Novel GPC3 Gene Mutation in Simpson-Golabi-Behmel Syndrome with Endocrine Anomalies: A Case Report.

Simpson-Golabi-Behmel syndrome (SGBS) represents a rare X-linked recessive syndrome with prenatal and postnatal overgrowth, coarse facial features, congenital malformations, organomegaly and an increased risk of tumors. Mutations on the GPC3 gene, encoding the glypican-3 protein, have previously been shown to cause the disease. In this report, a 12-year-old Chinese boy was hospitalized in our institution for some clinical features of SGBS. His serum endocrine evaluation showed hormone level abnormalities, including high prolactin, high testosterone, high thyroid-stimulating hormone (TSH) levels, and low estradiol levels. Whole exome sequencing (WES) was performed in the patient for mutation analysis and a novel hemizygous mutation, c.185delT, p.(Leu62Cysfs*22), on the GPC3 gene, was identified. The mother was a heterozygous carrier. The SGBS patients might present with endocrine anomalies, which adds to the clinical heterogeneity of the disease. The novel GPC3 mutation c.185delT expands the mutational spectrum of the GPC3 gene.

LINC00240 sponges miR-4465 to promote proliferation, migration, and invasion of hepatocellular carcinoma cells via HGF/c-MET signaling pathway.

OBJECTIVE: LINC00240, as a novel long non-coding RNAs (lncRNAs), has never been studied in hepatocellular carcinoma (HCC). This research reported the expression and function of LINC00240 in HCC. PATIENTS AND METHODS: LINC00240 expression in 180 HCC patients was downloaded from the Cancer Genome Atlas (TCGA) database. HCC patients' survival was analyzed via Kaplan­Meier analysis. The expression of LINC00240, miR-4465 and HGF in Hep3B and Huh7 cells were regulated by transfection. Cell viability was determined by MTT assay. Transwell experiment was used for the detection of cells migration and invasion abilities. The interaction between LINC00240, miR-4465 and HGF was reflected by Luciferase reporter assay. LINC00240, miR-4465, HGF and p-c-MET expression in HCC cells were researched by real-time quantitative polymerase chain reaction (RT-qPCR) and Western blot. RESULTS: TCGA data showed that high LINC00240 expression was markedly associated with lower survival of HCC patients (p = 0.036). LINC00240 expression was aberrantly upregulated in HCC cells. Silencing of LINC00240 significantly reduced HCC cells viability, migration and invasion. miR-4465 was a target gene of LINC00240. Silencing of LINC00240 reduced HCC cells viability, migration and invasion via directly promoting miR-4465 expression. HGF was target gene of miR-4465. miR-4465 up-regulation obviously suppressed HGF and p-c-MET expression. According to rescue experiment, LINC00240 silencing inhibited HCC cells viability, migration and invasion by suppressing HGF/c-MET signaling pathway via targeting miR-4465. CONCLUSIONS: LINC00240 sponges miR-4465 to promote HCC cells proliferation, migration and invasion via HGF/c-MET signaling pathway.

The Dose-Response Associations of Sedentary Time with Chronic Diseases and the Risk for All-Cause Mortality Affected by Different Health Status: A Systematic Review and Meta-Analysis.

