Hemangioma of the Rib: A Rare Case Report and Literature Review.

Hemangiomas of the rib are extremely rare benign neoplasm. Here we present a case in a 47-year-old female, detected by chest X-ray and underwent a surgical resection. Histologically, the tumor was composed of a homogeneous conglomerate, irregular, thin walled and dilated blood vessels containing red blood cells, supported by fibrous stroma and intermingled to regular bone trabeculae. The postoperative courses were uneventful, and there was no recurrence during 64 months follow-up.

Dual Diagnosis of Ellis-van Creveld Syndrome and Hearing Loss in a Consanguineous Family.

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a "blended" phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.

[Application of CT scan in diagnosis of pathological type and origin of metastatic ovarian tumors].

OBJECTIVE: To evaluate the application of CT scan in diagnosis of pathological types and origins of metastatic ovarian tumors. METHODS: Clinical data, histopathological results and CT images of 43 patients with pathologically-proved metastatic ovarian tumor were retrospectively analyzed. Diagnostic values of CT imaging for pathological type and origin of metastatic ovarian tumors were evaluated. RESULTS: The pathological types of metastatic ovarian tumor were related to the size of the lesion (P<0.01), while not related to the sites of lesion (unilateral or bilateral), the cystic-solid and mixed lesions with or without separation (all P>0.05). Metastatic ovarian tumors of colorectal origin were usually unilateral lesions, and showed cystic or cystic-solid masses, while those of gastric origin were usually bilateral lesions, and showed solid or solid-based masses. CONCLUSIONS: CT imaging may be of value in diagnosis of pathological types and origin of metastatic ovarian tumor.

Lung cancer with concurrent EGFR mutation and ROS1 rearrangement: a case report and review of the literature.

ROS1 rearrangement has recently emerged as a new molecular subtype in non-small cell lung cancer, and is predominantly found in lung adenocarcinomas compared with other oncogenes such as EGFR, KRAS, or ALK. Patients who have both mutations are extremely rare. Here we report a 50-year-old female diagnosed with adenocarcinoma with sarcomatoid differentiation, who was shown to have EGFR and ROS1 mutations. The patient was treated surgically and received three cycles of adjuvant postoperative chemotherapy. In addition, we reviewed the previously reported cases and related literature. This presentation will provide further understanding of the underlying molecular biology and optimal treatment for non-small cell lung cancer patients with more than one driver mutation.

Mutation Screening of Candidate Genes in Patients with Nonsyndromic Sagittal Craniosynostosis.

BACKGROUND: Craniosynostosis is a condition that includes the premature fusion of one or multiple cranial sutures. Among various craniosynostosis forms, sagittal nonsyndromic craniosynostosis is the most prevalent. Although different gene mutations have been identified in some craniosynostosis syndromes, the cause of sagittal nonsyndromic craniosynostosis remains largely unknown. METHODS: To screen for candidate genes for sagittal nonsyndromic craniosynostosis, the authors sequenced DNA of 93 sagittal nonsyndromic craniosynostosis patients from a population-based study conducted in Iowa and New York states. FGFR1-3 mutational hotspots and the entire TWIST1, RAB23, and BMP2 coding regions were screened because of their known roles in human nonsyndromic or syndromic sagittal craniosynostosis, expression patterns, and/or animal model studies. RESULTS: The authors identified two rare variants in their cohort. A FGFR1 insertion c.730_731insG, which led to a premature stop codon, was predicted to abolish the entire immunoglobulin-like III domain, including the ligand-binding region. A c.439C>G variant was observed in TWIST1 at its highly conserved loop domain in another patient. The patient's mother harbored the same variant and was reported with jaw abnormalities. These two variants were not detected in 116 alleles from unaffected controls or seen in the several databases; however, TWIST1 variant was found in a low frequency of 0.000831 percent in Exome Aggregation Consortium database. CONCLUSIONS: The low mutation detection rate indicates that these genes account for only a small proportion of sagittal nonsyndromic craniosynostosis patients. The authors' results add to the perception that sagittal nonsyndromic craniosynostosis is a complex developmental defect with considerable genetic heterogeneity. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Opposing needling promotes behavior recovery and exerts neuroprotection via the cAMP/PKA/CREB signal transduction pathway in transient MCAO rats.

