In vivo modeling of metastatic human high-grade serous ovarian cancer in mice.

Metastasis is responsible for 90% of human cancer mortality, yet it remains a challenge to model human cancer metastasis in vivo. Here we describe mouse models of high-grade serous ovarian cancer, also known as high-grade serous carcinoma (HGSC), the most common and deadliest human ovarian cancer type. Mice genetically engineered to harbor Dicer1 and Pten inactivation and mutant p53 robustly replicate the peritoneal metastases of human HGSC with complete penetrance. Arising from the fallopian tube, tumors spread to the ovary and metastasize throughout the pelvic and peritoneal cavities, invariably inducing hemorrhagic ascites. Widespread and abundant peritoneal metastases ultimately cause mouse deaths (100%). Besides the phenotypic and histopathological similarities, mouse HGSCs also display marked chromosomal instability, impaired DNA repair, and chemosensitivity. Faithfully recapitulating the clinical metastases as well as molecular and genomic features of human HGSC, this murine model will be valuable for elucidating the mechanisms underlying the development and progression of metastatic ovarian cancer and also for evaluating potential therapies.

Reduction of cycles of neoadjuvant chemotherapy for advanced epithelial ovarian, fallopian or primary peritoneal cancer (ROCOCO): study protocol for a phase III randomized controlled trial.

BACKGROUND: Primary debulking surgery (PDS) and adjuvant chemotherapy is the standard treatment for advanced ovarian, fallopian or primary peritoneal cancer. However, neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been introduced as an alternative, showing similar efficacy and decreased postoperative complications compared with PDS. Although there is still no evidence for whether three or four cycles of NAC used clinically could be adequate, reducing one cycle of NAC is expected to remove more visible tumours and thereby improve prognosis. Thus, we proposed with this study to evaluate the efficacy and safety of reducing one cycle of NAC for advanced ovarian, fallopian or primary peritoneal cancer. METHODS: This study is a prospective, multi-centre, open-label, randomized phase III trial. A total of 298 patients with advanced ovarian, fallopian or primary peritoneal cancer will be recruited and randomly assigned to either three (control group) or two cycles of NAC (experimental group). After the NAC, we will conduct IDS with maximal cytoreduction and then administer the remaining three or four cycles for a total of six cycles of adjuvant chemotherapy. The primary end point is progression-free survival, and the secondary end points are time to tumour progression, overall survival, tumour response after NAC, IDS and adjuvant chemotherapy, radiologic investigation after IDS, tumour response by positron emission tomography-computed tomography after NAC, quality of life, adverse events, success rate of optimal cytoreduction, surgical complexity, postoperative complications and safety of IDS. We will assess these factors at screening, at every cycle of chemotherapy, at IDS, after the completion of chemotherapy, every 3 months for the first 2 years after the planned treatment and every 6 months thereafter for 3 years. DISCUSSION: We hypothesize that reducing one cycle of NAC will contribute to more resection of visible tumours despite 10% reduction of optimal cytoreduction, which could improve survival. Moreover, two cycles of NAC may increase postoperative complications by 5% compared with three cycles, which may be acceptable. TRIAL REGISTRATION: This study has been prospectively registered at ClinicalTrials.gov on Oct. 2nd, 2018 (NCT03693248, URL: https://clinicaltrials.gov/ct2/show/NCT03693248).

Measure Theoretic Entropy of Discrete Geodesic Flow on Nagao Lattice Quotient.

The discrete geodesic flow on Nagao lattice quotient of the space of bi-infinite geodesics in regular trees can be viewed as the right diagonal action on the double quotient of PGL2Fq((t-1)) by PGL2Fq[t] and PGL2(Fq[[t-1]]). We investigate the measure-theoretic entropy of the discrete geodesic flow with respect to invariant probability measures.

A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity.

Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.

Obesity and aging diminish sirtuin 1 (SIRT1)-mediated deacetylation of SIRT3, leading to hyperacetylation and decreased activity and stability of SIRT3.

Sirtuin 3 (SIRT3) deacetylates and regulates many mitochondrial proteins to maintain health, but its functions are depressed in aging and obesity. The best-studied sirtuin, SIRT1, counteracts aging- and obesity-related diseases by deacetylating many proteins, but whether SIRT1 has a role in deacetylating and altering the function of SIRT3 is unknown. Here we show that SIRT3 is reversibly acetylated in the mitochondria and unexpectedly is a target of SIRT1 deacetylation. SIRT3 is hyperacetylated in aged and obese mice, in which SIRT1 activity is low, and SIRT3 acetylation at Lys57 inhibits its deacetylase activity and promotes protein degradation. Adenovirus-mediated expression of SIRT3 or an acetylation-defective SIRT3-K57R mutant in diet-induced obese mice decreased acetylation of mitochondrial long-chain acyl-CoA dehydrogenase, a known SIRT3 deacetylation target; improved fatty acid ß-oxidation; and ameliorated liver steatosis and glucose intolerance. These SIRT3-mediated beneficial effects were not observed with an acetylation-mimic SIRT3-K57Q mutant. Our findings reveal an unexpected mechanism for SIRT3 regulation via SIRT1-mediated deacetylation. Improving mitochondrial SIRT3 functions by inhibiting SIRT3 acetylation may offer a new therapeutic approach for obesity- and aging-related diseases associated with mitochondrial dysfunction.

