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1.  Genomic variations of the mevalonate pathway in porokeratosis 
eLife  null;4:e06322.
Porokeratosis (PK) is a heterogeneous group of keratinization disorders. No causal genes except MVK have been identified, even though the disease was linked to several genomic loci. Here, we performed massively parallel sequencing and exonic CNV screening of 12 isoprenoid genes in 134 index PK patients (61 familial and 73 sporadic) and identified causal mutations in three novel genes (PMVK, MVD, and FDPS) in addition to MVK in the mevalonate pathway. Allelic expression imbalance (AEI) assays were performed in 13 lesional tissues. At least one mutation in one of the four genes in the mevalonate pathway was found in 60 (98%) familial and 53 (73%) sporadic patients, which suggests that isoprenoid biosynthesis via the mevalonate pathway may play a role in the pathogenesis of PK. Significantly reduced expression of the wild allele was common in lesional tissues due to gene conversion or some other unknown mechanism. A G-to-A RNA editing was observed in one lesional tissue without AEI. In addition, we observed correlations between the mutations in the four mevalonate pathway genes and clinical manifestations in the PK patients, which might support a new and simplified classification of PK under the guidance of genetic testing.
eLife digest
Porokeratosis refers to a group of around twenty skin conditions that involve a build-up of a protein called keratin in skin cells. Keratin forms the tough fibres that give strength to hair and nails, and people suffering from porokeratosis develop hardened skin lesions. Porokeratosis is an uncommon condition; most cases are inherited and have been linked to exposure to ultraviolet light and having a weakened immune system.
Mutations in one gene called MVK are known to cause two forms of the disorder, but it is suspected that other genetic causes of porokeratosis will also be identified. The MVK gene encodes an enzyme that is involved in making chemicals called isoprenoids. This large and diverse class of chemicals provides the building blocks for making many other important molecules in all living species. Zhang, Li et al. have now analysed genetic material from 134 different porokeratosis patients to search for mutations in other genes involved in the production of isoprenoids. The patients examined include 61 people with a family history of the disorder, and 73 cases in which the condition seems to be a one-off occurrence.
This search identified mutations in three additional genes (called PMVK, MVD and FDPS) that are all linked to porokeratosis. Further analysis of these three genes and MVK revealed that about half of the patients with mutations in the MVK gene developed large lesions (that were over 5 centimetres in diameter). However, those with mutations in the other three genes did not develop such large lesions. Mutations in some of the newly identified genes were instead linked to porokeratosis affecting specific areas of the body; for example, PMVK and MVD mutations are linked to porokeratosis localized to the genitals and around the eyes, respectively. This means that, in the future, doctors might be able to simplify the diagnosis of the different varieties of porokeratosis based on information gained via genetic tests.
PMCID: PMC4511816  PMID: 26202976
porokeratosis; mevalonate pathway; genetic testing; human
2.  Overexpression of GOLPH3 is associated with poor prognosis and clinical progression in pancreatic ductal adenocarcinoma 
BMC Cancer  2014;14:571.
Golgi phosphoprotein 3 (GOLPH3) has been identified as an oncoprotein in various human cancers; however, its role in pancreatic ductal adenocarcinoma (PDAC) is unknown. We examined GOLPH3 expression levels and relationship with survival in patients with PDAC to establish the significance of GOLPH3 in the development and progression of PDAC.
Real-time qPCR and Western blotting were performed to analyze the expression levels of GOLPH3 mRNA and protein in paired PDAC tumor and adjacent non-tumor tissues. Immunohistochemistry was used to analyze the expression levels of GOLPH3 protein in paraffin-embedded tissues from 109 cases of PDAC. Univariate and multivariate analyses were performed to identify correlations between the immunohistochemical data for GOLPH3 expression and the clinicopathologic characteristics in PDAC.
Expression levels of GOLPH3 mRNA and protein were upregulated in PDAC lesions compared to paired adjacent noncancerous tissues. Expression of GOLPH3 was significantly correlated with clinical stage (P = 0.006), T classification (P = 0.021), N classification (P = 0.049) and liver metastasis (P = 0.035). Patients with high GOLPH3 expression had shorter overall survival times compared to those with low GOLPH3 expression (P = 0.007). Multivariate analysis revealed that GOLPH3 overexpression was an independent prognostic factor in PDAC.
Our findings suggest that GOLPH3 expression status may be a potential prognostic biomarker and therapeutic target in PCAC.
PMCID: PMC4133629  PMID: 25104140
3.  Low-grade endometrioid carcinoma of the ovary associated with undifferentiated carcinoma: case report and review of the literature 
The association of low-grade endometrioid carcinoma with undifferentiated carcinoma (UC) was first reported in endometrium carcinoma, termed with dedifferentiated carcinoma (DC). However, the coexistence of low-grade endometrioid carcinoma (LGEC) or serous carcinoma (LGSC) with UC has received minimal attention in ovary, and the behavior of this kind of neoplasm remains at further discussion. In this study, we reported a case of low-grade ovarian endometrioid carcinoma associated with UC and reviewed another four cases previously reported. We found a histological continuity between the LGEC and UC components in H&E section, which suggested a dedifferentiation from LGEC to UC components. In summary, this kind of pathological type has aggressive behavior and these patients have very poor prognosis regardless of the amount of undifferentiated carcinoma.