The aim of the present study was to investigate whether the cyclic adenosine 3',5'­monophosphate (cAMP)/protein kinase A(PKA)/cAMP­responsive element binding protein (CREB) signal transduction pathway triggered by γ­aminobutyric acid class B (GABA(B)) receptor activation is involved in neuroprotection against ischemia and behavioral recovery induced by opposing needling (ON). A total of 80 rats were randomly divided into four groups: A sham operation group, an ischemia group, an ON group and an ON group effectively inhibited by the GABA(B) receptor antagonist, CGP35384 (n=20/group). The behavior of the rats was assessed by their neurological deficit score, whereas the impairment of gait was examined using the CatWalk system. The volume of cerebral infarction was examined upon treatment with 2,3,5­triphenyltetrazolium chloride. The expression levels of CREB, GABA(B1) and GABA(B2) were examined by western blotting and reverse transcription­quantitative polymerase chain reaction, and the activity of adenylyl cyclase (AC), cAMP and PKA in the serum was detected using an enzyme­linked immunosorbent assay. In the present study, in comparison with other groups, the ON group exhibited a reduced score for the neurological deficit, the stride length and swing speed were improved, and the volume of infarction was reduced. However, these effects were reversed upon administration of CGP35384. Additionally, the expression levels of CREB, GABA(B1) and GABA(B2) were increased in the ON group. The levels of AC, cAMP and PKA in the serum were also increased in the ON group, whereas the addition of CGP35384 reversed these effects. The results of the present study demonstrated that ON markedly protected the brain against transient cerebral ischemic injury, and this effect was possibly mediated by the activation of the GABAB/cAMP/PKA/CREB signal transduction pathway. These findings implied that ON may be a potential therapeutic method for treating stroke.

Novel mutations in EVC cause aberrant splicing in Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive disorder characterized by disproportionate chondrodysplasia, postaxial polydactyly, nail dystrophy, dental abnormalities and in a proportion of patients, congenital cardiac malformations. Weyers acrofacial dysostosis (Weyers) is another dominantly inherited disorder allelic to EvC syndrome but with milder phenotypes. Both disorders can result from loss-of-function mutations in either EVC or EVC2 gene, and phenotypes associated with the two gene mutations are clinically indistinguishable. We present here a clinical and molecular analysis of a Chinese family manifested specific features of EvC syndrome. Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. In vitro minigene expression assay, RT-PCR and sequencing analysis demonstrated that c.384+5G>C mutation abolished normal splice site and created a new cryptic acceptor site within exon 4, whereas c.1465-1G>A mutation affected consensus splice junction site and resulted in full exon 11 skipping. These two aberrant pre-mRNA splicing processes both produced in-frame abnormal transcripts that possibly led to abolishment of important functional domains. To our knowledge, this is the first report of EVC mutations that cause EvC syndrome in Chinese population. Our data revealed that EVC splice site mutations altered splicing pattern and helped elucidate the pathogenesis of EvC syndrome.

[Association study between candidate genes on transforming growth factor-ß signaling pathway and the risk of non-syndromic cleft lip with or without cleft palate in Chinese populations].

