Role of protein tyrosine phosphatase receptor type M in epithelial ovarian cancer progression.

BACKGROUND: Epithelial ovarian cancer (EOC) is often diagnosed at advanced stages with low survival rates. Protein tyrosine phosphatase receptor type M (PTPRM) is involved in cancer development and progression; however, its role in EOC remains unclear. In this study,we aimed to detect PTPRM expression in ovarian epithelial tumors, analyze its relationship with the clinicopathological features and survival prognosis of patients with EOC, and provide a theoretical basis for new targets for EOC treatment. Fifty-seven patients with EOC treated at our hospital between January 2012-January 2014 were included; along with 18 borderline and 30 benign epithelial ovarian tumors and 15 normal ovarian and uterine tube tissue samples from patients surgically treated at our hospital during the same period. PTPRM expression was immunohistochemically detected, and we analyzed its relationship with clinicopathological features and prognosis. Associations between PTPRM expression and survival prognosis of patients with EOC were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan-Meier Plotter databases. RESULTS: PTPRM had the highest expression rates in normal ovarian and uterine tube tissues, followed by benign and borderline epithelial ovarian tumors; the lowest positive expression rate was observed in EOC tumors. PTPRM expression differed significantly among groups (P < 0.05). The positive PTPRM expression rate significantly decreased with age, progressing clinical stage, and tumor recurrence, and the larger the mass diameter, the higher the positive PTPRM expression rate. PTPRM expression was significantly lower in ovarian cancer compared with that in normal tissues in the GEPIA database (P < 0.05). The overall survival (OS) and disease-free survival(DFS) rates were higher in the PTPRM high-expression group, with statistically significant (P < 0.05) and insignificant (P > 0.05) differences, respectively. The OS rate of the high-expression group compared with the low-expression group in the Kaplan-Meier Plotter database was higher, although without statistical significance (P > 0.05), and progression-free survival(PFS) was higher with statistical significance (P < 0.05). CONCLUSION: PTPRM expression was low in patients with EOC, and the PTPRM positive-expression rate significantly decreased with progressing stages of EOC and tumor recurrence, suggesting that PTPRM acts as a tumor suppressor in EOC progression. Negative PTPRM expression may predict poor clinical outcomes in patients with EOC.

Peutz-Jeghers syndrome with gastric-type mucinous endocervical adenocarcinoma and sex-cord tumor with annular tubules: A case report.

Peutz-Jeghers syndrome (PJS) is a rare autosomal dominant genetic disorder characterized by mucocutaneous pigmentation and multiple hamartomatous polyps in the gastrointestinal tracts. About 11% of female PJS patients are diagnosed with Gastric-type endocervical adenocarcinoma (G-EAC) and about one third have a sex-cord tumor with annular tubules (SCTATs). Gastric-type endocervical adenocarcinoma is a special subtype of cervical adenocarcinoma which accounts for only 1-3%. Here we report a rare case of a 31-year-old woman affected with G-EAC and SCTAT accompanied by PJS. After surgery, we followed up for 5 years without recurrence.

Panguiarchaeum symbiosum, a potential hyperthermophilic symbiont in the TACK superphylum.

The biology of Korarchaeia remains elusive due to the lack of genome representatives. Here, we reconstruct 10 closely related metagenome-assembled genomes from hot spring habitats and place them into a single species, proposed herein as Panguiarchaeum symbiosum. Functional investigation suggests that Panguiarchaeum symbiosum is strictly anaerobic and grows exclusively in thermal habitats by fermenting peptides coupled with sulfide and hydrogen production to dispose of electrons. Due to its inability to biosynthesize archaeal membranes, amino acids, and purines, this species likely exists in a symbiotic lifestyle similar to DPANN archaea. Population metagenomics and metatranscriptomic analyses demonstrated that genes associated with amino acid/peptide uptake and cell attachment exhibited positive selection and were highly expressed, supporting the proposed proteolytic catabolism and symbiotic lifestyle. Our study sheds light on the metabolism, evolution, and potential symbiotic lifestyle of Panguiarchaeum symbiosum, which may be a unique host-dependent archaeon within the TACK superphylum.

