient.