Biomedical subjects

Ping An

Publications and source records attributed to Ping An.

At least 19 recordsLinked to original sources

PubMed2026

Recombinant Human Thrombopoietin Reduces the Need for Platelet Transfusion in Patients With Chronic Liver Disease and Thrombocytopenia.

Chronic liver disease (CLD)-related thrombocytopenia can limit the feasibility of invasive procedures. Recombinant human thrombopoietin (rhTPO) has demonstrated a favorable safety profile without hepatotoxicity. We evaluated the efficacy and safety of rhTPO in patients with CLD-related thrombocytopenia who were undergoing elective invasive procedures. In this multicenter, randomized (2:1), double-blind, placebo-controlled phase III trial, 120 adult Chinese patients with CLD-related thrombocytopenia (platelet count < 50 × 109/L) received rhTPO (n = 80) or placebo (n = 40) once daily for up to 5 or 7 days. The primary endpoint was the proportion of patients with sustained platelet counts ≥ 50 × 109/L from 24 h before invasive procedure to 7 days post-procedure, without requiring emergency bleeding management. The primary endpoint was achieved by 85.0% of patients in the rhTPO group versus 12.5% in the placebo group (p < 0.0001). Preoperatively, platelet counts ≥ 50 × 109/L were achieved in 92.5% and 20.0% of patients in the rhTPO and placebo groups, respectively (p < 0.0001). Platelet transfusion was avoided in 92.5% of rhTPO-treated patients versus 25.0% of placebo-treated patients (p < 0.0001). The median duration of platelet counts ≥ 50 × 109/L was significantly longer with rhTPO than with placebo (21.0 vs. 3.0 days, p = 0.0007). Treatment-related treatment-emergent adverse events (TEAEs) occurred in 12.5% of patients in both the rhTPO and placebo groups. No treatment-related serious adverse events were reported. Overall, rhTPO was effective and well tolerated in patients with CLD-related thrombocytopenia and may represent a viable therapeutic option for those undergoing elective invasive procedures. Trial Registration: www.chinadrugtrials.org.cn: number CTR20230919.

Humans↗

PubMed2026

Single-cell profiling reveals epithelial and immune responses in BK polyomavirus-infected human kidney biopsies.

INTRODUCTIONBK polyomavirus (BKV) infection is associated with injury and subsequent graft loss due to the extent of injury or rejection. However, the molecular mechanisms driving injury and subsequent adverse outcomes remain poorly understood.METHODSIn a cross-sectional study, single-cell RNA-seq from kidney allograft biopsies was used to assess cell type-specific responses between uninfected controls and 2 distinct phases of BKV infection: peaking (increasing viral blood titers) and resolving (decreasing viral titers following immunosuppression reduction).RESULTSGenes upregulated in BK viral nephropathy (BKVN) were enriched for polyomavirus infection hallmarks, including ribosome biogenesis, translation, and energy restructuring. Additionally, enriched pathways included wound healing, cellular stress, antigen presentation and immune signaling. Even without BKVN (peaking BK viremia alone), epithelial cells expressed signatures for wound healing, cellular stress, and extracellular matrix remodeling. In vivo tubular cell responses at single-cell resolution were validated against single cell transcriptomic data of BKV-infected cells in a cell culture model. Despite similarities, in vivo tubular cells underwent metabolic adaptation favoring fatty acid oxidation and proinflammatory responses not observed in culture models, likely due to an absent innate and adaptive immune system. Despite lymphopenia and immunosuppressive therapies, the proportion of recipient-derived intrarenal adaptive immune cells was increased in biopsies associated with peaking viremia alongside activation of innate immune responses. Adaptive immune cells exhibited persistent inflammatory signaling and remodeling of energy metabolism during the resolving phase of infection.CONCLUSIONThese not previously reported insights into BKV-associated injury may have implications for clinical management and improved allograft outcomes.

Humans↗

PubMed2006

Effect of plant harvest on methane emission from two constructed wetlands designed for the treatment of wastewater.