PURPOSE: To determine the dose-response associations of sedentary behaviour with cardiovascular diseases (CVD), cancer, and all-cause mortality, and to examine whether the sedentary-associated all-cause mortality risk was affected by appearance of diabetes and hypertension, physical activity, and body mass index (BMI). DESIGN: We carried out a systematic review and meta-analysis to search Medline, SportDiscus, and Web of Science for eligible studies. SETTINGS: Prospective cohort studies that reported sedentary time and CVD, cancer, and mortality incidents. MEASUREMENTS: Two authors independently extracted data based on predefined criteria. The effect estimates were evaluated by hazard ratios (HRs) with 95% confidences (CIs). RESULTS: Twenty-four studies met the inclusion criteria. Sitting time showed dose-response associations with CVD, cancer, and all-cause mortality, with each 1-hour increment of sitting time daily accounting for HRs 1.04 (95% CIs 1.02-1.07), 1.01 (1.00-1.02), and 1.03 (1.02-1.03), respectively. The link between sitting time and CVD and all-cause mortality was non-linear (pnon-linear < 0.0001). The relationship between TV viewing and CVD and all-cause mortality was dose-dependent, with HRs 1.07 (1.06-1.09) and 1.04 (1.01-1.06) for per 1-hour increment of TV time every day, respectively. The regression was curved (pnon-linear < 0.0001). When the analysis was stratified by the percentage of diabetes and hypertension, BMI values, and physical activity levels, we found that higher BMI and a greater percentage of diabetes and hypertension further increased all-cause mortality risk in the most sedentary populations, whereas higher physical activity levels decreased it. CONCLUSION: Sitting time and TV viewing significantly increased cardiovascular, cancer, and mortality risk; the associations were dose-dependent. More importantly, sedentary behaviour in combination with chronic diseases or high BMI increased all-cause mortality risk whereas physical activity was likely to alleviate the adverse associations.

Higher-Order Quantum Ghost Imaging with Ultracold Atoms.

Ghost imaging is a quantum optics technique that uses correlations between two beams to reconstruct an image from photons that do not interact with the object being imaged. While pairwise (second-order) correlations are usually used to create the ghost image, higher-order correlations can be utilized to improve the performance. In this Letter, we demonstrate higher-order atomic ghost imaging, using entangled ultracold metastable helium atoms from an s-wave collision halo. We construct higher-order ghost images up to fifth order and show that using higher-order correlations can improve the visibility of the images without impacting the resolution. This is the first demonstration of higher-order ghost imaging with massive particles and the first higher-order ghost imaging protocol of any type using a quantum source.

Hyperprolactinemia-inducing antipsychotics increase breast cancer risk by activating JAK-STAT5 in precancerous lesions.

BACKGROUND: Psychiatric medications are widely prescribed in the USA. Many antipsychotics cause serum hyperprolactinemia as an adverse side effect; prolactin-Janus kinase 2 (JAK2)-signal transducer and activator of transcription 5 (STAT5) signaling both induces cell differentiation and suppresses apoptosis. It is controversial whether these antipsychotics increase breast cancer risk. METHODS: We investigated the impact of several antipsychotics on mammary tumorigenesis initiated by retrovirus-mediated delivery of either ErbB2 or HRas or by transgenic expression of Wnt-1. RESULTS: We found that the two hyperprolactinemia-inducing antipsychotics, risperidone and pimozide, prompted precancerous lesions to progress to cancer while aripiprazole, which did not cause hyperprolactinemia, did not. We observed that risperidone and pimozide (but not aripiprazole) caused precancerous cells to activate STAT5 and suppress apoptosis while exerting no impact on proliferation. Importantly, we demonstrated that these effects of antipsychotics on early lesions required the STAT5 gene function. Furthermore, we showed that only two-week treatment of mice with ruxolitinib, a JAK1/2 inhibitor, blocked STAT5 activation, restored apoptosis, and prevented early lesion progression. CONCLUSIONS: Hyperprolactinemia-inducing antipsychotics instigate precancerous cells to progress to cancer via JAK/STAT5 to suppress the apoptosis anticancer barrier, and these cancer-promoting effects can be prevented by prophylactic anti-JAK/STAT5 treatment. This preclinical work exposes a potential breast cancer risk from hyperprolactinemia-inducing antipsychotics in certain patients and suggests a chemoprevention regime that is relatively easy to implement compared to the standard 5-year anti-estrogenic treatment in women who have or likely have already developed precancerous lesions while also requiring hyperprolactinemia-inducing antipsychotics.

[Effect of cigarette smoke exposure during pregnancy on offspring of ovarian development and oocyte DNA methylation in female mice].

