[Effects of canagliflozin on amino acid metabolism in atherosclerotic mice].

Objective: To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin. Methods: ApoE-/-mice fed on Western diet were randomly assigned into the model group (n=10) and the canagliflozin group (n=10). C57BL/6J mice fed on normal diet were chosen as the control group (n=10). Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks. The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices. PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase. Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS, respectively. Results: HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE-/-mice fed on Western diet for 14 weeks. Canagliflozin alleviated the severity of atherosclerosis in pathology. Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism, especially arginine synthesis in ApoE-/-mice. Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine, L-aspartic acid, tyrosine, L-hydroxyproline, and L-citrulline, but raised the hepatic level of L-arginine. Compared to the model group, the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues (P<0.05). Conclusion: Canagliflozin regulated the amino acid metabolism, reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.

[Yifei Sanjie Pills alleviates cancer-related skeletal muscle atrophy in mice possibly by lowering inflammatory insulin resistance].

OBJECTIVE: To evaluate the effects of Yifei Sanjie Pills (YFSJ) on weight, strength, pathology, glycogen and lipid contents and metabolism of skeletal muscles in tumor-bearing mice and explore the therapeutic mechanism of YFSJ for cancer-related skeletal muscle atrophy. METHODS: Sixteen female ICR mice bearing intraperitoneal Lewis lung adenocarcinoma xenografts were randomized into model group and YFSJ treatment group (daily dose of 4 g/kg for 21 days, n=8), with another 8 normal mice as the normal control group. The changes in body weight and gastrocnemius muscle weight of the mice were recorded. Liquid chromatography-mass spectrometry (LC-MS) was used to analyze the drug components in YFSJ entering the blood. Enzyme-linked immunosorbent assay was used to detect serum blood glucose and insulin concentrations and inflammatory cytokine levels in the serum and gastrocnemius. RNA-seq was performed to analyze the signaling pathways involved in the pathologies of the gastrocnemius muscle, and lipid contents in the muscle were observed using Oil red O staining. Adenosine triphosphatase staining was used to assess the metabolic intensity of the gastrocnemius muscle, and inflammatory cell infiltration and P-AKT level were evaluated using immunohistochemical staining; the contents of creatine kinase, lactate dehydrogenase and myoglobin in the gastrocnemius muscle were also detected. RESULTS: Treatment with YFSJ significantly increased skeletal muscle strength and gastrocnemius muscle weight (P < 0.001) and reduced the levels of gastrocnemius muscle injury markers in the tumor-bearing mice (P < 0.01). RNA-seq and LC-MS showed that YFSJ alleviated gastrocnemius muscle injury in the tumor-bearing mice possibly by improving inflammatory infiltration, insulin resistance and lipid metabolism (P < 0.05). YFSJ lowered inflammatory cytokine levels in both the serum and gastrocnemius muscle (P < 0.05), reduced pro-inflammatory cell infiltration, increased P-AKT level, and improved glycogen and lipid contents and metabolic levels in the gastrocnemius muscle. CONCLUSION: YFSJ alleviates cancer-related skeletal muscle atrophy possibly by reducing inflammatory insulin resistance.

A nomogram integrating ferroptosis-and immune-related biomarker for prediction of prognosis and diagnosis in kidney renal clear cell carcinoma.

OBJECTIVE: Approximately 60% of patients with kidney renal clear cell carcinoma (KIRC) die within the first 2-3 years. The prognosis for patients with KIRC and its metastases is poor. Ferroptosis and providing immunity are novel treatment targets for several cancers, including KIRC. Therefore, it is important to identify suitable ferroptosis- and immune-related signatures to predict the prognosis and diagnosis of patients with KIRC. MATERIALS AND METHODS: The corresponding data of patients with KIRC were obtained from the Cancer Genome Atlas. Univariate and multivariate Cox regression analyses were used to screen candidate biomarkers in patients with KIRC. RESULTS: We found that four FI-DEGs (BID, MET, LTB4R, and HMOX1) were independently associated with the overall survival of patients with KIRC. The prognosis and diagnosis model constructed using these four biomarkers could predict the outcome of KIRC, as measured by the receiver operating characteristic analyses. CONCLUSIONS: We identified 4 FI-DEGs that could be used as biomarkers in patients with KIRC. The present study not only contributes to understanding the roles of ferroptosis and immunity in the development of KIRC, but also to the diagnosis and prognosis of KIRC, although it remains to be further studied.

[Investigation on population dynamics and Echinococcus infections in small rodents around human settlement in Yushu City, Qinghai Province].

OBJECTIVE: To investigate the population dynamics and Echinococcus infections in small rodents around human settlement in Yushu City, Qinghai Province. METHODS: Rodents were captured using the mouse trap method in pastures from Batang Township and Longbao Township of Yushu City, Qinghai Province on May, August and October, 2018. The body weight and snout-vent length of all captured rodents were measured, and the species was identified according to the rodent morphology. Genomic DNA was extracted from rodent liver specimens and lesion specimens, and the mitochondrial cox1 gene of Echinococcus was amplified using PCR assay for identification of parasite species. In addition, the tissue specimens positive for PCR assay were sampled for pathological examinations. The prevalence of Echinococcus infections was estimated in rodents, and a phylogenetic tree was created based on Echinococcus cox1 gene sequences. RESULTS: A total of 285 small rodents were captured, including 143 Ochotona curzoniae (50.2%), 141 Lasiopodomys fuscus (49.5%), and 1 Neodon irene (0.3%), and there was a remarkable variation in habitat selection among these three rodent species. The number of L. fuscus correlated positively with vegetation coverage (r = 0.350, P = 0.264), with the greatest number seen in August, and the number of O. curzoniae negatively with vegetation coverage (r = -0.371, P = 0.235), with the highest number seen in August and the lowest number in May. The female/male ratios of O. curzoniae and voles were 1:0.96 and 0.82:1, respectively. The body weight (r = 0.519, P < 0.01) and snout-vent length (r = 0.578, P < 0.01) of O. curzoniae showed a tendency towards a rise with month, while the body weight (r = -0.401, P < 0.01) and snout-vent length (r = -0.570, P < 0.01) of voles presented a tendency towards a reduction with month. No Echinococcus infection was detected in voles, while 2.1% prevalence of E. shiquicus infection was seen in O. curzoniae. Phylogenetic analysis revealed consistent sequences of cox1 gene from E. shiquicus in Yushu City of Qinghai Province and Shiqu County, Ganzi Tibetan Autonomous Prefecture of Sichuan Province. CONCLUSIONS: The small rodents around the human settlement in Yushu City of Qinghai Province mainly include O. curzoniae and L. fuscus, with the greatest numbers seen in May and August, respectively. Following the concerted efforts for echinococcosis control, the prevalence of Echinococcus infections is low in small rodents around the human settlement in Yushu City; however, there is still a risk of echinococcosis transmission.

Clinical and genetic analysis of idiopathic normophosphatemic tumoral calcinosis in 19 patients.

