Retracted: Long Noncoding RNA TP73-AS1 Targets MicroRNA-329-3p to Regulate Expression of the SMAD2 Gene in Human Cervical Cancer Tissue and Cell Lines.

The Editors of Medical Science Monitor wish to inform you that the above manuscript has been retracted from publication due to concerns with the credibility and originality of the study, the manuscript content, and the Figure images. Reference: Mei Mei Guan, Qun Xian Rao, Miao Ling Huang, Li Juan Wang, Shao Dan Lin, Qing Chen, Chang Hao Liu. Long Noncoding RNA TP73-AS1 Targets MicroRNA-329-3p to Regulate Expression of the SMAD2 Gene in Human Cervical Cancer Tissue and Cell Lines. Med Sci Monit, 2019; 25: 8131-8141. DOI: 10.12659/MSM.916292.

Structures of the ADGRG2-Gs complex in apo and ligand-bound forms.

Adhesion G protein-coupled receptors are elusive in terms of their structural information and ligands. Here, we solved the cryogenic-electron microscopy (cryo-EM) structure of apo-ADGRG2, an essential membrane receptor for maintaining male fertility, in complex with a Gs trimer. Whereas the formations of two kinks were determinants of the active state, identification of a potential ligand-binding pocket in ADGRG2 facilitated the screening and identification of dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate and deoxycorticosterone as potential ligands of ADGRG2. The cryo-EM structures of DHEA-ADGRG2-Gs provided interaction details for DHEA within the seven transmembrane domains of ADGRG2. Collectively, our data provide a structural basis for the activation and signaling of ADGRG2, as well as characterization of steroid hormones as ADGRG2 ligands, which might be used as useful tools for further functional studies of the orphan ADGRG2.

Efficacy of neoadjuvant hyperthermic intraperitoneal chemotherapy in advanced high-grade serous ovarian cancer (the NHIPEC trial): study protocol for a randomised controlled trial.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an important treatment option for patients with ovarian cancer. Although intravenous NACT can improve optimal resection rates and decrease surgical morbidity and mortality, these advantages do not translate into a survival benefit. Ovarian carcinoma is mainly confined to the peritoneal cavity, which makes it a potential target for hyperthermic intraperitoneal chemotherapy (HIPEC). Our previous study showed that HIPEC could be used in the neoadjuvant setting, which was named neoadjuvant HIPEC (NHIPEC). Since hyperthermia is an excellent chemosensitiser, we hypothesised that the combination of NHIPEC and intravenous NACT could show superior efficacy to intravenous NACT alone. METHODS: This study is a single-centre, open-label, randomised (1:1 allocation ratio) phase 2 trial. A total of 80 patients will be randomly assigned into an experimental group (NHIPEC+intravenous NACT) or a control group (intravenous NACT). Patients in the experimental group will receive NHIPEC following laparoscopic evaluation, and four tubes will be placed via the laparoscopic ports, which will be used to administer NHIPEC. Then, perfusion with docetaxel (60-75 mg/m2) will be performed (43°C for 60 min, Day 0) followed by cisplatin (75 mg/m2, Day 1) infusion (43°C for 60 min) 24 hours later. After NHIPEC, two cycles of intravenous NACT will be given. Patients in the control group will receive three cycles of intravenous NACT. The primary endpoint is the proportion of patients who achieve a Chemotherapy Response Score (CRS) of 3 according to the CRS system. The secondary endpoints include progression-free survival, overall survival and the rates of complete resection and NHIPEC-related adverse events. ETHICS APPROVAL AND DISSEMINATION: This study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital (approval number: 2020-ky-050). Results will be submitted to peer-reviewed journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ChiCTR2000038173.

A Dose-Finding Trial for Hyperthermic Intraperitoneal Cisplatin in Gynecological Cancer Patients Receiving Hyperthermic Intraperitoneal Chemotherapy.

