[A preliminary study of the relationship between leptin and its receptor and primary hepatocellular carcinoma].
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Carcinoma, Hepatocellular↗
Biomedical subjects
Lei Shen
Publications and source records attributed to Lei Shen.
Possible involvement of leptin and leptin receptor in developing gastric adenocarcinoma.
AIM: To investigate the expression of leptin and leptin receptor (ob-R) in intestinal-type gastric cancer and precancerous lesions, and to explore the possible mechanism and role of the leptin system in developing intestinal-type gastric adenocarcinoma. METHODS: Immunohistochemistry was performed to examine the expression of leptin and leptin receptor in archival samples of gastric adenocarcinoma and preneoplastic lesions, including intestinal metaplasia and mild to severe gastric epithelial dysplasia. Positive staining was identified and percentage of positive staining was graded. RESULTS: Dual expression of leptin and leptin receptor were detected in 80% (16/20) intestinal metaplasia, 86.3% (25/30) mild gastric epithelial dysplasia, 86.7% (26/30) moderate gastric epithelial dysplasia, 93.3% (28/30) severe gastric epithelial dysplasia, 91.3% (55/60) intestinal-type gastric adenocarcinoma and 30.0% (9/30) diffuse-type gastric carcinoma. The percentage of dual expression of leptin and leptin receptor in intestinal-type gastric adenocarcinoma was significantly higher than that in diffuse-type gastric adenocarcinoma (c2 = 37.022, P<0.01). CONCLUSION: Our results indicate the presence of an autocrine loop of leptin system in the development of intestinal-type gastric adenocarcinoma.
Adenocarcinoma↗
Smad3 mediates TGF-beta1-induced collagen gel contraction by human lung fibroblasts.
Transforming growth factor-beta1 (TGF-beta1) is a key mediator in tissue repair and fibrosis. Using small interference RNA (siRNA), the role of Smad2 and Smad3 in TGF-beta stimulation of human lung fibroblast contraction of collagenous matrix and induction of alpha-SMA and the role of alpha-SMA in contraction were assessed. HFL-1 cells were transfected with Smad2, Smad3 or control-siRNA, and cultured in floating Type I collagen gels +/- -TGF-beta1. TGF-beta1 augmented gel contraction in Smad2-siRNA- and control-siRNA-treated cells, but had no effect in Smad3-siRNA-treated cells. Similarly, TGF-beta1 upregulated alpha-SMA in Smad2-siRNA- and control-siRNA-treated cells, but had no effect on Smad3-siRNA-treated cells. Alpha-SMA-siRNA-treated cells did not contact the collagen gels with or without TGF-beta1, suggesting alpha-SMA is required for gel contraction. Thus, Smad3 mediates TGF-beta1-induced contraction and alpha-SMA induction in human lung fibroblasts. Smad3, therefore, could be a target for blocking contraction of human fibrotic tissue induced by TGF-beta1.
Actins↗
High frequency of loss of heterozygosity in imprinted, compared with nonimprinted, genomic regions in follicular thyroid carcinomas and atypical adenomas.
CONTEXT: Many mammalian genes that are imprinted regulate cell growth, differentiation, and apoptosis. Because imprinting silences one of the two alleles, resulting in functional haploinsufficiency, we hypothesized that loss of heterozygosity (LOH) at an imprinted locus may result in the deletion of the only functional copy of an imprinted tumor suppressor gene. OBJECTIVE: The goal of this study was to specifically address this hypothesis that in thyroid neoplasias loss of imprinted loci becomes enriched during oncogenesis. DESIGN: In total, thyroid tissue was obtained from 72 patients with thyroid neoplasias comprising 34 follicular thyroid carcinomas (FTCs) and 38 follicular adenomas. We performed PCR-based LOH analysis of DNA from paired normal-tumor samples using 18 markers mapped to imprinted regions (IR) and 13 markers in nonimprinted regions (NIR). RESULTS: Overall LOH frequencies for the IR markers were 26% for the adenomas and 38% for the carcinomas. In the NIR, the overall LOH frequency was 23 and 26% for adenomas and FTCs, respectively. The difference in LOH frequencies between IR and NIR was statistically significant only for the carcinomas (P = 0.001), although there was a similar trend for the atypical adenomas (ATY, P = 0.06). CONCLUSIONS: Our observations suggest that IRs are more prone to genomic instability in FTCs. The fact that the ATY trended toward differential IR/NIR LOH, similar to FTC, may suggest that loss of IR might be instrumental in the adenoma-carcinoma sequence in thyroid carcinogenesis and that ATY could be an important intermediate in this pathway.
