第2卷，第2期

One of the major obstacles limiting the success of hematopoietic reconstitution appears to be the low efficiency of hematopoietic stem cell (HSC) engraftment in the recipient's bone marrow. Among the key factors regulating the hematopoietic reconstitution, the stromal-derived factor-1 (SDF-1) /chemokine receptor CXCR4 axis has long been known to be crucial due to its roles in HSC functions, such as homing/mobilization, engraftment, and quiescence. The SDF-1/CXCR4-mediated marrow engraftment processes have been mostly dissected through loss of function experiments involving SDF-1/CXCR4 signals. There have been no previously published reports indicating whether manipulation of the SDF-1/CXCR4 axis can lead to enhanced HSC engraftment in a competitive transplantation model using syngeneic mice. However, this notion is about to change in view of a recent discovery by a group of scientists from the NIH and several prominent universities. While studying one of the first reported cases of spontaneous remission of WHIM syndrome, a primary immunodeficiency disease caused by autosomal dominant gain-of-function CXCR4 mutations, this group of scientists, led by Dr. Philip Murphy, observed that the deletion of the mutant CXCR4 disease allele, together with another 163 genes from one copy of chromosome 2 in marrow HSC/progenitors, led to durable myeloid reconstitution of the patient's bone marrow. The authors then demonstrated in an analogous murine model that the loss of a CXCR4 WHIM allele in mouse bone marrow conferred enhanced engraftment compared with disease allele-bearing murine bone marrow cells, thus confirming that deletion of the mutant CXCR4 gene alone may have been sufficient to sustain the HSC marrow engraftment and correct the WHIM phenotype in the studied case. Further, the authors demonstrated that hemizygous CXCR4 bone marrow cells also have a competitive advantage over wild type cells in mice. This serendipitous discovery is certain to add a new twist to the paradigm of the SDF-1/CXCR4 axis, while raising the prospect of partial inactivation of CXCR4 as a novel strategy to improve the outcomes of HSC transplantation.

1451

Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy.

1479

Pancreatic cancer is one of the most lethal malignancies. Significant progresses have been made in understanding of pancreatic cancer pathogenesis, including appreciation of precursor lesions or premalignant pancreatic intraepithelial neoplasia (PanINs), description of sequential transformation from normal pancreatic tissue to invasive pancreatic cancer and identification of major genetic and epigenetic events and the biological impact of those events on malignant behavior. However, the currently used therapeutic strategies targeting tumor epithelial cells, which are potent in cell culture and animal models, have not been successful in the clinic. Presumably, therapeutic resistance of pancreatic cancer is at least in part due to its drastic desmoplasis, which is a defining hallmark for and circumstantially contributes to pancreatic cancer development and progression. Improved understanding of the dynamic interaction between cancer cells and the stroma is important to better understanding pancreatic cancer biology and to designing effective intervention strategies. This review focuses on the origination, evolution and disruption of stromal molecular and cellular components in pancreatic cancer, and their biological effects on pancreatic cancer pathogenesis.

1292

FOXA1 (also known as hepatocyte nuclear factor 3α, or HNF-3α) is a protein of the FKHD family transcription factors. FOXA1 has been termed as a pioneer transcription factor due to its unique ability of chromatin remodeling in which the chromatin can be decompacted to allow genomic access by nuclear hormone receptors, including androgen receptor (AR) and estrogen receptor (ER). In this review, we discuss our current understanding of FOXA1 regulation of prostatic and non-prostatic AR-chromatin targeting. We present an updated model wherein FOXA1: AR equilibrium in the nuclei defines prostatic AR binding profile, which is perturbed in prostate cancer with FOXA1 and/or AR de-regulation. Finally, we discuss recent efforts in exploring new horizons of AR-independent functions of FOXA1 in prostate cancer and interesting directions to pursue in future studies.

1266

Cancer stem cells (CSCs) or cancer initiating cells (CICs) maintain self-renewal and multilineage differentiation properties of various tumors, as well as the cellular heterogeneity consisting of several subpopulations within tumors. CSCs display the malignant phenotype, self-renewal ability, altered genomic stability, specific epigenetic signature, and most of the time can be phenotyped by cell surface markers (e.g., CD133, CD24, and CD44). Numerous studies support the concept that non-stem cancer cells (non-CSCs) are sensitive to cancer therapy while CSCs are relatively resistant to treatment. In glioblastoma stem cells (GSCs), there is clonal heterogeneity at the genetic level with distinct tumorigenic potential, and defined GSC marker expression resulting from clonal evolution which is likely to in fluence disease progression and response to treatment. Another level of complexity in glioblastoma multiforme (GBM) tumors is the dynamic equilibrium between GSCs and differentiated non-GSCs, and the potential for non-GSCs to revert (dedifferentiate) to GSCs due to epigenetic alteration which confers phenotypic plasticity to the tumor cell population. Moreover, exposure of the differentiated GBM cells to therapeutic doses of temozolomide (TMZ) or ionizing radiation (IR) increases the GSC pool both in vitro and in vivo. This review describes various subtypes of GBM, discusses the evolution of CSC models and epigenetic plasticity, as well as interconversion between GSCs and differentiated non-GSCs, and offers strategies to potentially eliminate GSCs.

