tbuckley/cabot-search huggingface dataset:
S57 Evaluation of circulating biomarkers in lymphangioleiomyomatosis
Authors: W. Y. C. Chang, L. M. Magowan, S. R. Johnson
Journal: Thorax (2010)

<h3>Rationale</h3> Lymphangioleiomyomatosis (LAM) is a rare disease of the lungs and lymphatics occurring almost exclusively in women, usually presenting before menopause. It is characterised by progressive cystic destruction of the lung parenchyma, obstruction of lymphatics, airways, and often progressive respiratory failure. Recent diagnostic criteria require lung biopsy in addition to HRCT in the absence of other features such as tuberous sclerosis, renal angiomyolipomas or chylous effusions. The clinical course of LAM varies significantly, and there are no good predictors of clinical progression. Vascular endothelial growth factor D (VEGFD) has been found to be increased in the serum of LAM patients but its role as a biomarker has never been examined prospectively. We aimed to see if: VEGF-D reduces the need for lung biopsy for diagnosis using a proposed cut off with an estimated test sensitivity for LAM of 86%, specificity of 91%, and a positive likelihood ratio of 9.6. VEGF-D is a useful predictor of severity when correlated with lung function data. <h3>Results</h3> Serum samples were taken from 34 LAM patients and 12 healthy controls and a significant difference in VEGF-D levels was seen (Patient median=768 pg/ml, IQR=417.6–1509, control median=329.5, IQR=288.6–489.0, p=0.0082, Mann–Whitney U test). However, using the proposed cut off of 574 pg/ml by <i>Young et al</i> (2008), only 1 patient in our cohort with a diagnosis of “probable” LAM would have avoided the need for a lung biopsy to confirm diagnosis. When correlated with lung function, only TLCO demonstrated a statistically significant negative correlation with VEGFD levels (r<sup>2</sup>=0.2143, p=0.0131). <h3>Conclusions</h3> Though an interesting research tool, the value of VEGFD as a biomarker in LAM has not been clearly demonstrated and there is currently insufficient evidence to advocate its role either to aid in diagnosis or prediction of outcome in LAM.
Targeting IL-18 by Employing a Recombinant IL-18 Peptide-based Vaccine Ameliorates TNBS-induced Murine Acute and Chronic Colitis
Authors: S. Moreno, Q. Guan, C. Weiss, Q. Gefei, C. Bernstein, Z. Peng
Journal: Journal of Allergy and Clinical Immunology (2012)
Genetic Demonstration of p47phox-Dependent Superoxide Anion Production in Murine Vascular Smooth Muscle Cells
Authors: Mark C. Lavigne, Harry L. Malech, Steven M. Holland, Thomas L. Leto
Journal: Circulation (2001)

Previous investigations provide evidence that an enzyme related to the phagocyte NADPH oxidase produces superoxide in the blood vessel wall. These data, however, are confounded by observations that both NADPH and NADH serve as substrates for superoxide production in vascular cells. To clarify this issue, we compared the superoxide-generating capabilities of vascular smooth muscle cells (VSMCs) derived from wild-type (p47phox(+/+); phagocyte oxidase) mice with those from mice that lack p47phox (p47phox(-/-); "knockout"), an essential component of the phagocyte NADPH oxidase.VSMCs were derived from aortic explants harvested from p47phox(+/+) or p47phox(-/-) mice. VSMCs from p47phox(+/+) but not those from p47phox(-/-) mice produced superoxide after stimulation by phorbol myristate acetate. Consistent with this, p47phox was detected only in p47phox(+/+) VSMCs. p47phox-transduced p47phox(-/-) but not enhanced green fluorescent protein-transduced p47phox(-/-) VSMCs generated significant levels of superoxide after stimulation by angiotensin II or platelet-derived growth factor-BB (PDGF-BB). Enhanced expression of recombinant p47phox in p47phox-transduced p47phox(-/-) cells correlated with superoxide production in these cells.These data provide direct functional proof that an oxidase requiring the p47phox component mediates superoxide release from VSMCs in the blood vessel wall in response to angiotensin II or PDGF-BB.
Secondary Somatic Mutations Restoring<i>BRCA1/2</i>Predict Chemotherapy Resistance in Hereditary Ovarian Carcinomas
Authors: Barbara Norquist, Kaitlyn A. Wurz, Christopher C. Pennil, Rochelle Garcia, Jenny Gross, Wataru Sakai, Beth Y. Karlan, Toshiyasu Taniguchi, Elizabeth M. Swisher
Journal: Journal of Clinical Oncology (2011)