Adenoma↗
Temporal-space-transforming pulse-shaping system with a knife-edge apparatus for a high-energy laser facility.
For the first time to our knowledge, in a high-energy laser facility with an output energy of 454.37 J, by using a temporal-space-transforming pulse-shaping system with our own design of a knife-edge apparatus, we obtained a quasi-square laser pulse.
Journal Article↗
Combining phylogenetic motif discovery and motif clustering to predict co-regulated genes.
MOTIVATION: We present a sequence-based framework and algorithm PHYLOCLUS for predicting co-regulated genes. In our approach, de novo discovery methods are used to find motifs conserved by evolution and then a Bayesian hierarchical clustering model is used to cluster these motifs, thereby grouping together genes that are putatively co-regulated. Our clustering procedure allows both the number of clusters and the motif width within each cluster to be unknown. RESULTS: We use our framework to predict co-regulated genes in the bacterium Bacillus subtilis using six other closely related bacterial species. Our predicted motifs and gene clusters are validated using several external sources and significant clusters are examined in detail. An extension to the discovery and clustering of two-block motifs can be used for inference about synergistic binding relationships between transcription factors. AVAILABILITY: Software and Supplementary Materials can be downloaded at http://stat.wharton.upenn.edu/~stjensen/research/phyloclus.html or http://www.fas.harvard.edu/~junliu/phyloclus.html CONTACT: stjensen@wharton.upenn.edu.
Algorithms↗
Genetic classification of benign and malignant thyroid follicular neoplasia based on a three-gene combination.
Thyroid carcinoma is a common endocrine cancer with a favorable prognosis if subjected to timely treatment. However, the clinical identification of follicular thyroid carcinoma (FTC) among patients with benign thyroid nodules is still a challenge. Preoperative fine needle aspiration-based cytology cannot always differentiate follicular carcinomas from benign follicular neoplasias. Because current methods fail to improve preoperative diagnosis of thyroid nodules, new molecular-based diagnoses should be explored. We conducted a microarray-based study to reveal the genetic profiles unique to FTC and follicular adenomas (FAs), to identify the most parsimonious number of genes that could accurately differentiate between benign and malignant follicular thyroid neoplasia. We confirmed our data by quantitative RT-PCR and immunohistochemistry in two independent validation sets with a total of 114 samples. We were able to identify three genes, cyclin D2 (CCND2), protein convertase 2 (PCSK2), and prostate differentiation factor (PLAB), that allow the accurate molecular classification of FTC and FA. Two independent validation sets revealed that the combination of these three genes could differentiate FTC from FA with a sensitivity of 100%, specificity of 94.7%, and accuracy of 96.7%. In addition, our model allowed the identification of follicular variants of papillary thyroid carcinoma with an accuracy of 85.7%. Three-gene profiling of thyroid nodules can accurately predict the diagnosis of FTC and FA with high sensitivity and specificity, thus identifying promising targets for further investigation to ultimately improve preoperative diagnosis.
Adenocarcinoma, Follicular↗
Smad3 mediates TGF-beta1 induction of VEGF production in lung fibroblasts.
Transforming growth factor-beta1 (TGF-beta1) is a key factor in a variety of physiological and pathological processes. Vascular endothelial growth factor (VEGF) is a key angiogenic factor, and vascular change is one of the features of airway remodeling. We examined the effect of TGF-beta1 on VEGF production by fibroblasts from mice lacking expression of Smad2 or Smad3 as well as human lung fibroblasts treated with or without Smad2 or Smad3 siRNA. TGF-beta1 stimulated VEGF production by fibroblasts from Smad2 deficient animals and wildtype animals. In contrast, TGF-beta1 did not affect VEGF production by fibroblasts from Samd3 deficient mice. Similarly, TGF-beta1 failed to stimulate VEGF production by HFL-1 cells treated with Samd3 siRNA but significantly increased VEGF production by the cells treated with Smad2 siRNA. These result suggest that TGF-beta1 stimulation of VEGF production by fibroblasts is regulated by Smad3 but not by Smad2 signaling.
