tbuckley/cabot-search huggingface dataset:
Prognostic Value of CCN3 in Osteosarcoma
Authors: Bernard Perbal, Monia Zuntini, Diana Zambelli, Massimo Serra, Marika Sciandra, Lara Cantiani, Enrico Lucarelli, Piero Picci, Katia Scotlandi
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Osteosarcoma, the most common bone tumor, lacks prognostic markers that could distinguish patients before therapy and drive treatment choices. We assessed the prognostic value of CCN1, CCN2, and CCN3 genes, involved in fundamental biological processes. Experimental Design: Expression of CCN1, CCN2, and CCN3 was measured by quantitative PCR in 45 newly diagnosed osteosarcomas. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations with osteoblastic differentiation and/or drug response genes were assessed in tumor cells using Spearman correlation and Fisher's exact tests. Results: CCN1 and CCN2 expression was associated with genes involved in commitment of mesenchymal stem cells toward osteoblasts and in early phases of osteoblastic differentiation (RUNX family genes; cadherin 4, 11, and 13; jun and fos; collagen I and SPARC). Although CCN3 is barely expressed in normal proliferating osteoblasts and mesenchymal stem cells, its expression was generally high in osteosarcoma and its level of expression did not correlate with any specific osteoblastic differentiation genes. High expression of CCN3 significantly correlated with worse prognosis in osteosarcoma. This may be only partly explained by the association with the expression of multidrug resistance–related protein 1 and 4, two ATP-binding cassette transporters that also acted as predictors of worse outcome in our study. Conclusions: Our study showed temporal and coordinated expression of CCN1, CCN2, and CCN3 genes during osteoblastic differentiation and highlighted significant differences between human normal and osteosarcoma cell differentiation in vitro. CCN1 and CCN2 expression shows no prognostic relevance in osteosarcoma. In contrast, assessment for CCN3 expression levels at diagnosis may represent a useful molecular tool to early identification of patients with different prognosis.
Randomised, double-blind, placebo-controlled trial of fructo-oligosaccharides in active Crohn's disease
Authors: J. L. Benjamin, C. R. H. Hedin, A. Koutsoumpas, S. C. Ng, N. E. McCarthy, A. L. Hart, M. A. Kamm, J. D. Sanderson, S. C. Knight, A. Forbes, A. J. Stagg, K. Whelan, J. O. Lindsay
Journal: Gut (2011)

<h3>Introduction</h3> The commensal intestinal microbiota drive the inflammation associated with Crohn9s disease. However, bacteria such as bifidobacteria and <i>Faecalibacterium prausnitzii</i> appear to be immunoregulatory. In healthy subjects the intestinal microbiota are influenced by prebiotic carbohydrates such as fructo-oligosaccharides (FOS). Preliminary data suggest that FOS increase faecal bifidobacteria, induce immunoregulatory dendritic cell (DC) responses and reduce disease activity in patients with Crohn9s disease. <h3>Aims and methods</h3> To assess the impact of FOS in patients with active Crohn9s disease using an adequately powered randomised double-blind placebo-controlled trial with predefined clinical, microbiological and immunological end points. Patients with active Crohn9s disease were randomised to 15 g/day FOS or non-prebiotic placebo for 4 weeks. The primary end point was clinical response at week 4 (fall in Crohn9s Disease Activity Index of ≥70 points) in the intention-to-treat (ITT) population. <h3>Results</h3> 103 patients were randomised to receive FOS (n=54) or placebo (n=49). More patients receiving FOS (14 (26%) vs 4 (8%); p=0.018) withdrew before the 4-week end point. There was no significant difference in the number of patients achieving a clinical response between the FOS and placebo groups in the ITT analysis (12 (22%) vs 19 (39%), p=0.067). Patients receiving FOS had reduced proportions of interleukin (IL)-6-positive lamina propria DC and increased DC staining of IL-10 (p&lt;0.05) but no change in IL-12p40 production. There were no significant differences in the faecal concentration of bifidobacteria and <i>F prausnitzii</i> between the groups at baseline or after the 4-week intervention. <h3>Conclusion</h3> An adequately powered placebo-controlled trial of FOS showed no clinical benefit in patients with active Crohn9s disease, despite impacting on DC function. ISRCTN50422530.
Genital involvement in pemphigus vulgaris (PV): Correlation with clinical and cervicovaginal Pap smear findings
Authors: Mukaddes Kavala, Filiz Topaloğlu Demir, Ilkin Zindanci, Burce Can, Zafer Turkoğlu, Ebru Zemheri, Osman Halit Cam, Ahmet Teksen
Journal: Journal of the American Academy of Dermatology (2015)
Development of Growth Hormone Secretagogues
Authors: Roy G. Smith
Journal: Endocrine Reviews (2005)

