Risk stratification and outcomes in 210 gynecologic perivascular epithelioid cell tumors (PEComas) cases.

OBJECTIVE: To better understand the risk stratification and outcomes of gynecologic PEComas. METHODS: Clinicopathological features and outcomes of gynecologic PEComas cases reported in both English and Chinese literature before September, 2020 were evaluated. The efficacy of three proposed criteria were compared to verify their practicability in gynecologic PEComas. The Chi-square test and Cox proportional hazard model were performed for statistical analysis. RESULTS: A total of 210 cases were retrieved: 95 from English literature and 115 from Chinese literature. The Flope criterion achieved an accuracy of 47% for detecting malignancy of gynecologic PEComas, 64.2% for the Schoolmeester criterion, and 63.8% for the WHO criterion. Both Chi-square test and uni-variate analysis showed that tumor size ≥ 5 cm, infiltrative growth pattern, mitotic rate ≥ 1/50 high per filed (HPF), high nuclear grade and cellularity, necrosis, and vascular invasion were significantly related to recurrence and/or metastasis (R/M) of gynecologic PEComas. Still only high mitotic rate (≥ 1/50 HPF), high nuclear grade and cellularity, and necrosis significantly influenced the long-term survival. Multi-variate analysis showed high nuclear grade and cellularity was an independent risk factor for R/M of gynecologic PEComas. No model was fitted for the death rate due to a small number of events. When defined malignant PEComas cases as meeting three or more out of six clinicopathologic features, the accuracy of such attempt was 62%, but the false-negative rate dropped by 37-55%. CONCLUSIONS: Gynecologic PEComas with three or more high-risk factors may be considered as malignant. Further efforts should be invested to look for new potential prognostic factors.

NONO and tumorigenesis: More than splicing.

The non-POU domain-containing octamer-binding protein NONO/p54nrb , which belongs to the Drosophila behaviour/human splicing (DBHS) family, is a multifunctional nuclear protein rarely functioning alone. Emerging solid evidences showed that NONO engages in almost every step of gene regulation, including but not limited to mRNA splicing, DNA unwinding, transcriptional regulation, nuclear retention of defective RNA and DNA repair. NONO is involved in many biological processes including cell proliferation, apoptosis, migration and DNA damage repair. Dysregulation of NONO has been found in many types of cancer. In this review, we summarize the current and fast-growing knowledge about the regulation of NONO, its biological function and implications in tumorigenesis and cancer progression. Overall, significant findings about the roles of NONO have been made, which might make NONO to be a new biomarker or/and a possible therapeutic target for cancers.

Predictive value of S100A9 for lymph node metastasis in cervical cancer. / S100A9对宫颈癌淋巴结转移的预测价值.

OBJECTIVES: Lymph node metastasis affects the initial treatment strategy for cervical cancer and is hard to be diagnosed in clinical practice.This paper aims to explore the relationship between calcium-binding A9 (S100A9) and lymph node metastasis (LNM) in cervical cancer, and to determine the predictive value of S100A9 for LNM in cervical cancer. METHODS: We performed a retrospective cohort study and collected the pathological data, follow-up data, and paraffin tissue samples of 99 patients with cervical cancer who underwent modified extensive or extensive hysterectomy plus pelvic lymphadenectomy at the Department of Gynecology, Xiangya Hospital, Central South University from January 2013 to December 2018. Immunohistochemistry was used to detect the expression of S100A9 in cervical cancer tissues, and the correlation between S100A9 expression and LNM of cervical cancer, or clinicopathological characteristics were analyzed. The receiver operating characteristic (ROC) curve was used to establish a predictive model for LNM of cervical cancer, and Chi-square test of four-grid table was used to evaluate the diagnostic value of S100A9 for LNM in cervical cancer. RESULTS: The expression of S100A9 was significantly correlated with LNM. The S100A9 immunohistochemical semi-quantitative score of the LNM group was significantly higher than that in the non-lymph node metastasis group (P<0.001). Moreover, the expression of S100A9 was significantly correlated with histological type, stromal invasion, lymphatic vessel invasion, or LNM (P<0.05). The cut-off of the ROC curve for predicting LNM was 5, with the Youden index of 0.649 and the area under the ROC curve of 0.863. The disease-free survival and overall survival in the S100A9 positive group were significantly shorter than those in the negative group (P<0.05). S100A9 alone had a sensitivity of 71.4%, a specificity of 91.5%, and an accuracy of 85.1% for diagnosing LNM. Imaging had a sensitivity of 32.1%, a specificity of 74.6%, and an accuracy of 60.9%. Combination of S100A9 with image examination in parallel test had a sensitivity of 85.7%, a specificity of 71.2%, and an accuracy of 75.9%, while combination of S100A9 and image examination in serial test had a sensitivity of 17.9%, a specificity of 98.3%, and an accuracy of 72.4%. CONCLUSIONS: S100A9 may be associated with LNM in cervical cancer. S100A9 shows a promising perspective in predicting LNM in cervical cancer. Combination of S100A9 and image examination in serial test has a high specificity for LNM.

