tbuckley/cabot-search huggingface dataset:
A flap course for orthopaedic surgeons in low-income countries: addressing a global health-care disparity
Authors: Kushal R Patel, Joseph N Carey, Amber M Caldwell, Rick R Coughlin, Scott L Hansen
Journal: The Lancet Global Health (2014)

The burden of complex orthopaedic trauma in low-income countries is compounded by insufficient plastic surgeons to assist in management of soft tissue injuries. To address this global health-care disparity, we created a soft tissue management course to train orthopaedic surgeons from low-income countries in flap reconstruction. The Institute for Global Orthopedics & Traumatology hosts a 3-day course to teach orthopaedic surgeons from low-income and middle-income countries flaps using cadaver dissection and didactic lectures. Precourse and postcourse assessments were used to evaluate the course's effect. In 4 years, 156 surgeons have attended the course from more than 25 different countries. Of 48 participants from the 2010 course, 90% indicated that soft tissue management training would be useful for upper extremity trauma cases and 96% for lower extremity trauma cases. A 1-year postcourse use survey was sent to all the surgeons attending the 2012 course, with 32 of 44 surgeons completing the survey. The respondents collectively undertook 594 flaps with 554 reported as successful (93•3%). Of the successful flaps, 116 flaps were believed to have prevented a subsequent amputation. 31 (97%) of 32 surgeons disseminated information to either colleagues or residents, and through dissemination of information a further 28 surgeons are now undertaking flaps. The skills and knowledge gained at this course by orthopaedic surgeons from low-income countries were recorded to be quickly and extensively used in their countries by our 1-year postcourse survey. This course represents a unique collaboration with physicians in low-income countries that might have the ability to provide a sustainable effect in addressing global health care disparities. None.
L1cam promotes tumor progression and metastasis and is an independent unfavorable prognostic factor in gastric cancer
Authors: Dong-liang Chen, Zhao-lei Zeng, Jing Yang, Chao Ren, De-shen Wang, Wen-jing Wu, Rui-hua Xu
Journal: Journal of Hematology & Oncology (2013)

Abstract Background Previous reports have demonstrated that L1cam is aberrantly expressed in various tumors. The potential role of L1cam in the progression and metastasis of gastric cancer is still not clear and needs exploring. Methods Expression of L1cam was evaluated in gastric cancer tissues and cell lines by immunohistochemistry and Western blot. The relationship between L1cam expression and clinicopathological characteristics was analyzed. The effects of L1cam on cell proliferation, migration and invasion were investigated in gastric cancer cell lines both in vitro and in vivo . The impact of L1cam on PI3K/Akt pathway was also evaluated. Results L1cam was overexpressed in gastric cancer tissues and cell lines. L1cam expression was correlated with aggressive tumor phenotype and poor overall survival in gastric cancer patients. Ectopic expression of L1cam in gastric cell lines significantly promoted cell proliferation, migration and invasion whereas knockdown of L1cam inhibited cell proliferation, migration and invasion in vitro as well as tumorigenesis and metastasis in vivo . The low level of phosphorylated Akt in HGC27 cells was up-regulated after ectopic expression of L1cam, whereas the high level of phosphorylated Akt in SGC7901 cells was suppressed by knockdown of L1cam. Moreover, the migration and invasion promoted by L1cam overexpression in gastric cancer cells could be abolished by either application of LY294002 (a phosphoinositide-3-kinase inhibitor) or knockdown of endogenous Akt by small interfering RNA. Conclusions Our study demonstrated that L1cam, overexpressed in gastric cancer and associated with poor prognosis, plays an important role in the progression and metastasis of gastric cancer.
Relative Bcl-2 Independence of Drug-Induced Cytotoxicity and Resistance in 518A2 Melanoma Cells
Authors: Luba Benimetskaya, Johnathan C. Lai, Anastasia Khvorova, Sijian Wu, Emily Hua, Paul Miller, Li-Ming Zhang, Cy A. Stein
Journal: Clinical Cancer Research (2004)