The GH secretagogues (GHS) were developed by reverse pharmacology. The objective was to develop small molecules with pharmacokinetics suitable for once-daily oral administration that would rejuvenate the GH/IGF-I axis. Neither the receptor nor the ligand that controlled pulse amplitude of hormone release was known; therefore, identification of lead structures was based on function. I reasoned that GH pulse amplitude could be increased by four possible mechanisms: 1) increasing GHRH release; 2) amplifying GHRH signaling in somatotrophs of the anterior pituitary gland; 3) reducing somatostatin release; and 4) antagonizing somatostatin receptor signaling. Remarkably, the GHS act through all four mechanisms to reproduce a young adult physiological GH profile in elderly subjects that was accompanied by increased bone mineral density and lean mass, modest improvements in strength, and improved recovery from hip fracture. Furthermore, restoration of thymic function was induced in old mice. The GHS receptor (GHS-R) was subsequently identified by expression cloning and found to be a previously unknown G protein-coupled receptor expressed predominantly in brain, pituitary gland, and pancreas. Reverse pharmacology was completed when the cloned GHS-R was exploited to identify an endogenous agonist (ghrelin) and a partial agonist (adenosine); ghsr-knockout mice studies confirmed that GHS are ghrelin mimetics.
On error management: lessons from aviation
Authors: R. L Helmreich
Journal: BMJ (2000)

Pilots and doctors operate in complex environments where teams interact with technology. In both domains, risk varies from low to high with threats coming from a variety of sources in the environment. Safety is paramount for both professions, but cost issues can influence the commitment of resources for safety efforts. Aircraft accidents are infrequent, highly visible, and often involve massive loss of life, resulting in exhaustive investigation into causal factors, public reports, and remedial action. Research by the National Aeronautics and Space Administration into aviation accidents has found that 70% involve human error.1

In contrast, medical adverse events happen to individual patients and seldom receive national publicity. More importantly, there is no standardised method of investigation, documentation, and dissemination. The US Institute of Medicine estimates that each year between 44 000 and 98 000 people die as a result of medical errors. When error is suspected, litigation and new regulations are threats in both medicine and aviation.

#### Summary points

In aviation, accidents are usually highly visible, and as a result aviation has developed standardised methods of investigating, documenting, and disseminating errors and their lessons

Although operating theatres are not cockpits, medicine could learn from aviation

Observation of flights in operation has identified failures of compliance, communication, procedures, proficiency, and decision making in contributing to errors

Surveys in operating theatres have confirmed that pilots and doctors have common interpersonal problem areas and similarities in professional culture

Accepting the inevitability of error and the importance of reliable data on error and its management will allow systematic efforts to reduce the frequency and severity of adverse events

Error results from physiological and psychological limitations of humans.2 Causes of error include fatigue, workload, and fear as well as cognitive overload, poor interpersonal communications, imperfect information processing, and flawed decision making.3 In both aviation …
Genetic Disruption of Cytosine DNA Methyltransferase Enzymes Induces Chromosomal Instability in Human Cancer Cells
Authors: Adam R. Karpf, Sei-ichi Matsui
Journal: Cancer Research (2005)

