African American Children’s Depressive Symptoms: The Prospective Effects of Neighborhood Disorder, Stressful Life Events, and Parenting

The prospective effects of observed neighborhood disorder, stressful life events, and parents’ engagement in inductive reasoning on adolescents’ depressive symptoms were examined using data collected from 777 African American families. Multilevel analyses revealed that stressful life events experienced at age 11 predicted depressive symptoms at age 13. Furthermore, a significant interaction between neighborhood disorder and parents’ engagement in inductive reasoning was found, indicating that parental use of inductive reasoning was a protective factor for depressive symptoms particularly for youths living in highly disordered neighborhoods. The importance of examining correlates of depressive symptoms from a contextual framework, focusing on individuals, families, and neighborhood contexts, is emphasized

Irisin treatment improves healing of dystrophic skeletal muscle

Background: Irisin is an exercise induced myokine that is shown to promote browning of adipose tissue and hence, increase energy expenditure. Furthermore, our unpublished results indicate that Irisin improves myogenic differentiation and induces skeletal muscle hypertrophy. Since exercise induced skeletal muscle hypertrophy improves muscle strength, we wanted to investigate if ectopic injection of Irisin peptide improves skeletal muscle function in a mouse model of muscular dystrophy. This utility of Irisin peptide is yet to be studied in animal models. Methods: In order to test this hypothesis, we expressed and purified recombinant murine Irisin peptide from E. coli. Three- to six-week-old male mdx mice were injected IP with either vehicle (dialysis buffer) or Irisin recombinant peptide for two or four weeks, three times-a-week. Results: Irisin injection increased muscle weights and enhanced grip strength in mdx mice. Improved muscle strength can be attributed to the significant hypertrophy observed in the Irisin injected mdx mice. Moreover, Irisin treatment resulted in reduced accumulation of fibrotic tissue and myofiber necrosis in mdx mice. In addition, Irisin improved sarcolemmal stability, which is severely compromised in mdx mice. Conclusion: Irisin injection induced skeletal muscle hypertrophy, improved muscle strength and reduced necrosis and fibrotic tissue in a murine dystrophy model. These results demonstrate the potential therapeutic value of Irisin in muscular dystrophy

Irisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy

Exercise induces expression of the myokine irisin, which is known to promote browning of white adipose tissue and has been shown to mediate beneficial effects following exercise. Here we show that irisin induces expression of a number of pro-myogenic and exercise response genes in myotubes. Irisin increases myogenic differentiation and myoblast fusion via activation of IL6 signaling. Injection of irisin in mice induces significant hypertrophy and enhances grip strength of uninjured muscle. Following skeletal muscle injury, irisin injection improves regeneration and induces hypertrophy. The effects of irisin on hypertrophy are due to activation of satellite cells and enhanced protein synthesis. In addition, irisin injection rescues loss of skeletal muscle mass following denervation by enhancing satellite cell activation and reducing protein degradation. These data suggest that irisin functions as a pro-myogenic factor in mice

Strategies for the Study of Neuropsychiatric Disorders Using Endophenotypes in Developing Countries: A Potential Databank from China

Endophenotypic research can be considered to be one of the most promising strategies to bridge the gap between genomic complexity and the phenotypic heterogeneity observed in neuropsychiatric disorders. However, despite the promising and systematic work initiated by our western counterparts, this research strategy is still not well known in developing countries. Thus, the purpose of this paper is to argue the merits and promise of a potentially useful database on phenotypes and endophenotypes for developing countries

Paraneoplastic secretion of multiple phosphatonins from a deep fibrous histiocytoma causing oncogenic osteomalacia

Context: Literature suggests that oncogenic osteomalacia is usually caused by a benign mesenchymal tumor secreting fibroblast growth factor subtype-23 (FGF-23), but the involvement of other phosphatonins has only been scarcely reported. We have previously published a seemingly typical case of oncogenic osteomalacia. Following curative neoplasm resection, we now report unique molecular characteristics and biology of this tumor. Case Description: A 25-year-old man had been diagnosed with severe oncogenic osteomalacia that gradually crippled him over 6 years. 68Ga-DOTA-TATE positron emission tomography/computed tomography scan localized the culprit tumor to his left sole, which on resection revealed a deep fibrous histiocytoma displaying a proliferation of spindle cells with storiform pattern associated with multinucleated giant cells resembling osteoclasts. Circulating FGF-23, which was elevated more than 2-fold, declined to undetectable levels 24 h after surgery. Microarray analysis revealed increased tumor gene expression of the phosphatonins FGF-23, matrix extracellular phosphoglycoprotein (MEPE) and secreted frizzled-related protein subtype 4, with elevated levels of all 3 proteins confirmed through immunoblot analysis. Differential expression of genes involved in bone formation and bone mineralization were further identified. The patient made an astonishing recovery from being wheelchair bound to fully self-ambulant 2 months postoperatively. Conclusion: This report describes oncogenic osteomalacia due to a deep fibrous histiocytoma, which coincidentally has been found to induce profound muscle weakness via the overexpression of 3 phosphatonins, which resolved fully upon radical resection of the tumor. Additionally, genes involved in bone formation and bone remodeling contribute to the molecular signature of oncogenic osteomalacia