The emission of methane from two constructed wetlands [a free water surface flow system (FWS) and a subsurface flow system (SF)], constructed for the treatment of waste water, was evaluated at different sites inhabited by reeds (Phragmites communis), to test the effects of plant harvest. High methane emission was recorded immediately after harvesting in both wetlands. Several days after harvesting, the emission decreased in the FWS but remained high in the SF. The variation was significantly influenced by temperature, with lower emission and higher dissolved CH(4) in water occurring at lower temperatures. Both the emission and concentration of dissolved CH(4) were also influenced significantly by water quality, wetland design, level of stalk butt left above the water level, etc. The methane flux was explained on the basis of rizhospheric methanogenic and methanotrophic microbial populations. FISH analysis indicated the presence of Type A and Type B methanotrophs in both wetlands, and the methane flux was directly influenced by the quantitative variation in methanogenic and methanotrophic bacteria in both wetlands.

Bacteria↗

PubMed2006

Signal transduction pathways mediating CCK-8S-induced gastric antral smooth muscle contraction.

AIM: To investigate the functional and molecular mechanisms by which sulfated cholecystokinin octapeptide (CCK-8S) regulates calcium mobilization in gastric antral smooth muscle cells (SMCs) of rats. METHODS: Isotonic contraction of antral strips was recorded using a polyphysiograph. Immunoprecipitation was used to determine the regulatory effect of protein kinase C (PKC) on regulating the phosphorylation of the type III inositol 1,4,5-triphosphate receptor (InsP(3)R3) in gastric SMCs. Alterations in the intracellular calcium ([Ca(2+)](i)) concentration were assayed using fura-2/AM-loaded microspectrofluorometry, and the L-type calcium current (I(Ca-L)) was recorded by patch-clamp techniques. RESULTS: CCK-8S (5 x 10(-8) mol/l) significantly increased the mean contractile amplitude of circular muscle by 61.85 +/- 12.67% and the frequency of longitudinal muscle by 57.91 +/- 15.70% in gastric antral strips, which were suppressed by dexloxiglumide or thapsigargin (TG) and BAPTA-AM (BA). Treatment with chelerythrine (5 x 10(-8) mmol/l) significantly inhibited the CCK-8S-increased phosphorylation of InsP(3)R3 in SMCs. The amplitudes of the CCK-8S-triggered [Ca(2+)](i) concentration oscillations were reduced in a dose-dependent manner when the SMCs were pretreated with increasing concentrations of PMA (from 10(-8) to 10(-5) mol/l). On removal of extracellular calcium or blocking I(Ca-L) by nifedipine, a smaller but significant rise in the [Ca(2+)](i) concentration was still elicited by CCK-8S. When [Ca(2+)](i) was depleted by the administration of 10(-5) mol/l TG and 10(-5) mol/l BA or blocked by the calcium-dependent chloride current (I(Cl-Ca)) by giving 5 x 10(-6) mol/l niflumic acid, the CCK-8S-intensified I(Ca-L) (from -56.42 +/- 6.57 to -88.54 +/- 5.71 pA) was apparently inhibited by 90.34 +/- 4.71% and 82.59 +/- 4.24%. CONCLUSIONS: These results demonstrate that the CCK-8S-evoked [Ca(2+)](i) concentration increase in gastric antral SMCs depends on the release of [Ca(2+)](i) stores which are negatively regulated by PKC-mediated phosphorylation of InsP(3)R3. Released calcium in turn activates I(Ca-L) through the activation of I(Cl-Ca), ultimately resulting in the contraction of the gastric smooth muscle.

Animals↗

PubMed2006

Effects of human TRIM5alpha polymorphisms on antiretroviral function and susceptibility to human immunodeficiency virus infection.

TRIM5alpha acts on several retroviruses, including human immunodeficiency virus (HIV-1), to restrict cross-species transmission. Using natural history cohorts and tissue culture systems, we examined the effect of polymorphism in human TRIM5alpha on HIV-1 infection. In African Americans, the frequencies of two non-coding SNP variant alleles in exon 1 and intron 1 of TRIM5 were elevated in HIV-1-infected persons compared with uninfected subjects. By contrast, the frequency of the variant allele encoding TRIM5alpha 136Q was relatively elevated in uninfected individuals, suggesting a possible protective effect. TRIM5alpha 136Q protein exhibited slightly better anti-HIV-1 activity in tissue culture than the TRIM5alpha R136 protein. The 43Y variant of TRIM5alpha was less efficient than the H43 variant at restricting HIV-1 and murine leukemia virus infections in cultured cells. The ancestral TRIM5 haplotype specifying no observed variant alleles appeared to be protective against infection, and the corresponding wild-type protein partially restricted HIV-1 replication in vitro. A single logistic regression model with a permutation test indicated the global corrected P value of <0.05 for both SNPs and haplotypes. Thus, polymorphism in human TRIM5 may influence susceptibility to HIV-1 infection, a possibility that merits additional evaluation in independent cohorts.