DNA methyltransferase 1 (DNMT1)-deficient mice are tumor-prone, and this has been proposed to result from the induction of genomic instability. To address whether loss of DNMT1, or the related protein DNMT3b, results in genomic instability in human cancer cells, we used a near-diploid human colorectal cancer cell line, HCT116, in which one or both DNMT genes were disrupted by homologous recombination. Array-based comparative genomic hybridization analyses indicated that double, but not single, DNMT knock-out cells display two specific alterations in regional DNA copy number, suggesting that DNMT deficiency and genomic DNA hypomethylation are not associated with widespread genomic amplifications or deletions in human cancer cells. However, spectral karyotype analyses revealed that DNMT-deficient HCT116 cells are highly unstable with respect to large-scale chromosomal alterations; furthermore, this effect is characterized by a high degree of individual cell heterogeneity. The induction of chromosomal alterations in DNMT-deficient cells was evidenced both by aneuploidy and by large increases in the number of novel chromosomal translocations. Studies of double knock-out cells indicated that the generation of chromosomal alterations is spontaneous and persistent in vitro, meeting the formal definition of genomic instability. In summary, we show that DNMT deficiency in human cancer cells results in constitutive genomic instability manifested by chromosomal translocations.
Breast Cancer Risk Among Male BRCA1 and BRCA2 Mutation Carriers
Authors: Y. C. Tai, S. Domchek, G. Parmigiani, S. Chen
Journal: JNCI Journal of the National Cancer Institute (2007)

Men who carry germline mutations in the BRCA2 gene have a higher risk of developing breast carcinoma than men in the general population. Men who carry germline mutations in the BRCA1 gene may also be at a higher risk for breast carcinoma, but this association is not as well established. We evaluated the risks of developing breast carcinoma for male BRCA1 and BRCA2 mutation carriers in the US population based on data from 1939 families with 97 male subjects with breast carcinoma that were collected from eight centers across the National Cancer Institute's Cancer Genetics Network. At all ages, the cumulative risks of male breast cancer were higher in both BRCA1 and BRCA2 mutation carriers than in noncarriers. The relative risks of developing breast cancer were highest for men in their 30s and 40s and decreased with increasing age. Both the relative and cumulative risks were higher for BRCA2 mutation carriers than for BRCA1 mutation carriers. The estimated cumulative risk of breast carcinoma for male BRCA1 mutation carriers at age 70 years was 1.2% (95% confidence interval [CI] = 0.22% to 2.8%) and for BRCA2 mutation carriers, 6.8% (95% CI = 3.2% to 12%).
Making Personalized Cancer Medicine a Reality: Challenges and Opportunities in the Development of Biomarkers and Companion Diagnostics
Authors: David R. Parkinson, Bruce E. Johnson, George W. Sledge
Journal: Clinical Cancer Research (2012)

The origins of this article stem from discussions at the American Association for Cancer Research Clinical and Translational Cancer Research Think Tank meeting held in San Francisco in early 2010. This article synthesizes the opinions and issues considered at that meeting, and discusses many of the important events that have since occurred in the field of personalized cancer medicine. Although investigators continue to make progress in better linking individual patient biology with risk determination, diagnosis, prognosis, and treatment selection, the pace of this progress continues to be limited by many of the issues identified in the meeting.
Recurrent viral infections in patients with past or present atopic dermatitis
Authors: I. RYSTEDT, I.L. STRANNEGARD, O. STRANNEGARD
Journal: British Journal of Dermatology (1986)

Histories of recurrent infections were obtained from 955 adults with past or present atopic dermatitis (AD) and from 199 controls. Patients who had previously been hospitalized in childhood because of severe AD had a significantly higher incidence of recurrent (>5 episodes per year) cold sores and upper respiratory tract infections as well as a higher incidence of herpes zoster, than non‐atopic controls. Patients with milder AD in childhood (never hospitalized) had lower incidence of these diseases, but as regards cold sores, the frequency of recurrent infections was still significantly higher than that of the controls. AD patients with past or present respiratory allergy had a slight but not statistically significant increased incidence of recurrent infections, as compared to AD patients without concomitant respiratory allergy. The factors predisposing to frequent infections appeared to be those related to severity of the atopic condition, i.e. ongoing AD, need for hospitalization in childhood and extent of dermatitis. The increased susceptibility to recurrent viral infections in AD patients is most probably related to dysfunctioning cell‐mediated immunity.
Alternative Splicing of the Cyclin D1 Proto-Oncogene Is Regulated by the RNA-Binding Protein Sam68
Authors: Maria Paola Paronetto, Manuela Cappellari, Roberta Busà, Simona Pedrotti, Roberta Vitali, Clay Comstock, Terry Hyslop, Karen E. Knudsen, Claudio Sette
Journal: Cancer Research (2009)