Combined effects of traffic air pollution and home environmental factors on preterm birth in China.

BACKGROUND: Although mounting evidence have linked traffic-related air pollution (TRAP) with increased risk of preterm birth (PTB), whether it can interact with indoor environmental factors remains unknown, and its window(s) susceptibility at the stage of gestation is unclear. OBJECTIVE: To explore PTB risk for prenatal exposure to traffic-related air pollution and home environmental factors during pregnancy, so as to identify critical window(s) in the combined effect of traffic air pollution and main home environmental factor(s) on PTB development. METHODS: A retrospective cohort study of 3,509 preschool children was performed in Changsha, China during 2011-2012. The PTB prevalence was reported by the parents based on a questionnaire. We estimated each mother's exposure to traffic-related air pollutant NO2 in different windows of gestation, including conception month, three trimesters, birth month, and whole gestation. Maternal exposure to home environmental factors was considered by renovation (new furniture/redecoration) in pregnancy, and mold/damp stains and window condensation during perinatal period. Associations of PTB with both ambient NO2 and home environmental factors, and their interactions on PTB were evaluated by logistic regression models using odds ratio (OR) with 95% confidence interval (CI). RESULTS: Traffic air pollutant NO2 exposure in utero was significantly associated with PTB, with adjusted odds ratio (OR) (95% CI) of 1.41 (1.00-1.98) for an IQR increase in NO2 exposure during whole pregnancy, particularly in the conception month and 1st trimester. We further found a positive relationship between perinatal exposure to mold/damp stains in the homes and PTB, OR (95% CI) = 1.73 (1.04-2.90). Especially, we detected a significant interaction between outdoor NO2 and indoor mold/damp stains on PTB risk. Male and female foetus were respectively more susceptible to perinatal mold/dampness at home and outdoor NO2 exposure in early gestation. CONCLUSION: Our finding indicates that both outdoor traffic air pollutant and indoor mold/dampness play key roles in PTB development, and their interaction effect in early pregnancy significantly increases PTB risk.

[Level of Sorcin expression influences chemoresistance and overall survival in patients with ovarian cancer].

OBJECTIVE: To investigate the correlation between soluble resistance-related calcium-binding protein (Sorcin) and chemoresistance or overall survival in patients with ovarian cancer.
 Methods: We detected the expression of Sorcin in 27 cases of chemoresistant ovarian cancer tissue and 37 cases of sensitive ovarian cancer tissue by immunohistochemistry, and analyzed the relationship between the protein and clinicopathological features or chemoresistance of ovarian cancer. Log-rank test was used to analyze the single factor impact on overall survival, Kaplan-Meier analysis was used to describe survival curve, and Cox proportional hazard model was used for multivariate analysis.
 Results: The immunoreactive scores for Sorcin in chemoresistant ovarian cancer tissues were higher than those in the sensitive ovarian cancer tissues (P<0.001). The levels of Sorcin inovarian cancer tissue did not show statistical significance with different ages, tumor stages, classifications, tissue types, degrees of ascites, omentums, and tumor metastases (P>0.05). The correlation between Sorcin and overall survival in resistant and sensitive ovarian cancer groups was not statistically significant (P>0.05), while there was a negative correlation between the expression of Sorcin and the overall survival of total cases (r=-0.326, P<0.05). Log-rank test showed that the drug resistance factor had a distinct impact on overall survival (P<0.001), and the Sorcin expression had an impact on overall survival (P<0.05). However, correlation between overall survival and the ages, ascites, omentum carcinoma, pathological types, pathological grade or FIGO staging was not significant (P>0.05). Cox proportional hazard model showed that drug resistance had a significant effect on overall survival (P<0.001), with a relative risk at 8.635, and the survival curve of the ovarian cancer sensitive group was obviously superior to that of ovarian cancer drug resistance group.
 Conclusion: Sorcin may be associated with drug resistance in ovarian cancer. The expression of Sorcin is correlated with the overall survival. The lower the Sorcin expression, the longer the survival time. Chemoresistance may act as an important independent prognostic factor for the poor prognosis for ovarian cancer.