Animals↗
Recurrent lumbar disc herniation after discectomy: outcome of repeat discectomy.
BACKGROUND: Recurrent disc herniation after discectomy is relatively lacking in specific studies and is usually reviewed along with other causes of failed disc surgery. The purpose of the current study was to address the outcome in the patients who had recurrent disc herniation treated with repeat discectomy and to identify the factors that may influence the outcome. METHODS: Thirty-nine patients who underwent repeat discectomy for recurrent lumbar disc herniation were retrospectively analyzed. Of these patients, 27 had recurrent disc herniation at the L4 to L5 level, 11 at the L5 to S1, and 1 at the L3 to L4. They almost had the typical presentation of sciatica. The time from prior discectomy to that of recurrence ranged 6 months to 17 years (average, 5 years and 4 months). The Japanese Orthopaedic Association (JOA) score averaged 12 (range, -3 to 18). All patients had a follow-up evaluation at 1 and 15 years (average, 7 years and 8 months) after surgery. RESULTS: Their JOA score increased to 12 to 29 (average, 24), with the recovery rate of 29% to 100% (average, 72%). Twenty-nine patients returned to their previous work status or normal daily activity, 7 had significant improvement, and 3 needed analgesic drugs although they had pain relief to different degrees. CONCLUSIONS: The outcomes of repeat discectomy for recurrent disc herniation were satisfactory. No factors such as age, sex, traumatic events, times of prior surgery, level of herniation, side of recurrence, pain-free interval, duration of recurrence symptoms, walking capacity, the preoperative JOA score, associated spinal stenosis, procedures of revision surgery, and dural tear were found to be of predictive value for a prognosis of revision surgery for recurrent disc herniation (P>.05).
Adult↗
[Evaluation of the value of ultrasonography in diagnosis of liver fibrosis in patients with chronic viral hepatitis].
OBJECTIVE: It is important to use noninvasive methods to differentiate liver fibrosis and liver cirrhosis. A prospective study was conducted to evaluate the validity of ultrasonography (US) in evaluating the severity of liver fibrosis in patients with chronic viral hepatitis in reference to the pathologic diagnosis of their liver biopsy specimens. METHODS: The liver fibrosis status of 324 chronic viral hepatitis patients was evaluated by both needle biopsy and US. Histologically their liver fibrosis was graded as S0-S4, and the inflammatory reaction in the liver was graded as G1-G4. The US examination included qualitative description of the liver surface and liver parenchyma, and the quantitative parameters were vascular diameters, blood flow volume and spleen size. RESULTS: US qualitative description of the liver surface and liver parenchyma was correlated to the severity of fibrosis and the degree of the inflammation seen in the liver biopsies. An analysis of US quantitative parameters showed that a cut-off value of 12.1 cm for the length of spleen had a sensitivity of 60.0%, and specificity of 75.3% in detecting early liver fibrosis. For other quantitative parameters, the cut-off values were 8mm for the diameter of the splenic vein, 30.5 cm/sec for maximal blood flow velocity in the portal vein and 12 mm in diameter of the main portal vein. The diagnostic sensitivities for these parameters were 60.0%, 78.6% and 76.7%; the diagnostic specificities were 78.1%, 66.9% and 44.6% respectively. CONCLUSION: Early cirrhosis can be detected by US, and the sonographic results were well paralleled with their pathologic diagnoses made by liver biopsies. Individual US parameter has limited sensitivity and specificity in diagnosing early cirrhosis. In clinical practice a combination of 2-3 parameters could be used to detect or exclude severe liver fibrosis.
Adult↗
[Investigation of extracellular signal-regulated protein kinase and lymphnode metastasis in oral squamous cell carcinoma].