Background: To identify the maximum tolerated dose (MTD) of hyperthermic intraperitoneal cisplatin at 43°C among gynecological cancer patients. Methods: In this Phase I dose-finding trial, Bayesian optimal interval (BOIN) design was used. We sought to explore the MTD with a target dose-limiting toxicity (DLT) rate of 20%, 4 prespecified doses (70 mg/m2, 75 mg/m2, 80 mg/m2 and 85 mg/m2), and 30 patients. Results: Between 2019 and 2020, 30 gynecologic cancer patients were enrolled. No patients received bevacizumab in subsequent treatment. The most common adverse events related to cisplatin were nausea and vomiting (100%), followed by tinnitus (26.7%) and kidney injury (23.3%). Of the seven patients with kidney injury, four had persistent renal impairment, and finally progressed into chronic kidney injury. DLTs were noted only in the dose level 4 group (85 mg/m2) and included acute kidney injury, pulmonary embolism, anemia, and neutropenia. When cisplatin was given at dose level four (85 mg/m2), the isotonic estimate of the DLT rate (22%) was closest to the target DLT rate of 20%. Therefore, 85 mg/m2 was selected as the MTD, with a 51% probability that the toxicity probability was greater than the target DLT rate. Conclusions: For gynecological cancer patients who received HIPEC for peritoneal metastases, the MTD of cisplatin in HIPEC at 43°C was 85 mg/m2. Our findings apply to patients who do not receive bevacizumab (ChiCTR1900021555).

The added value of CA125 normalization before interval debulking surgery to the chemotherapy response score for the prognostication of ovarian cancer patients receiving neoadjuvant chemotherapy for advanced disease.

Objective: To investigate whether CA125 normalization following neoadjuvant chemotherapy (NACT) can complement the chemotherapy response system (CRS) in the prognostication of patients with tubo-ovarian high-grade serous carcinoma (HGSC). Methods: In total, 118 HGSC patients who received NACT followed by interval debulking surgery (IDS) for FIGO stage IIIC-IV disease were included, and their clinical data were retrospectively reviewed. The primary endpoint was progression-free survival (PFS). Cox regression analysis was performed to identify predictors of PFS. Results: Following NACT, CRS3 was noted in 35 patients (29.7%), and CA125 normalization (≤ 35 U/ml) was noted in 54 patients (45.8%). Both CRS3 and CA125 normalization were identified as independent prognosticators of PFS. Combining these two factors, we stratified the 106 patients into three groups with different risks of recurrence: low-risk group (CRS3 + post-NACT CA125≤ 35 U/ml; n = 17, 14.4%), intermediate-risk group (CRS3 + post-NACT CA125 > 35 U/ml; n = 19, 16.1%) and high-risk group (CRS1-2; n= 82, 69.5%). The differences in PFS between the three groups were significant (log-rank test, P < 0.0001). In Cox regression analyses, the new stratification method was found to have an independent prognostic effect. Conclusion: Both the CRS system and the normalization of CA125 following NACT could reliably predict the risk of recurrence following primary treatment. The combination of the two factors refined the prognostic stratification of HGSC patients who were treated with NACT and IDS.

Comparison of two types of the triple incision technique in the treatment of patients with locally advanced vulvar cancer.

Objective: In 2012, we proposed and described a modified triple incision technique (MTIT) for vulvar cancer patients with locally advanced disease. The MTIT has undergone a series of modifications, and a modified MTIT (M-MTIT) has been developed. The purpose of this study was to introduce the M-MTIT and compare it with the MTIT. Study design: This was a retrospective cohort study. Fifty-seven vulvar cancer patients with clinical stage T2 (≥ 4 cm) or T3 disease were included. Of these patients, 28 underwent the MTIT and 29 underwent the M-MTIT. Data on surgery-related complications and survival outcomes were compared. Results: Patients who were treated with the M-MTIT developed significantly less surgery-related morbidities than patients treated with the MTIT (24.1% vs. 60.7%, P = 0.005). Wound breakdown was the most common complication in our cohort, which occurred less frequently in the M-MTIT group than in the MTIT group (10.3% vs. 35.7%, P = 0.022). Multivariate logistic regression analysis identified the M-MTIT as an independent predictor of a reduced risk of wound breakdown. The incidence of other complications, including lymphedema, wound infection and cellulitis, was lower in the M-MTIT group than in the MTIT group; however, the differences did not reach statistical significance. The median follow-up time of this study was 33 months. Kaplan-Meier survival graphs did not show significant differences in recurrence-free survival or overall survival between the two groups. Conclusions: The M-MTIT correlates with lower morbidity rates than the MTIT and does not compromise oncological safety. The M-MTIT can be considered a safe and feasible option for vulvar cancer patients with locally advanced disease.