Preoperative individual-target transcranial magnetic stimulation demonstrates an effect comparable to intraoperative direct electrical stimulation in language-eloquent glioma mapping and improves postsurgical outcome: A retrospective fiber-tracking and electromagnetic simulation study.

Background: Efforts to resection of glioma lesions located in brain-eloquent areas must balance the extent of resection (EOR) and functional preservation. Currently, intraoperative direct electrical stimulation (DES) is the gold standard for achieving the maximum EOR while preserving as much functionality as possible. However, intraoperative DES inevitably involves risks of infection and epilepsy. The aim of this study was to verify the reliability of individual-target transcranial magnetic stimulation (IT-TMS) in preoperative mapping relative to DES and evaluate its effectiveness based on postsurgical outcomes. Methods: Sixteen language-eloquent glioma patients were enrolled. Nine of them underwent preoperative nTMS mapping (n=9, nTMS group), and the other seven were assigned to the non-nTMS group and did not undergo preoperative nTMS mapping (n=7). Before surgery, online IT-TMS was performed during a language task in the nTMS group. Sites in the cortex at which this task was disturbed in three consecutive trials were recorded and regarded as positive and designated nTMS hotspots (HSnTMS). Both groups then underwent awake surgery and intraoperative DES mapping. DES hotspots (HSDES) were also determined in a manner analogous to HSnTMS. The spatial distribution of HSnTMS and HSDES in the nTMS group was recorded, registered in a single brain template, and compared. The center of gravity (CoG) of HSnTMS (HSnTMS-CoG)-based and HSDES-CoG-based diffusion tensor imaging-fiber tracking (DTI-FT) was performed. The electromagnetic simulation was conducted, and the values were then compared between the nTMS and DES groups, as were the Western Aphasia Battery (WAB) scale and fiber-tracking values. Results: HSnTMS and HSDES showed similar distributions (mean distance 6.32 ± 2.6 mm, distance range 2.2-9.3 mm, 95% CI 3.9-8.7 mm). A higher fractional anisotropy (FA) value in nTMS mapping (P=0.0373) and an analogous fiber tract length (P=0.2290) were observed. A similar distribution of the electric field within the brain tissues induced by nTMS and DES was noted. Compared with the non-nTMS group, the integration of nTMS led to a significant improvement in language performance (WAB scores averaging 78.4 in the nTMS group compared with 59.5 in the non-nTMS group, P=0.0321 < 0.05) as well as in brain-structure preservation (FA value, P=0.0156; tract length, P=0.0166). Conclusion: Preoperative IT-TMS provides data equally crucial to DES and thus facilitates precise brain mapping and the preservation of linguistic function.

Circ TYMP1 Inhibits Carcinogenesis and Cisplatin Resistance in Ovarian Cancer by Reducing Smad2/3 Phosphorylation via a MicroRNA-182A-3p/TGF1B Axis.

TYMP1 is a cancer driver in several human malignancies. However, its significance in ovarian cancer (ovarian carcinoma) remains uncertain. This research aims to understand the TYMP1's role in ovarian carcinoma carcinogenesis and cisplatin (DDP) resistance and its molecular ovarian marchionesses. Circ TYMP1 overexpression in ovarian carcinoma samples led to an accelerated tumor stage. Bioinformatics identified miR-182A-3p as the TYMP1's target transcript. Circ TYMP1 functioned as a sponge for miR-182A-3p, lowering its inhibitory effect on TGF1B. Downregulating circ TYMP1 decreased A2780-Res cell proliferation, invasion, and death resistance. Malignant ovarian carcinoma cells recovered following miR-182A-3p downregulation. TGF1B overexpression boosted A2780-Res cell proliferation, aggression, and cisplatin resistance while reducing Smad2/3 phosphorylation. TYMP1 sequesters miR-182A-3p and promotes TGF1B in ovarian carcinoma, boosting carcinogenesis and cisplatin resistance. This might lead to novel ovarian carcinoma treatments.

Efficacy and Safety of Anlotinib Combined with PD-1 Blockades for Patients with Previously Treated Epithelial Ovarian Cancer: A Retrospective Study.