Secondary somatic BRCA1/2 mutations may restore BRCA1/2 protein in hereditary ovarian carcinomas. In cell lines, BRCA2 restoration mediates resistance to platinum chemotherapy and poly (ADP-ribose) polymerase (PARP) inhibitors. We assessed primary and recurrent BRCA1/2-mutated ovarian carcinomas to define the frequency of secondary mutations and correlate these changes with clinical outcomes.Neoplastic cells were isolated with laser capture microdissection, and DNA was sequenced at the site of the known germline BRCA1/2 mutation. When secondary mutations were found that restored wild-type sequence, haplotyping was performed using single nucleotide polymorphisms in tumor and paired lymphocyte DNA to rule out retention of the wild-type allele.There were 64 primary and 46 recurrent ovarian carcinomas assessed. Thirteen (28.3%) of 46 (95% CI, 17.3% to 42.6%) recurrent carcinomas had a secondary mutation compared with two (3.1%) of 64 (95% CI, 1.0% to 10.7%) primary carcinomas (P = .0003, Fisher's exact test). Twelve (46.2%) of 26 (95% CI, 28.7% to 64.7%) platinum-resistant recurrences had secondary mutations restoring BRCA1/2, compared with one (5.3%) of 19 (95% CI, 1.2% to 24.8%) platinum-sensitive recurrences (P = .003, Fisher's exact test). Six (66.7%) of nine (95% CI, 34.8% to 87.8%) women with prior breast carcinoma had a recurrent carcinoma with a secondary mutation, compared with six (17.1%) of 35 (95% CI, 8.2% to 32.8%) with no history of breast carcinoma (P = .007, Fisher's exact test).Secondary somatic mutations that restore BRCA1/2 in carcinomas from women with germline BRCA1/2 mutations predict resistance to platinum chemotherapy and may also predict resistance to PARP inhibitors. These mutations were detectable only in ovarian carcinomas of women whom have had previous chemotherapy, either for ovarian or breast carcinoma.
Cultured Porcine Coronary Artery Smooth Muscle Cells
Authors: Thomas Christen, Marie-Luce Bochaton-Piallat, Pascal Neuville, Sander Rensen, Mireille Redard, Guillaume van Eys, Giulio Gabbiani
Journal: Circulation Research (1999)

Arterial intimal thickening after endothelial injury induced in rodents has proven to be a relatively unreliable model of restenosis for testing clinically useful compounds. The same has been found for cultured rat or rabbit vascular smooth muscle cells (SMCs). To test alternative possibilities, we have studied several differentiation features of porcine coronary artery SMCs, cultured up to the 5th passage after enzymatic digestion of the media. The effects of heparin, transforming growth factor (TGF)-beta1 or TGF-beta2, and all-trans-retinoic acid (tRA) on proliferation, migration, and differentiation of these cells also were examined. Porcine arterial SMCs in culture not only express high levels of alpha-smooth muscle (SM) actin but, contrary to rodent SMCs, also maintain an appreciable expression of SM myosin heavy chain isoforms 1 and 2, desmin, and smoothelin, a recently described late differentiation marker of vascular SMCs. We demonstrate for the first time that smoothelin is colocalized with alpha-SM actin in these cells. Finally, we show that in the porcine model, heparin is more potent than TGF-beta1 or TGF-beta2 and tRA in terms of inhibition of proliferation and migration and of increasing the expression of differentiation markers. This model should be a useful complement to in vivo studies of SMC differentiation and of pathological situations such as restenosis and atheromatosis.
A Japanese piebald patient with auburn hair colour associated with a novel mutation p.P832L in the<i>KIT</i>gene and a homozygous variant p.I120T in the<i>MC1R</i>gene
Authors: N. Oiso, K. Kishida, K. Fukai, T. Motokawa, N. Hosomi, T. Suzuki, Y. Mitsuhashi, R. Tsuboi, A. Kawada
Journal: British Journal of Dermatology (2009)