Identification of Ovarian Cancer Patients Most Likely to Achieve Chemotherapy Response Score 3 Following Neoadjuvant Chemotherapy: Development of a Predictive Nomogram.

Background: The chemotherapy response score (CRS) system is a reproducible prognostic tool for patients receiving neoadjuvant chemotherapy (NACT) for tubo-ovarian high-grade serous carcinoma (HGSC). Achieving CRS 3 following NACT can be used as a surrogate for progression-free survival (PFS) and overall survival (OS). This study aimed to identify predictors of CRS 3 and develop a predictive nomogram. Methods: Data were extracted from 106 HGSC patients receiving NACT. Logistic regression was used to identify independent predictors for CRS 3. A nomogram was established based on the multivariate regression model. Results: All patients received three cycles of NACT, and CRS 3 was observed in 24 (22.6%) patients. Compared with patients in the CRS 1-2 group, patients in the CRS 3 groups had significantly improved PFS (log-rank test P < 0.0001). The multivariate regression analysis identified post-NACT CA125, percent decrease in CA125, post-NACT human epididymis protein 4 (HE4), and post-NACT hemoglobin level as independent predictors of CRS 3. The Hosmer-Lemeshow test showed goodness-of-fit of this regression model (P = 0.272). The nomogram including these factors presented good discrimination (area under the curve = 0.82), good calibration (mean absolute error = 0.039), and a net benefit within the threshold probabilities of CRS 3 > 5%. Conclusions: We validated the prognostic role of the CRS system and developed a nomogram that predicts the possibility of CRS 3 following NACT. The nomogram helps to identify patients who would benefit the most from NACT. More studies are warranted to validate this model.

Evaluation of a novel monoclonal antibody mAb109 by immuno-PET/fluorescent imaging for noninvasive lung adenocarcinoma diagnosis.

Monoclonal antibodies are believed to be magic bullets and hold great potential for lots of biological process. About 100 µg of mAb109 was expressed in 5 × 106 cells after 10 days' immunization. 64Cu-NOTA-mAb109 was synthesized with the specific activity of 0.74 MBq/µg and high in vitro stability. The binding affinity of 64Cu-NOTA-mAb109 in A549 cells was determined to be 29.64 nM. 64Cu-NOTA-mAb109 displayed prominent tumor accumulation from 2 h to 60 h p.i. (9.34 ± 0.67 %ID/g). NIRF imaging of Cy5.5-mAb109 showed high accumulation till 9 days p.i., while tumors nearly can not be observed in negative groups, which was confirmed by autoradiography. Immunohistological study confirmed that mAb109 had strong and specific capacity to bind lung adenocarcinoma (concentration to 58 nM). Our study demonstrated mAb109 was a new platform for the development of novel agent for lung adenocarcinoma noninvasive imaging. The resulted 64Cu-NOTA-mAb109/Cy5.5-mAb109 show favorable imaging properties/specificity for A549 tumor and high sensitivity to human lung adenocarcinoma tissues.

Long Noncoding RNA TP73-AS1 Targets MicroRNA-329-3p to Regulate Expression of the SMAD2 Gene in Human Cervical Cancer Tissue and Cell Lines.

BACKGROUND Worldwide, mortality from cervical cancer in women remains high. This study aimed to investigate the expression of long noncoding RNA (lncRNA) TP73-AS1, microRNA-329-3p (miRNA-329-3p), and the SMAD2 gene and their regulatory relationships in human cervical cancer tissue and cervical cancer cell lines. MATERIAL AND METHODS Cervical cancer tissue samples (n=30) and normal control cervical tissues were studied. Cell proliferation and migration were investigated in HeLa and SiHa human cervical cancer cells using the MTT assay, crystal violet staining, wound healing assay, and the transwell assay. Expression of lncRNA TP73-AS1 and the SMAD2 gene were detected using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Enrichment of miR-329-3p was measured using the RNA immunoprecipitation assay (RIPA). Targeting relationships between TP73-AS1, miR-329-3p, and SMAD2 were identified using the dual-luciferase reporter assay. A subcutaneous xenograft model was established, tumor size was measured, and SMAD2 expression was detected using immunohistochemistry. RESULTS LncRNA TP73-AS1 was overexpressed in cervical cancer tissues and cells and was associated with reduced expression of miR-329-3p. Down-regulation of lncRNA TP73-AS1 inhibited cell proliferation, migration and invasion and increased miR-329-3p expression. Expression of SMAD2 down-regulated miR-329-3p and was associated with increased expression of TP73-AS1. LncRNA TP73-AS1 knockdown resulted in miR-329-3p silencing. In tumor xenografts, expression of TP73-AS1 reduced the tumor volume and down-regulated the expression levels of the SMAD2 gene. CONCLUSIONS LncRNA TP73-AS1 promoted proliferation of cervical cancer cell lines by targeting miR-329-3p to regulate the expression of the SMAD2 gene. A regulatory network was formed between lncRNA TP73-AS1, miR-329-3p, and SMAD2.

