第4卷，第3期

1178

Multifunctional factor progranulin (PGRN) plays an important role in lysosomes, and its mutations and insufficiency are associated with lysosomal storage diseases, including neuronal ceroid lipofuscinosis and Gaucher disease (GD). The first breakthrough in understanding the molecular mechanisms of PGRN as regulator of lysosomal storage diseases came unexpectedly while investigating the role of PGRN in inflammation. Challenged PGRN null mice displayed typical features of GD. In addition, GRN gene variants were identified in GD patients and the serum levels of PGRN were significantly lower in GD patients. PGRN directly binds to and functions as a chaperone of the lysosomal enzyme β-glucocerebrosidase (GCaase), whose mutations cause GD. In addition, its C-terminus containing granulin E domain, termed Pcgin (PGRN C-terminus for GCase Interaction), is required for the association between PGRN and GCase. The concept that PGRN acts as a chaperone of lysosomal enzymes was further supported and extended by a recent article showing that PGRN acts as a chaperone molecule of lysosomal enzyme cathepsin D (CSTD), and the association between PGRN and CSTD is also mediated by PGRN's C-terminal granulin E domain. Collectively, these reports suggest that PGRN may act as a shared chaperone and regulates multiple lysosomal enzymes.

1227

Bone tissue regeneration holds the potential to solve both osteoporosis and large skeletal defects, two problems associated with significant morbidity. The differentiation of mesenchymal stem cells into the osteogenic lineage requires a specific microenvironment and certain osteogenic growth factors. Neural EGF Like-Like molecule 1 (NELL-1) is a secreted glycoprotein that has proven, both in vitro and in vivo, to be a potent osteo-inductive factor. Furthermore, it has been shown to repress adipogenic differentiation and inflammation. NELL-1 can work synergistically with other osteogenic factors such as Bone Morphogenic Protein (BMP) -2 and -9, and has shown promise for use in tissue engineering and as a systemically administered drug for the treatment of osteoporosis. Here we provide a comprehensive up-to-date review on the molecular signaling cascade of NELL-1 in mesenchymal stem cells and potential applications in bone regenerative engineering.

1309

After the initiation of Human Microbiome Project in 2008, various biostatistic and bioinformatic tools for data analysis and computational methods have been developed and applied to microbiome studies. In this review and perspective, we discuss the research and statistical hypotheses in gut microbiome studies, focusing on mechanistic concepts that underlie the complex relationships among host, microbiome, and environment. We review the current available statistic tools and highlight recent progress of newly developed statistical methods and models. Given the current challenges and limitations in biostatistic approaches and tools, we discuss the future direction in developing statistical methods and models for the microbiome studies.

1259

With the rapid development of medicine, the studies of genes have become increasingly concerned by more people and being the contend of a great of researches. The next generation sequencing with its own advantages has been widely used in gene research nowadays. It has almost replaced the traditional sequencing methods (such as Sanger sequencing method), and played an important role in a variety of complex disease researches, including breast cancer. The next generation sequencing technology has the advantages of high speed, high throughput and high accuracy. It has been widely used in various cancers (such as prostate cancer, lung cancer, pancreatic cancer, liver cancer, etc.), especially in breast cancer. Moreover, the use of the next generation sequencing technology to make DNA sequence analysis and risk prediction has made a great contribution to the research of breast cancer. We will focus on the application of whole genome sequencing, exon sequencing and targeted gene sequencing in breast cancer gene research.

1225

There are no eternal individual lives so life continues by relaying with reproduction. Consequently, lifespan and fecundity are two essential genetic traits of life. The life history tradeoffs theory holds that there is an inverse relationship between lifespan and fecundity. This paper proposes two new concepts, i.e., "lifespan of pathogens" and treatment of infections by "antibiogenesis". The lifespan of pathogens is the time limitation of those tiny lives just as other large creatures. Notably, the lifespan of bacterium is the time interval from the cell division by which it is produced to next division by then its life ends and transforms to two new lives, or dies. Antibiogenesis means inhibiting generation of new lives. By the principle of life history tradeoffs, the lifespan of pathogens determines the speed of their proliferations and consequently the modality of infection. The treatment principle of antibiogenesis requires the duration of treatment to be determined by the lifespan of infected pathogens. The life history tradeoffs theory and the two concepts are helpful to understanding the pathobiology and shaping the clinical aspects of infectious diseases.

1202

The human epidermal growth factor receptor 2 (HER2) is overexpressed in 25%-30% of breast cancer patients. Anti-HER2 therapies have changed the aggressive course of HER2+ breast cancer. In spite of the therapeutic benefits, their cardiotoxicities are major concerns, especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2+ breast cancer. Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumabinduced severe cardiotoxicity while requiring additional anti-HER2 therapy. She received neoadjuvant anti-HER2 treatment for stage III breast caner. Due to severe reduction of cardiac ejection fraction (EF), she only received five doses of adjuvant transtuzumab. Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF. We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion. More importantly, the patient had one year of disease control without deterioration in her ejection fraction. We discussed the management of recurrent HER2+ breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.

