Circ_0012152 Accelerates Acute Myeloid Leukemia Progression through the miR-652-3p/SOX4 Axis.

OBJECTIVE: Acute myeloid leukemia (AML) is an aggressive hematological malignancy characterized by abnormal myeloid blast expansion. Recent studies have demonstrated that circular RNAs play a role in AML pathogenesis. In this study, we aimed to investigate the clinical significance of circ_0012152 in AML and elucidate its underlying molecular mechanism in the pathogenesis of this condition. METHODS: Circ_0012152 expression was detected by quantitative real-time polymerase chain reaction in samples obtained from 247 patients with AML and 40 healthy controls. A systematic analysis of clinical characteristics and prognostic factors was also conducted. Cell growth was assessed using the Cell Counting Kit-8 (CCK-8) assay, and apoptosis and cell cycle progression were evaluated by flow cytometry. Moreover, RNA pull-down was performed to identify target microRNAs, and transcriptome RNA sequencing and bioinformatics analyses were utilized to identify downstream mRNA targets. RESULTS: Circ_0012152 was significantly upregulated in samples from patients with AML and served as an independent adverse prognostic factor for overall survival (OS) (hazard ratio: 2.357; 95% confidence interval 1.258-4.415). The circ_0012152 knockdown reduced cell growth, increased apoptosis, and inhibited cell cycle progression in AML cell lines. RNA pull-down and sequencing identified miR-652-3p as a target microRNA of circ_0012152. Cell growth inhibition by circ_0012152 knockdown was significantly relieved by miR-652-3p inhibitors. We suggested that miR-652-3p targeted SOX4, as the decrease in SOX4 expression resulting from circ_0012152 knockdown was upregulated by miR-652-3p inhibitors in AML cells. CONCLUSION: Circ_0012152 is an independent poor prognostic factor for OS in AML, and it promotes AML cell growth by upregulating SOX4 through miR-652-3p.

A multicenter randomized, controlled clinical trial of adjuvant sintilimab for esophageal squamous cell carcinoma.

No adjuvant treatment has been established for patients who remain at high risk of recurrence and incidental pathologic lymph node metastasis for esophageal squamous cell carcinoma (ESCC). In this open-label, multicenter, phase III, randomized controlled trial, ESCC patients who did not achieve pathologic complete response after neoadjuvant chemotherapy plus surgery and clinical T1-2 N0 patients with incidental pathologic lymph node metastasis following initial surgery were randomized at a 2:1 ratio to receive either a sintilimab regimen or observational management (NCT05495152). The primary end point was disease-free survival for all randomized patients. The results of this randomized controlled trial addressed controversy regarding the survival benefits of adjuvant sintilimab treatment for patients with resected locally advanced ESCC. Clinical Trial Registration: NCT05495152 (ClinicalTrials.gov).

A multicenter clinical study: personalized medication for advanced gastrointestinal carcinomas with the guidance of patient-derived tumor xenograft (PDTX).

BACKGROUND: Establish patient-derived tumor xenograft (PDTX) from advanced GICs and assess the clinical value and applicability of PDTX for the treatment of advanced gastrointestinal cancers. METHODS: Patients with advanced GICs were enrolled in a registered multi-center clinical study (ChiCTR-OOC-17012731). The performance of PDTX was evaluated by analyzing factors that affect the engraftment rate, comparing the histological consistency between primary tumors and tumorgrafts, examining the concordance between the drug effectiveness in PDTXs and clinical responses, and identifying genetic variants and other factors associated with prognosis. RESULTS: Thirty-three patients were enrolled in the study with the engraftment rate of 75.8% (25/33). The success of engraftment was independent of age, cancer types, pathological stages of tumors, and particularly sampling methods. Tumorgrafts retained the same histopathological characteristics as primary tumors. Forty-nine regimens involving 28 drugs were tested in seventeen tumorgrafts. The median time for drug testing was 134.5 days. Follow-up information was obtained about 10 regimens from 9 patients. The concordance of drug effectiveness between PDTXs and clinical responses was 100%. The tumor mutation burden (TMB) was correlated with the effectiveness of single drug regimens, while the outgrowth time of tumorgrafts was associated with the effectiveness of combined regimens. CONCLUSION: The engraftment rate in advanced GICs was higher than that of other cancers and meets the acceptable standard for applying personalized therapeutic strategies. Tumorgrafts from PDTX kept attributes of the primary tumor. Predictions from PDTX modeling closely agreed with clinical drug responses. PDTX may already be clinically applicable for personalized medication in advanced GICs.