PMCID: PMC4129063  PMID: 25120828
Ovarian carcinoma; undifferentiated carcinoma; dedifferentiated carcinoma; low-grade endometrioid carcinoma
5.  The molecular and cellular basis of Apert syndrome 
Apert syndrome (AS) is a rare genetic and congenital disease characterized by craniosynostosis and syndactly of hands and feet. AS patients generally require lifelong management, however there are still no effective treatment methods except surgery. In recent years, research has made great progress in the pathogenesis of AS. FGFR2 mediates extracellular signals into cells and the mutations in the FGFR2 gene cause AS occurrence. Activated FGFs/FGFR2 signaling disrupt the balance of cell proliferation, differentiation and apoptosis via its downstream signal pathways. However, how the pathways transform the balance is not well understood and contradictions have occurred in different studies. In this review, we'll focus on these problems to get a better understanding of AS pathogenesis.
PMCID: PMC4204555  PMID: 25343114
Apert syndrome; FGFR2 gene; pathogenesis; signal pathways
6.  Development of Transgenic Minipigs with Expression of Antimorphic Human Cryptochrome 1 
PLoS ONE  2013;8(10):e76098.
Minipigs have become important biomedical models for human ailments due to similarities in organ anatomy, physiology, and circadian rhythms relative to humans. The homeostasis of circadian rhythms in both central and peripheral tissues is pivotal for numerous biological processes. Hence, biological rhythm disorders may contribute to the onset of cancers and metabolic disorders including obesity and type II diabetes, amongst others. A tight regulation of circadian clock effectors ensures a rhythmic expression profile of output genes which, depending on cell type, constitute about 3–20% of the transcribed mammalian genome. Central to this system is the negative regulator protein Cryptochrome 1 (CRY1) of which the dysfunction or absence has been linked to the pathogenesis of rhythm disorders. In this study, we generated transgenic Bama-minipigs featuring expression of the Cys414-Ala antimorphic human Cryptochrome 1 mutant (hCRY1AP). Using transgenic donor fibroblasts as nuclear donors, the method of handmade cloning (HMC) was used to produce reconstructed embryos, subsequently transferred to surrogate sows. A total of 23 viable piglets were delivered. All were transgenic and seemingly healthy. However, two pigs with high transgene expression succumbed during the first two months. Molecular analyzes in epidermal fibroblasts demonstrated disturbances to the expression profile of core circadian clock genes and elevated expression of the proinflammatory cytokines IL-6 and TNF-α, known to be risk factors in cancer and metabolic disorders.
PMCID: PMC3797822  PMID: 24146819
7.  A comparative proteomics study on matrix vesicles of osteoblast-like Saos-2 and U2-OS cells 
Matrix vesicles (MVs) play an important role in the initial stage of the process of bone mineralization, and are involved in multiple rare skeletal diseases with pathological mineralization or calcification. The aim of the study was to compare the proteomic profiling of osteoblast-like cells with and without mineralization ability (Saos-2 and U2-OS), and to identify novel mineralization-associated MV proteins. MVs were extracted using ExoQuick solution from mineralization-induced Saos-2 and U2-OS cells, and then were validated by transmission electron microscopy. A label-free quantitative proteomic method was used to compare the protein profiling of MVs from Saos-2 and U2-OS cells. Western-blots were used to confirm the expression of MVs proteins identified in proteomic studies. In our proteomic studies, we identified that 89 mineralization-related proteins were significantly up-regulated in Saos-2 MVs compared with U2-OS MVs. We further validated that two MVs proteins, protein kinase C α and ras-related protein Ral-A, were up-regulated in MVs of Saos-2 cells compared to those of U2-OS cells under mineralization-induction. Our findings suggest that protein kinase C α and ras-related protein Ral-A might be involved in bone mineralization as MVs components.