OBJECTIVE: To explore the association between 10 candidate genes on transforming growth factor-ß (TGFB) signaling pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) among Chinese populations, and to study the gene-environment interaction. METHODS: A total of 806 Chinese Han NSCL/P trios were ascertained from an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate the genes affecting risk to NSCL/P. The transmission disequilibrium test (TDT) was used to test for effects of 343 single nucleotide polymorphisms (SNPs) in 10 genes on TGFB signaling pathway including DCN, TGFB1, TGFB2, TGFB3, TGFBR1, TGFBR2, BAMBI, SMAD2, SMAD3 and SMAD4. The conditional regression models were used to test for gene-environment interaction. RESULTS: For TDT, although 19 SNPs showed nominal significant association with NSCL/P, no significant evidence of association was seen for all SNPs in 806 NSCL/P trios after Bonferroni correction. The interactions between genes and maternal smoking, environmental tobacco smoke, alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons. CONCLUSION: No evidence for SNP effect of genes on TGFB signaling pathway and significant gene-environment interaction was seen in our data.

MiR-376a and histone deacetylation 9 form a regulatory circuitry in hepatocellular carcinoma.

BACKGROUND/AIMS: Our previous study has demonstrated that down-regulation of miR-376a might contribute to the development of hepatocellular carcinoma (HCC), but the mechanism underlying this down-regulation remains obscure. METHODS/RESULTS: histone deacetylase (HDAC) inhibitor increased the level of miR-376a in L02 and Huh7 cells by up-regulating the acetylation level of histone 3 at the Maternally expressed 3 (Meg3) differentially methylated region (DMR). Interestingly, HDAC9, a histone deacetylase responsible for deacetylating lysine 18 of histone 3 (H3K18), was identified as the target of miR-376a. In addition, HDAC9 siRNA increased the expression of miR-376a by up-regulating the global histone H3K18 acetylation level, with Meg3 DMR included. Finally, miR-376a and HDAC9 were inversely correlated in HCC. CONCLUSION: HDAC9 plays an important role both as effects and targets of miR-376a.

Oral clefting in china over the last decade: 205,679 patients.

BACKGROUND: China is the most populated country and has one of the highest prevalences of oral clefting. The present study reports the epidemiology and surgical procedures performed on the largest reported cohort of individuals with clefting in China. METHODS: A retrospective review of patients who received cleft repair through Smile Train in China from 2000 to 2011 was conducted. Data on demographics, cleft characteristics, associated malformations, pregnancy and family history, and surgical technique were analyzed using SPSS (IBM, Chicago, Ill.). RESULTS: A total of 205,679 patients underwent 209,169 cleft procedures. Cleft lip and palate (42.7%) was most common followed by isolated cleft palate (32.4%) and isolated cleft lip (24.9%). Males accounted for 63.5% of cases. The average age at initial surgery was 6.12 years. By 2011, this decreased to 1.8 years of age for lip repair and to 5.9 years of age for palate repair. The preferred techniques were rotation-advancement (55%) for unilateral lip repair and Von-Langenbeck (38%) and pushback (39%) for palate repair. The percentages of cases with associated anomalies and surgical complications were 12.8% and 0.36%, respectively. CONCLUSIONS: This study provides insight into cleft care in China as it reports the largest cohort of cleft patients treated by surgeons to date. Our results generally follow trends previously reported in China and developed countries. The male:female ratio for cleft palate patients was higher than expected. The average age at primary repair is higher than recommended, but seems to be decreasing.

Joint testing of genotypic and gene-environment interaction identified novel association for BMP4 with non-syndromic CL/P in an Asian population using data from an International Cleft Consortium.