PURPOSE: Tumoral calcinosis is a rare clinicopathological entity characterized by ectopic soft-tissue calcification, typically periarticular. Normophosphatemic tumoral calcinosis is seldom reported in East Asian populations, and the preoperative diagnosis is often elusive. This study was performed to characterize the clinical profile of normophosphatemic tumoral calcinosis and investigate the presence of the SAMD9 gene mutation. METHODS: The clinical features, pathological examination findings, and outcomes of 19 subjects were retrospectively reviewed. All patients were analyzed for SAMD9 gene mutation using paraffin-embedded tumoral calcinosis specimens. RESULTS: Nineteen subjects were analyzed (7 males, 12 females). Their mean age at surgery, mean age at symptom onset, and median disease duration was 51.9 ± 17.3 (range 7-75) years, 49.1 ± 17.2 (range 7-74) years, and 1.3 (interquartile range 0.5-3.0) years, respectively. Lesions were located in the hand in 8 (42.1%) subjects; wrist in 5 (26.3%); shoulder in 2 (10.5%); and hip, knee, buttock, and scrotum in 1 (5.3%) subject each. The lesions in 17 (89.5%) subjects were located around the joints [small joints (hand and wrist) in 13 (68.4%) and large joints (shoulder, hip, and knee) in 4 (21.1%)]. Lesions occurred in the upper limbs in 15 (78.9%) subjects and in the lower limbs in 2 (10.5%). Multiple-lesion involvement (distal right index finger and middle finger) occurred in one (5.3%) subject. Symptoms included pain in 15 (78.9%) subjects, impaired mobility in 5 (26.3%), swelling in 5 (26.3%), numbness in 2 (10.5%), and an asymptomatic mass in 2 (10.5%). The serum inorganic phosphorus concentration was normal in all 19 subjects (mean 1.17 ± 0.15 mmol/L). The serum calcium concentration was normal in 18 subjects and low in 1. The serum alkaline phosphatase concentration was normal in all 19 subjects. Pathological examination indicated multiple nodules of calcified materials that manifested an amorphous or granular blue-purple crystal and were surrounded by proliferation of mononuclear or multinuclear macrophages, osteoclastic-like giant cells, fibroblasts, and chronic inflammatory cells. Notably, different phases of pathological manifestations were observed in the same microscopic field. During follow-up (0.5-65.0 months), no recurrence of tumoral calcinosis was observed in 18 (94.7%) subjects, but 1 subject developed in situ recurrence of an asymptomatic subcutaneous mass after 6 months postoperatively. Genetic analysis in all 19 subjects revealed no SAMD9 gene mutations. CONCLUSIONS: Most subjects were females and developed calcinosis in adulthood. Small joints (hand and wrist) and the upper limbs were frequently involved. The presence of different phases of pathological features in the same subject suggests that about half of the study participants had been misdiagnosed with another condition (such as gout, osteoarthritis, etc.). Complete surgical excision led to cure without recurrence during follow-up in majority of the study participants.

Accelerated aging effects on color, microhardness and microstructure of ICON resin infiltration.

OBJECTIVE: Infiltration resins provide an ideal treatment alternative for white spot lesions on teeth. The icon infiltrant has been widely used as a dental material for a few years, but there are some studies on the in vitro accelerated aging process and the change of hardness and microstructure on this material. The innovation of this work is to aim at investigating characteristics associated with this infiltrant resin and comparing the Icon infiltrant with universal Filtek Z350 and flowable Filtek Z350 resins when exposed to artificial accelerated aging. MATERIALS AND METHODS: Materials were prepared as disc-shaped specimens sized to 12 mm × 2.2 mm and were aged through exposure to 150 kJ/m2 in an artificial accelerated aging machine. Two-time points, 24 h after aging and 96 h after aging, were selected for evaluation in the following trials. The morphology was observed using a scanning electron microscopy. The standard CIEL*a*b* color system was employed for color measurements. Microhardness of all specimens was analyzed by a Knoop indenter. Chemical components were examined by Fourier transform infrared spectroscopy. RESULTS: Compared with universal Z350 and flowable Z350, the ICON infiltrant resin presented a uniform, slightly scratched surface before and after accelerated aging. The 24 h artificial accelerated aging of the three investigated materials resulted in acceptable color alterations, a ΔE* range of 2.52±0.63 for universal Z350, 2.43±0.59 for flowable Z350 and 3.31±0.32 for ICON. After 96 h aging, significant color changes were noted for universal Z350 (7.51±0.63) and ICON (4.70±0.69). The ICON infiltrant displayed reduced microhardness when compared to universal Z350 and flowable Z350. The absorption peaks of the chemical bonds were significantly altered after the accelerated aging process. CONCLUSIONS: Composed in a triethylene glycol dimethacrylate (TEGDMA) monomer-based network, the color stability and microhardness of the infiltrant resin provided suitable material for treating white spot lesions (WSLs), yet presented susceptibility under accelerated aging. Thus, osmotic resin therapy has strict limitations to be most effective.

[ß-catenin nuclear translocation represses thyroid cancer stem cells differentiating into cells with sodium-iodine symporter functional expression].