WDR79 mediates the proliferation of non-small cell lung cancer cells by regulating the stability of UHRF1.

WD repeat protein 79 (WDR79) is a member of the WD-repeat protein family characterized by the presence of a series of WD-repeat domains and is a scaffold protein that participates in telomerase assembly, Cajal body formation and DNA double strand break repair. Although previous studies have revealed that WDR79 is frequently overexpressed in non-small cell lung cancer (NSCLC) and promotes the proliferation of NSCLC cells, the underlying mechanism responsible for WDR79-mediated NSCLC proliferation is not fully understood. In this study, we report a novel molecular function of WDR79 that mediates NSCLC cell proliferation by controlling the stability of UHRF1. In the nucleus, WDR79 colocalized and interacted with UHRF1. As a result, overexpression of WDR79 stabilized UHRF1, whereas ablation of WDR79 decreased the level of UHRF1. Meanwhile, we showed that WDR79 can protect UHRF1 from poly-ubiquitination-mediated proteolysis, which facilitated the stabilization of UHRF1. We further demonstrated that WDR79 exerts a proliferation effect on NSCLC cells by stabilizing UHRF1. These findings reveal that WDR79 is a novel UHRF1 regulator by maintaining UHRF1 stability, and they also provide a clue as to how to explore WDR79 for potential therapeutic application in NSCLC.

Characterization of a DNA Aptamer for Ovarian Cancer Clinical Tissue Recognition and in Vivo Imaging.

BACKGROUNDS/AIMS: Ovarian cancer is the most lethal gynaecologic malignancy and is difficult to detect early. The inefficient early diagnosis of ovarian cancer is the main contributor to its high mortality rate. Aptamers, as chemical antibodies, are single-stranded DNA or RNA oligonucleotides that target cells or molecules with high affinity. METHODS: Binding ability of R13 was measured by flow cytometry analysis. Stability of R13 was tested in blood serum of an ovarian cancer patient. Internalization of R13 was verified by confocal microscope imaging. 80 cases ovarian cancer tissues, 10 cases normal ovary tissues in a microarray and 6 fallopian tube tissues were prepared for this study. R13's target ability was further confirmed in vivo tumor models in NOD/SCID mice. RESULTS: In this study, we found aptamer R13 bound to ovarian cancer cells with dissociation constants in the nanomolar range. Moreover, these results were further confirmed by tissue imaging. Next we demonstrated that the targets of R13 are membrane proteins and that its internalization occurs in a caveolae-mediated and clathrin-mediated manner. The target function of R13 was determined by imaging A2780 tumours in mouse models. CONCLUSION: These findings suggest that R13 is a promising novel tool to diagnose and deliver drugs to treat ovarian cancer.

[Correlations between the p-Akt-mTOR-p70S6K pathway and clinicopathological features or chemoresistance of ovarian cancer].