Galangin ameliorates severe acute pancreatitis in mice by activating the nuclear factor E2-related factor 2/heme oxygenase 1 pathway.

Acute pancreatitis (AP) is a common serious acute condition of the digestive system that remains a clinical challenge. Severe acute pancreatitis (SAP) in particular is characterized by high morbidity and mortality. The present study was designed to investigate the protective effect of Galangin (Gal), a natural flavonol obtained from lesser galangal, on L-arginine-induced SAP in mice and in AR42J cells. Amylase and lipase activities were measured and the histopathology of the pancreas, lung, and kidney was evaluated. Inflammation and oxidative stress were assessed using ELISA, western blotting, RT-PCR, and immunohistochemistry. Gal was shown to reduce proinflammatory cytokine production and reactive oxygen species (ROS) generation in vivo and in vitro. L-arginine treatment reduced the expression of components of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and the downstream protein heme oxygenase-1 (HO-1) in mice, whereas Gal increased their expression. Furthermore, the Nrf2/HO-1 pathway inhibitor brusatol prevented the anti-inflammatory and antioxidant effects of Gal in mice with SAP. Taken together, our results imply that Gal has protective effects in L-arginine-induced SAP that are induced by the upregulation of the Nrf2/HO-1 pathway, which has anti-inflammatory and antioxidant effects. Thus, Gal may represent a promising treatment for SAP.

Efficacy, Safety, and Correlative Biomarkers of Toripalimab in Previously Treated Recurrent or Metastatic Nasopharyngeal Carcinoma: A Phase II Clinical Trial (POLARIS-02).

PURPOSE: As yet, no checkpoint inhibitor has been approved to treat nasopharyngeal carcinoma (NPC). This study was aimed to evaluate the antitumor activity, safety, and biomarkers of toripalimab, a new programmed death-1 (PD-1) inhibitor for recurrent or metastatic NPC (RM-NPC) refractory to standard chemotherapy. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients with RM-NPC received 3 mg/kg toripalimab once every 2 weeks via intravenous infusion until confirmed disease progression or unacceptable toxicity. The primary end point was objective response rate (ORR). The secondary end points included safety, duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Among all 190 patients, the ORR was 20.5% with median DOR 12.8 months, median PFS 1.9 months, and median OS 17.4 months. Among 92 patients who failed at least two lines of systemic chemotherapy, the ORR was 23.9%. The ORRs were 27.1% and 19.4% in PD-L1+ and PD-L1- patients, respectively (P = .31). Patients with ≥ 50% decrease of plasma Epstein-Barr virus (EBV) DNA copy number on day 28 had significantly better ORR than those with < 50% decrease, 48.3% versus 5.7% (P = .0001). Tumor mutational burden had a median value of 0.95 muts/mega-base in the cohort and had no predictive value for response. Whole-exome sequencing results from 174 patients revealed that the patients with genomic amplification in 11q13 region or ETV6 genomic alterations had poor responses to toripalimab. CONCLUSION: The POLARIS-02 study demonstrated a manageable safety profile and durable clinical response of toripalimab in patients with chemorefractory metastatic NPC. An early decrease in plasma EBV DNA copy number correlated with favorable response.

Neoadjuvant chemotherapy versus neoadjuvant chemoradiotherapy for locally advanced oesophageal squamous cell carcinoma: a single-Centre, open-label, randomized, controlled, clinical trial (HCHTOG1903).