Objective: To confirm whether ß-catenin nuclear translocation in thyroid cancer stem cells can differentiate into thyroid cancer cells without functional membrane expression of sodium-iodine transporter (NIS) and be resistant to iodide 131 treatment. Methods: Thyroid cancer stem cells were firstly isolated as a side population (SP) from human thyroid cancer cell line FTC133. The SP cells from FTC133 were transfected with ß-catenin, and then differentiated. The cells were further collected for Western blot, Transwell and MTT assay to investigate the epithelial-mesenchymal transition (EMT) characteristics, tumor growth, invasion, and iodine uptake potency in vitro. Functional NIS expression and iodide uptake in differentiated cells were detected with immunofluorescent staining and iodide uptake assay, respectively. Subcutaneous severe combined immunodeficient (SCID) mice tumor model was induced with differentiated cancer cells to explore the in vivo effect of radioiodine treatment. Further immunohistochemical staining was performed to reveal the changes of functional proteins involved in tumor radioiodine treatment. Results: Side population was isolated from FTC133 accounting for about 0.03%, with high expression of stem cell markers and decreased expression of differentiated cell markers. Western blot showed prominent EMT phenotype in the differentiated cells from ß-catenin transfected stem cell model, with absence of epithelial expression of E-cadherin and cytokeratin 18, as well as abnormal expression of vimentin,fibronectin and urokinase-type plasminogen activator. Moreover,compared with cells differentiated from untransfected or empty plasmid transfected stem cells, in vitro proliferation markedly increased 85.4% and 81.0%, respectively (both P<0.01); while in vitro invasion augmented 78.8% and 84.4%, respectively (both P<0.01). Immunofluorescent staining identified that, after transfected with ß-catenin, differentiated cells underwent ß-catenin nuclear translocation and NIS localization transferred from membrane to plasma, compared with cells from untransfected or empty plasmid transfected stem cells. Cell iodide uptake in vitro decreased about 52.8% and 45.2%, respectively (both P<0.01). Furthermore, in vivo experiment further demonstrated that, cells differentiated from ß-catenin transfected stem cells were found with much higher tumor proliferation,tumor growth rate and larger tumor mass after radioiodine 131 treatment (both P<0.05). Conclusion: Induction of ß-catenin nuclear translocation in stem cells may generate differentiated thyroid cancer cells that are not sensitive to radioiodine treatment.

TIPE1 suppresses osteosarcoma tumor growth by regulating macrophage infiltration.

BACKGROUND: Osteosarcoma is the most common primary malignancy of the bone, and macrophages play a promotional role during osteosarcoma development and progression. TIPE1 is known to function as a tumor suppressor in diverse cancers by inducing cell arrest and apoptosis. However, the biological function of TIPE1 in osteosarcoma is still unclear. PURPOSE: The purpose of this study was to investigate the expression and function of TIPE1 in osteosarcoma. METHODS: In the present study, TIPE1 expression in osteosarcoma cancer cells was determined by qPCR and western blotting. A subcutaneous tumor model was established to investigate the potential anti-tumor activity of TIPE1 in osteosarcoma. Further, flow cytometry, western blotting, immunofluorescence staining, and ELISA were performed to clarify the underlying mechanism by which TIPE1 regulates growth of osteosarcoma. RESULTS: Our results suggest that TIPE1 is downregulated in osteosarcoma cancer cells, and ectopic expression TIPE1 significantly inhibited osteosarcoma tumor growth in vivo. Furthermore, TIPE1 inhibits the infiltration of macrophages in osteosarcoma tumor by suppressing MCP-1 expression in osteosarcoma cells. Further in vivo study revealed that inhibition of MCP-1/CCR2 axis by Bindarit blocked the inhibitory effect of TIPE1 on osteosarcoma growth. CONCLUSION: Collectively, our results demonstrate the anti-tumor role of TIPE1 in osteosarcoma and reveal a novel therapy target for osteosarcoma.

Methionine synthase A2756G polymorphism and lymphoma risk: a meta-analysis.