OBJECTIVE: To study the relationship between alpha seine/threonine-protein kinase (p-Akt)-serine/threonine-protein kinase (mTOR)-ribosomal protein S6 kinase (p70S6K) signaling pathway and clinicopathological features or chemoresistance of ovarian cancer.
 Methods: We checked the p-Akt, mTOR and p70S6K protein levels in 18 tissues with chemoresistance or 25 with chemosensitivity of ovarian cancer by immunohistochemistry technique, and analyzed the relationship between those proteins and clinicopathological features or chemoresistance of ovarian cancer.
 Results: The levels of p-Akt protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 50.00% and 66.67%, respectively, with no significant difference (P>0.05). The levels of these proteins in well-middle differentiated carcinoma and low differentiated carcinoma were 73.33% and 75.00%, respectively, with no significant difference (P>0.05). The levels of these proteins in I-II stage carcinoma, and III-IV stage carcinoma were 18.18% and 93.75%, respectively, with significant difference (P<0.05). The levels of mTOR protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 77.14%, 100.00% and 83.33%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 80.00% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 27.27% and 96.88%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in ovarian serous carcinoma, mucinous carcinoma and endometrioid carcinoma were 80.00%, 100.00% and 100.00%, respectively, with no significant difference (P>0.05). The levels of this protein in well-middle differentiated carcinoma and low differentiated carcinoma were 93.33% and 78.57%, respectively, with no significant difference (P>0.05). The levels of this protein in I-II stage carcinoma, and III-IV stage carcinoma were 45.45% and 96.88%, respectively, with significant difference (P<0.05). The levels of p-Akt protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 88.89% and 64.00%, respectively, with significant difference (P<0.05). The levels of mTOR protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 94.44% and 68.00%, respectively, with significant difference (P<0.05). The levels of p70S6K protein in tissue of chemoresistance and chemosensitivity of ovarian cancer were 100.00% and 72.00%, respectively, with significant difference (P<0.05).
 Conclusion: The p-Akt-mTOR-p70S6K signaling pathway may take part in invasion and metastasis of ovarian cancer. The up-regulation of these proteins may be associated with the chemoresistance of ovarian cancer, and these proteins may have potential to be the prognostic markers for the chemoresistance of ovarian cancer.

[Opioid µ receptors mediate the stress-induced spatial reference memory impairment].

Learning/memory impairment is one of the most serious problems induced by stress, and the underlying mechanisms remain unclear. Opiates and opioid receptors are implicated in multiple physiological functions including learning and memory. However, there is no clear evidence whether the endogenous opioid system is involved in the formation of the stress-induced spatial reference memory impairment. The aim of the present study was to evaluate the role of µ opioid receptor in the stress-induced spatial reference memory impairment by means of Morris water maze (MWM) test in a mouse elevated platform stress model. The mice were trained in the MWM for four trials a session for 4 consecutive days after receiving the elevated platform stress, and intracerebroventricular injection of µ opioid receptor agonist DAMGO, antagonist CTAP or saline. Retention of the spatial training was assessed 24 h after the last training session with a 60-s free-swim probe trial using a new starting position. The results showed that intracerebroventricular injection of µ opioid receptor agonist DAMGO but not antagonist CTAP before MWM training impaired the memory retrieval of mice. Elevated platform stress before MWM training also impaired memory retrieval, which could be reversed by pre-injection of CTAP, and aggravated by DAMGO. These results suggest that endogenous opioid system may play a crucial role in the formation of the stress-induced memory impairment.

[Expression of Annexin A1 in paclitaxel-resistant ovarian carcinoma and its clinical significance].

OBJECTIVE: To investigate the correlation of Annexin A1 (ANXA1) expression with paclitaxel response and clinicopathological features of ovarian carcinoma. METHODS: The expression levels of ANXA1 in ovarian carcinoma SKOV3/Taxol-25 and SKOV3 cell lines were detected by Western blot and real time-PCR. The expression of ANXA1 protein in 42 specimens of ovarian carcinoma was examined by immunhistochemistry. The correlation of ANXA1 expression with paclitaxel response and clinicopathological features of ovarian carcinoma was analyzed. RESULTS: The expression level of ANXA1 was significantly lower in SKOV3/Taxol-25 cell line than that in SKOV3 cell line (P<0.05). The positive specimens of ANXA1 expression in paclitaxel-resistant tissues (14/20) were significantly lower than those in the sensitive ones (21/22, P<0.05), and there was also a significant difference between the mild and the strong positive specimens (P<0.01). The expression of ANXA1 protein showed no correlation with the type of mophology and histological grade of ovarian cancer (P>0.05), but it was correlated with the clinical stage(P<0.05). CONCLUSION: ANXA1 expression is downregulated in paclitaxel-resistant ovarian carcinoma, which might be a valuable predictor for paclitaxel susceptibility of ovarian carcinoma.