1549

In mammals, a thermogenic mechanism exists that increases heat production and consumes energy. Recent work has shed light on the cellular and physiological mechanisms that control this thermogenic circuit. Thermogenically active adipocytes, namely brown and closely related beige adipocytes, differentiate from progenitor cells that commit to the thermogenic lineage but can arise from different cellular origins. Thermogenic differentiation shares some features with general adipogenesis, highlighting the critical role that common transcription factors may play in progenitors with divergent fates. However, thermogenic differentiation is also discrete from the common adipogenic program and, excitingly, cells with distinct origins possess thermogenic competency that allows them to differentiate into thermogenically active mature adipocytes. An understanding of this thermogenic differentiation program and the factors that can activate it has led to the development of assays that are able to measure thermogenic activity both indirectly and directly. By combining these assays with appropriate cell models, novel therapeutic approaches to combat obesity and its related metabolic disorders by enhancing the thermogenic circuit can be developed.

1395

Platelets play critical roles in hemostasis and thrombosis. Emerging evidence indicates that they are versatile cells and also involved in many other physiological processes and disease states. Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life threatening bleeding disorder caused by fetal platelet destruction by maternal alloantibodies developed during pregnancy. Gene polymorphisms cause platelet surface protein incompatibilities between mother and fetus, and ultimately lead to maternal alloimmunization. FNAIT is the most common cause of intracranial hemorrhage in full-term infants and can also lead to intrauterine growth retardation and miscarriage. Proper diagnosis, prevention and treatment of FNAIT is challenging due to insufficient knowledge of the disease and a lack of routine screening as well as its frequent occurrence in first pregnancies. Given the ethical difficulties in performing basic research on human fetuses and neonates, animal models are essential to improve our un-derstanding of the pathogenesis and treatment of FNAIT. The aim of this review is to provide an overview on platelets, hemostasis and thrombocytopenia with a focus on the advancements made in FNAIT by utilizing animal models.

1572

This review summarizes the data on the functional significance of ubiquitous (NKCC1) and renal-specific (NKCC2) isoforms of electroneutral sodium, potassium and chloride cotransporters. These carriers contribute to the pathogenesis of hypertension via regulation of intracellular chloride concentration in vascular smooth muscle and neuronal cells and via sensing chloride concentration in the renal tubular fluid, respectively. Both NKCC1 and NKCC2 are inhibited by furosemide and other high-ceiling diuretics widely used for attenuation of extracellular fluid volume. However, the chronic usage of these compounds for the treatment of hypertension and other volume-expanded disorders may have diverse side-effects due to suppression of myogenic response in microcirculatory beds.

1488

Current estimates indicate that the hepatitis C (HCV) is the leading cause of mortality around the world, with infection rates steadily increasing in Egypt. The dual therapy for this silent epidemic with pegylated-interferon-α2b/ribavirin has markedly improved the successrates in genotype-4 patients. It was reported that apoptosis plays a vital mechanistic role in limiting viral replication. P53, a key regulator of apoptosis, induces CD95 gene expression and subsequently initiates apoptotic cascade to be activated. The current study examined the impact of P53 rs1042522 and CD95 rs1800682 polymorphisms on the treatment response. Three groups of 240 volunteers were enrolled in this study; 86 in sustained virological responders group, 74 in non-responders group, and 80 in control group. All patients had HCV genotype-4a and were interferon treatment naïve. Quantizations of HCV-RNA by qRT-PCR and histological scores were performed for all patients. In addition, genotyping of HCV-RNA, P53 rs1042522 Arg/Pro and CD95 rs1800682 A/G polymorphisms were investigated inall subjects. It was resulted that P53 Pro/Pro homozygous genotype has high significant increase, while CD95 A/A homozygous genotype has high significant decrease when comparing non-responders with responders. Finally, it was concluded that Pro variant of P53 rs1042522 may be used as a genetic predictor for non-responsiveness, while A/A variant of CD95 rs1800682 may be used as a sensitive biomarker for responsiveness to antiviral therapy of HCV genotype-4a infection. In addition, low prolactin, high total testosterone, and high GH levels may provide promising biomarkers for early prediction of the response when associated with these genetic polymorphisms.

1379

X-linked redegreen color blindness is the most widespread form of vision impairment. The study aimed to determine the prevalence and gene frequencies of redegreen color vision impairments among children of six different human populations of Jammu province. A total of 1028 healthy subjects (6-15 years of age) were selected from five Muslim populations and the color vision impairments were determined using the Ishihara's test of color deficiency. The gene frequency was calculated using Hardye Weinberg equilibrium method. The prevalence of color vision deficiency (CVD) ranged from 5.26% to 11.36% among males and 0.00%-3.03% among females of six different populations. The gender based differences in the frequency of CVD was found to be statistically significant (p<0.0001), with a higher prevalence among male (7.52%) as compared to female (0.83%) children. We observed high frequency of deutan as compared to protan defects. The incidences of deuteranomaly (5.68%) and deuteranopia (2.27%) were higher among male children of Syed population while the frequencies of protanomaly (1.94%), protanopia (1.28%) and achromacy (2.27%) were the highest among male subjects of Khan, Malik and Syed populations, respectively. The allele and genotype frequencies showed cogent differences among six populations. The population based assessment of CVDs help patients to follow adaptive strategies that could minimize the risks of the disease.

1516