OBJECTIVE: The association between methionine synthase (MS) A2756G polymorphism and lymphoma risk was studied with conflicting results. The present meta-analysis aimed to investigate the overall association between MS A2756G polymorphism and lymphoma risk. MATERIALS AND METHODS: We searched PubMed and Embase databases until March 30, 2017, for articles that assessed the association between MS A2756G polymorphism and lymphoma risk. Statistical analyses were performed using the Revman 5.0 software. RESULTS: A total of 14 articles involving 4,156 cases and 6,407 controls were included in this meta-analysis. Combined analysis revealed no association between this polymorphism and lymphoma susceptibility (OR = 0.92, 95% CI: 0.74-1.16, p = 0.50 for GG vs. GA+AA). Subgroup analysis by ethnicity showed decreased lymphoma risk with the MS A2756G gene polymorphism among Caucasians in GG+GA vs. AA and G vs. A models, but not among Asians. Subgroup analysis by disease type suggested that GG homozygous and G alleles were not associated with risks of non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), the subtype of NHL including the diffuse large B-cell lymphoma and follicular lymphoma. CONCLUSIONS: The results in this meta-analysis suggest no association between the MS A2756G polymorphism and lymphoma risk; however, the GG homozygous and G alleles could decrease the lymphoma risk in Caucasians.

The polymorphism of XRCC1 and coronary artery disease risk: a meta-analysis.

OBJECTIVE: Coronary artery disease (CAD) is a life-threatening disease and is caused by various factors, with genetic variation being an important risk factor. The association between X-ray repair cross-complementing group 1 (XRCC1) polymorphisms and CAD has been extensively studied with conflicting results. We performed a meta-analysis to investigate the overall association between XRCC1 polymorphisms and CAD risk. MATERIALS AND METHODS: We searched PubMed and Embase databases until October 19, 2016. The total number and distribution of genotypes, genotyping methods, and ethnicity were extracted. Overall and subgroup analyses were performed. RESULTS: A total of seven publications involving 1.862 subjects and 1.568 controls were included in this meta-analysis. The Arg399Gln and Arg194Trp polymorphisms of XRCC1 were analyzed. The results indicated that the XRCC1 Arg399Gln homozygous GG genotype showed no association with CAD risk [GG vs. GA+AA: odd's ratio (OR) = 0.95, 95% confidence interval (CI) = 0.82-1.11, p = 0.53] both in the overall and subgroups evaluation. However, the XRCC1 Arg194Trp homozygous TT genotype was associated with an increased CAD risk [(TT vs. TC+CC: OR =1.52, 95%CI = 1.16-2.00, p=0.003)]. Subgroup analysis based on ethnicity showed a significant increase in the association of CAD risk and the Arg194Trp gene polymorphism among the Asian population. CONCLUSIONS: This meta-analysis suggested that TT genotype in the Arg194Trp polymorphism contributes to the CAD susceptibility, particularly in the Asian population.

[Clinicopathologic analysis of extranodal non-hodgkin lymphoma of the sinonasal cavities: a 15-case report].

Objective:To investigate the clinical manifestation, imaging and histological features of different histological subtypes of non-Hodgkin's lymphoma of nasal cavity and paranasal sinuses.Method:Fifteen NHL patients of the sinonasal region were collected from the Department of Otolaryngology of Peking University Third Hospital from 2010 to 2016. HE staining and immunohistochemical staining were performed. The clinical characteristics and imaging features of different subtypes were described and analyzed.Result::We analyzed a total of 6 patients with localized sinonasal diffuse large B cell lymphoma and 9 patients with localized sinonasal extranodal NK/T cell lymphoma. The age distribution for these two subtypes is very distinct. The median age of the patients with localized sinonasal extranodal NK/T cell lymphoma was 39 years. There were 5 males and 4 females. Nine sinonasal NHLs were NK/T-cell lymphoma, nasal type, all of which were infected with EBV. The median age of the patients with localized sinonasal diffuse large B cell lymphoma was 64 years. There were 3males and 3 females. Symptoms for patients with SN-DLBCL and SN-ENKTL were significantly different in epiphora, proptosis, diplopia and nasal congestion (P=0.18, 0.004, 0.18, 0.18). Imaging features for patients with SN-DLBCL and SN-ENKTL were significantly different in tumor extended to orbit and inferior turbinate (P>0.05). Positive staining for CD 56 was detected in 9 patients, for CD 3 in 9 patients, for EBER in 9 patients. The Hans algorithm identified 1 patient with the germinal center B-cell (GCB) subtype and 5 with the non-GCB subtype.Compared with the control group, the observation group was significantly better than the control group (P < 0.01).Conclusion:Early symptoms of epiphora, proptosis, diplopia, and images finding with orbital invasion should be highly suspected of diffuse large B cell lymphoma. Positive staining for CD 56 and EBER were detected in all patients with extranodal NK/T cell lymphoma, and positive staining for CD20 was detected in all patients with SN-DLBCL.

