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Mo Tang,1 Lihao Gao,2 Bin He,1 Yufei Yang1 1Oncology Department, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 2Smart City Business Unit, Baidu Inc., Beijing, People’s Republic of ChinaCorrespondence: Yufei YangXiyuan Hospital of China Academy of Chinese Medical Sciences, No. 1 Xiyuan Caochang Road, Haidian District, Beijing, 100091, People’s Republic of ChinaEmail yyf93@vip.sina.comLihao GaoSmart City Business Unit, Baidu Inc., No. 51 Dezhen Road, Haidian District, Beijing, 100091, People’s Republic of ChinaEmail gaolihao@baidu.comPurpose: The present study aimed to develop prognostic prediction models based on machine learning (ML) for non-metastatic colon cancer (CRC), which can provide a precise quantitative risk assessment and serve as an assistive method for treatment strategy development. The possibility of improving prediction accuracy using nonlinear methods compared to linear methods was investigated.Patients and Methods: A cancer-specific survival (CSS) model constructed using logistic regression, extreme gradient boosting (XGBoost), and random forest algorithms was trained on the Surveillance, Epidemiology, and End Results datasets for 15,254 patients with non-metastatic CRC (split into training [70%] and internal validation [30%] datasets) and externally validated with an outpatient cohort of 311 cases from Xiyuan Hospital in China. A Chinese cohort was also used to develop recurrence and metastasis (R&M) models for CRC patients. The experiments for each model were performed 100 times to obtain average scores and 95% confidence intervals. The model performance was evaluated using the area under the receiver operating characteristic curve (AUC) values.Results: The XGBoost approach showed the highest AUC values of 0.86 (0.84– 0.88), 0.82 (0.81– 0.83), and 0.81 (0.79– 0.82) for one-, three-, and five-year CSS cohorts, respectively, along with a relatively high generalization ability. The XGBoost approach also performed best for the R&M model, with the AUC values of 0.71 (0.64– 0.79), 0.79 (0.74– 0.86), and 0.89 (0.82– 0.95) for one-, three-, and five-year R&M cohorts, respectively. The rankings of predictor importance for the CSS and R&M models were different, and the higher model accuracy was associated with more prognostic predictors.Conclusion: Three different ML algorithms for developing prognostic prediction models for non-metastatic CRC were compared. The predictive performance results showed that the nonlinear XGBoost approach performed best, suggesting that it can be used for quantifying the prognostic risk. It was also demonstrated that the model performance can be improved when more prognostic predictors are considered.Keywords: colon cancer, machine learning, extreme gradient boosting, prognostic prediction models more...

Background CD109 was involved in the tumorigenesis and progression of various cancers via TGF-β1 signalling and STAT3 activation. As CD109 is strongly expressed in cervical squamous cell carcinoma, this study was conducted to investigate its functional characteristics in cervical cancer. Methods CD109 expression was examined by immunohistochemistry (IHC) with cervical tissue microarray. The effects of CD109 expression were examined on migration, cell proliferation, spheroid formation and soft-agar colony-formation assay. Meanwhile, cervical cancer cell lines with high CD109 expression were chosen for the functional study using siRNA knockdown and CRISPR/Cas9 knockout. Results IHC demonstrated an upregulation of CD109 in the cell membrane of cervical squamous cell carcinoma. CD109( + ) cells isolated by flow-cytometric sorting displayed enhanced migration, cell proliferation, sphere-forming and anchorage-independent cell growth ability. In contrast, silencing of CD109 expression could reverse the in vitro and in vivo tumorigenic and aggressive properties. Furthermore, CD109 induced EGFR-mediated STAT3 phosphorylation known to be responsible for cell migration, proliferation and maintenance of CSC phenotype. Conclusion Abundant CD109( + ) populations in cervical cancer cells potentially contributed to carcinogenesis and aggressiveness, whereas silencing of CD109 expression could reverse those properties. CD109 mediates cervical tumorigenicity and aggressiveness via CD109/EGFR/STAT3 signalling. more...

Background Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. Methods Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. Results We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH−CD44– subsets exerted the opposite effects. Conclusion Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management. more...