BACKGROUND: Neoadjuvant therapy plus oesophagectomy has been accepted as the standard treatment for patients with potentially curable locally advanced oesophageal cancer. No completed randomized controlled trial (RCT) has directly compared neoadjuvant chemotherapy and neoadjuvant chemoradiation in patients with oesophageal squamous cell carcinoma (ESCC). The aim of the current RCT is to investigate the impact of neoadjuvant chemotherapy plus surgery and neoadjuvant chemoradiotherapy plus surgery on overall survival for patients with resectable locally advanced ESCC. METHODS: This open label, single-centre, phase III RCT randomized patients (cT2-T4aN + M0 and cT3-4aN0M0) in a 1:1 fashion to receive either the CROSS regimen (paclitaxel 50 mg/m2; carboplatin (area under the curve = 2), q1w, 5 cycles; and concurrent radiotherapy, 41.4 Gy/23 F, over 5 weeks) or neoadjuvant chemotherapy (paclitaxel 175 mg/m2; and cisplatin 75 mg/m2, q21d, 2 cycles). Assuming a 12% 5-year overall survival difference in favour of the CROSS regimen, 80% power with a two-sided alpha level of 0.05 and a 5% dropout each year for an estimated 3 years enrolment, the power calculation requires 456 patients to be recruited (228 in each group). The primary endpoint is 5-year overall survival, with a minimum 5-year follow-up. The secondary endpoints include 5-year disease-free survival, toxicity, pathological complete response rate, postoperative complications, postoperative mortality and quality of life. A biobank of pre-treatment and resected tumour tissue will be built for translational research in the future. DISCUSSION: This RCT directly compares a neoadjuvant chemotherapy regimen with a standard CROSS regimen in terms of overall survival for patients with locally advanced ESCC. The results of this RCT will provide an answer for the controversy regarding the survival benefits between the two treatment strategies. TRIAL REGISTRATION: NCT04138212, date of registration: October 24, 2019.

Tip of the iceberg: roles of circRNAs in hematological malignancies.

Circular RNAs (circRNAs) are a new class of covalently closed RNA molecules whose 3'- and 5'-ends are linked by a back-splicing event. Emerging evidence has shown that circRNAs play a vital role in the occurrence and development of many diseases and are promising biomarkers and therapeutic targets. However, knowledge of circRNAs in hematological malignancies is limited. In this review, the biogenesis, categories, characteristics, and functions of circRNAs are summarized, especially the roles of circRNAs in hematopoiesis and hematological malignancies.

L-Type Cav 1.2 Calcium Channel-α-1C Regulates Response to Rituximab in Diffuse Large B-Cell Lymphoma.

PURPOSE: One third of patients with diffuse large B-cell lymphoma (DLBCL) succumb to the disease partly due to rituximab resistance. Rituximab-induced calcium flux is an important inducer of apoptotic cell death, and we investigated the potential role of calcium channels in rituximab resistance. EXPERIMENTAL DESIGN: The distinctive expression of calcium channel members was compared between patients sensitive and resistant to rituximab, cyclophosphamide, vincristine, doxorubicin, prednisone (RCHOP) regimen. The observation was further validated through mechanistic in vitro and in vivo studies using cell lines and patient-derived xenograft mouse models. RESULTS: A significant inverse correlation was observed between CACNA1C expression and RCHOP resistance in two independent DLBCL cohorts, and CACNA1C expression was an independent prognostic factor for RCHOP resistance after adjusting for International Prognostic Index, cell-of-origin classification, and MYC/BCL2 double expression. Loss of CACNA1C expression reduced rituximab-induced apoptosis and tumor shrinkage. We further demonstrated direct interaction of CACNA1C with CD20 and its role in CD20 stabilization. Functional modulators of L-type calcium channel showed expected alteration in rituximab-induced apoptosis and tumor suppression. Furthermore, we demonstrated that CACNA1C expression was directly regulated by miR-363 whose high expression is associated with worse prognosis in DLBCL. CONCLUSIONS: We identified the role of CACNA1C in rituximab resistance, and modulating its expression or activity may alter rituximab sensitivity in DLBCL.

