Objective To design a novel bromodomain-containing protein 4(BRD4)and histone deacetylase(HDAC)dual-target inhibitor(11b),and to elucidate its therapeutic efficacy and mechanisms in suppressing prostate cancer through epigenetic regulation.Methods BRD4 and HDAC expression levels were assessed via immunohistochemistry(IHC)using prostate cancer tissue microarrays.The inhibitory activity of 11b was screened across three prostate cancer cell lines,with the half-maximal inhibitory concentration(IC50)determined by CCK-8 assay.Western blot was employed to analyze changes in the expression of target proteins,including BRD4,c-Myc proto-oncogene protein(c-Myc),and Ac-H3K27,with parallel comparisons to single-target agents,including suberoylanilide hydroxamic acid(SAHA),a HDAC inhibitor,and JQ-1,a BRD4 inhibitor.Cell invasion and proliferation were evaluated using Transwell and colony formation assays,and the autophagy mechanism was validated using 3-methyladenine(3-MA),an autophagy inhibitor.A PC-3 xenograft model was established in nude mice.Then,11b(7.5 mg/kg or 15 mg/kg),normal saline,SAHA,and JQ-1 were administered via intraperitoneal injection,and their tumor growth inhibition effects were observed.The percentage of target protein-positive cells and the expression levels of target genes were quantified via IHC and RT-PCR,respectively.Results BRD4 and HDAC expression levels were both higher in tumor tissues than those in normal tissues(P<0.01).11b exhibited the strongest inhibitory activity against PC-3 cells(IC50=8.28 μmol/L),outperforming SAHA(22.61 μmol/L)and JQ-1(22.09 μmol/L).Treatment with 11b reduced BRD4 and c-Myc expression by(41.58±3.28)%and(63.21±6.91)%,respectively(P<0.01),and increased the Ac-H3K27 level to 6.52-fold that of the negative control(NC)group(P<0.01),demonstrating greater modulation than either SAHA or JQ-1 did.The in vitro experiment showed that 8 μmol/L 11b treatment reduced PC-3 colony formation and migration by 97.5%and 96.3%,respectively(P<0.001),and co-treatment with 3-MA reversed its cytotoxic effects.The in vivo experiment showed that 11b at both 7.5 mg/kg and 15 mg/kg significantly reduced tumor volume and weight compared with the control,SAHA,and JQ-1 groups(all P<0.01),with the proportion of percentage of target protein-positive cells and the expression of target genes showing trends consistent with in vitro findings.Conclusion The dual-target inhibitor 11b exerts potent antitumor effects in prostate cancer by synergistically modulating the BRD4/HDAC pathways.11b demonstrates therapeutic efficacy superior to that of the single-target agents SAHA and JQ-1 in suppressing prostate cancer progression,highlighting its potential for clinical translation.