EGFR and HER2 expression in primary cervical cancers and corresponding lymph node metastases: Implications for targeted radiotherapy

<p>Abstract</p> <p>Background</p> <p>Proteins overexpressed on the surface of tumor cells can be selectively targeted. Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are among the most often targeted proteins. The level and stability of expression in both primary tumors and corresponding metastases is crucial in the assessment of a receptor as target for imaging in nuclear medicine and for various forms of therapy. So far, the expression of EGFR and HER2 has only been determined in primary cervical cancers, and we have not found published data regarding the receptor status in corresponding metastatic lesions. The goal of this study was to evaluate whether any of these receptors are suitable as target for clinical diagnosis and therapy.</p> <p>Methods</p> <p>Expression of EGFR and HER2 was investigated immunohistochemically in both lymph node metastases and corresponding primary cervical cancers (n = 53). HER2 and EGFR expression was scored using HercepTest criteria (0, 1+, 2+ or 3+).</p> <p>Results</p> <p>EGFR overexpression (2+ or 3+) was found in 64% (35/53) of the primary cervical tumors and 60% (32/53) of the corresponding lymph node metastases. There was a good concordance between the primary tumors and the paired metastases regarding EGFR expression. Only four patients who had 2+ or 3+ in the primary tumors changed to 0 or 1+ in lymph node metastases, and another two cases changed the other way around. None of the primary tumors or the lymph node metastases expressed HER2 protein.</p> <p>Conclusion</p> <p>The EGFR expression seems to be common and stable during cervical cancer metastasis, which is encouraging for testing of EGFR targeted radiotherapy. HER2 appears to be of poor interest as a potential target in the treatment of cervical cancer.</p

EGFR Tyrosine Kinase Inhibitors Activate Autophagy as a Cytoprotective Response in Human Lung Cancer Cells

Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer

Do intrauterine or genetic influences explain the foetal origins of chronic disease? A novel experimental method for disentangling effects

Background There is much evidence to suggest that risk for common clinical disorders begins in foetal life. Exposure to environmental risk factors however is often not random. Many commonly used indices of prenatal adversity (e.g. maternal gestational stress, gestational diabetes, smoking in pregnancy) are influenced by maternal genes and genetically influenced maternal behaviour. As mother provides the baby with both genes and prenatal environment, associations between prenatal risk factors and offspring disease maybe attributable to true prenatal risk effects or to the "confounding" effects of genetic liability that are shared by mother and offspring. Cross-fostering designs, including those that involve embryo transfer have proved useful in animal studies. However disentangling these effects in humans poses significant problems for traditional genetic epidemiological research designs. Methods We present a novel research strategy aimed at disentangling maternally provided pre-natal environmental and inherited genetic effects. Families of children aged 5 to 9 years born by assisted reproductive technologies, specifically homologous IVF, sperm donation, egg donation, embryo donation and gestational surrogacy were contacted through fertility clinics and mailed a package of questionnaires on health and mental health related risk factors and outcomes. Further data were obtained from antenatal records. Results To date 741 families from 18 fertility clinics have participated. The degree of association between maternally provided prenatal risk factor and child outcome in the group of families where the woman undergoing pregnancy and offspring are genetically related (homologous IVF, sperm donation) is compared to association in the group where offspring are genetically unrelated to the woman who undergoes the pregnancy (egg donation, embryo donation, surrogacy). These comparisons can be then examined to infer the extent to which prenatal effects are genetically and environmentally mediated. Conclusion A study based on children born by IVF treatment and who differ in genetic relatedness to the woman undergoing the pregnancy is feasible. The present report outlines a novel experimental method that permits disaggregation of maternally provided inherited genetic and post-implantation prenatal effects