Risk reduction of endometrial and ovarian cancer after bisphosphonates use: A meta-analysis.

OBJECTIVE: Recent epidemiological studies have investigated the associations between the use of bisphosphonates and the development of endometrial cancer and ovarian cancer; these studies have shown controversial results. Hence, this meta-analysis was conducted to evaluate the changes in the risks of developing endometrial and ovarian cancers after using bisphosphonates based on current evidence. METHODS: A comprehensive search was performed in the MEDLINE, EMBASE, and Web of Science databases through January 2017. The summary relative risk (RR) estimates for the effects of the use of bisphosphonates on the risks of developing endometrial and ovarian cancers were calculated using a random-effects model. RESULTS: Seven studies were included with a total of 6471 endometrial cancer cases (7 studies with 213,920 participants) and 6783 ovarian cancer cases (4 studies with 105,507 participants). This meta-analysis suggested that any use of bisphosphonates was associated with a significant 27% reduction in the risk of endometrial cancer (RR = 0.73, 95% CI: 0.58-0.93, P = 0.012), but the reduction in the risk of ovarian cancer (RR = 0.81, 95% CI: 0.58-1.14, P = 0.227) was not significant. The protective effects of the use of bisphosphonates against endometrial cancer are mainly found in postmenopausal women (RR = 0.53, 95% CI: 0.34-0.93, P = 0.012) or in those who have taken bisphosphonates for longer than 1 year (RR = 0.57, 95% CI: 0.35-0.93, P = 0.024). CONCLUSION: This meta-analysis suggests that the use of bisphosphonates is associated with a reduction in the risk of endometrial cancer but not ovarian cancer.

A retrospective clinical study of comparing paclitaxel plus S-1 versus paclitaxel plus cisplatin as the first-line treatment for patients with advanced esophageal squamous cell carcinoma.

BACKGROUND: In advanced esophageal squamous cell carcinoma (ESCC), paclitaxel plus cisplatin are considered as active and tolerable. The current clinical study was conducted to retrospectively compare the efficacy and safety of first-line paclitaxel/S-1(PS) and paclitaxel/cisplatin(TP) regimens in advanced ESCC. RESULTS: The overall response rate of PS was slightly, but not significantly, higher (25 patients, 46%) than that of TP (23 patients, 39%, P = 0.432). Median overall survival (OS) was similar for PS and TP (11.5 months vs. 10.4 months, p = 0.37). However PS had longer median progression-free survival than TP (PFS: 5.5 months vs5.0months, p = 0.04). When compared with PS, more grade 3 or 4 adverse events were recorded for TP, including leukopenia, neutropenia, anemia, anorexia and vomiting (P < 0.05). No treatment-related deaths were recorded in either group. PATIENTS AND METHODS: Between 2008 and 2014, all patients diagnosed with advanced ESCC and treated with paclitaxel/S-1 or paclitaxel/cisplatin at Cancer Hospital Affiliated to Zhengzhou University were analyzed retrospectively. One hundred and thirteen patients were included in this study. Disease control rates and progression-free survival (PFS) and overall survival (OS) were recorded. Survival analysis was calculated by using Kaplan-Meier method. CONCLUSIONS: The PS option improves PFS and its OS is similar to TP. Moreover, the PS regimen is an effective and safe first-line treatment for ESCC with less hematological and non-hematological toxicity.

Weekly nanoparticle albumin-bound paclitaxel in combination with cisplatin versus weekly solvent-based paclitaxel plus cisplatin as first-line therapy in Chinese patients with advanced esophageal squamous cell carcinoma.