The added value of fasting blood glucose to serum squamous cell carcinoma antigen for predicting oncological outcomes in cervical cancer patients receiving neoadjuvant chemotherapy followed by radical hysterectomy.

OBJECTIVE: To determine the combination of fasting blood glucose (FBG) with squamous cell carcinoma antigen (SCCA) assessments in the prediction of tumor responses to chemotherapy and pretreatment prognostication among patients receiving neoadjuvant chemotherapy (NACT) for locally advanced cervical cancer (LACC). METHODS: Data of 347 LACC patients were retrospectively reviewed. Receiver operating characteristic (ROC) curves were constructed, and areas under the curves (AUCs) were compared to evaluate the ability to predict complete response (CR) following NACT. Patients were stratified into groups with low and high levels of SCCA and FBG and combined into low- or high-SCCA and low- or high-FBG groups. Cox regression analysis was performed to identify determinants of recurrence-free survival (RFS) and overall survival (OS). RESULTS: The AUCs were 0.70, 0.68, and 0.66 for SCCA, FBG, and a combination of SCCA and FBG for predicting CR following NACT, respectively; however, the differences among AUCs were not significant (P = .496). Pretreatment SCCA and FBG levels were identified as independent predictors of RFS and OS. The high-SCCA/high-FBG group showed significantly worse prognosis than the low-SCCA/low-FBG group. After adjusting for other variables, high-SCCA/high-FBG remained independently associated with an increased risk of tumor recurrence and death. CONCLUSION: SCCA, FBG, and a combination of SCCA and FBG could acceptably predict CR following NACT. Pretreatment SCCA and FBG levels were independent prognostic factors. The combination of SCCA and FBG levels refined the prognostic stratification of LACC patients, which allowed the group of patients with the highest risk of recurrence and death to be identified.

Accumulation and distribution of arsenic and cadmium in winter wheat (Triticum aestivum L.) at different developmental stages.

Arsenic (As) and cadmium (Cd) are known to be toxic to humans, and elevated concentrations have been documented in food crops worldwide. However, little is known regarding their uptake, translocation, and distribution in wheat plants during plant development. A series of experiments were conducted to investigate the spatial distribution and dynamics of As and Cd in two wheat cultivars (cv. JN12 and JM85; the latter is a low grain Cd accumulator) at different developmental stages. Root concentrations of As decreased by 84%, and those of Cd by 67%, from tillering to maturity. In contrast, As concentrations in the stems increased 3.1-fold. A significant decrease in root As accumulation was observed at the mature stage, whereas root Cd accumulation decreased largely at the elongation stage. The concentrations of Cd in all leaves and As in new leaves increased as plant growth advanced. However, As concentrations in old leaves decreased significantly from grain filling to maturity. In both cultivars, the upward transfer toward younger parts of shoots was greater in the case of Cd than of As. The remobilization of As and Cd from stems and roots differed between the two cultivars. Arsenic concentrations in rachis, glumes, and grain in JM85 were significantly higher than those in JN12, whereas As concentrations in roots and stems did not differ between the cultivars. Grain Cd was significantly higher in JN12 than in JM85, but Cd concentrations in rachis and glumes were similar between the cultivars. The difference in grain Cd concentration between the two cultivars depended on root and stem Cd remobilization and redistribution from rachis to glumes and grain; in contrast, accumulation of As in grain was influenced by As remobilization from the leaves and stem to the spike.

Association Between HIF-1 Alpha Gene Polymorphisms and Response in Patients Undergoing Neoadjuvant Chemotherapy for Locally Advanced Cervical Cancer.