The psychophysiology of Mastermind: Characterizing response times and blinking in a high-stakes television game show.

Television game shows have proven to be a valuable resource for studying human behavior under conditions of high stress and high stakes. However, previous work has focused mostly on choices-ignoring much of the rich visual information that is available on screen. Here, we take a first step to extracting more of this information by investigating the response times and blinking of contestants in the BBC show Mastermind. In Mastermind, contestants answer rapid-fire quiz questions while a camera slowly zooms in on their faces. By labeling contestants' behavior and blinks from 25 episodes, we asked how accuracy, response times, and blinking varied over the course of the game. For accuracy and response times, we tested whether contestants responded more accurately and more slowly after an error-exhibiting the "post-error increase in accuracy" and "post-error slowing" which has been repeatedly observed in the lab. For blinking, we tested whether blink rates varied according to the cognitive demands of the game-decreasing during periods of cognitive load, such as when pondering a response, and increasing at event boundaries in the task, such as the start of a question. In contrast to the lab, evidence for post-error changes in accuracy and response time was weak, with only marginal effects observed. In line with the lab, blinking varied over the course of the game much as we predicted. Overall, our findings demonstrate the potential of extracting dynamic signals from game shows to study the psychophysiology of behavior in the real world.

Spleen Toxicity of Organophosphorus Flame Retardant TDCPP in Mice and the Related Mechanisms.

Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) is an organophosphorus flame retardant that has been utilized in recent years as a primary replacement for polybrominated diphenyl ethers (PBDEs) in a wide variety of fire-sensitive applications. However, the impact of TDCPP on the immune system has not been fully determined. As the largest secondary immune organ in the body, the spleen is considered to be an important study endpoint for determining immune defects in the body. The aim of this study is to investigate the effect of TDCPP toxicity on the spleen and its possible molecular mechanisms. In this study, for 28 consecutive days, TDCPP was administered intragastrically (i.g), and we assessed the general condition of mice by evaluating their 24 h water and food intake. Pathological changes in spleen tissues were also evaluated at the end of the 28-day exposure. To measure the TDCPP-induced inflammatory response in the spleen and its consequences, the expression of the critical players in the NF-κB pathway and mitochondrial apoptosis were detected. Lastly, RNA-seq was performed to identify the crucial signaling pathways of TDCPP-induced splenic injury. The results showed that TDCPP intragastric exposure triggered an inflammatory response in the spleen, likely through activating the NF-κB/IFN-γ/TNF-α/IL-1ß pathway. TDCPP also led to mitochondrial-related apoptosis in the spleen. Further RNA-seq analysis suggested that the TDCPP-mediated immunosuppressive effect is associated with the inhibition of chemokines and the expression of their receptor genes in the cytokine-cytokine receptor interaction pathway, including four genes of the CC subfamily, four genes of the CXC subfamily, and one gene of the C subfamily. Taken together, the present study identifies the sub-chronic splenic toxicity of TDCPP and provides insights on the potential mechanisms of TDCPP-induced splenic injury and immune suppression.

Quantitative proteomic study of human lung squamous carcinoma and normal bronchial epithelial acquired by laser capture microdissection.

OBJECTIVE: To investigate the differential protein profile of human lung squamous carcinoma (HLSC) and normal bronchial epithelium (NBE) and provide preliminary results for further study to explore the carcinogenic mechanism of HLSC. METHODS: Laser capture microdissection (LCM) was used to purify the target cells from 10 pairs of HLSC tissues and their matched NHBE, respectively. A stable-isotope labeled strategy using iTRAQ, followed by 2D-LC/Q-STAR mass spectrometry, was performed to separate and identify the differential expression proteins. RESULTS: A total of 96 differential expression proteins in the LCM-purified HLSC and NBE were identified. Compared with NBE, 49 proteins were upregulated and 47 proteins were downregulated in HLSC. Furthermore, the expression levels of the differential proteins including HSPB1, CKB, SCCA1, S100A8, as well as S100A9 were confirmed by western blot and tissue microarray and were consistent with the results of quantitative proteomics. CONCLUSION: The different expression proteins in HLSC will provide scientific foundation for further study to explore the carcinogenic mechanism of HLSC.