Adolescent↗

PubMed2006

[The lethal effect of combined MDR1 antisense RNA with oxaliplatin and 5-FU on drug-resistant rectal carcinoma cells].

OBJECTIVE: To observe the lethal effect of multidrug resistance gene (MDR1) antisense RNA combined with oxaliplatin and 5-FU on drug-resistant rectal carcinoma cells. METHODS: PC-MDR1 plasmid including MDR1 was constructed with gene cloning techniques. The drug-resistant cancer cells (8348R) were transferred with the plasmids, and the positive neoplasm cells were selected with G418. Green fluorescent protein (GFP) gene was used as a reporting gene to monitor the gene transfer efficiency under the influence of oxaliplatin and 5-FU. The cytotoxicity and therapeutic effects of MDR1 anti-sense RNA combined with oxaliplatin and 5-FU were evaluated by colony-forming rate and MTT assay. RESULTS: A significant decrease of biological activity was observed in 8348R cells transferred with PC-MDR1, cell cycles were blocked in S phase, or in G2/M phase, and apoptosis rate of the cells increased. With treatment of oxaliplatin, the plasmid transfer efficiency in the drug-resistant cancer cells was improved about 18 times. Using an IC(50) dose of oxaliplatin and 5-FU combined with (MDR1) anti-sense RNA, 75 percent of 8348R cells were killed, which was significant higher than that of the control cells. CONCLUSIONS: Combined MDR1 antisense RNA with oxaliplatin and 5-FU has a synergistic effect of killing drug-resistant cancer cells and may be a promising method for treating drug-resistant rectal carcinoma.

Antineoplastic Agents↗

PubMed2006

Genetic variation in the CCL18-CCL3-CCL4 chemokine gene cluster influences HIV Type 1 transmission and AIDS disease progression.

CCL3 (MIP-1 alpha), CCL4 (MIP-1 beta), and CCL18 (DC-CK1/PARC/AMAC-1) are potent chemoattractants produced by macrophages, natural killer cells, fibroblasts, mast cells, CD4(+) T cells, and CD8(+) T cells. CCL3 and CCL4 are natural ligands for the primary human immunodeficiency virus type 1 (HIV-1) coreceptor CCR5 and are also known to activate and enhance the cytotoxicity of natural killer cells. Genomic DNAs from >3,000 participants enrolled in five United States-based natural-history cohorts with acquired immunodeficiency syndrome (AIDS) were genotyped for 21 single-nucleotide polymorphisms (SNPs) in a 47-kb interval on chromosome 17q12 containing the genes CCL3, CCL4, and CCL18. All 21 SNPs were polymorphic in African Americans (AAs), whereas 7 of the 21 had minor-allele frequencies <0.01 in European Americans (EAs). Substantial linkage disequilibrium was observed in a 37-kb interval containing 17 SNPs where many pairwise D' values exceeded 0.70 in both racial groups, but particularly in EAs. Four and three haplotype blocks were observed in AAs and EAs, respectively. Blocks were strongly correlated with each other, and common haplotype diversity within blocks was limited. Two significant associations are reported that replicate an earlier study. First, among AA members of the AIDS Link to the Intravenous Experience cohort of injection drug users, frequencies of three correlated SNPs covering 2,231 bp in CCL3 were significantly elevated among highly exposed, persistently HIV-1-uninfected individuals compared with HIV-1-infected seroconvertors (P = .02-.03). Second, seven highly correlated SNPs spanning 36 kb and containing all three genes were significantly associated with more-rapid disease progression among EAs enrolled in the Multicenter AIDS Cohort Study cohort (P = .01-.02). These results reiterate the importance of chemokine gene variation in HIV-1/AIDS pathogenesis and emphasize that localized linkage disequilibrium makes the identification of causal mutations difficult.