Characterization of SMAD3 function in skeletal muscle growth

Smad3 is a key intracellular signaling mediator for Myostatin and TGF-β1, two TGF-β superfamily members and are key regulators of skeletal muscle growth and homeostasis. Despite extensive studies about the functions and signaling of Myostatin/TGF-β1, little is known about the regulatory role of Smad3 in muscle growth. Thus the main emphasis of this thesis is to investigate the role of Smad3 in post-natal myogenesis. Firstly, this thesis demonstrated that there is pronounced skeletal muscle atrophy in Smad3-null mice and this is due to increased Myostatin expression. Enhanced Myostatin signaling promoted sarcomeric protein degradation through the ubiquitin proteasome system in Smad3-null skeletal muscle. Increased Myostatin level also resulted in impaired SC proliferation, and reduced self-renewal resulting in reduced SC number in Smad3-null mice. Therefore, treatment of Smad3-null myotubes with Myostatin antagonist significantly increased the expression of sarcomeric proteins. Consistent with this result, double knockout (DKO) mouse (Smad3-/-/Myostatin-/-) had improved muscle weights and in vitro myogenic capacity when compared to that of Smad3-null mice. Therefore, up-regulated Myostatin expression is partially responsible for the muscle atrophy in Smad3-null mice. To further validate the impaired SC function found in Smad3-null mice, muscle regeneration induced by notexin injection was analyzed. Smad3-null mice showed impaired M. tibialis anterior (TA) muscle regeneration, with a reduced inflammatory response and less activated myoblasts and nascent myofibers formation. Moreover, Smad3-null regenerated muscle had remarkable reduced oxidative enzyme activity, which might be due to impaired mitochondrial biogenesis since the expression of TFAM, the master regulator of mitochondrial biogenesis, was down-regulated. Furthermore, Smad3 deficiency led to reduced scar tissue formation in the regenerated muscle. Most importantly, similar to the uninjured muscle, Smad3-null muscle had consistently up-regulated Myostatin expression during the course of muscle regeneration. Therefore, the inhibitory role of Myostatin on muscle growth may be one major molecular mechanism underlying the impaired muscle regeneration of Smad3-null mice. To advance our understanding of molecular mechanisms through which Smad3 regulates muscle growth and metabolism, gene expression analysis of Smad3-null muscle was performed. In total, 25 up-regulated and 31 down-regulated genes (P<0.05, fold change ≥ 1.5 or ≤ -1.5) were identified in Smad3-null muscle when compared to Wild-type control muscles. Altered gene expression changes may help to explain the muscle phenotype seen in Smad3-null mice. Up-regulated expression of genes encoding two inflammatory cytokines (S100a8 and S100a9), may help to explain the systemic inflammation observed in Smad3-null mice. Furthermore, down-regulated expression of 5 genes encoding ECM components in Smad3-null muscle suggests an indispensable role of Smad3 in muscle fibrosis. In addition, down-regulated expression of Pkm2, and up-regulated expression of Dlat suggests a reduced glycolysis and pyruvate oxidation in Smad3-null muscle. In conclusion, results presented in this thesis highlight the essential role of Smad3 in post-natal myogenesis. Using in vitro and in vivo myogenesis models, I demonstrated that Smad3 deficiency led to defective post-natal myogenesis, atrophied musculature and impaired muscle regeneration. Up-regulated Myostatin levels partially contribute to the post-natal myogenic defects in Smad3-null mice. Moreover, this thesis also sheds light on the regulatory role of Smad3 in skeletal muscle metabolism, as well as ECM synthesis.DOCTOR OF PHILOSOPHY (SBS

Pubertal transition, stressful life events, and the emergence of gender differences in adolescent depressive symptoms.

This study examined the role of both pubertal and social transitions in the emergence of gender differences in depressive symptoms during adolescence. This study generated the following findings: (a) Gender differences in depressive symptoms emerged during 8th grade and remained significant through 12th grade, (b) Pubertal status in 7th grade was related to adolescent depressive symptoms over time, (c) Early-maturing girls represented the group with the highest rate of depressive symptoms, (d) Depressive symptoms measured in 7th grade predicted subsequent symptom levels throughout the secondary school years, (e) Recent stressful life events were associated with increased depressive symptoms, (f) Early-maturing girls with higher levels of initial symptoms and more recent stressful life events were most likely to be depressed subsequently. The findings demonstrate the importance of the interaction between the pubertal transition and psychosocial factors in increasing adolescent vulnerability to depressive experiences. One of the most consistent findings in the mental health litera-ture is the significant gender difference in depression among adults (Nolen-Hoeksema, 1991). Rates of depression are approximately 2 to 3 times higher among women than men (Culbertson, 1997)