Objective: To explore the effects of cigarette smoke exposure during pregnancy on the quality of oocytes and the whole genome DNA methylation in the offspring of female mice during the period of germinal vesicle (GV) . Methods: The pregnant 7 d mice were divided into 3 groups, exposure on the 0, 0.5, 1 lit cigarettes cabinet (volume 18 L) , at 9 am and 3 pm for 1 h twice daily, until delivery. When the mice were 6 weeks old, the organ index and the number of follicles in the ovary were detected by weighing and making HE stained sections. GV stage oocytes were obtained by Hoechst 33342 staining and indirect immunofluorescence to detect the quality of oocytes, chromatin configuration and whole genome DNA methylation level. Results: Compared with the control group and low dose group, the offspring ovarian organ index of female mice in the high dose group decreased, the difference was statistically significant (P<0.05) . Compared with the control group, the number of follicular oocytes in low dose group and high dose group female mice offspring decreased, the zona pellucida oocytes diameter decreased, and the zona pellucida thickness increased, the differences were statistical significance (P<0.05) . Compared with control group and low dose group, in the high dose group, the oocytes nucleus diameter of the female mice offspring decreased, the proportion of nucleolus surrounded type chromatin configuration (SN) decreased, and the proportion of nucleoil not surrounded type (NSN) increased, the relative fluorescence intensity of 5MeC decreased, the differences were statistically significant (P<0.05) . Conclusion: Exposure to cigarette smoke during pregnancy may reduce indicators of offspring ovarian organ index, female rat follicle number and oocyte quality change, the high dose group can lead to oocyte chromatin structure and DNA methylation level anomaly.

Luminal epithelial cells within the mammary gland can produce basal cells upon oncogenic stress.

In the normal mammary gland, the basal epithelium is known to be bipotent and can generate either basal or luminal cells, whereas the luminal epithelium has not been demonstrated to contribute to the basal compartment in an intact and normally developed mammary gland. It is not clear whether cellular heterogeneity within a breast tumor results from transformation of bipotent basal cells or from transformation and subsequent basal conversion of the more differentiated luminal cells. Here we used a retroviral vector to express an oncogene specifically in a small number of the mammary luminal epithelial cells and tested their potential to produce basal cells during tumorigenesis. This in-vivo lineage-tracing work demonstrates that luminal cells are capable of producing basal cells on activation of either polyoma middle T antigen or ErbB2 signaling. These findings reveal the plasticity of the luminal compartment during tumorigenesis and provide an explanation for cellular heterogeneity within a cancer.

Prognostic and assessment value of hyperglycemia and glycosylated hemoglobin in critical patients.

Hyperglycemia is common in critical patients and high blood glucose levels have a negative effect on their prognosis. The aim of this study was to investigate the effect of hyperglycemia and glycosylated hemoglobin (GHb) in critical patients. A total of 648 critical patients were enrolled in the study and received a random blood glucose test when they entered the emergency department. If blood glucose was more than 11.1 mM, a GHb test was followed within 24 h. All patients were followed up for 28 days. According to diabetes mellitus (DM) history, GHb value, and outcome of follow-up, patients were divided into different groups, and mortality rates were calculated, respectively. Hyperglycemia was found in 67.44% (437/648) of patients, and 51.49% (225/437) and 48.51% (212/437) had normal and elevated GHb levels, respectively. At the end of the follow-up period, 14 of the normal GHb patients and 32 of the elevated GHb patients died (6.22 and 15.09%, respectively). In the normal GHb group, 53 had a DM history, 23 were newly diagnosed with DM, and 149 had hospital-related hyperglycemia (HRH); the mortality rates were 11.32% (6/53), 8.70% (2/23), and 4.03% (6/149), respectively. In the elevated GHb group, 114 had a DM history, 83 were newly diagnosed with DM, and 15 had HRH; the mortality rates were 13.16% (15/114), 19.27% (16/83), and 6.67% (1/15), respectively. Hyperglycemia and GHb might play important roles in the prognosis and assessment for critical patients, and the prognosis would vary according to the different causes of hyperglycemia.

Functionalized upconversion nanoparticles: versatile nanoplatforms for translational research.