Abstract Purpose: Inhibition of the function of Bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy. G3139 (Genasense) is a phosphorothioate anti–Bcl-2 antisense oligonucleotide, but its mechanism of action is uncertain. The aim of the present work is to investigate inhibition of Bcl-2 expression in 518A2 melanoma cells, the cell line on which recent phase II and phase III clinical trials employing this agent were based. Experimental Design: We down-regulated the expression of Bcl-2 protein by two different strategies in these cells: one employing G3139 and controls, and the other using a small interfering RNA approach. Cell viability after treatment with oligonucleotides or small interfering RNA and cytotoxic agents including gemcitibine, DDP, docetaxel, and thapsigargin was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. A 518A2 melanoma cell line stably overexpressing Bcl-2 protein was constructed and treated with either these cytotoxic agents or G3139. Results: The cytotoxic effects of either G3139 or small interfering RNA treatment of 518A2 melanoma cells are Bcl-2 independent. In addition, in the Bcl-2–overexpressing cells, only a modest increment in chemoresistance was observed, and treatment with G3139 not only did not down-regulate Bcl-2 expression but produced essentially identical toxicity as was observed in the wild-type or mock-transfected cells. Conclusions: Our results suggest that the mechanism whereby G3139 produces drug-induced cytotoxicity in the 518A2 melanoma line is not dependent on levels of Bcl-2. These findings emphasize the nonsequence specific effects of this phosphorothioate oligonucleotide and call into question the validity of Bcl-2 as a target in this cell line.
The role of eHealth and mHealth in tuberculosis and tobacco control: a WHO/ERS consultation
Authors: Dennis Falzon, Mario Raviglione, Elisabeth H. Bel, Christina Gratziou, Douglas Bettcher, Giovanni Battista Migliori
Journal: European Respiratory Journal (2015)

Both tuberculosis (TB) and tobacco consumption are major global public health concerns. About 9 million new cases of TB emerge each year and 1.5 million people die from the disease, despite the fact that TB is eminently curable in the large majority of cases with an affordable course of drugs [1]. Tobacco is the largest preventable cause of death in the world: almost 6 million people die from tobacco use and exposure each year, accounting globally for 6% of all female and 12% of all male deaths [2]. This number is set to increase to 8 million in 2030, or 10% of all deaths projected to occur that year. The burden of tobacco use is greatest in low- and middle-income countries and, unchecked, this trend is likely to increase in coming decades. There is a strong association between smoking and TB [3, 4]. Smoking substantially increases the risk of contracting TB and dying from it. Recent studies of risk factors have attributed more than 20% of global TB incidence to smoking [5]. As a result, smoking cessation is one of the interventions that can prevent TB and, among those who already developed the disease, improve its outcomes [6]. eHealth and mHealth in tuberculosis and tobacco control: WHO/ERS consultation <http://ow.ly/Owy38> D. Bettcher, D. Falzon and M. Raviglione are staff members of the World Health Organization (WHO). The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the decisions or policies of WHO. The authors acknowledge the contribution of numerous individuals who helped in the preparation of the consultation ([www.who.int/tb/areas-of-work/digital-health/en/][1]). [1]: http://www.who.int/tb/areas-of-work/digital-health/en/
Systemic elastin degradation in chronic obstructive pulmonary disease
Authors: John D Maclay, David A McAllister, Roberto Rabinovich, Imran Haq, Scott Maxwell, Stephen Hartland, Martin Connell, John T Murchison, Edwin J R van Beek, Robert D Gray, Nicholas L Mills, William MacNee
Journal: Thorax (2012)