E‐mail: naoiso@med.kindai.ac.jp Conflicts of interest: none declared. Piebaldism (MIM 172800) is an inherited disorder characterized by congenital poliosis and leucoderma on the frontal scalp, forehead, ventral trunk and extremities. Some patients with piebaldism have café‐au‐lait spots. Piebaldism is caused by a mutation of the KIT protooncogene encoding c‐kit, and shows autosomal dominant inheritance.1 2–3 Red hair colour (RHC) can be observed in as many as 6% or more Icelanders,4 although it is apparently rare in Asians. RHC is associated with inactive variants of the melanocortin‐1 receptor (MC1R) gene and is believed to be recessive.5 MC1R is a seven transmembrane G‐protein‐coupled receptor. Certain variants are related to the RHC phenotype of fair skin, poor tanning ability and elevated risk of freckles, solar lentigines, malignant melanoma, basal cell carcinoma and squamous cell carcinoma.6 A 1‐year‐old Japanese girl presented with aberrant hair and skin colour. Physical examination revealed: (i) poliosis on the frontal region of the scalp; (ii) auburn hair colour on the other regions of the scalp; (iii) leucoderma on the forehead, the ventral trunk, knees and elbows; (iv) fair skin on the face except for the forehead, and on the dorsal trunk, upper arms and thighs; and (v) multiple café‐au‐lait spots on regions of both leucoderma and fair skin (Fig. 1a, b). Her irides were symmetrically brown. There was no family history of the disease or parental consanguinity.
Advances in motor neurone disease
Authors: Dirk Bäumer, Kevin Talbot, Martin R Turner
Journal: Journal of the Royal Society of Medicine (2014)

Motor neurone disease (MND), the commonest clinical presentation of which is amyotrophic lateral sclerosis (ALS), is regarded as the most devastating of adult-onset neurodegenerative disorders. The last decade has seen major improvements in patient care, but also rapid scientific advances, so that rational therapies based on key pathogenic mechanisms now seem plausible. ALS is strikingly heterogeneous in both its presentation, with an average one-year delay from first symptoms to diagnosis, and subsequent rate of clinical progression. Although half of patients succumb within 3-4 years of symptom onset, typically through respiratory failure, a significant minority survives into a second decade. Although an apparently sporadic disorder for most patients, without clear environmental triggers, recent genetic studies have identified disease-causing mutations in genes in several seemingly disparate functional pathways, so that motor neuron degeneration may need to be understood as a common final pathway with a number of upstream causes. This apparent aetiological and clinical heterogeneity suggests that therapeutic studies should include detailed biomarker profiling, and consider genetic as well as clinical stratification. The most common mutation, accounting for 10% of all Western hemisphere ALS, is a hexanucleotide repeat expansion in C9orf72. This and several other genes implicate altered RNA processing and protein degradation pathways in the core of ALS pathogenesis. A major gap remains in understanding how such fundamental processes appear to function without obvious deficit in the decades prior to symptom emergence, and the study of pre-symptomatic gene carriers is an important new initiative.
The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2)
Authors: Andrew Hesketh, Wenqiong Joan Chen, Jamie Ryding, Sherman Chang, Mervyn Bibb
Journal: Genome biology (2007)

Regulation of production of the translational apparatus via the stringent factor ppGpp in response to amino acid starvation is conserved in many bacteria. However, in addition to this core function, it is clear that ppGpp also exhibits genus-specific regulatory effects. In this study we used Affymetrix GeneChips to more fully characterize the regulatory influence of ppGpp synthesis on the biology of Streptomyces coelicolor A3(2), with emphasis on the control of antibiotic biosynthesis and morphological differentiation.Induction of ppGpp synthesis repressed transcription of the major sigma factor hrdB, genes with functions associated with active growth, and six of the thirteen conservons present in the S. coelicolor genome. Genes induced following ppGpp synthesis included the alternative sigma factor SCO4005, many for production of the antibiotics CDA and actinorhodin, the regulatory genes SCO4198 and SCO4336, and two alternative ribosomal proteins. Induction of the CDA and actinorhodin clusters was accompanied by an increase in transcription of the pathway regulators cdaR and actII-ORF4, respectively. Comparison of transcriptome profiles of a relA null strain, M570, incapable of ppGpp synthesis with its parent M600 suggested the occurrence of metabolic stress in the mutant. The failure of M570 to sporulate was associated with a stalling between production of the surfactant peptide SapB, and of the hydrophobins: it overproduced SapB but failed to express the chaplin and rodlin genes.In S. coelicolor, ppGpp synthesis influences the expression of several genomic elements that are particularly characteristic of streptomycete biology, notably antibiotic gene clusters, conservons, and morphogenetic proteins.
3 Critical Challenges for Global Health Security
Authors: Lawrence O. Gostin
Journal: JAMA (2015)