The design, application, and translation of targeted multimodality molecular imaging probes based on nanotechnology have attracted increasing attentions during the last decade and will continue to play vital roles in cancer diagnosis and personalized medicine. With the growing awareness of drawbacks of traditional organic dyes and quantum dots, biocompatible lanthanide ion doped upconversion nanoparticles have emerged as promising candidates for clinically translatable imaging probes, owing to their unique features that are suitable for future targeted multimodal imaging in living subjects. In this review, we summarized the recent advances in the field of functionalized upconversion nanoparticles (f-UCNP) for biological imaging and therapy in vivo, and discussed the future research directions, obstacles ahead, and the potential use of f-UCNP in translational research.

Keratin 6a marks mammary bipotential progenitor cells that can give rise to a unique tumor model resembling human normal-like breast cancer.

Progenitor cells are considered an important cell of origin of human malignancies. However, there has not been any single gene that can define mammary bipotential progenitor cells, and as such it has not been possible to use genetic methods to introduce oncogenic alterations into these cells in vivo to study tumorigenesis from them. Keratin 6a is expressed in a subset of mammary luminal epithelial cells and body cells of terminal end buds. By generating transgenic mice using the Keratin 6a (K6a) gene promoter to express tumor virus A (tva), which encodes the receptor for avian leukosis virus subgroup A (ALV/A), we provide direct evidence that K6a(+) cells are bipotential progenitor cells, and the first demonstration of a non-basal location for some biopotential progenitor cells. These K6a(+) cells were readily induced to form mammary tumors by intraductal injection of RCAS (an ALV/A-derived vector) carrying the gene encoding the polyoma middle T antigen. Tumors in this K6a-tva line were papillary and resembled the normal breast-like subtype of human breast cancer. This is the first model of this subtype of human tumors and thus may be useful for preclinical testing of targeted therapy for patients with normal-like breast cancer. These observations also provide direct in vivo evidence for the hypothesis that the cell of origin affects mammary tumor phenotypes.

Charge inversion at minute electrolyte concentrations.

Anionic dimyristoylphosphatidic acid monolayers spread on LaCl3 solutions reveal strong cation adsorption and a sharp transition to surface overcharging at unexpectedly low bulk salt concentrations. We determine the surface accumulation of La3+ with anomalous x-ray reflectivity and find that La3+ compensates the lipid surface charge by forming a Stern layer with approximately 1 La3+ ion per 3 lipids below a critical bulk concentration, ct approximately 500 nM. Above ct, the surface concentration of La3+ increases to a saturation level with approximately 1 La3+ per lipid, thus implying that the total electric charge of the La3+ exceeds the surface charge. This overcharge is observed at approximately 4 orders of magnitude lower concentration than predicted in ion-ion correlation theories. We suggest that transverse electrostatic correlations between mobile ions and surface charges (interfacial Bjerrum pairing) may contribute to the charge inversion.

Regulation of microtubule assembly by human EB1 family proteins.

The EB1 family proteins are highly conserved microtubule-associated proteins. The EB1 protein in yeast has been shown to play an important role in regulating microtubule dynamics and chromosome segregation. Human EB1 family proteins include EB1, RP1 and EBF3. Although EB1 and RP1 have been shown to associate with microtubules, the subcellular localization of endogenous EBF3 had not been characterized. The function of human EB1 family proteins was also not clear. We therefore investigated the cellular localization of EBF3 and the regulation of microtubule organization by EB1 family proteins. As do EB1 and RP1, EBF3 was found to colocalize with microtubules, preferentially at their plus ends, throughout the cell cycle. Moreover, there was a very strong EBF3 signal at the centrosome in interphase cells and at the spindle poles in mitotic cells. When EB1 family proteins were overexpressed, they associated with the entire microtubule cytoskeleton. In addition, EB1 and EBF3 induced microtubule bundling in some cells overexpressing these proteins. These microtubule bundles were more resistant to nocodazole and were more acetylated than regular microtubules. Our results demonstrate for the first time that human EB1 family proteins could regulate microtubule assembly and stability.

[Cloning, sequence analysis and high-level expression in Escherichia coli and activity assay of pac-1 gene from Schizosaccharmyces pombe].