Objective:To study and compare the prognosis of different pathological subtypes of renal cell carcinoma (RCC).Methods:Clinicopathological and prognostic data of 1 346 cases of postoperative renal cell carcinoma during July 2002 to June 2014 in West China Hospital were collected retrospectively.There were 839 males and 507 females, aged (55.1±13.4)years, including 1 120 cases of clear cell RCC, 62 cases of papillary RCC, 79 cases of chromophobe RCC and 85 cases of the other pathological types respectively. ECOG 0 and ≥1 were 911 and 435 cases, with; T 1, T 2, T 3 and T 4 of 1 019, 177, 102 and 48 cases respectively; WHO nuclear grade for well, intermediate, poor differentiation and unknown were 587, 530, 85 and 144 cases separately.Tumor size <5cm, 5-10cm, ≥10cm and unknown were 685, 541, 104 and 16 cases.Combined with necrosis or sacromatoid differentiation were 200/1 146 and 27/1 319 cases separately. Meanwhile, data of 80 439 cases from Surveillance, Epidemiology, and End Results Program (SEER) were also collected.There were 51 371 males and 29 068 females, aged (60.9±12.4) years; , with 66 261, 8 680, 5 022 and 476 cases of White, Black, Asian, American native, or unknown race separately. There were 62 600 of clear cell RCC, 12 170 of papillary RCC, 4 354 of chromophobe RCC and 1 315 of other pathological types, with T 1, T 2, T 3 and T 4 of 55 332, 8 687, 15 516 and 904 cases respectively; WHO nuclear grade for well, intermediate and poor differentiation were 52 323, 22 700 and 5 416 cases separately.Tumor size <5cm, 5-10cm, ≥10cm were 46 741, 25 760 and 7 938 cases respectively. Kaplan-Meier survival analysis were performed on these two group of cases, with different factors between subgroups (gender, age, pathological types, tumor stage, size and nuclear grade) evaluated by log-rank test. To evaluate accuracy of outcome prediction models of SSIGN, Leibovich and UISS score, concordance index of these models were evaluated. Results:In 1 346 cases of our cohort, those with chromophobe RCC were well prognostic, survival were relatively better in clear cell RCC than that of papillary RCC, and worst prognosis were demonstrated in those with other types of RCC (5 year overall survival rate: 97.5%, 87.9%, 79.7% and 68.4% separately). Poor prognosis were seen in those older than 50 years, with poor T stage or nuclear grade, large tumor size and tumors with necrosis or sacromatoid differentiation ( P<0.05). In 80 439 seer cases, the best prognosis was also seen in chromophobe RCC and the worst in other type of RCC separately (5 year overall survival rate: 96.3% and 85.3%). In addition, longer survival was seen in papillary RCC than clear cell RCC (5 year overall survival rate: 92.5% and 88.9%). However, similar results with our cohort were seen in Asian and American native subgroup of SEER cases (95.1%, 88.6%, 86.7%, 80.2% for chromophobe, clear cell, papillary and other types of RCC respectively). Poor prognosis were seen in those older than 50 years, males, Asian/ American Indian, poor T stage or nuclear grade and large tumor size ( P<0.05). Concordance index for SSIGN, Leibovich and UISS models in our cohort were 0.763-0.781, 0.725-0.752 and 0.641-0.660, respectively. The chromophobe RCC subgroup was relative better based on predictive value of prognosis models(c-index of UISS of 0.670-0.781, SSIGN and Leibovich of 0.733-0.903). Conclusions:In Asian RCC population, prognosis of chromophobe RCC is best, clear cell RCC is slightly better than papillary RCC, and the prognosis of other types of RCC is the worst. Concordance index of SSIGN and Leibovich in our cohort were higher than that of UISS, and the use value for predictive model was better in the chromophobe RCC subgroup.

Objective To evaluate the benefit of radical prostatectomy (RP) in patients with lymph node-positive prostate cancer.Methods A systematic review of the studies about radical prostatectomy for the prognosis of node-positive prostate cancer was performed.An electronic search was completed on the basis of PubMed,Embase,Cochrane library,China Biology Medicine disc (CBM),China National Knowledge Infrastructure (CNKI),VIP and Wanfang database from inception up to November 2018.The outcomes are overall survival (OS) and cancer-specific survival (CSS).Results Six studies incorporating 7 890 patients were eligible for the present meta-analysis.6 247 patients underwent RP,the remaining 1 643 patients did not undergo RP.Lymph node-positive patients treated with RP had improved OS (HR =0.55,95％ CI 0.49-0.62,P ＜0.001) and CSS (HR =0.49,95％ CI 0.42-0.57,P ＜ 0.001).Conclusions Radical prostatectomy may be a beneficial option for patients with lymph node metastases at initial diagnosis,which also improve the OS and CSS.More randomized controlled trials are needed to give more evidence further.

OBJECTIVETo investigate the expression of prostaglandin transporter (PGT) in colorectal cancer (CRC) tissues and its relationship with clinicopathological features.