Human cyclin D1 is expressed as two isoforms derived by alternate RNA splicing, termed D1a and D1b, which differ for the inclusion of intron 4 in the D1b mRNA. Both isoforms are frequently upregulated in human cancers, but cyclin D1b displays relatively higher oncogenic potential. The splicing factors that regulate alternative splicing of cyclin D1b remain unknown despite the likelihood that they contribute to cyclin D1 oncogenicity. In this study, we report that Sam68, an RNA-binding protein frequently overexpressed in prostate cancer cells, enhances splicing of cyclin D1b and supports its expression in prostate cancer cells. Chromatin immunoprecipitation and RNA coimmunoprecipitation experiments showed that Sam68 is recruited to the human CCND1 gene encoding cyclin D1 and that it binds to cyclin D1 mRNA. Transient overexpression and RNAi knockdown experiments indicated that Sam68 acts to enhance endogenous expression of cyclin D1b. Minigene reporter assays showed that Sam68 directly affected alternative splicing of CCND1 message, with a preference for the A870 allele that is known to favor cyclin D1b splicing. Sam68 interacted with the proximal region of intron 4, and its binding correlated inversely with recruitment of the spliceosomal component U1-70K. Sam68-mediated splicing was modulated by signal transduction pathways that elicit phosphorylation of Sam68 and regulate its affinity for CCND1 intron 4. Notably, Sam68 expression positively correlates with levels of cyclin D1b, but not D1a, in human prostate carcinomas. Our results identify Sam68 as the first splicing factor to affect CCND1 alternative splicing in prostate cancer cells, and suggest that increased levels of Sam68 may stimulate cyclin D1b expression in human prostate cancers.
Valproate, in Combination with Pemetrexed and Cisplatin, Provides Additional Efficacy to the Treatment of Malignant Mesothelioma
Authors: Fabian Vandermeers, Pascale Hubert, Philippe Delvenne, Céline Mascaux, Bogdan Grigoriu, Arsène Burny, Arnaud Scherpereel, Luc Willems
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Present chemotherapeutic regimens are marginally efficient in tumor cells being particularly resistant to radiotherapy and/or chemotherapy. We hypothesized that unresponsiveness of tumors to conventional therapeutic agents might be due to inappropriate gene expression resulting from epigenetic modifications and leading to transcriptional silencing. The goal of this study was to evaluate the anticancer effect of a histone deacetylase inhibitor, valproate, on mesothelioma cells in combination with pemetrexed and cisplatin, the usual first-line regimen of chemotherapy for this tumor. Experimental Design and Results: We show that valproate augments apoptosis induced by pemetrexed and cisplatin in mesothelioma cell lines and in tumor cells from patient's biopsies. Onset of apoptosis involves both extrinsic and intrinsic pathways requiring enzymatic activities of caspases 8 and 9, respectively. Valproate but not suberoylanilide hydroxamic acid efficiently stimulates the production of reactive oxygen species. The free radical scavenger N-acetylcysteine inhibits apoptosis, indicating that reactive oxygen species are major mediators of valproate activity. As expected, valproate alone or combined with pemetrexed and cisplatin triggers hyperacetylation of histone H3. Bid protein processing in truncated t-Bid and cytochrome c release from mitochondria are significantly increased in the presence of valproate, providing a mechanistic rationale for improvement of the proapoptotic efficacy of cisplatin and pemetrexed. Finally, valproate when combined with pemetrexed and cisplatin prevents tumor growth in mouse models of epithelioid mesothelioma. Conclusions: These observations support the potential additional efficacy of valproate in combination with pemetrexed and cisplatin for treatment of malignant mesothelioma.
Opportunistic screening for alcohol use disorders in primary care: comparative study
Authors: Simon Coulton, Colin Drummond, Darren James, Christine Godfrey, J Martin Bland, Steve Parrott, Timothy Peters
Journal: BMJ (2006)