1176

In clinical practice, the important hygienic prevention of bacterial pathogen spread is disinfection of potentially contaminated area. Benzalkonium bromide and chlorhexidine acetate are commonly used disinfectants with a broad spectrum of antimicrobial effect. It is vital to inhibit the spread of pathogen in hospital. However, a large number of pathogens with the decreased antiseptic susceptibility have been isolated from clinical samples which showed an increased minimal inhibitory concentration (MIC) against those antiseptics. These resistant pathogens are the major causes for nosocomial cross-infections in hospital. The present study demonstrated the utility of Oxford plate assay system in determining the potential disinfectant resistance of bacteria. The microbiological assay is based on the inhibitory effect of tested disinfectants upon the strains of Staphylococcus aureus and Escherichia coli. Statistical analysis of the bioassay results indicated the linear correlation (r = 0.87-0.99, P < 0.01) between the diameter of growth inhibition zone and the log dosage of the tested disinfectants. Moreover, comparison of inhibitory efficacy of benzalkonium bromide upon 29 S. aureus strains isolated from clinical samples by both Oxford plate method and broth dilution method showed that the diameter of growth inhibition zone has significantly negative correlation with the minimal inhibitory concentration (MIC) (r = -0.574, P < 0.001). These results suggest that the Oxford plate is a simple and time-saving method in detecting potential clinical disinfectant resistance and its usefulness for routine surveillance of pathogenic resistance to disinfectants warrants further investigation.

1347

Obesity is a common disorder that has a significant impact on human health as it may lead to many serious diseases and sometimes morbidity. Previous genome-wide association studies (GWAS) confirmed that there is a relationship between some variants in the first intron of the fat mass and obesity associated (FTO) gene and obesity in adults and children in different ethnic groups. In our study, the association of the FTO rs9939609 and rs17817449 variants with obesity was investigated in Egyptian children and adolescents. We examined rs9939609 and rs17817449 polymorphisms in 100 control and 100 obese cases, we used the restriction fragment length polymorphism (RFLP) technique to genotype the samples. The current study showed that there were no significant differences (P > 0.05) between the cases and controls in both variants of rs17817449 and rs9939609 polymorphisms.However, there were significant correlations between rs17817449 and cholesterol and between rs9939609 and LDL. In Current Study although the two variants (rs9939609 and rs17817449) didn't show an association with obesity, but there was a correlation between the lipid profile and these two variants.

1224

Vitamin D deficiency might contribute to the pathogenesis of metabolic syndrome and could cause immune disturbance. The aim of this study is to analyze the associations between Vitamin D receptor (VDR) gene polymorphism, serum 25-hydroxy vitamin D, metabolic and inflammatory biomarkers in Egyptian obese women. The study included 201 obese women with vitamin D deficiency and 249 obese matched age healthy controls with sufficient vitamin D levels. Their age ranged between 25 and 35 years. Inflammatory biomarkers (interleukin-6 and C-reactive protein) and serum 25(OH)D were measured by enzyme-linked immunosorbent assay. Insulin resistance (IR) was determined by the homeostasis model assessment of insulin resistance (HOMA-IR). Vitamin D receptor (VDR) gene polymorphisms of FokI, ApaI, and TaqI were studied by PCR using the restriction fragment length polymorphism (RFLP) technique. Obese women with vitamin D deficiency had significant higher values of inflammatory and metabolic parameters compared to controls. Multivariable-logistic regression showed associations between 25(OH)D deficiency and metabolic components when comparing cases with controls. Moreover, cases carrying polymorphic alleles showed significant lower levels of serum 25(OH)D and higher HOMA-IR, blood pressure levels and lipid parameters compared to those with the wild type homozygote in obese cases with vitamin D deficiency. Vitamin D deficiency in Egyptian obese women with vitamin D deficiency is associated with abnormal metabolic components and abnormal inflammatory biomarkers. Moreover, VDR polymorphisms play important role in immune and inflammation status.

1358

Genetic factors and gene polymorphisms leading to the onset of autoimmune response in autoimmune hepatitis (AIH) are still not full elucidated. Since the CTLA-4 molecule is a key modulator of the lymphocytes responses we hypothezied that deficiencies or mutations in the gene encoding CTLA4 protein may be involved in AIH susceptibility and trigger the autoimmune response. We investigated 3 distinct polymorphic sites (+49A > G, CT60 G > A and-318C > T) of the CTLA4 gene in 50 AIH patients and 100 healthy controls using the KASP genotyping technology. A significant positive association with AIH susceptibility was found for the GG genotype in +49 position of the CTLA4 gene which was significantly higher in AIH patients compared to controls (28% vs 9%, p = 0.003, OR = 3.93[1.56-9.88]). The CTLA4 A/A genotype in position CT60 was more significantly frequent in controls comparing to AIH patients and could be considered as a protective genotype for the tunisian patients. CTLA4 genotyping in position -318 did not show any statistically significant difference in genotype or allele distribution. The CTLA4 gene polymorphism in position +49 is associated to AIH susceptibility in the Tunisian population. Mutation in the CTLA4 gene may lead to a modification of the CTLA4 protein structure that could have functional relevance in AIH pathogenesis and onset.

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