OBJECTIVE: More effective regimens for advanced esophageal squamous cell carcinoma (ESCC) are urgently needed. Therefore, a retrospective study concerning the efficacy and safety of nanoparticle albumin-bound paclitaxel plus cisplatin (nab-TP) versus solvent-based paclitaxel plus cisplatin (sb-TP) as a first-line therapy was conducted in Chinese patients with advanced ESCC. METHODS: From June 2009 to June 2015, 32 patients were treated with nab-paclitaxel (125 mg/m2) on the first and eighth days (30 minutes infusion) and cisplatin (75 mg/m2) on the second day every 21 days (nab-TP arm). Also, 43 patients were treated with solvent-based paclitaxel (80 mg/m2) intravenously on the first and eighth days and the same dose of cisplatin (sb-TP arm). The two groups were compared in terms of objective response rate (ORR), disease control rate, progression-free survival (PFS), overall survival (OS), and safety profile. OS and PFS were estimated using Kaplan-Meier methods to determine associations between chemotherapy regimens and survival outcomes. RESULTS: Nab-TP demonstrated a higher ORR (50% vs 30%; P=0.082) and disease control rate (81% vs 65%; P=0.124) than sb-TP. Median OS was similar for nab-TP and sb-TP (12.5 vs 10.7 months; P=0.269). However, nab-TP resulted in a longer median PFS (6.1 months [95% confidence interval: 5.3-6.9]) than sb-TP (5.0 months [95% confidence interval: 4.4-5.6]) (P=0.029). The most common adverse events included anemia, leukopenia, neutropenia, febrile neutropenia, and thrombocytopenia in both the groups and no statistically significant differences were observed between the groups. With statistically significant differences, significantly less grade ≥3 peripheral neuropathy, arthralgia, and myalgia occurred in the nab-TP arm (all P<0.05). Dose reduction, treatment delays, and second-line therapy were similar between the two regimens. There were no treatment-related deaths in either group. CONCLUSION: Nab-paclitaxel plus cisplatin is found to be an effective and tolerable option for advanced ESCC in the People's Republic of China.

Chinese expert consensus on cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal malignancies.

Locoregional spread of abdominopelvic malignant tumors frequently results in peritoneal carcinomatosis (PC). The prognosis of PC patients treated by conventional systemic chemotherapy is poor, with a median survival of < 6 mo. However, over the past three decades, an integrated treatment strategy of cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been developed by the pioneering oncologists, with proved efficacy and safety in selected patients. Supported by several lines of clinical evidence from phases I, II and III clinical trials, CRS + HIPEC has been regarded as the standard treatment for selected patients with PC in many established cancer centers worldwide. In China, an expert consensus on CRS + HIPEC has been reached by the leading surgical and medical oncologists, under the framework of the China Anti-Cancer Association. This expert consensus has summarized the progress in PC clinical studies and systematically evaluated the CRS + HIPEC procedures in China as well as across the world, so as to lay the foundation for formulating PC treatment guidelines specific to the national conditions of China.

Expression of activating transcription factor 7 is correlated with prognosis of colorectal cancer.

BACKGROUND: It is important to identify some tumor-related factors for early detection, treatment, and evaluation of prognosis in colorectal cancer (CRC). In our study, we investigated the clinical and prognostic role of activating transcription factor 7 (ATF7) in CRC. MATERIALS AND METHODS: Expression of ATF7 was detected with immunohistochemistry in 72 cases with complete follow-up data and post-operation tissue specimens. Correlation between ATF7 and other clinicopathological factors was calculated with Chi-square test and the impact of ATF7 on survival were analyzed with Log-rank test and Cox regression models. RESULTS: Among 72 cases, ATF7 expression was detected in 43 cases (59.7%) and 29 cases (40.3%) without ATF7 expression. The correlation between ATF7 expression and pathological stage was investigated (P = 0.041). The 5-year overall survival (OS) of with or without ATF7 expression was 79% versus 51% respectively (P < 0.001) and the 5-year progression free survival (PFS) was 74% versus 41% (P < 0.001). The media OS was 69 months versus 52 months (P = 0.002) and the media PFS was 65 months versus 42 months (P = 0.002). ATF7 expression and numbers of lymph nodes involvement were prognostic factors for OS according to univariated and multivariated analysis and for PFS it was ATF7 expression and lymph nodes involvement. CONCLUSION: It is negatively related between ATF7 expression and pathological stage and positive correlation with OS and PFS in CRC. ATF7 expression is a favorable factor for survival of patients with CRC.