Chemokine CCL3↗

PubMed2006

Disruption of estrogen receptor DNA-binding domain and related intramolecular communication restores tamoxifen sensitivity in resistant breast cancer.

A serious obstacle to successful treatment of estrogen receptor (ER)-positive human breast cancer is cell resistance to tamoxifen (TAM) therapy. Here we show that the electrophile disulfide benzamide (DIBA), an ER zinc finger inhibitor, blocks ligand-dependent and -independent cell growth of TAM-resistant breast cancer in vitro and in vivo. Such inhibition depends on targeting disruption of the ER DNA-binding domain and its communication with neighboring functional domains, facilitating ERalpha dissociation from its coactivator AIB1 and concomitant association with its corepressor NCoR bound to chromatin. DIBA does not affect phosphorylation of HER2, MAPK, AKT, and AIB1, suggesting that DIBA-modified ERalpha may induce a switch from agonistic to antagonistic effects of TAM on resistant breast cancer cells.

Animals↗

PubMed2006

Low frequency of telomerase RNA mutations among children with aplastic anemia or myelodysplastic syndrome.

Mutations in TERC, the RNA component of telomerase, result in autosomal dominant dyskeratosis congenita (DC), a rare bone marrow failure syndrome. TERC mutations have been detected in a subset of patients previously diagnosed with aplastic anemia and myelodysplastic syndrome (MDS), and these TERC mutations are clinically relevant as patients with DC respond poorly to conventional therapies. We aimed to determine the frequency of TERC mutations in pediatric patients with aplastic anemia and MDS who required a hematopoietic stem cell transplant. We obtained 284 blood samples from the National Donor Marrow Program Research Sample Repository from children and adolescents with bone marrow failure who underwent an unrelated stem cell transplant. We screened these samples for mutations in the TERC gene using direct DNA sequencing. We found 2 patients with sequence alterations in TERC. We identified a 2 base pair deletion (-240delCT) in a 4-year-old child with MDS and a single nucleotide alteration (-99-->CG) in a 1-year-old child with juvenile myelomonocytic leukemia. Screening for TERC gene mutations is unlikely to diagnose occult DC in children with severe bone marrow failure who require a hematopoietic stem cell transplant.

Adolescent↗

PubMed2006

Thalidomide in rat liver cirrhosis: blockade of tumor necrosis factor-alpha via inhibition of degradation of an inhibitor of nuclear factor-kappaB.

BACKGROUND/AIMS: Thalidomide inhibited tumor necrosis factor-alpha (TNF-alpha) effectively in many trials. The aim of this study was to investigate the effect of thalidomide on the expression of nuclear factor-kappaB (NF-kappaB), inhibitor of NF-kappaB (IkappaB) and TNF-alpha in a rat model of liver cirrhosis. METHODS: Liver cirrhosis was achieved by intraperitoneal injection of carbon tetrachloride thrice weekly, and thalidomide (10 or 100 mg/kg/day) was given daily by intragastric route for 8 weeks. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), prealbumin (PA), hyaluronic acid (HA) and laminin (LN), and hydroxyproline (HYP), NF-kappaBp65, alpha-smooth muscle actin (alpha-SMA) protein and TNF-alpha mRNA were studied in the liver, IkappaBalpha and TNF-alpha protein in the cytoplasm and NF-kappaBp65 protein in the nucleus. RESULTS: Compared with nontreated cirrhotic rats, the histopathology of rats given thalidomide (100 mg/kg) was significantly better. Serum ALT, AST, HA and LN and HYP content in the liver were significantly decreased and PA was elevated (p < 0.01) in this group; the expression of TNF-alpha mRNA and protein, NF-kappaBp65 and alpha-SMA were significantly decreased and IkappaBalpha protein was also elevated (p < 0.01). CONCLUSION: Thalidomide downregulates NF-kappaB-induced TNF-alpha and activates hepatic stellate cells (HSC) via inhibition of IkappaB degradation to prevent liver cirrhosis.

Actins↗

PubMed2006

Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study.

Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.

Black People↗

PubMed2006

[Target lethal effect of recombinant soluble Fas coupled with protein kinase C inhibitor on colorectal carcinoma cells].

OBJECTIVE: To study the target killing effect of soluble Fas(sFas) coupled with protein kinase C(PKC) inhibitor on colorectal carcinoma cells. METHODS: The extracellular region of Fas protein was cloned and amplified by RT-PCR, and the expressing vector pGEX-4T-1-sFas was constructed. The sFas protein was purified by GST fusion protein purification system and coupled with Calphostin C(one kind of PKC inhibitor). The killing effect of soluble Fas coupled with PKC inhibitor on FasL-positive colorectal carcinoma cells was detected. RESULTS: After amplifying and cloning, the extracellular region of Fas protein, a 571 bp fragment, was proved by limited enzyme cutting and DNA sequencing. The expressed and purified protein was identified by Western Blot after transformed into E. coli BL21. The coupled sFas-Calphostin C showed suppressant activity on PKC kinase by the PKC kinase activity assay kit. The growth suppression rate of FasL-positive colorectal carcinoma HR-8348 cells treated with sFas-Calphostin C was significantly higher than that of FasL-negative cells, but the killing effect of sFas-Calphostin C on normal human monocyte was not obvious. Compared with 5-Fu alone, the growth suppression rate of FasL-positive colorectal carcinoma HR-8348 cells was significantly raised by sFas-Calphostin C combined with 5-Fu. CONCLUSION: The recombinant of soluble Fas and PKC inhibitor shows target killing effect on colorectal carcinoma cells.

Colorectal Neoplasms↗

PubMed2006

[The effect and mechanism of cholecystokinin octapeptide induced-gastric dysmotility on bile regurgitation during stress].

OBJECTIVE: To illustrate the existence of bile regurgitation under stress condition, and explore the possible effects and related mechanism of changes of cholecystokinin octapeptide (CCK-8) on stress-induced bile regurgitation in rats. METHODS: (1) Changes in plasma CCK-8 and gastric bile concentration were measured by using radioimmunoassay while simultaneously calculating gastric ulcer index and intragastric pH; (2) Each isolated gastric strips were suspended in a tissue chamber to record the contractile responses by polyphysiograph; (3) The responsiveness of gastric smooth muscle cells (SMCs) to sulfated cholecystokinin octapeptide (CCK-8S) were examined using fura-2-loaded microfluorimetric measurement of intracellular calcium concentration ([Ca(2+)] i); (4) The current of L-type calcium channels (I(CaL)) of SMCs were recorded by patch-clamp techniques. RESULTS: (1) Compared with the normal control, plasma CCK-8 [from (2.23 +/- 0.88) pmol/L to (10.80 +/- 3.82) pmol/L] and gastric bile concentration [from (37.93 +/- 23.76) micromol/L to (1316.00 +/- 197.36) micromol/L] significantly increased during the stress (P < 0.01) and both simultaneously reached the peak at the time point of 2 h after stress; ulcer index (from 0.62 +/- 0.23 to 32.01 +/- 16.11) and intragastric pH (from 1.06 +/- 1.20 to 5.29 +/- 1.25) apparently increased (P < 0.01); (2) Significant changes to CCK-8S were found in the mean contractile amplitude and frequency of circular muscle and longitudinal muscle of gastric antrum and pylorus; (3) CCK-8S-evoked significant increase in [Ca(2+)] i [from (65.8 +/- 7.4) nmol/L to (472.1 +/- 35.6) nmol/L, P < 0.01] could be suppressed by CCK-A receptor antagonist; whereas a small but significant increases were still elicited by CCK-8S under condition of the removal of extracellular calcium; (4) CCK-8S-intensified calcium current I(Ca-L) [from (-56.42 +/- 6.57) pA to (-88.54 +/- 5.71) pA, P < 0.01)] apparently inhibited by respective administration of nifedipine, Ca(2+)-ATPase inhibitors or calcium dependent chloride channel blocker (P < 0.01). CONCLUSIONS: Gastric mucosal damage induced by bile regurgitation is closely connected with gastric antrum and pylorus dysmotility evoked by CCK-8 during the stress. CCK-8S-evoked [Ca(2+)] i increase in gastric antrum and pylorus SMC depends on the release of intracellular calcium stores which activates L-type voltage-dependent calcium channels through the activation of calcium dependent chloride channels.