[Clinically predictive factors of Gleason score upgrading in patients after radical prostatectomy].

OBJECTIVE: To assess the discrepancy between preoperative needle biopsy (NB) Gleason score and pathological specimen Gleason score (GS) after radical prostatectomy, and to explore the risk factors of postoperative upgrading of GS. METHODS: We retrospectively evaluated 160 patients who suffered from biopsy proved prostatic carcinoma and performed radical prostatectomy. Age of the patients was 57-82 years, with the average age of 71.6; prebiopsy prostate specific antigen (PSA) was 0.31-40.32 µg/L,with the average PSA of 11.29 µg/L; body mass index (BMI) was 16.41-32.04 kg/m(2), with the average BMI of 23.63 kg/m(2); prostate volume (PV) was 9.52-148.46 mL, with the average PV of 40.19 mL. All the patients included in the study had complete information for clinical variables, including age, BMI, prebiopsy PSA level, PV, number of biopsy cores obtained, percentage, clinical stage, and biopsy GS. Grading of NB Gleason score was compared with their corresponding radical prostatectomy specimens, and the discrepancy between the NB and prostatectomy specimens GS assessed. Upgrading was defined as any increase in the pathological GS over that of the biopsy GS as a total sum of primary and secondary grades or a change in the order of primary and secondary grades towards higher ones. Univariable and multivariable Logistic regression analyses were used to identify predictors of pathological grading changes. RESULTS: Of the 160 patients, the specimen GS was upgraded in 49 (30.6%) patients and remained with no change in 82 (51.3%) patients. Univariate and multivariate regression analysis showed that prostate volume and biopsy GS were independent predictors with postoperative upgrading of GS. Age, BMI, PSA before needle biopsy, clinical stage and needle number showed no statistical significance (P>0.05). CONCLUSION: Lower biopsy GS and smaller prostate volume are increased risks for clinically upgrading of GS after radical prostatectomy. This fact should be kept in mind when deciding on therapy decisions for patients with prostate cancer.

[Clinically predictive factors of Gleason score upgrading in patients after radical prostatectomy].

OBJECTIVE: To assess the discrepancy between preoperative needle biopsy (NB) Gleason score and pathological specimen Gleason score (GS) after radical prostatectomy, and to explore the risk factors of postoperative upgrading of GS. METHODS: We retrospectively evaluated 160 patients who suffered from biopsy proved prostatic carcinoma and performed radical prostatectomy. Age of the patients was 57-82 years, with the average age of 71.6; prebiopsy prostate specific antigen (PSA) was 0.31-40.32 µg/L,with the average PSA of 11.29 µg/L; body mass index (BMI) was 16.41-32.04 kg/m2, with the average BMI of 23.63 kg/m2; prostate volume (PV) was 9.52-148.46 mL, with the average PV of 40.19 mL. All the patients included in the study had complete information for clinical variables, including age, BMI, prebiopsy PSA level, PV, number of biopsy cores obtained, percentage, clinical stage, and biopsy GS. Grading of NB Gleason score was compared with their corresponding radical prostatectomy specimens, and the discrepancy between the NB and prostatectomy specimens GS assessed. Upgrading was defined as any increase in the pathological GS over that of the biopsy GS as a total sum of primary and secondary grades or a change in the order of primary and secondary grades towards higher ones. Univariable and multivariable Logistic regression analyses were used to identify predictors of pathological grading changes. RESULTS: Of the 160 patients, the specimen GS was upgraded in 49 (30.6%) patients and remained with no change in 82 (51.3%) patients. Univariate and multivariate regression analysis showed that prostate volume and biopsy GS were independent predictors with postoperative upgrading of GS. Age, BMI, PSA before needle biopsy, clinical stage and needle number showed no statistical significance (P>0.05). CONCLUSION: Lower biopsy GS and smaller prostate volume are increased risks for clinically upgrading of GS after radical prostatectomy. This fact should be kept in mind when deciding on therapy decisions for patients with prostate cancer.

MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail.

MicroRNAs (miRNAs) deregulation is frequent in human gastric cancers (GCs), but the role of specific miRNAs involved in this disease remains elusive. MiR-22 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here, we found that the expression of miR-22 was significantly reduced in clinical GC tissues compared with paired adjacent normal tissues, and was significantly correlated with a more aggressive phenotype of GC in patients, and miR-22 low expression correlated with poor overall survival. The introduction of miR-22 markedly suppressed GC cell growth, migration and invasion, and inhibition of miR-22 promoted GC cell proliferation, migration and invasion in vitro. We further demonstrated that miR-22 acted as tumor suppressors through targeting extracellular matrix (ECM) remodeling member matrix metalloproteinase 14 (MMP14) and epithelial-to-mesenchymal transition (EMT) inducer Snail in GC. Moreover, ectopic expression of MMP14 or Snail restored inhibitory effects of miR-22 on cell migration and invasion in GC cells, and a negative relationship between the miR-22 expression and MMP14 or Snail mRNA levels was observed in GC. Finally, overexpression of miR-22 suppressed tumor growth, peritoneal dissemination and pulmonary metastasis in vivo. Taken together, we identified that miR-22 is a potent tumor suppressor in GC. MiR-22 downregulation promotes GC invasion and metastasis by upregulating MMP14 and Snail, and then inducing ECM remodeling and EMT. These findings provide a better understanding of the development and progression of GC and may be an important implication for future therapy of the GC.

MicroRNA-141 inhibits tumor growth and metastasis in gastric cancer by directly targeting transcriptional co-activator with PDZ-binding motif, TAZ.

Gastric cancer (GC) is a biologically heterogeneous disease accompanying various genetic and epigenetic alterations, and the molecular mechanisms underlying this disease are complex and not completely understood. Increasing evidence shows that abnormal microRNA (miRNA) expression is involved in GC tumorigenesis, but the role of specific miRNAs involved in this disease remains elusive. MiR-141 was previously reported to act as tumor suppressors or oncogenes in diverse cancers. However, their accurate expression, function and mechanism in GC are largely unclear. Here we found that the expression of miR-141 was significantly reduced in GC compared with paired adjacent normal tissues and was significantly correlated with a more aggressive phenotype of GC in patients. Ectopic expression of miR-141 mimics in GC cell lines resulted in reduced proliferation, invasion and migration, and inhibition of miR-141 in GC cell lines promoted cell proliferation, invasion and migration in vitro. We further demonstrated that miR-141 acted as tumor suppressors through targeting transcriptional co-activator with PDZ-binding motif (TAZ) in GC. Moreover, the inverse relationship between miR-141 and its target was verified in patients and xenograft mice. Finally, overexpression of miR-141 suppressed tumor growth and pulmonary metastasis in nude mice. Take together, we identified that miR-141 is a potent tumor suppressor in the stomach, and its growth inhibitory effects are, in part, mediated through its downstream target gene, TAZ. These findings implied that miR-141 might be employed as novel prognostic markers and therapeutic targets of GC.

MicroRNA-25 promotes gastric cancer migration, invasion and proliferation by directly targeting transducer of ERBB2, 1 and correlates with poor survival.