<h3>Background</h3> Development of emphysema and vascular stiffness in chronic obstructive pulmonary disease (COPD) may be due to a common mechanism of susceptibility to pulmonary and systemic elastin degradation. <h3>Objectives</h3> To investigate whether patients with COPD have evidence of systemic elastin degradation in the skin. <h3>Methods</h3> The authors measured cutaneous elastin degradation using immunohistochemistry (percentage area of elastin fibres) in sun-exposed (exposed) and non-sun-exposed (non-exposed) skin biopsies in 16 men with COPD and 15 controls matched for age and cigarette smoke exposure. Quantitative PCR of matrix metalloproteinase (MMP)-2, -9, -12 and tissue inhibitor of metalloproteinase-1 mRNA and zymography for protein expression of MMP-2 and -9 were performed on homogenised skin. Arterial stiffness and emphysema severity were measured using carotid-femoral pulse wave velocity and quantitative CT scanning. <h3>Results</h3> Skin elastin degradation was greater in exposed and non-exposed skin of patients with COPD compared with controls (exposed, mean (SD); 43.5 (12.1)% vs 26.3 (6.9)%, p&lt;0.001; non-exposed 22.4 (5.2)% vs 18.1 (4.3)%, p=0.02). Cutaneous expression of MMP-9 mRNA and proMMP-9 concentrations was increased in exposed skin of COPD patients (p=0.004 and p=0.02, respectively) and was also associated with increased skin elastin degradation (r=0.62, p&lt;0.001 and r=0.47, p=0.01, respectively). In the entire cohort of ex-smokers, cutaneous elastin degradation was associated with emphysema severity, FEV<sub>1</sub> and pulse wave velocity. <h3>Conclusions</h3> Patients with COPD have increased skin elastin degradation compared with controls, which is related to emphysema severity and arterial stiffness. Systemic elastin degradation due to increased proteolytic activity may represent a novel shared mechanism for the pulmonary, vascular and cutaneous features of COPD.
Identification of an Inactivating Cysteine Switch in Protein Kinase Cε, a Rational Target for the Design of Protein Kinase Cε–Inhibitory Cancer Therapeutics
Authors: Feng Chu, John M. Koomen, Ryuji Kobayashi, Catherine A. O'Brian
Journal: Cancer Research (2005)

Abstract Critical roles played by some protein kinases in neoplastic transformation and progression provide a rationale for developing selective, small-molecule kinase inhibitors as antineoplastic drugs. Protein kinase Cε (PKCε) is a rational target for cancer therapy, because it is oncogenic and prometastatic in transgenic mouse models. PKCε is activated by sn-1,2-diacylglycerol (DAG). Attempts to develop selective PKCε inhibitors that block activation by DAG or compete with ATP have not yet met with success, suggesting a need for new strategies. We previously reported that cystamine and a metabolic cystine precursor inactivate PKCε in cells in a thiol-reversible manner. In this report, we first determined that PKCε became resistant to inactivation by disulfides when Cys452 was replaced with alanine by site-specific mutagenesis of human PKCε or a constitutively active PKCε mutant. These results showed that the disulfides inactivated PKCε by thiol-disulfide exchange, either upon Cys452 S-thiolation or by rearrangement to an intra-protein disulfide. Mass spectrometric analysis of peptide digests of cystamine-inactivated, carbamidomethylated PKCε detected a peptide S-cysteaminylated at Cys452, indicating that Cys452 S-cysteaminylation is a stable modification. Furthermore, PKCε inactivation by N-ethylmaleimide was Cys452 dependent, providing corroborative evidence that PKCε inhibitors can be designed by targeting Cys452 with small molecules that stably modify the residue. Cys452 is an active site residue that is conserved in only 11 human protein kinase genes. Therefore, the PKCε-inactivating Cys452 switch is a rational target for the design of antineoplastic drugs that selectively inhibit PKCε.
Comment on Wędrychowicz et al. Like-Triple Diabetes as First Manifestation of MODY2 in an Overweight Teenager With Transient Multiple Antibodies. Diabetes Care 2014;37:e66–e67
Authors: Fernando M.A. Giuffrida, Sergio A. Dib, André F. Reis
Journal: Diabetes Care (2014)

We read with interest the article by Wedrychowicz et al. (1). Maturity-onset diabetes of the young (MODY) is a heterogeneous group of monogenic forms of diabetes. Differential diagnosis with common forms such as type 1 and type 2 diabetes frequently poses a challenge to clinicians, especially in MODY forms caused by transcription factors. Glucokinase ( GCK )-MODY stands out in this regard for displaying a rather constant phenotype (2).