METHODSThe mRNA and protein levels of PGT were determined by real-time PCR, Western blot and immunohistochemical methods in cancer tissues and adjacent normal tissue from 80 patients with colorectal cancer and their relationship with clinicopathological features was analyzed.

RESULTSCompared with the adjacent normal tissue of colorectal cancer, the PGT mRNA relative expression (0.57 ± 0.33 vs. 2.33 ± 1.20) and the PGT protein expression in cancer tissues decreased significantly [PGT/GAPDH 0.45 ± 0.16 vs. 0.78 ± 0.23, integral A 718.7 ± 359.4 vs. 10412.0 ± 6423.3, average A 0.03 ± 0.01 vs. 0.12 ± 0.09, all P<0.01]. Lower mRNA and protein expressions of PGT in colorectal cancer were associated with depth of invasion T3 to T4 and TNM stage III( to IIII( (P<0.01), while not associated with gender, age, tumor location and differentiation degree (all P>0.05).

CONCLUSIONExpression levels of PGT mRNA and protein in colorectal cancer tissue are significantly down-regulation. PGT expression is associated with invasion depth and late stages.

Colorectal Neoplasms ; Down-Regulation ; Humans ; Neoplasm Invasiveness ; Neoplasm Staging ; Organic Anion Transporters ; RNA, Messenger

Objective To investigate the expression of prostaglandin transporter (PGT) in colorectal cancer (CRC) tissues and its relationship with clinicopathological features. Methods The mRNA and protein levels of PGT were determined by real-time PCR , Western blot and immunohistochemical methods in cancer tissues and adjacent normal tissue from 80 patients with colorectal cancer and their relationship with clinicopathological features was analyzed. Results Compared with the adjacent normal tissue of colorectal cancer , the PGT mRNA relative expression (0.57 ±0.33 vs. 2.33 ±1.20) and the PGT protein expression in cancer tissues decreased significantly [PGT/GAPDH 0.45 ±0.16 vs. 0.78 ±0.23, integral A 718.7 ±359.4 vs. 10412.0 ±6423.3, average A 0.03 ±0.01 vs. 0.12 ±0.09, all P<0.01]. Lower mRNA and protein expressions of PGT in colorectal cancer were associated with depth of invasion T3 to T4 and TNM stage Ⅲ to Ⅳ (P<0.01), while not associated with gender, age, tumor location and differentiation degree (all P>0.05). Conclusion Expression levels of PGT mRNA and protein in colorectal cancer tissue are significantly down-regulation. PGT expression is associated with invasion depth and late stages.

Objective To investigate the expression of prostaglandin transporter (PGT) in colorectal cancer (CRC) tissues and its relationship with clinicopathological features. Methods The mRNA and protein levels of PGT were determined by real-time PCR , Western blot and immunohistochemical methods in cancer tissues and adjacent normal tissue from 80 patients with colorectal cancer and their relationship with clinicopathological features was analyzed. Results Compared with the adjacent normal tissue of colorectal cancer , the PGT mRNA relative expression (0.57 ±0.33 vs. 2.33 ±1.20) and the PGT protein expression in cancer tissues decreased significantly [PGT/GAPDH 0.45 ±0.16 vs. 0.78 ±0.23, integral A 718.7 ±359.4 vs. 10412.0 ±6423.3, average A 0.03 ±0.01 vs. 0.12 ±0.09, all P<0.01]. Lower mRNA and protein expressions of PGT in colorectal cancer were associated with depth of invasion T3 to T4 and TNM stage Ⅲ to Ⅳ (P<0.01), while not associated with gender, age, tumor location and differentiation degree (all P>0.05). Conclusion Expression levels of PGT mRNA and protein in colorectal cancer tissue are significantly down-regulation. PGT expression is associated with invasion depth and late stages.