The Schizosaccharmyces pombe pac-1 gene product is a kind of dsRNA dependent ribonuclease, which has potential to degrade the dsRNA viral genome, the replication form of ssRNA viral genome and viroid genome. Therefore, to introduce the pac-1 gene into plants conferring them resistance to viruses is a new method of establishing the anti-virus transgenic plant. The pac-1 gene from the S. pmobe genome DNA isolated from China was cloned by means of PCR amplification. The pac-1 gene was inserted into the cloning vector pGEM-7Zf(+) by using restriction endonuclease Kpn I/BamHI. Sequencing analysis shows that it is a complete gene with 1095 necleotides. Compared to the reported pac-1 gene, its homology is significant, but with 5 nucleotides differences, leading to only one amino acid difference. Pac-1 gene was inserted into the prodaryotic expression vector pET-21(a) by using the restriction endonuclase Nde I/BamHI. It was induced by the IPTG in E. coli BL21 harbouring the recombinant vector pET-pac-1. The pac-1 gene product is analyzed by the SDS-PAGE. The result shows the product of pac-1 gene exists in the supernatant part as soluble form and in the precipitant part as inclusion bodies after the cells were lysed by ultrasonic wave. The supernatant was applied to detect the enzyme activity of pac-1 gene product. We concluded that pac-1 gene has the biological activity of degrading the CMV-dsRNA.

New alternating ferro- and antiferromagnetic one-dimensional complexes. Synthesis, characterization, crystal structure, and magnetic properties of.

The preparation, X-ray crystal structure, and magnetic properties of alternating 1,1- and 1,3-azido-bridged copper(II) complex [Cu(4,4'-dmbpy)(N3)2]n (1, 4,4'-dmbpy = 4,4'-dimethylbipyridine) have been reported. It crystallizes in triclinic system, space group P1, a = 7.9903(1) A, b = 9.3545(9) A, c = 10.754(2) A, alpha = 113.485(1) degrees, beta = 101.399(1) degrees, gamma = 101.897(1) degrees, Z = 2. The magnetic properties of 1 have been investigated in the temperature range 1.5-300 K. Alternating antiferromagnetic (-J = 191.0 cm(-1)) interaction through a 1,3-N3- bridge and ferromagnetic (J = 297.1 cm(-1)) interaction through a 1,1-N3- bridge are obtained for 1 by analyzing the magnetic susceptibility data with the Hamiltonian H = -Jsigma(S2iS2i-1--alphaS2iS2i+1). It's derivatives ([Mn(4,4'-dmbpy)(N3)2]n (2), [Ni(4,4'-dmbpy)(N3)2]n (3), and [Fe(4,4'-dmbpy)(N3)2]n (4) and the heterometallic derivatives [NiMn(4,4'-dmbpy)2(N3)4]n (5) and [CuMn(4,4'-dmbpy)2(N3)4]n (6) have also been synthesized and characterized by electronic and IR spectra. The X-ray powder diffraction and the magnetic properties of 6 have also been discussed.

Prediction of protein (domain) structural classes based on amino-acid index.

A protein (domain) is usually classified into one of the following four structural classes: all-alpha, all-beta, alpha/beta and alpha + beta. In this paper, a new formulation is proposed to predict the structural class of a protein (domain) from its primary sequence. Instead of the amino-acid composition used widely in the previous structural class prediction work, the auto-correlation functions based on the profile of amino-acid index along the primary sequence of the query protein (domain) are used for the structural class prediction. Consequently, the overall predictive accuracy is remarkably improved. For the same training database consisting of 359 proteins (domains) and the same component-coupled algorithm [Chou, K.C. & Maggiora, G.M. (1998) Protein Eng. 11, 523-538], the overall predictive accuracy of the new method for the jackknife test is 5-7% higher than the accuracy based only on the amino-acid composition. The overall predictive accuracy finally obtained for the jackknife test is as high as 90.5%, implying that a significant improvement has been achieved by making full use of the information contained in the primary sequence for the class prediction. This improvement depends on the size of the training database, the auto-correlation functions selected and the amino-acid index used. We have found that the amino-acid index proposed by Oobatake and Ooi, i.e. the average nonbonded energy per residue, leads to the optimal predictive result in the case for the database sets studied in this paper. This study may be considered as an alternative step towards making the structural class prediction more practical.