Efficacy of gemcitabine combined with oxaliplatin, L-asparaginase and dexamethasone in patients with newly-diagnosed extranodal NK/T-cell lymphoma.

There is currently no standard first-line regimen for patients with extranodal natural killer (NK)/T-cell lymphoma (ENKTCL). In this study, we investigated the efficacy and toxicity of gemcitabine (GEM) combined with oxaliplatin (L-OHP), L-asparaginase (L-ASP) and dexamethasone (DXM) (GOLD regimen) as a systemic treatment scheme for newly-diagnosed ENKTCL cases. A total of 55 patients were recruited at the Henan Province Cancer Hospital and the Cancer Center of Sun Yat-sen University between May, 2008 and August, 2012. The GOLD regimen included a 14-day treatment cycle with GEM (1,000 mg/m2) on day 1, L-OHP (100 mg/m2) on day 1, L-ASP (10,000 U/m2) on days 1-5 and DXM (20 mg b.i.d.) on days 1-4. The response rate, survival rate and treatment toxicity were analyzed. The overall response rate was 91% (48/55) with a complete response in 62% (34/55) and a partial response in 29% (15/55) of the patients. For all patients, the 1-, 2- and 3-year progression-free survival (PFS) rate was 86, 64 and 57% and the overall survival (OS) 91, 80 and 74%, respectively. The 1-year PFS in patients with stage I/II vs. those with III/IV disease was 87 vs. 66% (P<0.001) and the 1-year OS was 98 vs. 75%, respectively (P<0.001). No chemotherapy-related mortality or severe complications were recorded. In conclusion, the GOLD regimen was found to be highly effective and safe for the treatment of patients with newly-diagnosed ENKTCL.

Global in vivo terminal amino acid labeling for exploring differential expressed proteins induced by dialyzed serum cultivation.

Taking advantage of reliable metabolic labeling and accurate isobaric MS2 quantification, we developed a global in vivo terminal amino acid labeling (G-IVTAL) strategy by combining metabolic labeling and isotopic dimethyl labeling for quantifying tryptic peptides. With G-IVTAL, the scale of qualitative and quantitative data can be increased twofold compared with in vivo termini amino acid labeling (IVTAL) in which Lys-N and Arg-C are used for digestion. As a result, up to 81.78% of the identified proteins have been confidently quantified in G-IVTAL-labeled HepG2 cells. Dialyzed serum has been used in most SILAC studies to ensure complete labeling. However, dialysis requires the removal of low molecular weight hormones, cytokines, and cellular growth factors, which are essential for the cell growth of certain cell lines. To address the influence of dialyzed serum in HepG2 growth, the G-IVTAL strategy was applied to quantify the expression differences between dialyzed serum- and normal serum-cultured HepG2 cells. Finally, we discovered 111 differentially expressed proteins, which could be used as references to improve the reliability of the SILAC quantification. Among these, by using western blotting, the differential expressions of MTDH, BCAP31, and GPC3 were confirmed as being influenced by dialyzed serum. The experimental results demonstrate that the G-IVTAL strategy is a powerful tool to achieve accurate and reliable protein quantification.

[Inhibitory effects of celecoxib combined with capecitabine on H22 hepatoma mice and its mechanism].