To evaluate the efficacy and relative costs of different screening methods for the identification of alcohol use disorders in an opportunistic screening programme in primary care in the United Kingdom.Comparative study.Six general practices in south Wales.194 male primary care attendees aged 18 or over who completed an alcohol use disorders identification test (AUDIT) questionnaire.Scores on alcohol use disorders identification test and measures of gamma-glutamyltransferase, aspartate aminotransferase, per cent carbohydrate deficient transferrin, and erythrocyte mean cell volume. Hazardous alcohol consumption, weekly binge consumption, and monthly binge consumption were ascertained using the time line follow back method over the previous 180 days. Alcohol dependence was determined using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Unit costs were established from published resource references and from actual costs of analysing the biochemical tests.A significant correlation was observed be alcohol consumption and score on the alcohol use disorders identification test (Pearson's correlation coefficient r = 0.74) and measures of gamma-glutamyltransferase (r = 0.20) and per cent carbohydrate deficient transferrin (r = 0.36) but not aspartate aminotransferase (r = 0.08) or erythrocyte mean cell volume (r = 0.02). The alcohol use disorders identification test exhibited significantly higher sensitivity, specificity, and positive predictive value than all of the biochemical markers for hazardous consumption (69%, 98%, and 95%), weekly binge consumption (75%, 90%, and 71%), monthly binge consumption (66%, 97%, and 91%), and alcohol dependence (84%, 83%, and 41%). The questionnaire was also more cost efficient, with a lower cost per true positive for all consumption outcomes.The alcohol use disorders identification test questionnaire is an efficient and cost efficient diagnostic tool for routine screening for alcohol use disorders in primary care.
Improved Glycemic Control and Risk of ESRD in Patients with Type 1 Diabetes and Proteinuria
Authors: Jan Skupien, James H. Warram, Adam Smiles, Andrzej Galecki, Robert C. Stanton, Andrzej S. Krolewski
Journal: Journal of the American Society of Nephrology (2014)

Most patients with type 1 diabetes (T1D) and proteinuria have poor glycemic control and a high risk of ESRD. We investigated whether long-term improvement of glycemic control reduces risk of ESRD in a prospective 7- to 15-year follow-up observation of 349 patients with CKD stages 1-3 enrolled in the Joslin Proteinuria Cohort of adults with T1D. All patients developed proteinuria between 1990 and 2004 and were followed until 2011 to ascertain onset of ESRD and deaths unrelated to ESRD. Furthermore, we analyzed data from 279 patients with ≥3 years of clinic follow-up available to assess the level of glycemic control after enrollment. Average HbA1c during the 5 years before study enrollment (prebaseline) was compared with HbA1c (postbaseline) averaged during the first half of follow-up (median, 5.1 years). Median prebaseline HbA1c was 9.3%, decreasing to 8.7% postbaseline. Cumulative risk of ESRD after 15 years was significantly lower for patients whose HbA1c decreased than for those whose HbA1c increased or remained poor (29% versus 42%; P<0.001). The difference between these groups was not visible at 5 years of follow-up but became visible at 10 and 15 years of follow-up. In multivariate Cox regression analysis of ESRD risk, the hazard ratio corresponding to a 1-percentage point improvement in postbaseline HbA1c was 0.76 (95% confidence interval, 0.63 to 0.91; P=0.003). In conclusion, results of this study suggest that long-term sustained improvement in HbA1c decelerates eGFR loss and delays the onset of ESRD in patients with T1D and proteinuria.
The Nervous Child
Authors: E. M. Creak
Journal: BMJ (1951)

Under the 1944 Education Act every local authority is empowered to provide help for the maladjusted child.This may take the form of a special school, either day pr, more usually, residential, or special classes within an ordinary school.Just as clinics are provided for sight and hearing disorders, so clinics are provided for the treatment of the maladjusted child.Further, a depart- ment of psychiatry is now the rule rather than the exception in the general and teaching hospitals, so that a number of clinics dealing with the problems of the nervous child have also been set up by the regional hospital boards.As, however, it is estimated that 1 to 1.5% of all children will require some psychological help, it is quite obvious that even the growing number of child- guidance clinics and trained workers in child psychiatry will be inadequate to meet these requirements.The family doctor is therefore no stop-gap substitute for the fully staffed child-guidance clinic.He is in many cases the front line of the attack on childhood neurosis, and is in a good position to carry it, for he probably knows the home setting and will have watched the situation as it developed.Who is better able to assess the con- tributions, for or against, made by the grandparents, or the schoolteacher, or the next-door neighbours ?Methods of Approach Because the teaching of child psychiatry can hardly be said to have existed in the curriculum of the pre-1939 medical student, there is still a tendency for doctors to regard the more severe behaviour problems of children as something which only an expert can touch, or to swing