[Preliminary study of the prohibitin protein and paclitaxel resistance in ovarian cancer].

OBJECTIVE: To determine the effect of RNA interference with transferred pshRNA/PHB on the biological characteristics of paclitaxel-resistant ovarian cancer cell lines. METHODS: Western blot and real time-PCR were used to assay the expression of PHB protein and mRNA in SKOV3/Taxol-25 and SKOV3 cell lines. The SKOV3/Taxol-25 cell lines were transiently transfected by 3 target-specific small hairpin RNA (shRNA) interference fragments with fluorescent protein named the pshRNA427/PHB1, pshRNA248/PHB2, and pshRNA136/PHB3. The empty plasmid transfection via vehicle Lipofectamine2000 served as a negative control. The expression levels of PHB protein and mRNA were detected by Western blot and real time-PCR after the transfection for 48 h. The silence effect of PHB1 and PHB3 groups was obvious. PHB1, PHB3, and the negative control groups were used for the following experiments. MTT and flow cytometry assay were used to test the cell proliferation, IC50 of paclitaxel, and cell apoptosis in the 3 groups. RESULTS: The expression levels of PHB protein and mRNA (2(-ΔΔCt)) were significantly higher in SKOV3/Taxol-25 cell line than those in SKOV3 cell line (P<0.05). The expression levels of PHB protein and mRNA were significantly lower in the PHB1 and PHB3 groups than those in the negative control group (P<0.05). The cell proliferations in the PHB1 and PHB3 groups were obviously slower than those in the negative control group after transfection for 48 h and 72 h (P<0.05). The IC50 of paclitaxel in the PHB1 and PHB3 groups significantly decreased after transfection for 72 h compared with the negative control group(P<0.05). The cell apoptotic rate in the PHB1 and PHB3 groups significantly increased after transfection for 48 h compared with the negative control group (P<0.05). CONCLUSION: The shRNA/PHB can effectively suppress the expression of PHB gene in paclitaxel-resistant ovarian cancer cell lines. The cell proliferation in paclitaxel-resistant cell lines with removed PHB gene is significantly reduced. The apoptotic rate and the paclitaxel sensitivity of resistant cell lines with removed PHB gene are significantly increased. PHB gene is related to paclitaxel-resistance and interfering PHB gene expression may reduce paclitaxel resistance in ovarian cancer.

Lateral Flow Strip Assay for Detection of Mycoplasma hyorhinis Based on a Pair of Sandwich-Type Aptamers.

Mycoplasma hyorhinis is a normal flora in swine respiratory tract and also often found in multiple human tumor tissues, which is considered to be highly correlated with human tumors. Due to the detection of Mycoplasma hyorhinis mainly relies on PCR-based assay at present, thus it is critical for developing a novel assay for rapid detection and providing support diagnosis evidence. In our work, we screened and characterized a high affinity aptamer zyb1 that can recognize Mycoplasma hyorhinis based on infectious cell-SELEX. On this basis, we developed a lateral flow strip assay by using zyb1 and another aptamer AP15-1 to form a sandwich-type aptasensor. Using this new lateral flow strip assay biosensor, Mycoplasma hyorhinis could be detected within the detectable limit as low as 1 × 10³ CCU/mL. Therefore, our study successfully developed a convenient and effective lateral flow strip for Mycoplasma hyorhinis detection and demonstrated the potential of utilizing aptamer for the development of point-of-care testing products for mycoplasma detection.

Effect of Apatinib Plus Pegylated Liposomal Doxorubicin vs Pegylated Liposomal Doxorubicin Alone on Platinum-Resistant Recurrent Ovarian Cancer: The APPROVE Randomized Clinical Trial.