BACKGROUND: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common disorder with complex etiology. The Bone Morphogenetic Protein 4 gene (BMP4) has been considered a prime candidate gene with evidence accumulated from animal experimental studies, human linkage studies, as well as candidate gene association studies. The aim of the current study is to test for linkage and association between BMP4 and NSCL/P that could be missed in genome-wide association studies (GWAS) when genotypic (G) main effects alone were considered. METHODOLOGY/PRINCIPAL FINDINGS: We performed the analysis considering G and interactions with multiple maternal environmental exposures using additive conditional logistic regression models in 895 Asian and 681 European complete NSCL/P trios. Single nucleotide polymorphisms (SNPs) that passed the quality control criteria among 122 genotyped and 25 imputed single nucleotide variants in and around the gene were used in analysis. Selected maternal environmental exposures during 3 months prior to and through the first trimester of pregnancy included any personal tobacco smoking, any environmental tobacco smoke in home, work place or any nearby places, any alcohol consumption and any use of multivitamin supplements. A novel significant association held for rs7156227 among Asian NSCL/P and non-syndromic cleft lip and palate (NSCLP) trios after Bonferroni correction which was not seen when G main effects alone were considered in either allelic or genotypic transmission disequilibrium tests. Odds ratios for carrying one copy of the minor allele without maternal exposure to any of the four environmental exposures were 0.58 (95%CI = 0.44, 0.75) and 0.54 (95%CI = 0.40, 0.73) for Asian NSCL/P and NSCLP trios, respectively. The Bonferroni P values corrected for the total number of 117 tested SNPs were 0.0051 (asymptotic P = 4.39*10(-5)) and 0.0065 (asymptotic P = 5.54*10(-5)), accordingly. In European trios, no significant association was seen for any SNPs after Bonferroni corrections for the total number of 120 tested SNPs. CONCLUSIONS/SIGNIFICANCE: Our findings add evidence from GWAS to support the role of BMP4 in susceptibility to NSCL/P originally identified in linkage and candidate gene association studies.

The LIF-mediated molecular signature regulating murine embryo implantation.

The establishment of a receptive uterus is the prime requirement for embryo implantation. In mice, the E2-induced cytokine leukemia inhibitory factor (LIF) is essential in switching the uterine luminal epithelium (LE) from a nonreceptive to a receptive state. Here we define the LIF-mediated switch using array analysis and informatics to identify LIF-induced changes in gene expression and annotated signaling pathways specific to the LE. We compare gene expression profiles at 0, 1, 3, and 6 h, following LIF treatment. During the first hour, the JAK-STAT signaling pathway is activated and the expression of 54 genes declines, primarily affecting LE cytoskeletal and chromatin organization as well as a transient reduction in the progesterone, TGFbetaR1, and ACVR1 receptors. Simultaneously 256 genes increase expression, of which 42 are transcription factors, including Sox, Kfl, Hes, Hey, and Hox families. Within 3 h, the expression of 3987 genes belonging to more than 25 biological process pathways was altered. We confirmed the mRNA and protein distribution of key genes from 10 pathways, including the Igf-1, Vegf, Toll-like receptors, actin cytoskeleton, ephrin, integrins, TGFbeta, Wnt, and Notch pathways. These data identify novel LIF-activated pathways in the LE and define the molecular basis between the refractory and receptive uterine phases. More broadly, these findings highlight the staggering capacity of a single cytokine to induce a dynamic and complex network of changes in a simple epithelium essential to mammalian reproduction and provide a basis for identifying new routes to regulating female reproduction.

Evidence of gene-environment interaction for two genes on chromosome 4 and environmental tobacco smoke in controlling the risk of nonsyndromic cleft palate.

Nonsyndromic cleft palate (CP) is one of the most common human birth defects and both genetic and environmental risk factors contribute to its etiology. We conducted a genome-wide association study (GWAS) using 550 CP case-parent trios ascertained in an international consortium. Stratified analysis among trios with different ancestries was performed to test for GxE interactions with common maternal exposures using conditional logistic regression models. While no single nucleotide polymorphism (SNP) achieved genome-wide significance when considered alone, markers in SLC2A9 and the neighboring WDR1 on chromosome 4p16.1 gave suggestive evidence of gene-environment interaction with environmental tobacco smoke (ETS) among 259 Asian trios when the models included a term for GxE interaction. Multiple SNPs in these two genes were associated with increased risk of nonsyndromic CP if the mother was exposed to ETS during the peri-conceptual period (3 months prior to conception through the first trimester). When maternal ETS was considered, fifteen of 135 SNPs mapping to SLC2A9 and 9 of 59 SNPs in WDR1 gave P values approaching genome-wide significance (10(-6)

Electro-acupuncture at points of Zusanli and Quchi exerts anti-apoptotic effect through the modulation of PI3K/Akt signaling pathway.