BACKGROUND The aim of the study was to assess whether HIF-1α polymorphisms have an effect on the response to chemotherapy of locally advanced cervical cancer (LACC) patients treated with platinum-based neoadjuvant chemotherapy (NACT) and radical surgery. MATERIAL AND METHODS We conducted a retrospective study in 162 LACC patients. Hypoxia-inducible factor 1α C1772T and G1790A genetic polymorphisms were ascertained using direct sequencing methods. RESULTS The C1772T polymorphism was significantly related to response to chemotherapy (P=0.002), and there was an increased chance of treatment response in patients with the C/C genotype (OR=4.7; 95% CI: 1.67-13.49; P=0.004). The C1772T polymorphism was also associated with poor tumor grade (adjusted OR, 2.98; 95% CI: 1.08-8.13; P=0.037). However, The G1790A polymorphism was not associated with response (P>0.05). CONCLUSIONS The C1772T polymorphism was significantly related to response to chemotherapy and poor tumor grade. Our results may help to better manage individual patients and to improve clinical decision making regarding use of NACT.

Can radical parametrectomy be omitted in occult cervical cancer after extrafascial hysterectomy?

BACKGROUND: Occult invasive cervical cancer discovered after simple hysterectomy is not common, radical parametrectomy (RP) is a preferred option for young women. However, the morbidity of RP was high. The aim of our study is to assess the incidence of parametrial involvement in patients who underwent radical parametrectomy for occult cervical cancer or radical hysterectomy for early-stage cervical cancer and to suggest an algorithm for the triage of patients with occult cervical cancer to avoid RP. METHODS: A total of 13 patients with occult cervical cancer who had undergone RP with an upper vaginectomy and pelvic lymphadenectomy were included in this retrospective study. Data on the clinicopathologic characteristics of the cases were collected. The published literature was also reviewed, and low risk factors for parametrial involvement in early-stage cervical cancer were analyzed. RESULTS: Of the 13 patients, 9 had a stage IB1 lesion, and 4 had a stage IA2 lesion. There were four patients with grade 1 disease, seven with grade 2 disease, and two with grade 3 disease. The median age of the entire patients was 41 years. The most common indication for extrafascial hysterectomy was cervical intraepithelial neoplasia 3. Three patients had visible lesions measuring 10-30 mm, in diameter and ten patients had cervical stromal invasions with depths ranging from 4 to 9 mm; only one patient had more than 50% stromal invasion, and four patients had lymph-vascular space invasion (LVSI). Perioperative complications included intraoperative bowel injury, blood transfusion, vesico-vaginal fistula, and ileus (1 case for each). Postoperative pathologic examination results did not show residual disease or parametrial involvement. One patient with positive lymph nodes received concurrent radiation therapy. Only one patient experienced recurrence. CONCLUSIONS: Perioperative complications following RP were common, whereas the incidence of parametrial involvement was very low among selected early-stage cervical cancer patients. Based on these results, we thought that patients with very low-risk parametrial involvement(tumor size ≤ 2 cm, no LVSI, less than 50% stromal invasion, negative lymph nodes) may benefit from omitting RP. Further prospective data are warranted.

Acupuncture for preventing complications after radical hysterectomy: a randomized controlled clinical trial.

We aimed to investigate the preventive effects of acupuncture for complications after radical hysterectomy. A single-center randomized controlled single-blinded trial was performed in a western-style hospital in China. One hundred and twenty patients after radical hysterectomy were randomly allocated to two groups and started acupuncture from sixth postoperative day for five consecutive days. Sanyinjiao (SP6), Shuidao (ST28), and Epangxian III (MS4) were selected with electrical stimulation and Zusanli (ST36) without electrical stimulation for thirty minutes in treatment group. Binao (LI14) was selected as sham acupuncture point without any stimulation in control group. The main outcome measures were bladder function and prevalence of postoperative complications. Compared with control group, treatment group reported significantly improved bladder function in terms of maximal cystometric capacity, first voiding desire, maximal flow rate, residual urine, and bladder compliance, and decreased bladder sensory loss, incontinence, and urinary retention on fifteenth and thirtieth postoperative days. Treatment group showed significant advantage in reduction of urinary tract infection on thirtieth postoperative day. But no significant difference between groups was observed for lymphocyst formation. By improving postoperative bladder function, early intervention of acupuncture may provide a valuable alternative method to prevent bladder dysfunctional disorders and urinary tract infection after radical hysterectomy.