Effect of antiangiogenic agents on experimental animal models of hepatocellular carcinoma.

A new therapeutic strategy for treating metastasis in hepatocellular carcinoma (HCC) has entailed the use of antiangiogenic agents such as suramin, BB-94 (Batimastat), TNP-470, and carboxyamido-triazole (CAI, a synthetic inhibitor of non-excitable calcium channels that reversibly inhibits angiogenesis). These agents have been used to treat metastatic model of HCC in nude mouse (LCI-D20 mouse model). The results of these studies are summarized in this paper with emphasis on the inhibitory effects of the drugs on tumour growth, angiogenesis, invasion and metastasis in LCI-D20 mouse models. The results suggest that all of the agents used can significantly inhibit tumour growth, angiogenesis, invasion and metastasis of human HCC in nude mouse models, and may be candidates for the control of recurrence and metastasis after HCC resection.

Effects of matrix metalloproteinase inhibitor BB-94 on liver cancer growth and metastasis in a patient-like orthotopic model LCI-D20.

BACKGROUND/AIMS: The aim of this study was to try to understand the effects of the synthetic matrix metalloproteinase inhibitor Batimastat (BB-94) on hepatocellular carcinoma (HCC). METHODOLOGY: An orthotopic metastatic human hepatocellular carcinoma in nude mice model (LCI-D20) was used to study primary tumor growth, local invasion and metastasis of HCC. MTT assay was used to study the effects of BB-94 on cytotoxin and proliferation of HCC cell line SMMC-7721 in vitro. A gelatine zymograph was used to study the expression of MMPs in the LCI-D20 tumor tissue. RESULTS: BB-94 can inhibit primary tumor growth, local invasion, intrahepatic and lung metastasis, as well as prolong survival. BB-94 did not affect the proliferation of HCC cells in vitro. LCI-D20 tumor tissue expresses MMP-2 and MMP-9. CONCLUSIONS: BB-94 has a cytostatic therapeutic effect on HCC.

[The role of MMP-2 in the invasion and metastasis of hepatocellular carcinoma (HCC)].

OBJECTIVES: To get insights into the role of MMP-2 in the invasion and metastasis of hepatocellular carcinoma (HCC), and to find a method to judge the invasion and metastasis of HCC through MMP-2. METHODS: Zymograph and immunohistochemistry were used to study the content and types of positive cells of MMP-2 in the HCC, and statistical methods were used to analyse the association between the content of MMP-2 and the pathological indexes of HCC. RESULTS: MMP-2 was expressed by all the normal liver, HCC and surrounding liver parenchyma. The increase of MMP-2 and the presence of the active type of MMP-2 were related to the invasion and metastasis of HCC. The content of MMP-2 in HCC being higher than that in surrounding liver parenchyma was an important index to judge the invasion and metastasis of the HCC. The positive cells of MMP-2 found in immunohistochemistry were normal hepatocytes, cholangioepithelial cells, Ito cells, regenerated hepatocytes, new generated cholangioepithelial cells, and HCC cells. CONCLUSION: MMP-2 was related to the invasion and me astasis of HCC. The content of MMP-2 in HCC being higher than that in surrounding liver parenchyma could be bused as an important index to judge the invasion and metastasis of HCC.

Metabolic factors capable of inducing Agrobacterium vir gene expression are present in rice (Oryza sativa L.).

The effects of exudates and extracts from suspension cultures or various parts of rice (Oryza sativa L.) plants on induction of vir (virulence) gene expression in Agrobacterium tumefaciens were examined. Only leaf extracts from panicle-differentiating plants to flowering plants were able to strongly induce activation and expression of vir genes. This induction was similar to that observed with 2 µM acetosyringone (AS), yet there was no synergy between AS and rice extracts. Responses to vir-inducing metabolites and signal molecules were different among various vir loci. These results demonstrate that one or more inducing factors for vir gene expression are also present in rice, but only in specific parts and developmental stages.