Management of Endometrial Hyperplasia: A Survey of Members of the Korean Gynecologic Oncology Group.

OBJECTIVES: This study aimed to investigate the current management of endometrial hyperplasia (EH) in Korea. MATERIALS AND METHODS: This was an electronic survey, which included 40 questions, that was distributed to the members of the Korean Gynecologic Oncology Group in 2014. RESULTS: In total, 50 (69%) of 72 members responded to the survey. The oral progestogens were the most popular choices for managing EH without atypia (simple hyperplasia(SH), 64%; complex hyperplasia (CH), 52%). In the case of CH with atypia, most of the gynecologist respondents would perform hysterectomy (95.9%). For fertility preservation, the oral progestogens were the most popular choices (SH, 75.5%; CH, 56.3%), followed by the levonorgestrel-releasing intrauterine system (LNG-IUS). More than 70% of the respondents reported use of dilatation and curettage as a follow-up method. CONCLUSIONS: Our survey results show that most of Korean gynecologic oncologists still prefer oral progestogens for conservative management of EH, notwithstanding the many successful reports on the LNG-IUS. As a follow-up evaluation method, dilatation and curettage is mostly used. To identify the optimum therapy, a randomized controlled trial comparing the LNG-IUS with continuous oral progestogens is required. Furthermore, a large-scale prospective study to confirm the most reliable technique for follow-up evaluation is necessary.

Multi-institution, Prospective, Randomized Trial to Compare the Success Rates of Single-port Versus Multiport Laparoscopic Hysterectomy for the Treatment of Uterine Myoma or Adenomyosis.

STUDY OBJECTIVE: To compare the operative outcomes of patients undergoing either single-port or multiport laparoscopic hysterectomy (LH). METHODS: Two hundred fifty-six women scheduled for LH for symptomatic myoma and/or adenomyosis from 8 tertiary teaching hospitals were randomized to single-port or multiport groups. Primary outcome was conversion and/or complication proportion of the planned procedure to determine whether the success proportion of the single-port approach was not inferior to that of the multiport approach. Secondary outcomes were postoperative pain and operative scar. RESULTS: Demographic parameters including age, body mass index, parity, and history of vaginal and cesarean delivery were comparable between the 2 groups. The primary outcome of a combined conversion and/or complication rate was similar between the single-port and multiport groups at 8% and 10.3%, respectively. Conversions were similar between the groups with 4% of single-port cases and .8% of multiport cases. Transfusions were the most frequent complication required in 4.0% of single-port cases and 7.9% of multiport cases, with no difference between the groups. Concerning secondary outcomes, postoperative pain score and patient and observer scar assessment were not different between the 2 groups. Although not a specific outcome measure, there was no difference between the groups in blood loss, operative time, and postoperative hospital stay. CONCLUSION: Single-port LH is not inferior to multiport LH in terms of conversion and/or complications rates, including transfusion. However, the single-port approach did not have any advantage over multiport LH with regard to pain or cosmetic outcomes. These findings were demonstrated by multi-institutional surgeons in Korea.

Gynecologic Cancer InterGroup (GCIG) consensus review for mullerian adenosarcoma of the female genital tract.

Mullerian adenosarcomas of the female genital tract are rare malignancies, originally described in the uterus, the most common site of origin, but they may also arise in extrauterine locations. Uterine adenosarcomas make up 5% of uterine sarcomas and tend to occur in postmenopausal women. They are usually low-grade tumors and are characterized by a benign epithelial component with a malignant mesenchymal component, which is typically a low-grade endometrial stromal sarcoma but can also be a high-grade sarcoma. Tumors that exhibit a high-grade sarcomatous overgrowth have a worse outcome. Adenosarcomas have been described as being midway along the spectrum between benign adenofibromas and carcinosarcomas. They generally have a good prognosis with the exception of deeply invasive tumors or those with high-grade sarcomatous overgrowth. Extrauterine adenosarcomas also have a higher risk for recurrence. In view of their rarity, there have not been any clinical trials in mullerian adenosarcomas and relatively little research. This article reviews the current knowledge and provides recommendation for the management of mullerian adenosarcomas.