We agree with the authors that the incidental association of obesity with GCK mutations can act as a diagnostic confounder. Moreover, coexistence of clinical features of both type 1 and type 2 diabetes is well described in …
An Essential Role of Cytosolic Phospholipase A2α in Prostaglandin E2–mediated Bone Resorption Associated with Inflammation
Authors: Chisato Miyaura, Masaki Inada, Chiho Matsumoto, Tomoyasu Ohshiba, Naonori Uozumi, Takao Shimizu, Akira Ito
Journal: The Journal of Experimental Medicine (2003)

Prostaglandin E (PGE)2 produced by osteoblasts acts as a potent stimulator of bone resorption. Inflammatory bone loss is accompanied by osteoclast formation induced by bone-resorbing cytokines, but the mechanism of PGE2 production and bone resorption in vivo is not fully understood. Using cytosolic phospholipase A2α (cPLA2α)-null mice, we examined the role of cPLA2α in PGE2 synthesis and bone resorption. In bone marrow cultures, interleukin (IL)-1 markedly stimulated PGE2 production and osteoclast formation in wild-type mice, but not in cPLA2α-null mice. Osteoblastic bone marrow stromal cells induced the expression of cyclooxygenase (COX)-2 and membrane-bound PGE2 synthase (mPGES) in response to IL-1 and lipopolysaccharide (LPS) to produce PGE2. Osteoblastic stromal cells collected from cPLA2α-null mice also induced the expression of COX-2 and mPGES by IL-1 and LPS, but could not produce PGE2 due to the lack of arachidonic acid release. LPS administration to wild-type mice reduced femoral bone mineral density by increased bone resorption. In cPLA2α-null mice, however, LPS-induced bone loss could not be observed at all. Here, we show that cPLA2α plays a key role in PGE production by osteoblasts and in osteoclastic bone resorption, and suggest a new approach to inflammatory bone disease by inhibiting cPLA2α.
Evolutionary Genomics of Chromoviruses in Eukaryotes
Authors: Benjamin Gorinsek, Franc Gubensek, Dusan Kordis
Journal: Molecular Biology and Evolution (2004)

The diversity, origin, and evolution of chromoviruses in Eukaryota were examined using the massive amount of genome sequence data for different eukaryotic lineages. A surprisingly large number of novel full-length chromoviral elements were found, greatly exceeding the number of the known chromoviruses. These new elements are mostly structurally intact and highly conserved. Chromoviruses in the key Amniota lineage, the reptiles, have been analyzed by PCR to explain their evolutionary dynamics in amniotes. Phylogenetic analyses provide evidence for a novel centromere-specific chromoviral clade that is widespread and highly conserved in all seed plants. Chromoviral diversity in plants, fungi, and vertebrates, as shown by phylogenetic analyses, was found to be much greater than previously expected. The age of plant chromoviruses has been significantly extended by finding their representatives in the most basal plant lineages, the green and the red algae. The evolutionary origin of chromoviruses has been found to be no earlier than in Cercozoa. The evolutionary history and dynamics of chromoviruses can be explained simply by strict vertical transmission in plants, followed by more complex evolution in fungi and in Metazoa. The currently available data clearly show that chromoviruses indeed represent the oldest and the most widespread clade of Metaviridae.
Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis
Authors: Chao Wang, Yuanlin Zhao, Xing Gao, Le Li, Yuan Yuan, Fang Liu, Lijun Zhang, Jie Wu, Peizhen Hu, Xiumin Zhang, Yu Gu, Yuqiao Xu, Zhe Wang, Zengshan Li, Huizhong Zhang, Jing Ye
Journal: Hepatology (2014)

Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD‐binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller‐sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5 ‐deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPARα stimulated by the increased NEFA levels. Meanwhile, Plin5 ‐deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)‐mediated lipolysis by competitively binding to comparative gene identification‐58 (CGI‐58) and disrupting the interaction between CGI‐58 and ATGL. Conclusion : Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity. (H epatology 2015;61:870–882)
Interrater reliability and aspects of validity of the myositis damage index
Authors: S. M. Sultan, E. Allen, R. G. Cooper, S. Agarwal, P. Kiely, C. V. Oddis, J. Vencovsky, I. E. Lundberg, M. Dastmalchi, M. G. Hanna, D. A. Isenberg
Journal: Annals of the Rheumatic Diseases (2011)

To test the interrater reliability, internal consistency and aspects of validity of the myositis damage index (MDI) in the assessment of damage in adult patients with idiopathic inflammatory myopathy (IIM).95 patients were assessed in six centres as part of this cross-sectional international study. Two parts of a MDI were used to assess disease damage, the MDI and the myositis damage score (MYODAM). The myositis disease activity assessment tool (MDAAT) was used to assess disease activity. Interrater reliability was assessed using intraclass correlation coefficient (ICC). Spearman's rank correlation coefficient was used to measure the convergent validity of cross-sectional scores between the two parts of the damage tool and to determine the correlation between the respective components of the damage and activity tools.In general, the damage index appears to have good interrater reliability for most of the systems with an ICC greater than 0.65. Convergent validity between the two parts of the damage tool showed good correlation for the individual organ systems (r>0.8). There were weak correlations between some parts of the MDI and corresponding components of the MDAAT.The MDI is a comprehensive tool to assess damage in patients with myositis. With physician education and emphasis to record items that have been diagnosed since the myositis diagnosis, the MDI will provide a valuable tool to assess damage in future clinical trials and longitudinal studies.
Psychological Status in Childhood Cancer Survivors: A Report From the Childhood Cancer Survivor Study
Authors: Lonnie K. Zeltzer, Christopher Recklitis, David Buchbinder, Bradley Zebrack, Jacqueline Casillas, Jennie C.I. Tsao, Qian Lu, Kevin Krull
Journal: Journal of Clinical Oncology (2009)

Psychological quality of life (QOL), health-related QOL (HRQOL), and life satisfaction outcomes and their associated risk factors are reviewed for the large cohort of survivors and siblings in the Childhood Cancer Survivor Study (CCSS). This review includes previously published manuscripts that used CCSS data focused on psychological outcome measures, including the Brief Symptom Inventory (BSI-18), the Medical Outcomes Survey Short Form-36 (SF-36), the Cantril Ladder of Life, and other self-report questionnaires. Comparisons and contrasts are made between siblings and survivors, and to normative data when available, in light of demographic/health information and abstracted data from the medical record. These studies demonstrate that a significant proportion of survivors report more symptoms of global distress and poorer physical, but not emotional, domains of HRQOL. Other than brain tumor survivors, most survivors report both good present and expected future life satisfaction. Risk factors for psychological distress and poor HRQOL are female sex, lower educational attainment, unmarried status, annual household income less than $20,000, unemployment, lack of health insurance, presence of a major medical condition, and treatment with cranial radiation and/or surgery. Cranial irradiation impacted neurocognitive outcomes, especially in brain tumor survivors. Psychological distress also predicted poor health behaviors, including smoking, alcohol use, fatigue, and altered sleep. Psychological distress and pain predicted use of complementary and alternative medicine. Overall, most survivors are psychologically healthy and report satisfaction with their lives. However, certain groups of childhood cancer survivors are at high risk for psychological distress, neurocognitive dysfunction, and poor HRQOL, especially in physical domains. These findings suggest targeting interventions for groups at highest risk for adverse outcomes and examining the positive growth that remains despite the trauma of childhood cancer.