Importance: There are substantial unmet therapeutic needs in patients with platinum-resistant recurrent ovarian cancer (PROC), and novel therapeutic strategies should be explored. Objective: To evaluate the efficacy and safety of treatment with apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) plus pegylated liposomal doxorubicin (PLD) for PROC. Design, Setting, and Participants: The APPROVE trial was performed as an open-label, randomized clinical trial at 11 hospitals in China between March 22, 2018, and November 16, 2020. Patients with histologically confirmed ovarian cancer who had experienced disease progression during or within 6 months of discontinuing any prior line of treatment with platinum-based chemotherapy were eligible. This primary analysis was based on data that were current as of January 28, 2021. Interventions: Patients received PLD alone (40 mg/m2, intravenously, every 4 weeks, for up to 6 cycles) or PLD plus apatinib (250 mg, orally, daily). Main Outcomes and Measures: The primary end point was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumours (RECIST), version 1.1, in the intent-to-treat population. Results: In total, 152 female patients were randomized, with 78 (51.3%) in the apatinib plus PLD group (median age, 54 years; range, 22-76 years) and 74 (48.7%) in the PLD group (median age, 56 years; range, 33-72 years). The median follow-up duration was 8.7 months (IQR, 4.7-14.1 months). The median PFS was 5.8 months (95% CI, 3.8-8.8) for treatment with apatinib plus PLD vs 3.3 months (95% CI, 2.1-3.8) for PLD (hazard ratio, 0.44; 95% CI, 0.28-0.71; P < .001). The median overall survival was 23.0 months (95% CI, 18.9 to not reached) with treatment with apatinib plus PLD vs 14.4 months (95% CI, 12.1-23.4) with PLD (hazard ratio, 0.66; 95% CI, 0.40-1.09). The most frequent grade 3 or higher treatment-emergent adverse events were decreased neutrophil counts (11 [14.9%] in the apatinib plus PLD group vs 6 [8.3%] in the PLD group), hypertension (6 [8.1%] vs none), and decreased white blood cell count (5 [6.8%] vs 3 [4.2%]). Two patients receiving treatment with apatinib plus PLD experienced grade 2 fistulas. Conclusions and Relevance: This randomized clinical trial found that treatment with apatinib plus PLD showed promising efficacy and manageable toxic effects in patients with PROC and may be a new alternative treatment option in this setting. Trial Registration: Clinicaltrials.gov Identifier: NCT04348032.

ERK-mediated Cytoplasmic Retention of USP11 Contributes to Breast Cancer Cell Proliferation by Stabilizing Cytoplasmic p21.

Breast cancer ranks as the most frequently diagnosed cancer among women worldwide. Elevated cytoplasmic p21 levels are often found in breast cancer tissues and related to a poor prognosis. However, the underlying mechanisms that lead to the stabilization of cytoplasmic p21 protein, which normally has a very short half-life, remain obscure. In this study, we found that there was a strong correlation between p21 and USP11 in the cytoplasm of breast cancer tissues and cells. Furthermore, we revealed that ERK1/2 phosphorylated USP11 at the Ser905 site, which promoted the cytoplasmic localization of USP11. In the cytoplasm, USP11 colocalized and interacted with p21. As a result, USP11 catalyzed the removal of polyubiquitin chains bound to cytoplasmic p21 and resulted in its stabilization. Functionally, USP11-mediated stabilization of cytoplasmic p21 induced breast cancer cell proliferation in vitro and in vivo. Our findings provide the first evidence that ubiquitinated p21 in the cytoplasm can be recycled through USP11-mediated deubiquitination, and we identified the USP11-p21 axis in the cytoplasm as a potential therapeutic target for breast cancer control.

The relationship of haplotype in lactotransferrin and its expression levels in Chinese Han ovarian cancer.