Animals↗

PubMed2005

[Expression of metallothionein and FasL in colorectal cancer and its clinical significance].

OBJECTIVE: To study the expression of metallothionein (MT) and FasL in colorectal cancer and their relation to lymph node and liver metastasis. METHODS: Immunohistochemistry and quantitative RT-PCR were used to detect expression of MT and FasL in protein and mRNA levels in 93 cases of colorectal cancer. RESULTS: The rates of MT expression in primary foci, non-cancerous colon mucosa, lymph node metastasis and liver metastasis were 58.1%, 32.3%, 81.1%, 64.3% respectively. And the rates of FasL expression were 41.9%, 19.4%, 62.3%, and 92.9% respectively. The positive rates of MT and FasL in primary foci, liver and lymph node metastasis were higher than that in non-cancerous mucosa (chi(2) = 35.2421, 57.5152, P < 0.01). MT expression rate in lymph node metastasis was higher than that in primary foci (chi(2) = 8.0565, P < 0.01). In liver metastasis, FasL expression rate was higher than in lymph node metastasis and primary foci (chi(2) = 8.6674, 22.4455, P < 0.01). The positive rates of MT and FasL in Dukes stage C and D were higher than that in Dukes stage A and B (chi(2) = 18.8871, 25.1650, P < 0.01). And higher rates of MT and FasL expression were observed in low differentiation adenocarcinoma and mucus adenocarcinoma than in middle-high differentiation adenocarcinoma (chi(2) = 11.1546, 9.2239, P < 0.05). High MT mRNA level was found in lymph node metastasis and high FasL mRNA level in liver metastasis. CONCLUSIONS: Enhanced expression of MT and FasL was associated significantly with lymph node and liver metastasis of colorectal cancer. Assay of MT and FasL expression has prognostic values for colorectal cancer patients.

Adult↗

PubMed2005

Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband.

Beckwith-Wiedemann syndrome (BWS) is congenital disorder whose molecular etiology is related to genetic and epigenetic mutations on 11p15. The majority of cases of BWS are sporadic, but a substantial proportion are familial, with an unknown inheritance pattern, although autosomal dominant and sex-dependent inheritance have been proposed. We tested the hypothesis that in familial BWS, autosomal dominant inheritance is the primary mode of transmission underlying familial instances. Segregation analysis was performed in 291 families ascertained with an affected child. Individuals were considered to have BWS if they had two of five major features: macroglossia, macrosomia, hypoglycemia at birth, abdominal wall defect, and ear pits or creases. Models of inheritance were tested using pedigree analysis package (PAP) parameterized for a discrete trait. A total of 291 families of an affected proband were included in the study. The analysis was based on a revised general model that included a boundary solution. Sporadic and environmental models were rejected. Overall, the results suggested Mendelian inheritance but under recessive or additive mode of inheritance, which fit the data equally well rather than dominant inheritance. However, the presence of families in the cohort consistent with dominant and sex-dependent inheritance suggest familial BWS may be a heterogeneous group comprised of different inheritance patterns. Familial BWS does not appear to be consistent with autosomal dominant transmission, and is likely a complex mixture of different inheritance patterns.

Beckwith-Wiedemann Syndrome↗

PubMed2005

[Proteome study of colorectal cancer genesis and hepatic metastasis].