PURPOSE: To study the relationship between the expression of extracellular signal-regulated protein kinase (ERK) and the differentiation degree and lymphnode metastasis in oral squamous cell carcinoma. METHODS: Immunohistochemical staining was used in 41 cases of OSCC to investigate the expression of ERK protein. Student's t test were used for statistical analysis. RESULTS: A significant relationship was observed between the expression intensity of ERK protein and clinicopathological features of OSCC (P<0.01). A significant relationship was observed between the expression intensity of ERK protein and lymph node metastasis of OSCC(P<0.05). No correlation between the expression intensity of ERK protein and cell differentiation degree of OSCC (P>0.05) was found. CONCLUSIONS: Activation of ERK may play a strong role in the development of OSCC. Intensive expression of ERK protein may be an important presage marker in OSCC patients.
Carcinoma, Squamous Cell↗
[The expression of PTEN and PKB in salivary adenoid cystic carcinoma and its clinical significance].
PURPOSE: To investigate the expression of PTEN and PKB in salivary adenoid cystic carcinoma (SACC) and its clinical significance. METHODS: The expression of PTEN and PKB in 63 cases SACC were evaluated by SP immunohistochemistry. SPSS 11.5 software was used for chi-square test. RESULTS: In 38 cases, both non-cancer tissue near by cancer and cancer tissue, 21 (55.26%) cases cancer tissue PTEN expression positive were found, 32 (84.21%) cases the non-cancer tissue near by cancer PTEN expression positive were found. There was significant difference in cancer tissue and non-cancer tissue near by cancer (P<0.05). 31 (81.58%) cases cancer tissue PKB expression positive were found, 20 (52.63%) cases the non-cancer tissue near by cancer PKB expression positive were found. There was significant difference in cancer tissue and non-cancer tissue near by cancer (P<0.01). In 25 cases with metastasis, 9 (36%) cases PTEN expression positive were found; in 38 cases with non-metastasis, 26 (68.42%) cases PTEN expression positive were found; there was significant difference in cases of metastasis and non-metastasis (P<0.05). In 25 cases with metastasis, 24 (96%) cases PKB expression positive were found; in 38 cases with non-metastasis, 27 (71.05%) cases PKB expression positive were found; There was significant difference in cases of metastasis and non-metastasis (P<0.05). PTEN expression and PKB expression were no significant difference between the different sex, age and sorts of pathology. PTEN and PKB were negatively correlated (P<0.01). CONCLUSIONS: The expression of PTEN and PKB may be related to the occurrence and progress of salivary adenoid cystic carcinoma,PTEN and PKB may have effect on metastasis.
Carcinoma, Adenoid Cystic↗
Human T lymphotropic virus type-1 p30II alters cellular gene expression to selectively enhance signaling pathways that activate T lymphocytes.
BACKGROUND: Human T-lymphotropic virus type-1 (HTLV-1) is a deltaretrovirus that causes adult T-cell leukemia/lymphoma and is implicated in a variety of lymphocyte-mediated disorders. HTLV-1 contains both regulatory and accessory genes in four pX open reading frames. pX ORF-II encodes two proteins, p13II and p30II, which are incompletely defined in the virus life cycle or HTLV-1 pathogenesis. Proviral clones of the virus with pX ORF-II mutations diminish the ability of the virus to maintain viral loads in vivo. Exogenous expression of p30II differentially modulates CREB and Tax-responsive element-mediated transcription through its interaction with CREB-binding protein/p300 and represses tax/rex RNA nuclear export. RESULTS: Herein, we further characterized the role of p30II in regulation of cellular gene expression, using stable p30II expression system employing lentiviral vectors to test cellular gene expression with Affymetrix U133A arrays, representing approximately 33,000 human genes. Reporter assays in Jurkat T cells and RT-PCR in Jurkat and primary CD4+ T-lymphocytes were used to confirm selected gene expression patterns. Our data reveals alterations of interrelated pathways of cell proliferation, T-cell signaling, apoptosis and cell cycle in p30II expressing Jurkat T cells. In all categories, p30II appeared to be an overall repressor of cellular gene expression, while selectively increasing the expression of certain key regulatory genes. CONCLUSIONS: We are the first to demonstrate that p30II, while repressing the expression of many genes, selectively activates key gene pathways involved in T-cell signaling/activation. Collectively, our data suggests that this complex retrovirus, associated with lymphoproliferative diseases, relies upon accessory gene products to modify cellular environment to promote clonal expansion of the virus genome and thus maintain proviral loads in vivo.