Purpose: This study was to investigate the efficacy and safety of anlotinib combined with programmed cell death protein 1 (PD-1) blockades for patients with previously treated advanced epithelial ovarian cancer (EOC). Patients and Methods: Present study was designed as a retrospective study, a total of 32 patients with advanced EOC who progressed after at least two lines previously available standard therapy were included in this study. All the patients were administered with anlotinib combined with PD-1 blockades administration. Clinical activity was implemented and analyzed, which was assessed according to the change of target lesion by imaging evidence and all the subjects were followed up regularly. Safety profile were collected and documented during the treatment. Univariate analysis was carried out using log rank test and multivariate analysis were adjusted by Cox regression analysis. Results: The best overall response suggested that partial response was noted in 12 patients, stable disease was observed in 14 patients, progressive disease was found in 6 patients. Therefore, the objective response rate (ORR) of the 32 patients was 37.5% (95% CI: 21.1-56.3%), disease control rate (DCR) of the patients was 81.3% (95% CI: 63.6-92.8%). The median follow-up duration of this study was 17.5 months (follow-up range: 0.9-33.5 months). And the median PFS and OS of the 32-patient cohort was 6.8 months (95% CI: 2.64-10.96) and 18.5 months (95% CI: 14.08-22.92), respectively. The most common treatment-related adverse reactions were fatigue (68.8%), nausea and vomiting (56.3%), hypertension (50.0%) and diarrhea (40.6%). Multivariate Cox regression analysis for PFS indicated that ECOG performance status and FIGO stage were independent factors to predict PFS of patients with previously treated EOC. Conclusion: Anlotinib combined with PD-1 blockades demonstrated promising efficacy and tolerable safety profile for patients with previously treated advanced EOC preliminarily. The conclusion should be confirmed in more patients with advanced EOC subsequently.

A Successfully Treated Multiple Metastatic Choriocarcinoma Coexistent With Live Fetus: A Case Report and Literature Review.

Management of metastatic choriocarcinoma coexistent with live fetus is tricky for gynecologists. There is no consensus on treatment because of its rarity. We present a unique case of gestational choriocarcinoma with multiple metastases, who received EP chemotherapy in the third trimester. At 31 + 5 weeks, a healthy male baby was delivered by cesarean section. Then, she received six cycles of EMA/CO as postpartum chemotherapy. Her beta-human chorionic gonadotropin (ß-hCG) level decreased to the normal range, and the metastases vanished. The patient had no clinical symptoms 4 years after discharge, and the baby was also free from this disease. Short tandem repeat polymorphism (STR) analysis was performed to determine the genotype of the choriocarcinoma, placenta, and normal curettage tissue of the maternal uterine. Comparing the polymorphic genetic markers revealed that the tumor was gestational choriocarcinoma, but did not originate from the coexistent pregnancy. In spite of extensive metastases, antepartum chemotherapy is an effective and safe treatment for patients with gestational choriocarcinoma concurrent with pregnancy. STR analysis can be useful in distinguishing gestational choriocarcinoma from non-gestational, as well as the causative pregnancy, and serve as a helpful examination tool for guiding clinical management.

Long non-coding RNA NPBWR1-2 affects the development of ovarian cancer via multiple microRNAs.

Ovarian cancer has a high incidence rate and mortality in gynaecologic malignancies. Epithelial ovarian cancer (EOC) accounts for >95% of ovarian cancer cases. Most of the patients with EOC are difficult to diagnose in early stage. The aim of the present study was to compare the long non-coding (lnc)RNA expression profiles of five ovarian cancer cell lines (IGROV1, A2780, SKOV3, ES2, and Hey) and an ovarian epithelial cell line (IOSE80) in order to identify differentially expressed lncRNAs and their associated microRNAs (miRNAs). The expression profiles of lncRNAs and mRNAs in these cell lines were determined by microarray gene analysis and reverse transcription-quantitative PCR. lncRNA neuropeptides B and W receptor 1-2 (NPBWR1-2) overexpression was induced in the SKOV3 cell line. Cell viability, proliferation, migration, invasion and apoptosis were evaluated using MTT, colony-formation, Transwell and flow cytometry assays, respectively. The microarray results indicated that several lncRNAs were differentially expressed in the five ovarian cancer cell lines compared with the normal ovarian epithelial cell line. Compared with IOSE80, lncRNA NPBWR1-2 was downregulated by more than two-fold in all five ovarian cancer cell lines. Moreover, NPBWR1-2 overexpression in the SKOV3 cell line decreased cell viability, inhibited proliferation, migration and invasion, and promoted apoptosis compared with the control cells. A total of 20 miRNAs, which are involved in tumorigenesis and development, were predicted to be associated with NPBWR1-2 by bioinformatics analysis. The results of the present study suggest that lncRNA NPBWR1-2 affects the occurrence and development of ovarian cancer via multiple miRNAs, providing a theoretical basis for the development of novel clinical treatments.