OBJECTIVE: To evaluate the inhibitory effect and its mechanism of celecoxib combined with capecitabine on the growth of implanted H22 hepatoma in mice. METHODS: Tumor model was established by hypodermical injection of H22 cells in BALB/c nude mice. Forty mice were equally randomly divided into 4 groups: control group, celecoxib group (receiving 100 mg/kg celecoxib), capecitabine group (receiving 755 mg/kg capecitabine), and combined treatment group (receiving 100 mg/kg of celecoxib and 755 mg/kg of capecitabine). From the third post-implantation day, each mouse was given relevant drug (or normal saline) by oral gavage. Fifteen days later, all mice were sacrificed and the tumor tissues were measured. The mRNA and protein levels of nuclear factor kappa-B (NF-ΚB) p65 and cyclooxygenase (COX)-2 in tumor tissues were detected by the quantitative polymerase chain reaction (qPCR)and Western blotting, respectively. RESULTS: The tumor inhibition rate was 30.2% in celecoxib group and 49.9% in capecitabine group, which was significantly lower than that (75.4%) in the combined treatment group (P<0.01,P<0.05, respectively). qPCR showed a significant decrease of the mRNA expression of COX-2 in celecoxib group and combined treatment group when compared with control group (P<0.001), but no significant change in NF-ΚB p65.Capecitabine had no significant effects on the mRNA expression of COX-2 and NF-ΚB p65. Western blotting showed that celecoxib and combined treatment significantly inhibited the protein expression of COX-2 and NF-ΚB p65(P<0.05), but not capecitabine. CONCLUSION: Celecoxib can enhance the antitumor effect of capecitabine by inhibiting the expressions of COX-2 and NF-ΚB p65 in mice bearing H22 implanted tumor.

p63 Expression is a prognostic factor in colorectal cancer.

p63 is highly expressed in some malignant tumors and is associated with tumorigenesis, invasion and metastasis. The aim of our study was to evaluate the clinical significance of p63 in colorectal cancer (CRC). p63 expression was detected by immunohistochemistry in 66 CRC patients. Correlations between p63 expression and clinicopathological factors, progression-free survival (PFS) and overall survival (OS) were analyzed. Among the 66 CRC cases, 31 cases (47%) exhibited a high score of p63 expression, while 35 cases (53%) were marked with a low score. The p63 level correlated with peritumoral deposits (p=0.021). The 5-year OS rates in the low p63 score and high p63 score groups were, respectively, 49% and 74% (p<0.001). The 5-year PFS rates in the low p63 score and high p63 score groups were, respectively, 44% and 71% (p<0.001). Univariate analysis revealed that p63 expression was correlated with OS and PFS. Multivariate analysis suggested that p63 expression was an independent prognostic factor for OS (p=0.035). In conclusion, p63 was negatively correlated with peritumoral deposits and positively associated with OS and PFS in CRC. The data suggest that p63 is a potential prognostic factor for CRC.

A novel quantitative proteomics workflow by isobaric terminal labeling.

Quantification by series of b, y fragment ion pairs generated from isobaric-labeled peptides in MS2 spectra has recently been considered an accurate strategy in quantitative proteomics. Here we developed a novel MS2 quantification approach named quantitation by isobaric terminal labeling (QITL) by coupling (18)O labeling with dimethylation. Trypsin-digested peptides were labeled with two (16)O or (18)O atoms at their C-termini in H(2)(16)O or H(2)(18)O. After blocking all ε-amino groups of lysines through guanidination, the N-termini of the peptides were accordingly labeled with formaldehyde-d(2) or formaldehyde. These indistinguishable, isobaric-labeled peptides in MS1 spectra produce b, y fragment ion pairs in the whole mass range of MS2 spectra that can be used for quantification. In this study, the feasibility of QITL was first demonstrated using standard proteins. An accurate and reproducible quantification over a wide dynamic range was achieved. Then, complex rat liver samples were used to verify the applicability of QITL for large-scale quantitative analysis. Finally, QITL was applied to profile the quantitative proteome of hepatocellular carcinoma (HCC) and adjacent non-tumor liver tissues. Given its simplicity, low-cost, and accuracy, QITL can be widely applied in biological samples (cell lines, tissues, and body fluids, etc.) for quantitative proteomic research.

[Long-term effect on radiofrequency heat-coagulation endometrial ablation in the treatment of anovulatory dysfunctional uterine bleeding].