Apoptosis↗
Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity.
Tumor vaccines represent a promising therapeutic approach, but thus far have achieved only limited success in the clinic. The major challenge is to find a means of overcoming inhibitory immune regulatory mechanisms and eliciting effective T-cell responses to antigens preferentially expressed by tumor cells. Here we show that the stimulatory capacity of dendritic cells (DCs) and the magnitude of adaptive immunity are critically regulated by the suppressor of cytokine signaling (SOCS) 1 in DCs. Silencing SOCS1 in antigen-presenting DCs strongly enhances antigen-specific anti-tumor immunity. Our findings indicate that SOCS1 represents an inhibitory mechanism for qualitatively and quantitatively controlling antigen presentation by DCs and the magnitude of adaptive immunity. This study has implications for understanding the regulation of antigen presentation and for developing more effective tumor vaccines by silencing the critical brake in antigen presentation.
Animals↗
Combined total genome loss of heterozygosity scan of breast cancer stroma and epithelium reveals multiplicity of stromal targets.
Recent breast cancer studies have highlighted the importance of interactions between cancer epithelium and tumor stroma. Recently, the focus of solid tumor investigations has shifted from mutations in carcinomatous epithelium to disturbances of tissue organization in cancer. The genetic basis of this microenvironment, however, remains to be clarified. To begin to resolve this problem, a total genome loss of heterozygosity (LOH) scan was done on epithelial and stromal DNA from 134 sporadic invasive breast carcinomas. In addition to detecting more frequent LOH at three loci in stroma than in epithelium, we found strong evidence that LOH frequencies were significantly elevated in specific regions of each chromosome. We detected 57 markers, which were preferentially lost either in stroma (n = 38) or epithelium (n = 19), relative to the background LOH frequencies on their respective chromosomes. This multiplicity of stromal cell LOH, and hence loss of genetic material, provides a possible mechanism for interpatient variation in host-stromal response to invading adenocarcinoma cells. This is consistent with a model in which initial, random LOH occurs equally among epithelium and stroma, but subsequent clonal selection is driven by factors, which appear to be distinctly different between malignant epithelial and surrounding stromal cells. Genetic alterations in stroma did not mimic those in epithelium, but they could play a different and parallel role in carcinogenesis and tumor progression, probably by modifying some features specific to breast cancer.
Breast Neoplasms↗
Multiparametric flow cytometric analysis of inter-patient variation in STAT1 phosphorylation following interferon Alfa immunotherapy.
BACKGROUND: Regulation of gene expression by signal transducer and activator of transcription 1 (STAT1) within host tissues mediates the antitumor effects of interferon alfa (IFN alpha). We used a novel flow cytometric assay to examine phosphorylation-mediated activation of STAT1 within immune effector cell subsets following in vitro or in vivo IFN alpha treatments. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors (n = 17) or melanoma patients (n = 19) were treated in vitro with interferon alfa-2b (IFN alpha-2b) or phosphate-buffered saline (PBS) and subjected to multiparametric flow cytometry to measure the levels of phosphorylated STAT1 (P-STAT1) within immune cell subsets. We similarly analyzed PBMCs isolated from melanoma patients before and 1 hour after immunotherapy with IFN alpha-2b. All statistical tests were two-sided. RESULTS: P-STAT1 levels in all major immune cell subsets increased within 15 minutes of in vitro IFN alpha-2b treatment of PBMCs; the increase was most pronounced in T lymphocytes and monocytes. Relatively low doses of IFN alpha-2b (i.e., 10(2)-10(3) IU/mL) induced maximal STAT1 activation in vitro. Compared with melanoma patients, healthy donors had higher basal levels of P-STAT1 (specific fluorescence [Fsp]; i.e., Fsp(PBS), the level of P-STAT1 in PBS-treated cells) in total PBMCs, natural killer (NK) cells, and T cells (mean Fsp(PBS) in total PBMCs: 5.5 in healthy donors versus 1.6 in patients, difference = 3.9, 95% confidence interval [CI] = 1.4 to 6.5, P =.004; mean Fsp(PBS) in NK cells: 4.6 in healthy donors versus 0.9 in patients, difference = 3.7, 95% CI = 1.7 to 5.7, P =.001; mean Fsp(PBS) in T cells: 6.8 in healthy donors versus 0.9 in patients, difference = 5.9, 95% CI = 2.5 to 9.3, P =.002). P-STAT1 was detected in the NK and T cells of two patients who received IFN alpha-2b immunotherapy (20 MU/m2 [MU = million units], administered by intravenous injection). P-STAT1 levels in the PBMCs of a patient treated sequentially with 5 MU/m2 and 10 MU/m2 IFN alpha-2b (administered by subcutaneous injection) also increased in response to treatments with IFN alpha-2b but did not increase further with the increased dosage of IFN alpha-2b. CONCLUSION: This flow cytometry method can be used to monitor STAT1 activation within subsets of immune cells from patients undergoing IFN alpha immunotherapy.