Supplementary Material 1. The comparison of baseline characteristics between participants in and out of the study

Supplemental material, sj-doc-2-ict-10.1177_15347354211058169 for Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis by Mo Tang, Bin He, Jiawei Zhai and Lei Wang in Integrative Cancer Therapies more...

Supplemental material, sj-doc-5-ict-10.1177_15347354211058169 for Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis by Mo Tang, Bin He, Jiawei Zhai and Lei Wang in Integrative Cancer Therapies more...

Supplemental material, sj-doc-4-ict-10.1177_15347354211058169 for Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis by Mo Tang, Bin He, Jiawei Zhai and Lei Wang in Integrative Cancer Therapies more...

Supplemental material, sj-doc-1-ict-10.1177_15347354211058169 for Oral Chinese Patent Medicine Combined With Oxaliplatin-Based Chemotherapy Regimen for the Treatment of Colorectal Cancer: A Network Meta-Analysis by Mo Tang, Bin He, Jiawei Zhai and Lei Wang in Integrative Cancer Therapies more...

AIM The aim of the present study was to investigate the safety and efficacy of low-dose mifepristone combined with self-administered misoprostol for termination of early pregnancy. METHODS A total of 533 women seeking medical abortion in early pregnancy (≤49 days since the last menstrual period) were divided randomly into hospital- (H-Mis, 250) and self- (S-Mis, 283) administered misoprostol groups. Women in two groups took 100 mg of oral mifepristone in hospital followed by 200 μg of sublingual misoprostol 24 h later in hospital or home. The primary outcome parameter was complete abortion without surgical intervention. Secondary outcomes were uterine bleeding, return of regular menses, side effects and patient acceptability. RESULTS High rates of complete abortion were observed for both the H-Mis group (243/250; 94.8%) and the S-Mis group (266/283; 94.0%). No significant differences in outcomes (complete abortion/failure rates) or side effects were observed between the two groups. General satisfaction rates were similar for the two groups (H-Mis, 231/250, 92.4%; S-Mis, 263/283, 92.9%; P > 0.05). Higher convenience of administration (H-Mis, 211/250, 84.4%; S-Mis, 270/283, 95.4%; P < 0.05) and privacy protection (H-Mis, 214/250, 85.6%; S-Mis, 267/283, 94.3%; P < 0.05) satisfaction rates were obtained for the S-Mis group than for the H-Mis group. CONCLUSION Self-administered sublingual misoprostol is as safe and effective as hospital-administered misoprostol following low-dose mifepristone to terminate early pregnancy (≤49 days of amenorrhoea) with fewer side effects. more...

Simple Summary Nuclear receptor related-1 protein (Nurr1) emerges as a therapeutic target in multiple malignancies and immunotherapies. Previous studies have highlighted its association with clinicopathological parameters, tumorigenesis and therapeutic resistance in cancers. In addition, recent studies unraveled its contribution to the suppression of antitumor immunity, suggesting that inhibition of Nurr1 is a potential method to repress cancer aggressiveness and disrupt tumor immune tolerance. In line with this evidence, the present review provides the roles of Nurr1 in tumor progression and the associated underlying molecular mechanisms. Moreover, the significance of Nurr1 in promoting immune tolerance and potential strategies for Nurr1 inhibition are highlighted. Abstract Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy. more...