Chromosomal DNA sequence polymorphisms may contribute to individuality, confer risk for diseases, and most commonly are used as genetic markers in association study. The iron-binding protein lactoferrin inhibits bacterial growth by sequestering essential iron and also exhibits antitumor, anti-inflammatory, and immunoregulatory activities. The gene coding for lactotransferrin (LTF) is polymorphic, with the occurrence of several common alleles in the general population. This genetically determined variation can affect LTF functions. In this study, we determined the distribution of LTF gene polymorphisms (rs1126477, rs1126478, rs2073495, and rs9110) in the Chinese Han population and investigated whether these polymorphisms were associated with increased risk of ovarian carcinoma in the Chinese. It was found that the rs1126477 was correlated significantly with ovarian cancer. The frequency of A allele of rs1126477 was significantly higher in 700 ovarian cancer patients compared with that in the control group of 700 cases (P< 0.01, χ(2)= 6.79). The frequency of AA genotype was significantly higher in ovarian cancer patients compared with that in the control group (P< 0.05, χ(2)= 6.49). AA genotype is the risk factor of ovarian cancer. The odds ratio (OR) was 2.24 and the 95% confidence interval (CI) was 1.08-4.59, respectively. The 'A-G-C-C' haplotype constructed with rs1126477, rs1126478, rs2073495, and rs9110 was the risk factor to be ovarian cancer. The expression of LTF gene was lower in individuals with 'A-G-C-C' haplotype compared with that in individuals without 'A-G-C-C' haplotype. These findings suggested that rs1126477 could play important roles in ovarian carcinoma physiological processes in the Chinese.

[Expression of EVEC in ovarian carcinoma and its biological significance].

OBJECTIVE: To investigate the expression of EVEC in ovarian carcinoma and explore its biological significance. METHODS: The expression of EVEC in 22 specimens of normal ovarian tissues and 63 specimens of ovarian cancers was detected by RT-PCR and Western blotting analysis, respectively. RESULTS: RT-PCR showed that the expression level of EVEC in stage I-II ovarian cancer (0.199 ± 0.014) was significantly higher than that in stage III-IV ovarian cancer (0.155 ± 0.015, P < 0.05), and significantly lower than that in normal ovarian tissues (0.415 ± 0.055, P < 0.05). There was no significant difference between the expression levels of EVEC in primary sites and that in corresponding metastatic sites of ovarian cancer (P > 0.05). Furthermore, the results of Western blot also showed that the protein expression level of EVEC in stage I-II ovarian cancer was also significantly lower than that in normal ovarian tissues (0.179 ± 0.026 vs. 0.543 ± 0.032, P < 0.05), and higher than that in stage III-IV ovarian cancer (0.179 ± 0.026 vs. 0.115 ± 0.023, P < 0.05). The EVEC expression level in the epiploic metastasis of stage I-II ovarian cancer was significantly higher than that of stage III-IV ovarian cancer (0.201 ± 0.028 vs. 0.101 ± 0.037, P < 0.05). The expression of EVEC in ovarian carcinoma had no correlation with age, pathologic classification and histological grade (P > 0.05). CONCLUSIONS: EVEC is closely related with carcinoma metastasis. The expression of EVEC in ovarian cancer and its metastatic sites was remarkably decreased. EVEC may play a negative role in the development and metastasis of ovarian cancer and may be a valuable marker in estimation of the prognosis for patients.

[Clinical features and prognosis of cervical cancer in young women].

OBJECTIVE: To investigate the prevalence, etiology, clinical presentation and pathological features, treatment and prognosis of cervical cancer in young women. METHODS: Clinical data of 132 young women with cervical cancer were reviewed. RESULTS: Positive rate of human papillomavirus 18 was high in young women with cervical cancer. The primary clinical presentation of young patients with cervical cancer was contact bleeding of vagina, and the signs were out-expanding of cervical mass. The percentage of adenocarcinoma increased. The main treatment for cervical cancer was surgery. The patients had radical hysterectomy plus ovarian transplantation, none of whom had ovarian metastases and menopause syndrome. Prognosis of most patients was good. CONCLUSION: Contact bleeding is a significant symptom in young women with cervical cancer. Surgery is first considered in the treatment. Preoperative neoadjuvant chemotherapy can be used in patients with locally advanced and late stage cervical cancer. Ovarian transplantation during operation can retain the ovary function.