OBJECTIVE: To investigate long-term effect on radiofrequency heat-coagulation (RF) endometrial ablation in treatment of anovulatory dysfunctional uterine bleeding (DUB). METHODS: From Jul. 2001 to Nov. 2009, 1196 patients with DUB who were failed by medical treatment (including 127 patients with dysmenorrheal) were enrolled into this study in Jinan Millitary General Hospital. Those patients were divided into two groups according to age: 427 patients at age of or more than 45 years (average age 48 years) in Group A who were treated by RF procedure for amenorrhea;769 patients at age of less than 45 years old (average 37 years) in group B were treated by RF for controlling excessive menstrual bleeding. All the patients had the results of menstrual score (pictorial blood loss assessment chart, PBAC), hemoglobin (Hb), endometrial curettage pathology and hysteroscopy examination immediately after RF procedure; Some patients still had another endometrial curettage pathology and clinical results in 6 months after RF. The mean follow-up time was 72 months (range: 6 to 100 months). The evaluation criterion for RF treatment was to use optimal and significant effect measurements. For group A, the optimal treatment effect (cure) was defined as bleeding cessation and achieving amenorrhea that continued for more than 12 months after treatment. For group B, the optimal treatment effect(cure) was also defined as bleeding cessation and resuming normal menstruation which continued for more than 12 months after treatment. Significant treatment effect was defined as irregular, minor bleeding, but PBAC score less than 100 within 12 months. If patient symptoms and PBAC scores did not change compared with those before treatment, the treatment was defined as failure. For dysmenorrhea, the optimal treatment effect was disappearance for more than 12 months, the significant treatment effect was remission, and treatment failure was not changed from the pre-treatment baseline. The effective rate was the sum of that of the optimal and significant effect. One hundred and twenty-five patients with DUB treated by agents at the same time were chosen as control group. RESULTS: (1) The recent and long-term effective rates for bleeding cessation by RF:the total recent effective rates within 1 months were 94.82% (1134/1196), including 96.5% (412/427) in group A and 93.9% (722/769) in group B. The total curative rates for dysmenorrheal were 82.7% (105/127), including 86.4% (38/44) in group A and 80.7% (67/83) in group B. Pathology examination after hysteroscopy immediately after RF showed a completely and whole destroyed endometrium in group A, and a little rested endometrium in group B. The long-term effect rates for bleeding cessation by RF after 12, 24 and 36 months were 92.55% (969/1047), 93.9% (866/922) and 93.7% (609/650), respectively. PBAC and Hb in group A and group B within 12, 24, 36 and more than 36 months were improved significantly (P < 0.05). (2) COMPLICATIONS: the major complication was irregular minor bleeding in 1 to 2 months after treatment, the rate was 8.03% (96/1196). The second one was menorrhea in 3 months after RF, the rate was 5.18% (62/1196). This condition was corrected by the second RF. No hysterectomy was performed on those patients. CONCLUSION: RF is the safe, efficient and minimal invasive procedure in treatment for DUB. The mechanism of keeping long-term curative effect and preventing recurrence is due to endometrium inactivation and fibrosis by thermocoagulation.

PTEN tumor suppressor plays less prognostic role than P53 tumor suppressor in diffuse large B-cell lymphoma.

The phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and P53 tumor suppressors are among the most commonly inactivated or mutated genes in human cancers, whose pathways cross-talk and interact in a complementary mode. In order to understand their roles and relationship in diffuse large B-cell lymphoma (DLBCL), we examined their expression and evaluated their prognostic significance in 62 patients with DLBCL treated with standard chemotherapy. Results showed that PTEN protein was lost in 23 (37.1%) cases, and the loss was associated with the activation of PI3K/AKT pathway, but was not associated with patient's clinical outcome. P53 mutation protein was detected in 30 (48.4%) cases and was associated with poor survival. Results of multivariate analysis showed that P53 mutation but not PTEN loss is associated with short survival in patients with DLBCL. PTEN status has no effect on P53 mutation-associated poor survival. We conclude that PTEN may play less prognostic role than P53 and that P53 mutation protein should be considered as a predictive factor of the need for a more aggressive therapy in patients with DLBCL who express P53.