Comparison of neoadjuvant treatments followed by radical surgery or chemoradiation on quality of life in patients with stage IB2-IIA cervical cancer.

OBJECTIVE: To compare quality of life (Qol) of patients with stage IB2-IIA cervical cancer treated by neoadjuvant treatments followed by radical surgery (NTS) or standard chemoradiation (CRT). METHODS: Patients with stage IB2-IIA cervical cancer during 2006-2012 were treated with NTS or CRT and were invited to participate. The Functional Assessment of Cancer Therapy-Cervix (FACT-Cx) Questionnaire was used to assess patient Qol. A multivariable linear regression analysis was performed to identify factors associated with Qol. RESULTS: In total, 90 (78.3%) out of 115 eligible patients completed the questionnaires. No significant differences were found in Qol between treatment groups, except that patients after NTS reported higher scores in the social/family well-being (e.g. satisfaction with sexual life, close relationships with partner or friends, and support from friends) than those after CRT, in particular, during 2-3 years after treatment. Results of multivariate analysis indicated that NTS was associated with better social/family functioning, while advanced stage of cervical cancer, lower family income and lower education were associated with impaired Qol in different domains. CONCLUSIONS: Although self-reported Qol after treatment were not significantly different, NTS treated patients reported better social/family functioning than CRT treated patients, such as satisfaction with their sexual life and close relationships with partner or friends, during 2-3 years post treatment. These results were helpful for physicians to make treatment decisions while considering treatment-related Qol, and moreover, for rehabilitation and supportive care of patients after treatment. Further validation of our findings in randomized, controlled clinical trials is warranted.

Alterations of protein glycosylation in embryonic stem cells during adipogenesis.

The understanding of adipose tissue development is crucial for the treatment of obesity-related diseases. Adipogenesis has been extensively investigated at the gene and protein levels in recent years. However, the alterations in protein glycosylation during this process remains unknown, particularly that of parthenogenetic embryonic stem cells (pESCs), a type of ESCs with low immunogenicity and no ethical concerns regarding their use. Protein glycosylation markedly affects cell growth and development, cell-to-cell communication, tumour growth and metastasis. In the present study, the adipogenic potentials of J1 ESCs and pESCs were first compared and the results demonstrated that pESCs had lower adipogenic potential compared with J1 ESCs. Lectin microarray was then used to screen the alteration of protein glycosylation during adipogenesis. The results revealed that protein modification of GlcNAc and α-1-2-fucosylation increased, whereas α-1-6­fucosylation, α-2-6-sialylation and α-1-6-mannosylation decreased in J1 ESCs and pESCs during this process. In addition, α-1-3-mannosylation decreased only in pESCs. Lectin histochemistry and quantitative polymerase chain reaction of glycosyltransferase confirmed the results obtained by lectin microarray. Therefore, protein glycosylation of ESCs was significantly altered during adipogenesis, indicating that protein glycosylation analysis is not only helpful for studying the mechanism of adipogenesis, but may also be used as a marker to monitor adipogenic development.

Directing the Differentiation of Parthenogenetic Stem Cells into Tenocytes for Tissue-Engineered Tendon Regeneration.