Introduction: Cervical cancer is a common genital tract cancer. Although abundant screening and vaccination are beneficial for reducing the disease burden, the molecular mechanism underlying tumorigenicity and aggressiveness are not fully understood. Human papillomavirus (HPV) E6 protein was found to be responsible in the development of cervical cancer. Membrane complement regulatory proteins (mCRP), such as CD46, CD55, CD59, control complement activation on the surface of tumour cells and suggested to be important in contributing tumorigenesis in various types of cancers. In our recent study, we have reported that HPV E6 protein enriches the expression of CD55 in cervical cancer cells, which would further promote radio-resistance and cancer aggressiveness. In the present study, we would characterize the functional role of other two mCRPs CD46 and CD59 in contributing cervical carcinogenesis. We would further examine if triple knockout of CD46, CD55, CD59 would have synergistic effect on blockage of tumorigenesis in cervical cancer. Material and method: Flow cytometry was performed to analyse the expression level of CD46, CD55 and CD59 in cervical cell lines C33A, C4-1, CaSki, SiHa, and a HPV18-E6-overexpressing stable clone (18E6-5, origin C33A cells). In order to investigate the effect on the blockage of those mCRPs, 18E6-5 clone with high CD46, CD55 and CD59 expression were chosen for in vitro functional study using and CRISPR/Cas9 knockout. Results and discussion: The percentage of CD46(+), CD55(+) and CD59(+) cells were high in C4-1, CaSki, SiHa and 18E6-5 lines. The C33A cells demonstrate a low CD55(+) subpopulation while high CD46(+) and CD59(+) subpopulations. We found that single knockout of CD46 or CD59 supressed cell proliferation, sphere-forming, anchorage-independent cell growth capability, and sensitized cells to radiation treatment. In addition, triple knockout of CD46, CD55, CD59 remarkably inhibited those effects comparing with the effects of single and double knockout. Conclusion: Silencing of CD46, CD55, CD59 expression abolished the tumorigenic, radio-resistant and aggressive effects in cervical cancer cells, with triple knockout displayed the highest blockage effects. Those mCRPs would be responsible for tumorigenicity, radio-resistance and cancer aggressiveness in cervical cancer. Citation Format: Xuetang Mo, Thomas Ho-Yin Leung, Michelle Kwan-Yee Siu, Hextan Yuen-Sheung Ngan. Elucidating the potential role of membrane complement regulatory proteins (CD46, CD55, CD59) in tumorigenesis of cervical cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3816. more...

Introduction Cervical cancer is a common genital tract cancer. Radiotherapy is the mainstay of management for advanced cervical cancer. Response to radiation varies widely which may be explained by the existence of cancer stem-like cells (CSCs). Since CSCs is implicated in cervical cancer and demonstrated a high degree of resistance to radiation, the identification of novel CSC markers could be critical to specifically target the cervical CSC. In our pilot study, we established attached and spheroid cells from primary cervical tumour tissue. Multiple ‘stemness’ genes were detected in spheroid cells which indicated primary cervical cancer tissue harboured CSCs population. cDNA microarray analysis was performed to compare cDNA expression profile and CD109 was significantly up-regulated in spheroid cells. Therefore, we hypothesise that CD109 may serve as a potential cervical CSCs marker. Material and methods Flow cytometry was performed to analyse the CD109 expression and isolate the CD109 positive and negative sub-populations in cervical cancer cells. Following the sorting, cell proliferation and migration assay were performed. In order to investigate the effect on the blockade of CD109, SiHa, Caski and C4-1 cells were transfected with CD109 siRNAs. XTT assay, migration and invasion assay and spheroid formation assay were performed. Immunohistochemistry (IHC) was performed for the detection of CD109 expression in cervical cancer tissue microarray (TMA). Results and discussions The post-sorted CD109 (+) cells grew remarkably faster and have stronger migration capability than CD109(-) cells in Caski and C4-1. The CD109 knockdown cells with siRNA exhibited a slower cell growth, decreasing migration and self-renewal ability, as compared with the control group in SiHa, Caski and C4-1 cells. IHC of TMA indicated that CD109 was highly expressed in cancer cases than that in normal/benign cases. Conclusion CD109 increased cell proliferation rate and migration ability in post-sorted cervical cancer cell lines Caski and C4-1. On the contrary, CD109 knockdown reduced cell growth, migration and self-renewal capability in cervical cancer SiHa, Caski and C4-1 cells. Cervical carcinoma showed high expression of CD109 protein by IHC. Further in vivo and in vitro functional assays are essential to characterise the CD109-positive sub-population in cervical cancer which may provide more information of cervical CSCs-related properties and resistance of radiation therapy, with the underlying molecular mechanism involved. more...

Tropidia namasiae C. K. Liao, T. P. Lin & M. S. Tang, a new species of Tropidia Lindl. (Orchidaceae, Epidendroideae, Tropidieae) from the Namasia District in southwestern Taiwan, is described and illustrated. The species is mainly characterized by its subopposite and ovate to lanceolate leaves and dorsal sepals (3.5–4 mm), the smallest observed among species of Tropidia in Taiwan. The new species is closely related to T. angustifolia C. L. Yeh & C. S. Leou, but differs in leaf shape, size, and number as well as the number of flowers per raceme. Morphological similarities between these two species can be seen in the shapes of the floral lip and column, as well as lengths of the leaf blades. A key to the six species of Tropidia in Taiwan is also provided. more...