OBJECTIVETo explore the feasibility and clinical significance of the detection of serum neutrophil gelatinase-associated lipocalin (NGAL) in human colorectal cancer.

METHODSLevels of NGAL in serum samples from 133 healthy people, 125 colorectal polyps patients and 100 colorectal cancer patients respectively were determined by sandwich ELISA assay. Relationship of NGAL level with clinicopathological features of colorectal cancer patients was analyzed. The optimal cut-off value of serum NGAL for diagnosing colorectal cancer was determined by ROC curve and compared with CEA and CA19-9. Univariate and multivariate analyses were performed to examine the relationship of NGAL level with the prognosis of patients with colorectal cancer.

RESULTSThe median serum NGAL protein level in 100 colorectal cancer cases was 67.96 (53.30-79.86) μg/L, significantly higher than that in healthy people and colorectal polyps patients. The differences were statistically significant (all P<0.01). Serum NGAL protein level was significantly associated with tumor diameter, TNM stage, lymph node metastasis and vascular involvement (P<0.05). The optimal cut-off point of serum NGAL protein level for diagnosing colorectal cancer was 49.78 μg/L, and the sensitivity and specificity were 88% and 81% respectively. As for colorectal cancer patients with stage I, the sensitivity of serum NGAL (78.9%) was significantly higher as compared to CA19-9 (31.6%) and CEA (36.8%); as for those with stage II, the sensitivity of serum NGAL(88.0%) was also significantly higher compared to CA19-9 (48.0%) and CEA (52.0%). Kaplan-Meier analysis showed that patients with positive NGAL (≥49.78 μg/L) had worse survival than those with negative NGAL (P=0.002). Multivariate analysis showed that NGAL was an independent prognostic factor (HR=2.060, 95%CI:1.023-4.150, P=0.043).

CONCLUSIONSNGAL can be served as the novel malignant biological phenotype marker for human colorectal cancer and can be used for the risk stratification. NGAL may be an independent prognostic factor in colorectal cancer.

Acute-Phase Proteins ; Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; blood ; Case-Control Studies ; Colorectal Neoplasms ; blood ; diagnosis ; Early Detection of Cancer ; Female ; Humans ; Lipocalin-2 ; Lipocalins ; blood ; Male ; Middle Aged ; Prognosis ; Proto-Oncogene Proteins ; blood

Objective To explore the feasibility and clinical significance of the detection of serum neutrophil gelatinase-associated lipocalin (NGAL) in human colorectal cancer. Methods Levels of NGAL in serum samples from 133 healthy people, 125 colorectal polyps patients and 100 colorectal cancer patients respectively were determined by sandwich ELISA assay. Relationship of NGAL level with clinicopathological features of colorectal cancer patients was analyzed. The optimal cut-off value of serum NGAL for diagnosing colorectal cancer was determined by ROC curve and compared with CEA and CA19-9. Univariate and multivariate analyses were performed to examine the relationship of NGAL level with the prognosis of patients with colorectal cancer. Results The median serum NGAL protein level in 100 colorectal cancer cases was 67 . 96 ( 53 . 30-79 . 86 ) μg/L , significantly higher than that in healthy people and colorectal polyps patients. The differences were statistically significant (all P<0.01). Serum NGAL protein level was significantly associated with tumor diameter, TNM stage, lymph node metastasis and vascular involvement (P<0.05). The optimal cut-off point of serum NGAL protein level for diagnosing colorectal cancer was 49.78 μg/L, and the sensitivity and specificity were 88%and 81%respectively. As for colorectal cancer patients with stage Ⅰ, the sensitivity of serum NGAL (78.9%) was significantly higher as compared to CA19-9 (31.6%) and CEA (36.8%);as for those with stage Ⅱ, the sensitivity of serum NGAL (88.0%) was also significantly higher compared to CA19-9 (48.0%) and CEA (52.0%). Kaplan-Meier analysis showed that patients with positive NGAL (≥49.78 μg/L) had worse survival than those with negative NGAL (P=0.002). Multivariate analysis showed that NGAL was an independent prognostic factor (HR=2.060, 95%CI:1.023-4.150, P=0.043). Conclusions NGAL can be served as the novel malignant biological phenotype marker for human colorectal cancer and can be used for the risk stratification. NGAL may be an independent prognostic factor in colorectal cancer.