PMCID: PMC4204581  PMID: 25343104
Matrix vesicle; osteoblasts; mineralization; proteomics
8.  A systematic review of genetic skeletal disorders reported in Chinese biomedical journals between 1978 and 2012 
Little information is available on the prevalence, geographic distribution and mutation spectrum of genetic skeletal disorders (GSDs) in China. This study systematically reviewed GSDs as defined in “Nosology and Classification of genetic skeletal disorders (2010 version)” using Chinese biomedical literature published over the past 34 years from 1978 to 2012. In total, 16,099 GSDs have been reported. The most frequently reported disorders were Marfan syndrome, osteogenesis imperfecta, fibrous dysplasia, mucopolysaccharidosis, multiple cartilaginous exostoses, neurofibromatosis type 1 (NF1), osteopetrosis, achondroplasia, enchondromatosis (Ollier), and osteopoikilosis, accounting for 76.5% (12,312 cases) of the total cases. Five groups (group 8, 12, 14, 18, 21) defined by “Nosology and Classification of genetic skeletal disorders” have not been reported in the Chinese biomedical literature. Gene mutation testing was performed in only a minor portion of the 16,099 cases of GSDs (187 cases, 1.16%). In total, 37 genes for 41 different GSDs were reported in Chinese biomedical literature, including 43 novel mutations. This review revealed a significant imbalance in rare disease identification in terms of geographic regions and hospital levels, suggesting the need to create a national multi-level network to meet the specific challenge of care for rare diseases in China.
PMCID: PMC3492206  PMID: 22913777
Rare diseases; Genetic skeletal diseases; China; Bibliographic study
9.  The tumorigenic and angiogenic effects of MGSA/GRO proteins in melanoma 
Journal of leukocyte biology  2000;67(1):53-62.
Continuous expression of the MGSA/GROα, β, or γ chemokine bestows tumor-forming capacity to the immortalized murine melanocyte cell line, melan-a. The mechanism for this transformation is unclear, although both autocrine and paracrine processes are possible because melan-a cells as well as endothelial cells express a low level of the receptor for this ligand. To further define the role of MGSA/GRO proteins in melanocyte transformation, two types of experiments were designed to neutralize the biological effects of MGSA/GRO in the transfected melan-a clones: (1) the effect of neutralizing antiserum to MGSA/GRO proteins on melan-a tumor growth was assessed; (2) the tumor-forming capacity of melan-a clones expressing ELR motif-mutated forms of MGSA/GRO with compromised receptor affinity was compared to the tumor-forming capacity of clones expressing wild-type MGSA/GRO. These experiments revealed that SCID mice inoculated with MGSA/GROα- or γ-expressing melan-a cells and subsequently treated with antiserum to the respective chemokine exhibited decreased tumor growth. This reduction in tumor growth was accompanied by declining angiogenic activity in MGSA/GROγ-expressing tumors. Moreover, athymic nude mice injected with melan-a cells expressing ELR-mutant forms of MGSA/GROα exhibited markedly impaired tumor-forming capacity compared with those mice injected with melan-a clones expressing wild-type MGSA/GRO. These data suggest that continuous expression of MGSA/GRO proteins may facilitate tumor growth by stimulating the growth of microvessels into the tumor (paracrine) and by affecting melanocyte growth (autocrine).
PMCID: PMC2669312  PMID: 10647998
chemokines; angiogenesis
10.  Potential role for Duffy antigen chemokine-binding protein in angiogenesis and maintenance of homeostasis in response to stress 
Journal of leukocyte biology  2002;71(1):141-153.
CXC chemokines, which induce angiogenesis, have glutamine-leucine-arginine amino acid residues (ELR motif) in the amino terminus and bind CXCR2 and the Duffy antigen chemokine-binding protein. Duffy, a seven transmembrane protein that binds CXC and CC chemokines, has not been shown to couple to trimeric G proteins or to transduce intracellular signals, although it is highly expressed on red blood cells, endothelial cells undergoing neovascularization, and neuronal cells. The binding of chemokines by Duffy could modulate chemokine responses positively or negatively. Positive regulation could come through the presentation of chemokine to functional receptors, and negative regulation could come through Duffy competition with functional chemokine receptors for chemokine binding, thus serving as a decoy receptor. To determine whether Duffy has a role in angiogenesis and/or maintenance of homeostasis, we developed transgenic mice expressing mDuffy under the control of the preproendothelin promoter/enhancer (PPEP), which directs expression of the transgene to the endothelium. Two PPEP-mDuffy-transgenic founders were identified, and expression of the transgene in the endothelium was verified by Northern blot, RT-PCR, and immunostaining of tissues. The phenotype of the mice carrying the transgene appeared normal by all visual parameters. However, careful comparison of transgenic and nontransgenic mice revealed two phenotypic differences: mDuffy-transgenic mice exhibited a diminished angiogenic response to MIP-2 in the corneal micropocket assay, and mDuffy-transgenic mice exhibited enhanced hepatocellular toxicity and necrosis as compared with nontransgenic littermates in response to overdose of acetaminophen (APAP; 400 mg/kg body weight). Morover, APAP treatment was lethal in 50% of the mDuffy-transgenic mice 24 h post challenge, and 100% of the nontransgenic litter-mates survived this treatment at the 24 h time point. Our data suggest that enhanced expression of mDuffy on endothelial cells can lead to impaired angiogenic response to chemokines and impaired maintenance of homeostasis in response to toxic stresses.
PMCID: PMC2665273  PMID: 11781390
hepatocellular toxicity; acetaminophen; chemotactic cytokines; MIP-2; CXCR2

Results 1-10 (10)