Uniparental parthenogenesis yields pluripotent stem cells without the political and ethical concerns surrounding the use of embryonic stem cells (ESCs) for biomedical applications. In the current study, we hypothesized that parthenogenetic stem cells (pSCs) could be directed to differentiate into tenocytes and applied for tissue-engineered tendon. We showed that pSCs displayed fundamental properties similar to those of ESCs, including pluripotency, clonogenicity, and self-renewal capacity. pSCs spontaneously differentiated into parthenogenetic mesenchymal stem cells (pMSCs), which were positive for mesenchymal stem cell surface markers and possessed osteogenic, chondrogenic, and adipogenic potential. Then, mechanical stretch was applied to improve the tenogenic differentiation of pMSCs, as indicated by the expression of tenogenic-specific markers and an increasing COL1A1:3A1 ratio. The pSC-derived tenocytes could proliferate and secrete extracellular matrix on the surface of poly(lactic-co-glycolic) acid scaffolds. Finally, engineered tendon-like tissue was successfully generated after in vivo heterotopic implantation of a tenocyte-scaffold composite. In conclusion, our experiment introduced an effective and practical strategy for applying pSCs for tendon regeneration. Stem Cells Translational Medicine 2017;6:196-208.

Preclinical study of mouse pluripotent parthenogenetic embryonic stem cell derivatives for the construction of tissue-engineered skin equivalent.

BACKGROUND: Embryonic stem cell (ESC) derivatives hold great promise for the construction of tissue-engineered skin equivalents (TESE). However, harvesting of ESCs destroys viable embryos and may lead to political and ethical concerns over their application. In the current study, we directed mouse parthenogenetic embryonic stem cells (pESCs) to differentiate into fibroblasts, constructed TESE, and evaluated its function in vivo. METHODS: The stemness marker expression and the pluripotent differentiation ability of pESCs were tested. After embryoid body (EB) formation and adherence culture, mesenchymal stem cells (MSCs) were enriched and directed to differentiate into fibroblastic lineage. Characteristics of derived fibroblasts were assessed by quantitative real-time PCR and ELISA. Functional ability of the constructed TESE was tested by a mouse skin defects repair model. RESULTS: Mouse pESCs expressed stemness marker and could form teratoma containing three germ layers. MSCs could be enriched from outgrowths of EBs and directed to differentiate into fibroblastic lineage. These cells express a high level of growth factors including FGF, EGF, VEGF, TGF, PDGF, and IGF1, similar to those of ESC-derived fibroblasts and mouse fibroblasts. Seeded into collagen gels, the fibroblasts derived from pESCs could form TESE. Mouse skin defects could be successfully repaired 15 days after transplantation of TESE constructed by fibroblasts derived from pESCs. CONCLUSIONS: pESCs could be induced to differentiate into fibroblastic lineage, which could be applied to the construction of TESE and skin defect repair. Particularly, pESC derivatives avoid the limitations of political and ethical concerns, and provide a promising source for regenerative medicine.

Directing parthenogenetic stem cells differentiate into adipocytes for engineering injectable adipose tissue.

The selection of appropriate seed cells is crucial for adipose tissue engineering. Here, we reported the stepwise induction of parthenogenetic embryonic stem cells (pESCs) to differentiate into adipogenic cells and its application in engineering injectable adipose tissue with Pluronic F-127. pESCs had pluripotent differentiation capacity and could form teratomas that include the three primary germ layers. Cells that migrated from the embryoid bodies (EBs) were selectively separated and expanded to obtain embryonic mesenchymal stem cells (eMSCs). The eMSCs exhibited similar cell surface marker expression profiles with bone morrow mesenchymal stem cells (BMSCs) and had multipotent differentiation capacity. Under the induction of dexamethasone, indomethacin, and insulin, eMSCs could differentiate into adipogenic cells with increased expression of adipose-specific genes and oil droplet depositions within the cytoplasm. To evaluate their suitability as seed cells for adipose tissue engineering, the CM-Dil labelled adipogenic cells derived from eMSCs were seeded into Pluronic F-127 hydrogel and injected subcutaneously into nude mice. Four weeks after injection, glistering and semitransparent constructs formed in the subcutaneous site. Histological observations demonstrated that new adipose tissue was successfully fabricated in the specimen by the labelled cells. The results of the current study indicated that pESCs have great potential in the fabrication of injectable adipose tissue.