We evaluated the neuroprotective effect of electro-acupuncture (EA) on cerebral ischemia-reperfusion (IR) injury and deeply investigated the relationship between this neuroprotective effect and PI3K/Akt pathway. Rats underwent focal cerebral IR injured by suture method and received the in vivo therapeutic efficacy of EA at points of Zusanli(ST36) and Quchi(LI11) after the operation. We found that the EA treatment significantly (p<0.05) improved neurological deficit and cerebral infarction. Furthermore, EA profoundly activated PI3K/Akt signaling resulted in the inhibition of cerebral cell apoptosis in the ischemic penumbra. Simultaneously EA increased the expression of PI3K, p-Akt, p-Bad and Bcl-2 at the protein level and the expression of Bcl-2 at the mRNA level. On the contrary, EA inhibited the Bax and cleaved Caspase-3-positive expression. The selective PI3K inhibitor LY294002 compromised EA-induced neuroprotective effects and reduced the elevation of p-Akt, p-Bad and Bcl-2 levels. Our data suggested that the PI3K/Akt pathway played a critical role in mediating the neuroprotective effects of EA treatment at points of Zusanli and Quchi after the ischemic stroke.

Solitary fibrous tumors of pleura and lung: report of twelve cases.

PURPOSE: Solitary fibrous tumors (SFTs) of pleura and lung are rare primary tumors that arise from the submesothelial tissue and usually show a benign clinical course. Immuno-histochemical analysis is used to make the diagnosis. We have reviewed our experience to obtain a better understanding of this disease. METHODS: In this study, we reviewed 12 patients who had undergone a surgical resection for treatment of benign solitary fibrous tumors (SFTs) of pleura and lung during the period from 2006 to 2012. RESULTS: Following excision, the most essential characteristic on histopathology was nonatypical spindle-shaped tumor cells on a collagenous background. Keloid-type collagen, hypocellular and hypercellular areas could be observed in all the cases. On immuno-histochemical analysis, we found that mesenchymal markers such as CD34, bcl-2 and vimentin were positive, and S-100 protein and desmin were negative. In addition, Ki-67 was positive in approximately 5% of the tumor cells, but C-kit protein was not detected. If the result for CD34 was negative, expression of bcl-2 was positive. Complete resection was performed through thoracotomy, including 8 cases that involved video-assisted thoracic surgery (VATS). The postoperative courses were uneventful, and there was no recurrence during 3-65 (mean 25) months of follow-up. CONCLUSIONS: Complete resection of SFTs is usually curative. Morphological and pathological features are important in distinguishing them from other tumors and in predicting clinical behaviour.

[Association study for gene polymorphism of folic acid/homocysteine metabolic pathway and nonsyndromic cleft lip with or without cleft palate in Chinese populations].

OBJECTIVE: To explore the association between 18 candidate genes encoding enzymes on the folate/homocysteine metabolism pathway and non-syndromic cleft lip with or without cleft palate (NSCL/P) in Chinese populations. METHODS: A total of 806 NSCL/P trios were drawn by an international consortium, which conducted a genome-wide association study using a case-parent trio design to investigate genes affecting risks to NSCL/P. The transmission disequilibrium test (TDT) was used for deviation from Mendelian expectations for 257 SNPs in 18 folate/homocysteine metabolism-related genes. The interactions between markers in these gene and environmental risk factors were also tested using conditional Logistic regressions. RESULTS: Although four SNPs (rs6428977, rs12060264, rs7730643 and rs4920037) showed nominal significant association with NSCL/P in the TDT on 806 NSCL/P trios (P<0.05), no significant evidence of linkage and association remained in all the SNPs after Bonferroni correction. Similar tests for interactions between genes and maternal smoking, environmental tobacco smoke, alcohol consumption and multi-vitamin supplementation during pregnancy did not attain statistical significance after correction for multiple comparisons. CONCLUSION: Folate/homocysteine metabolism-related genes could not influence the risk of NSCL/P.