OBJECTIVE: To study differential proteins and their biological functions associated with colorectal cancer genesis and hepatic metastasis by proteomics and molecular biology techniques. METHODS: Isoelectric focusing/SDS acrylamide gel two-dimensional electrophoresis was used to analyse the expression of differential proteins from normal colorectal mucosa, primary cancer lesion and hepatic metastasis region. Liquid chromatography/mass spectrometry (LC-MS/MS) was used to identify the differential proteins. Transfection of colorectal cancer lovo cells was performed with the differential protein cDNA, and the changes of cell biological behavior was observed. RESULTS: Significant difference in protein expression was found on two-dimensional electrophoresis. Thirteen differential protein spots were analysed and identified. Human carbonic anhydrase II was detected in normal colorectal mucosa but not in primary cancer lesion and hepatic metastasisnegion. Phosphoglycerate kinase 1, fumarate hydratase and aldolase A were expressed in primary cancer. Expression of homo sapiens arginase and homo sapiens glutathione S-transferase A3 was found in hepatic metastasisnegion, but not in primary cancer lesion. After transfection with human carbonic anhydrase II cDNA, the lovo cells changed obviously with reduction in invasiveness, chemotaxy motor ability and tolerance. CONCLUSION: Differential expression of proteins was found between colorectal cancer genesis and hepatic metastasisnegion. No carbonic anhydrase II expression and enhanced expression of sapiens arginase and sapiens glutathione S-transferase A3 are related with biological behavior of colorectal cancer cell and facilitate hepatic metastasis.

Adult↗

PubMed2005

Combined liposome-mediated cytosine deaminase gene therapy with radiation in killing rectal cancer cells and xenografts in athymic mice.

PURPOSE: The aim of this study was to assess the antitumor efficacy of combination of cytosine deaminase (CD) suicide gene therapy with radiation and to grope for new therapeutic strategy for local recurrent rectal cancer. EXPERIMENTAL DESIGN: HR-8348 cell line of human rectal cancer was used to assess efficiency of transfection with plasmid pEGFP-N1 and PXJ41-CD. The cells were exposed to radiation followed by liposome-mediated transfection. Cell inhibition assay was done with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. Antitumor efficacy of combined liposome-mediated CD suicide gene therapy with radiation was determined by treatment of nude mice bearing HR-8348 cancer cell xenograft. RESULTS: The efficiency of liposome-mediated CD gene transfection can be improved by radiation. With radiation at 2, 4, 6, and 8 Gy, the efficiency of liposome-mediated transfection increased from 21.3% to 62.2%, 78.0%, 83.2%, and 87.8%, respectively. CD expression was enhanced as well. Cancer cell inhibition experiment showed that combined liposome-mediated CD gene therapy with radiation had much stronger antitumor effect. With HR-8348 tumor xenograft model, suppression of tumor xenograft was observed. Compared with control group, tumor volume was inhibited by 81.5%, 48.5%, and 37.4%, respectively, in the combined CD/5-fluorocytosine with radiation group, CD/5-fluorocytosine group, and radiation group and the wet weight of tumor was decreased by 80%, 41.7%, and 37.7%, respectively. CONCLUSION: These findings suggested that combination of liposome-mediated CD gene therapy with radiation is a safer and efficient anticancer method. Its therapeutic efficacy may meet clinical treatment on local recurrent rectal cancer.

Animals↗

PubMed2005

A combinatorial code for splicing silencing: UAGG and GGGG motifs.

Alternative pre-mRNA splicing is widely used to regulate gene expression by tuning the levels of tissue-specific mRNA isoforms. Few regulatory mechanisms are understood at the level of combinatorial control despite numerous sequences, distinct from splice sites, that have been shown to play roles in splicing enhancement or silencing. Here we use molecular approaches to identify a ternary combination of exonic UAGG and 5'-splice-site-proximal GGGG motifs that functions cooperatively to silence the brain-region-specific CI cassette exon (exon 19) of the glutamate NMDA R1 receptor (GRIN1) transcript. Disruption of three components of the motif pattern converted the CI cassette into a constitutive exon, while predominant skipping was conferred when the same components were introduced, de novo, into a heterologous constitutive exon. Predominant exon silencing was directed by the motif pattern in the presence of six competing exonic splicing enhancers, and this effect was retained after systematically repositioning the two exonic UAGGs within the CI cassette. In this system, hnRNP A1 was shown to mediate silencing while hnRNP H antagonized silencing. Genome-wide computational analysis combined with RT-PCR testing showed that a class of skipped human and mouse exons can be identified by searches that preserve the sequence and spatial configuration of the UAGG and GGGG motifs. This analysis suggests that the multi-component silencing code may play an important role in the tissue-specific regulation of the CI cassette exon, and that it may serve more generally as a molecular language to allow for intricate adjustments and the coordination of splicing patterns from different genes.

Alternative Splicing↗