The results of a dissolution kinetics study of smithsonite ore in ammonium chloride are presented. Effect of stirring speed, ore particle size, reaction temperature, and the concentration of ammonium chloride on zinc dissolution rate are determined. The results obtained show that leaching of about 91.2% of zinc is achieved using 84–110 μm ore particle size at a reaction temperature of 90 °C for 240 min reaction time with 5 mol/L ammonium chloride. The solid/liquid ratio was maintained constant at 1:10 g/mL. Leaching kinetics indicates that chemical reaction at the new particle surface and the diffusion through the inert particle pores together are the rate control steps. A corresponding mixed control model is found suitable to explain the relationship between the reaction time and the fraction of zinc leached. The apparent activation energy of this process is determined to be 21.3 kJ/mol. more...

Study question What is the efficacy of maintaining or restoring non-pregnant status with low-dose mifepristone combined with misoprostol administered before expected menstruation? Summary answer Low-dose mifepristone and misoprostol administered at the time of expected menstruation was effective and safe in maintaining or restoring non-pregnant status, with no obvious menstrual disturbance. What is known already Menstrual regulation involves the medical or mechanical stimulation of uterine sloughing in women with up to 2-3 weeks of menstrual delay. Low-dose mifepristone plus misoprostol is efficacious for termination of ultra-early pregnancy (≤ 35 days of amenorrhoea) with no obvious menstrual disturbance. Study design, size, duration A total of 678 women fulfilled all criteria and were recruited. Seventeen women dropped out after deciding to remain pregnant and 11 others were lost to follow-up. Thus, data from 650 women who completed the procedure were included in analyses. Participants were enrolled at any time during their menstrual cycle and administered medication 1 day before expected menstruation. The end of the study was defined on a per-patient basis as the date of completion of the post-treatment menstrual cycle. The primary outcome was the efficacy of abortion induction (for pregnant women) or menstrual regulation (for non-pregnant women). Participants, setting, methods Women with regular menstrual cycles (25-35 days) were voluntarily recruited for this study between February 2012 and December 2014. Serum β-hCG was measured before mifepristone intake. Mifepristone (50 mg) was administered orally 1 day before expected menstruation and 200 µg misoprostol was administered orally on the day of expected menstruation. Efficacy, disturbance in bleeding patterns in the treatment and post-treatment cycles, satisfaction with the treatment, and subsequent contraception preference were analysed. Main results and the role of chance Retrospective analysis of serum β-hCG levels at admission indicated that 23.3% (158/678) of the women were pregnant. The success rate for pregnancy termination was 98.6% (136/138). Two women (1.5%, 2/138) had ongoing pregnancy that was subsequently terminated surgically. The overall bleeding induction rate within 7 days was 98.3% (639/650), with 100% (138/138) in pregnant participants and 97.9% (501/512) in non-pregnant participants. Most pregnant and non-pregnant participants experienced no significant menstrual disturbance during the treatment [96.3% (131/136) versus 97.6% (489/501)] or post-treatment [97.8% (133/136) versus 98.4% (493/501)] menstrual cycle. The general rate of satisfaction with the treatment was 96.7% (618/639). Generally, 36.0% (230/639) of participants preferred to use the regimen as a routine contraception method versus the 64.0% (409/639) who preferred to use it as a remedy for pregnancy prevention after unprotected sex (P Limitations, reasons for caution Study participants were recruited from a single region; further studies should include participants from multiple centres in different cities and nations. Given the uncertain efficacy of regimen reuse, the assessment of efficacy was based solely on the first treatment administration. Studies with larger samples and long-term follow-up may provide more data on whether repeated use of this regimen hampers its efficacy. Wider implications of the findings Menstrual regulation with low-dose mifepristone and misoprostol at expected menstruation can be efficacious and highly acceptable to maintain or restore non-pregnant status, which may have potential for routine contraception. more...