Antineoplastic Agents↗
CDw75 is a significant histopathological marker for gastric carcinoma.
AIM: To study the expression of CDw75 in patients with gastric carcinoma and to correlate CDw75 expression with progression of the tumor. METHODS: Immunohistochemical method was used to examine the expression of CDw75 in 72 cases of the gastric carcinoma and adjacent normal gastric mucosa, and the percentage of the cells positively stained with CDw75 was calculated using a computer-aided microscopic image analysis system. RESULTS: CDw75 was not expressed in normal gastric mucosa but detected in 37 of the 72 neoplastic gastric lesions. The expression of CDw75 was associated with the tumor progression as indicated by its close correlation with the depth of the tumor infiltration (chi(2)=18.415, P<0.01), TNM stage (chi(2)=10.419, P<0.05) and lymph node metastasis (chi(2)=6.675, P<0.01). The overall survival rate of the patients with positive CDw75 expression (32.4%) was significantly lower than that of the patients without CDw75 expression (71.4%) (P<0.01). There was no significant correlation between the expression of CDw75 and the sex and age and histological type of patients (P>0.05). CONCLUSION: These findings suggest that the expression of CDw75 is a significant histopathological marker for more advanced stage of gastric carcinoma and indicates a poor prognosis for the patients.
Adult↗
Coexistence of phosphotyrosine-dependent and -independent interactions between Cbl and Bcr-Abl.
Cbl is one of the major tyrosine-phosphorylated proteins in Bcr-Abl-expressing cells. A direct association between the SH2 domain of Bcr-Abl and tyrosine-phosphorylated Cbl has been demonstrated. The purpose of this study was to determine if and how unphosphorylated Cbl and Bcr-Abl may associate. Interactions between Cbl and Bcr-Abl were investigated in yeast two- and three-hybrid systems, gel overlay assays, and immunoprecipitates from mammalian cells expressing wild-type and the Y177F mutant of Bcr-Abl. No direct interaction between Bcr-Abl and unphosphorylated Cbl was observed. Bcr-Abl did, however, associate with Grb2, an adaptor protein that binds tyrosine 177 of Bcr-Abl. Additionally, Grb2 interacted with Cbl. In a yeast three-hybrid assay, Grb2 mediated an interaction between Cbl and Bcr-Abl that was dependent on a functional Grb2 binding site. This interaction was confirmed in vitro using purified proteins. In cells expressing Bcr-Abl with a mutation in the Grb2 binding site, binding of Cbl to Bcr-Abl was significantly reduced, but Cbl tyrosine phosphorylation was maintained. Imatinib treatment of these cells further reduced but did not abrogate Cbl binding, reflecting residual kinase activity. Multiple phosphotyrosine-dependent and -independent interactions stabilize the interaction between Cbl and Abl. Grb2 or another, yet unidentified, protein may mediate an initial interaction between Cbl and Bcr-Abl that is independent of Cbl tyrosine phosphorylation. Following this initial interaction, Cbl can then become tyrosine phosphorylated and interact with the SH2 domain of Bcr-Abl, further stabilizing the complex.
Adaptor Proteins, Signal Transducing↗