The second deletion mutation in exon 8 of EDA gene in an XLHED pedigree.

BACKGROUND: X-linked hypohidrotic ectodermal dysplasia (XLHED) is characterized by hypodontia, hypohidrosis, sparse hair and characteristic facial features and is caused by mutation in the ectodysplasin A (EDA) gene. OBJECTIVE: In this study we report on a large Chinese XLHED family and investigate the molecular genetics of the defect. METHODS: All individuals of the family were examined by clinical and radiographic examinations. The EDA gene was sequenced in the whole family and in 150 controls. RESULTS: Three male patients had classic XLHED phenotype. A novel one-nucleotide deletion mutation (c.855delG) in exon 8 which caused premature termination of the polypeptide at amino acid 307 was confirmed. The mutant lost parts of the TNF domain may prevent transmission of the intracellular downstream signal. This was the second deletion mutation in exon 8 that was reported in a Chinese individual. CONCLUSIONS: Our findings suggested deletion mutations in exon 8 might be specific to the Chinese population.

Methylation state of the EDA gene promoter in Chinese X-linked hypohidrotic ectodermal dysplasia carriers.

INTRODUCTION: Hypodontia, hypohidrosis, sparse hair and characteristic faces are the main characters of X-linked hypohidrotic ectodermal dysplasia (XLHED) which is caused by genetic ectodysplasin A (EDA) deficiency. Heterozygous female carriers tend to have mild to moderate XLHED phenotype, even though 30% of them present no obvious symptom. METHODS: A large Chinese XLHED family was reported and the entire coding region and exon-intron boundaries of EDA gene were sequenced. To elucidate the mechanism for carriers' tempered phenotype, we analyzed the methylation level on four sites of the promoter of EDA by the pyrosequencing system. RESULTS: A known frameshift mutation (c.573-574 insT) was found in this pedigree. Combined with the pedigrees we reported before, 120 samples comprised of 23 carrier females from 11 families and 97 healthy females were analyzed for the methylation state of EDA promoter. Within 95% confidence interval (CI), 18 (78.26%) carriers were hypermethylated at these 4 sites. CONCLUSION: Chinese XLHED carriers often have a hypermethylated EDA promoter.

Correction: Methylation State of the EDA Gene Promoter in Chinese X-Linked Hypohidrotic Ectodermal Dysplasia Carriers.

[This corrects the article DOI: 10.1371/journal.pone.0062203.].

A genome-wide association study identifies susceptibility loci for nonsyndromic sagittal craniosynostosis near BMP2 and within BBS9.

Sagittal craniosynostosis is the most common form of craniosynostosis, affecting approximately one in 5,000 newborns. We conducted, to our knowledge, the first genome-wide association study for nonsyndromic sagittal craniosynostosis (sNSC) using 130 non-Hispanic case-parent trios of European ancestry (NHW). We found robust associations in a 120-kb region downstream of BMP2 flanked by rs1884302 (P = 1.13 × 10(-14), odds ratio (OR) = 4.58) and rs6140226 (P = 3.40 × 10(-11), OR = 0.24) and within a 167-kb region of BBS9 between rs10262453 (P = 1.61 × 10(-10), OR = 0.19) and rs17724206 (P = 1.50 × 10(-8), OR = 0.22). We replicated the associations to both loci (rs1884302, P = 4.39 × 10(-31) and rs10262453, P = 3.50 × 10(-14)) in an independent NHW population of 172 unrelated probands with sNSC and 548 controls. Both BMP2 and BBS9 are genes with roles in skeletal development that warrant functional studies to further understand the etiology of sNSC.