Gastric cancer (GC) is one of the most common tumors and the molecular mechanism underlying its metastasis is still largely unclear. Here, we show that miR-25 was overexpressed in plasma and primary tumor tissues of GC patients with tumor node metastasis stage (III or IV) or lymph node metastasis. MiR-25 inhibition significantly decreased the metastasis, invasion and proliferation of GC cells in vitro, and reduced their capacity to develop distal pulmonary metastases and peritoneal dissemination in vivo. Furthermore, miR-25 repressed transducer of ERBB2, 1 (TOB1) expression by directly binding to TOB1-3'-UTR, and the inverse correlation was observed between the expressions of miR-25 and TOB1 mRNA in primary GC tissues. Moreover, the loss of TOB1 increased the metastasis, invasion and proliferation of GC cells, and the restoration of TOB1 led to suppressed metastasis, invasion and proliferation. The receiver operating characteristics analysis yielded an area under the curve value of 0.7325 in distinguishing the GC patients with death from those with survival. The analysis of optimal cutoff value revealed poor survival in GC patients with high plasma concentrations of miR-25 (>0.2333 amol/µl). Taken together, miR-25 promotes GC progression by directly downregulating TOB1 expression, and may be a noninvasive biomarker for the prognosis of GC patients.

p57Kip2 is an unrecognized DNA damage response effector molecule that functions in tumor suppression and chemoresistance.

The DNA damage response (DDR) helps to maintain genome integrity, suppress tumorigenesis and mediate the radiotherapeutic and chemotherapeutic effects on cancer. Here we report that p57Kip2, a cyclin-dependent kinase (CDK) inhibitor implicated in the development of tumor-prone Beckwith-Wiedemann syndrome, is an effector molecule of the DNA-damage response. Genotoxic stress induces p57Kip2 expression via the bone morphogenetic protein-Smad1 and Atm-p38MAPK-Atf2 pathways in p53-proficient or -deficient cells and requires the Smad1-Atf2 complex that facilitates their recruitment to the p57Kip2 promoter. Elevated p57Kip2 induces G1/S phase cell cycle arrest but inhibits cell death in response to DNA damage and acts in parallel with p53 to suppress cell transformation and tumor formation. p57Kip2 is also upregulated in stage I and II clinical rectal tumor samples, likely due to genome instability of precancerous and/or early cancer cells. Targeting p57Kip2 in primary rectal cancer cells and tumor models resulted in increased sensitivity to doxorubicin, suggesting that p57Kip2 has a role in chemoresistance, which is consistent with its pro-survival function. These findings place p57Kip2 in DDR and uncover molecular mechanisms by which p57Kip2 suppresses tumorigenesis and causes chemoresistance.

The changes of muscle FGF-6 expression at different time points after exercise-induced muscle damage / Cambios de expresión de FGF-6 muscular en diferentes puntos del tiempo después del daño muscular inducido por ejercicio

OBJECTIVE: To investigate the changes of fibroblast growth factor (FGF)-6 expression in the regeneration and repair process after exercise-induced muscle damage (EIMD) and the relationship with skeletal muscle regeneration and repair. METHODS: The expression of FGF-6 at different time points was examined by reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry staining after a downhill treadmill exercise. Skeletal muscle injury and regeneration at different times after EIMD was assessed by haematoxylin and eosin (H & E) staining. RESULTS: The FGF-6 protein expression was initially elevated, followed by a gradual reduction, while the changes of FGF-6 mRNA were almost all raised after the treadmill exercise. CONCLUSION: The results point out that FGF-6 is closely related to skeletal muscle regeneration and repair, probably implying a dual function in muscle regeneration.

OBJETIVO: Investigar los cambios de expresión del factor de crecimiento fibroblástico (FGF)-6 en el proceso de regeneración y reparación después de daño muscular inducido por el ejercicio (DMIE) y la relación con la reparación y regeneración del músculo esquelético. MÉTODOS: La expresión de FGF-6 en diferentes tiempos fue examinada mediante reacción en cadena de la polimerasa con transcriptasa inversa (RT-PCR) y tinción inmunohistoquímica, después de un ejercicio de carrera descendente en cinta rodante. La lesión del músculo esquelético y la regeneración en diferentes momentos después del DMIE, fueron evaluadas mediante hematoxilina y eosina (H & E). RESULTADOS: La expresión de la proteína FGF-6 fue elevada al principio, seguida por una reducción gradual, mientras que los cambios de FGF-6 mRNA fueron casi todos incrementados tras los ejercicios en la cinta rodante. CONCLUSIÓN: Nuestros resultados señalan que FGF-6 se relaciona estrechamente con la regeneración del músculo esquelético, lo que probablemente implica una función dual en la regeneración muscular.