International institutions are poised to make one of the most momentous decisions about the futureof global health security since the formation of the World Health Organization (WHO) in 1948. By the end of this year, 5 global commissions will have published major critiques of global health preparedness, all spurred by the Ebola epidemic, which exposed deep flaws in the international system. These commiss ions inc lude the WHO’s independent Ebola Interim Assessment Panel, which reported in July that senior leaders failed to respond effectively during the crisis in West Africa, calling for “significant transformation” of the agency (http://bit.ly/1JS5lQe); the WHO Review Committee on the International Health Regulations (IHR), which held its first meeting in Geneva late August (http://bit .ly/1E5thKN); the Harvard/London School of Hygiene and Tropical Medicine Independent Panel on Ebola; the Global Health Risk Framework Commission of the National Academy of Medicine (formerly the Institute of Medicine); and the United Nations (UN) secretary-general formed a High-Level Panel, which includes sitting heads of state to provide political support for major reforms of the global health system (http://bit.ly/1PgRHIk). All the reports will feed into the January meeting of the WHO executive board, with the final decisions taken by the World HealthAssembly inMay2016.Thereareconcerns that 5 commissions will prove to be costly andduplicative.Moreover, there isno assurance that their recommendations will leadtothemeaningfulandenduringchanges now so badly needed in the global health landscape.
"Internet Patients" Turn to Support Groups to Guide Medical Decisions
Authors: J. Smith
Journal: JNCI Journal of the National Cancer Institute (1998)

People facing all types of illnesses often seek advice or offer it through internet support gronps. "Internet Patients" Turn to Support Groups to Guide Medical DecisionsT"I 2 57PI.ltheir support groups via e-mail listserves, electronic bulletin boards, or chat rooms.By sharing experiences and referring each other to print articles and web sites, patients have become more aware of the issues and their options regarding diagnosis, treatment, and recovery.Among the things Easlick learned on-line is that there is no established protocol for treating prostate cancer, although surgery is commonly recommended.However, brachytherapyplacing radioactive "seeds" into or near the affected gland -intrigued Easlick; implanting seeds is less invasive than regular surgery, its proponents say, and .,.F2fIMl loois COI!J)OSe
Mir31-3P Expression in Patients with Advanced Lepidic Adenocarcinoma (L-ADC) Treated with EGFR Tki in Ifct 0401 and 0504 Trials
Authors: R. Thiebaut, M. Wislez, C. Vazart, V. Decaulne, J. Mazieres, S. Friard, P. Merle, F. Morin, F. Liebaert, J. Cadranel
Journal: Annals of Oncology (2015)
MAJOR ADVERSE CARDIAC EVENTS IN CHILDREN WITH WILLIAMS BEUREN SYNDROME UNDERGOING SURGERY: AN ANALYSIS OF THE SOCIETY OF THORACIC SURGEONS CONGENITAL HEART SURGERY DATABASE
Authors: Christoph P. Hornik, Robert Jaquiss, Jeffrey Jacobs, Marshall Jacobs, Sara Pasquali, Amelia Wallace, Kevin Hill
Journal: Journal of the American College of Cardiology (2014)
EULAR points to consider when establishing, analysing and reporting safety data of biologics registers in rheumatology
Authors: W. G. Dixon, L. Carmona, A. Finckh, M. L. Hetland, T. K. Kvien, R. Landewe, J. Listing, P. J. Nicola, U. Tarp, A. Zink, J. Askling
Journal: Annals of the Rheumatic Diseases (2010)

The introduction of biological therapies for the treatment of rheumatic diseases has drawn attention to the limitations of traditional means of assessing drug safety. Consequently, a series of European academic biologics registers dedicated to this task have been established. Increasing reliance upon safety data generated from observational drug registers makes it important to convert the lessons learned from such registers into recommendations for rheumatologists embarking upon the establishment of future registers, or analysing and reporting from new and existing registers.The Task Force encompassed 11 scientists from European Rheumatology drug registers. Through an informal inventory of critical elements in the establishment of existing rheumatoid arthritis drug registers, of analytical strategies used and of limitations of their results, several 'points to consider'--beyond established generic guidelines for observational registers/studies but with particular relevance to biologics registers on safety in rheumatology--were assembled. For each 'point to consider', contextual and methodological background and examples were compiled.A set of seven points to consider was assembled for the establishment of new drug registers with a focus on purpose, population to be targeted, data collection, handling and storage as well as ethical and legal considerations. For analysis and reporting, nine points to consider were assembled (setting, participant, variable, statistical method, descriptive data, outcome data, main results, other analyses and limitations).Thoughtful design and planning before the establishment of biologics registers will increase their sustainability, versatility and raw data quality. Harmonisation of analyses and reporting from such registers will improve interpretation of drug safety studies.
STROBE and reporting observational studies in dermatology
Authors: S.M. Langan, J. Schmitt, P.J. Coenraads, A. Svensson, E. Von Elm, H.C. Williams
Journal: British Journal of Dermatology (2010)

The STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) initiative (http://www.strobe‐statement.org/) is a recent major development about which all who undertake and report observational research in dermatology should be aware.1 The STROBE criteria aim to assess and improve the quality of reporting of epidemiological studies, but are not necessarily a measurement of the quality of the research. Clarity of reporting is a necessary criterion of judging study quality. For example, if a small poorly designed study is clearly reported as such, then at least readers will be able to see its shortcomings, as opposed to being left to guess what exactly was done in the study. One of the challenges authors of scientific articles face is to ensure that readers will understand what was planned, what was done, what the key findings were and what the results mean, so that the research can be interpreted appropriately. In an international initiative, experts comprising methodologists, researchers and journal editors have, through an involved iterative process, developed clear guidance for authors on how to improve the quality of reporting of observational research. Specific checklists of essential items which should be reported for case–control, cohort and cross‐sectional studies have been developed.2Table 1 shows a combined STROBE checklist for reporting of these three types of studies. A recent extension of STROBE has been the development of STrengthening the REporting of Genetic Association studies (STREGA) to improve reporting of genetic epidemiological studies.3
NFκB, heat shock proteins, HSF-1, and inflammation
Authors: A KNOWLTON
Journal: Cardiovascular Research (2005)

See article by Y. Chen and R.W. Currie [1] (pages 66–75) in this issue. 

Investigators are beginning to unravel the intricate relationship between NFκB, heat shock proteins (HSPs), and heat shock factor (HSF)-1. New information is added to this complex picture with the novel finding that HSF-1 modulates AP-1 activation, adding yet another layer of complexity [1]. HSF-1, a transcription factor for the heat shock proteins, is a key component of the heat shock response. The activation of HSF-1 drives the increase in HSPs in response to injury or stress. NFκB, a critical regulatory transcription factor, has both pro-inflammatory and anti-apoptotic effects. Activation of the heat shock response yields activation of HSF-1 and increased transcription of the heat shock proteins. The heat shock proteins have an array of protective properties, including refolding denatured proteins, protecting folded proteins and targeting irreversibly denatured proteins for removal. However, it is increasingly evident that there are other mechanisms by which the … 

*Molecular and Cellular Cardiology, Genomics and Biomedical Sciences Facility, Rm 6317, University of California, Davis, 451 East Health Sciences Way, Davis, CA 95616, United States. Tel.: +1 530 752 5461; fax: +1 530 754 7167. Email address: aaknowlton{at}ucdavis.edu
Efficacy and Safety of Paroxetine Treatment for Chronic PTSD: A Fixed-Dose, Placebo-Controlled Study
Authors: Randall D. Marshall, Katherine L. Beebe, Mary Oldham, Rocco Zaninelli
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: This study evaluated the efficacy and safety of paroxetine for the treatment of patients with chronic posttraumatic stress disorder (PTSD). METHOD: Outpatients with chronic PTSD according to DSM-IV criteria and a score of 50 or more on the Clinician-Administered PTSD Scale, part 2, were randomly assigned to take placebo (N=186), 20 mg/day of paroxetine (N=183), or 40 mg/day of paroxetine (N=182) for 12 weeks. Efficacy was assessed by examining the change in total score from baseline to endpoint on the Clinician-Administered PTSD Scale, part 2, and rates of response (“very much improved” or “much improved”) for global improvement on the Clinical Global Impression scale. RESULTS: Paroxetine-treated patients in both dose groups demonstrated significantly greater improvement on primary outcome measures compared to placebo-treated patients in the intent-to-treat analysis. Moreover, paroxetine treatment resulted in statistically significant improvement compared to placebo on all three PTSD symptom clusters (reexperiencing, avoidance/numbing, and hyperarousal), social and occupational impairment, and comorbid depression. Paroxetine was effective for both men and women. Treatment response did not vary by trauma type, time since trauma, or severity of baseline PTSD or depressive symptoms. Both doses were well tolerated. CONCLUSIONS: Doses of 20 and 40 mg/day of paroxetine are effective and well tolerated in the treatment of adults with chronic PTSD.