Objective To explore the feasibility and clinical significance of the detection of serum neutrophil gelatinase-associated lipocalin (NGAL) in human colorectal cancer. Methods Levels of NGAL in serum samples from 133 healthy people, 125 colorectal polyps patients and 100 colorectal cancer patients respectively were determined by sandwich ELISA assay. Relationship of NGAL level with clinicopathological features of colorectal cancer patients was analyzed. The optimal cut-off value of serum NGAL for diagnosing colorectal cancer was determined by ROC curve and compared with CEA and CA19-9. Univariate and multivariate analyses were performed to examine the relationship of NGAL level with the prognosis of patients with colorectal cancer. Results The median serum NGAL protein level in 100 colorectal cancer cases was 67 . 96 ( 53 . 30-79 . 86 ) μg/L , significantly higher than that in healthy people and colorectal polyps patients. The differences were statistically significant (all P<0.01). Serum NGAL protein level was significantly associated with tumor diameter, TNM stage, lymph node metastasis and vascular involvement (P<0.05). The optimal cut-off point of serum NGAL protein level for diagnosing colorectal cancer was 49.78 μg/L, and the sensitivity and specificity were 88%and 81%respectively. As for colorectal cancer patients with stage Ⅰ, the sensitivity of serum NGAL (78.9%) was significantly higher as compared to CA19-9 (31.6%) and CEA (36.8%);as for those with stage Ⅱ, the sensitivity of serum NGAL (88.0%) was also significantly higher compared to CA19-9 (48.0%) and CEA (52.0%). Kaplan-Meier analysis showed that patients with positive NGAL (≥49.78 μg/L) had worse survival than those with negative NGAL (P=0.002). Multivariate analysis showed that NGAL was an independent prognostic factor (HR=2.060, 95%CI:1.023-4.150, P=0.043). Conclusions NGAL can be served as the novel malignant biological phenotype marker for human colorectal cancer and can be used for the risk stratification. NGAL may be an independent prognostic factor in colorectal cancer.

BACKGROUND:Based on the integration of virtual reality technology with acupoints, acupuncture can be expressed three-dimensional y.
OBJECTIVE:To explore the structure of points through reconstructing digitalized three-dimensional visualization of Neiguan (PC6) structure based on VOXEL-MAN and Micro-XCT.
METHODS:Muscles and other tissues adjacent with Neiguan (PC6) were segmented and merged based on the VOXEL-MAN system combined with the anatomical knowledge of acupoints;nerves and blood vessels were performed with three-dimensional reconstruction;the needle-inserting animation of Neiguan (PC6) was obtained by running script file. Three-dimensional visualization and virtual needle-inserting researches of Neiguan (PC6) were performed. Nature of the acupoints was detected by the Micro-XCT-200 machine additional y.
RESULTS AND CONCLUSION:The visualization of the anatomical structure of local Neiguan (PC6) was completed, and the localization and expression of Neiguan (PC6) in the digitized virtual human were realized. The Neiguan (PC6) structure was researched with Micro-XCT-200, and showed there was no new tissue. Local three-dimensional reconstruction of the acupoint structure could help to display the anatomical structure of acupoints and simulate the acupuncture process. It could also help to observe the relationship between the needle body and the surrounding tissues during needle-inserting, which supplying a good basis not only for exploring the security of needle-inserting, but also for improving the clinical effect of acupuncture. The research on the structure of acupoint Neiguan (PC6) by Micro-XCT-200 provides further experimental evidence for the hypothesis of three-dimensional acupoint.