Comparison of Long-Term Outcomes in Early-Stage Endometrial Cancer: Robotic Single-Site vs. Multiport Laparoscopic Surgery.

The purpose of this study was to establish the noninferiority of robotic single-site (RSS) surgery compared with multiport laparoscopic (MPL) surgery in surgical outcomes and overall survival for early endometrial cancer. This study was conducted retrospectively in a single center and included 421 patients who underwent either RSS (n = 146) or MPL (n = 275) surgery between 2014 and 2022. In terms of perioperative outcomes, the RSS group had a longer operating time than the MPL surgery group (mean (standard deviation [SD]) RSS 97.55 [29.79] vs. MPL 85.56 [26.13], p < 0.001). However, no significant differences in estimated blood loss or perioperative complications were found between the groups (p = 0.196 and p = 0.080, respectively). The patients in the RSS group were discharged earlier than those in the MPL group (mean [SD]): 4.06 [3.24] vs. 9.39 [4.76], p < 0.001). Regarding oncologic outcomes, no significant differences in the type of therapy, disease stage, tumor grade, histopathological type, or lymphovascular invasion were found between the groups. No statistically significant differences were found in the disease-free (p = 0.27) and overall survival rates (p = 0.5) either. In conclusion, this study suggests that RSS and MPL surgery are both safe and effective options for staging operations in patients with early-stage endometrial cancer.

Prophylactic effect of a peptide vaccine targeting TM4SF5 against colon cancer in a mouse model.

Expression of transmembrane 4 superfamily member 5 protein (TM4SF5) was implicated in hepatocellular carcinoma (HCC) and colon cancer. Previously, we have shown that immunization with TM4SF5 peptide-CpG-DNA-liposome complex induces production of TM4SF5-specific antibodies and protects mice from HCC progression in an allograft model. Here, we confirmed expression of TM4SF5 in the mouse colon cancer cell line CT-26 and found that anti-TM4SF5 antibody inhibits growth of CT-26 cells. We then immunized mice with TM4SF5 peptide-CpG-DNA-liposome complex and transplanted CT-26 cells to investigate the vaccination effects. Robust production of TM4SF5-specific antibodies was induced by challenge with CT-26 cells and the tumor growth was significantly suppressed in the immunized mice. The peptide vaccine targeting TM4SF5 consequently showed a prophylactic effect against colon cancer development in a mouse model. These results suggest that the peptide vaccine can be potentially applied in humans to treat colon cancer.

Regulatory role of osteopontin in malignant transformation of endometrial cancer.

Osteopontin (OPN) involves in the tumor-promoting or metastasis in human endometrial cancer. Depletion of OPN gene expression in endometrial cancer cells was significantly decreased in cell viability and the cells undergo apoptotic cell death. The status of OPN in THESC, RL95, Hec1A and Ishikawa cell lines were analyzed by RT-PCR and western blot. After OPN-siRNA transfection, mRNA and protein expression levels of OPN were determined in Hec1A and Ishikawa cells. Cell proliferation and cell cycle distribution were observed by MTT and flow cytometry analysis. DNA fragmentation assay was used to measure cell apoptosis. Cell migration was assessed by wound healing assay. Depletion of OPN gene expression in endometrial cancer cell lines (Hec1A and Ishikawa cells) reproducibly changed their ability of proliferation. Concomitant changes were seen in the expression of OPN binding cell surface receptors, cell cycle-regulatory genes, cell invasion and colony formation nature of the tumor cells. Decreased colonizing potential in the absence of OPN was reversed in the presence of recombinant OPN. Inhibition of anchorage-independent growth was observed in the presence of metabolic inhibitors of the PI3K, Src and integrin signaling cascades, which was ameliorated in the presence of exogenously added OPN. Our result showed the role of OPN in endometrial cancer, in particular on the malignancy-promoting aspects of OPN that may pave way for new approaches to the clinical management of endometrial cancer.

The synergistic apoptotic interaction of Indole-3-Carbinol and Genistein with TRAIL on endometrial cancer cells.

Induction of apoptosis in target cells is a key mechanism by which chemotherapy promotes cell killing. The purpose of this study was to determine whether Indole-3-Carbinol (I3C) and Genistein in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induce apoptosis in endometrial cancer cell (Ishikawa) and to assess apoptotic mechanism. The MTT assay and flow cytometry were performed to determine cell viability and cell cycle. The induction of apoptosis was measured by caspase-3 activity test, DNA fragmentation assay, annexin V binding assay and western blot analysis. There was no effect in cell growth inhibition and cell cycle progression alone or in two-combination. However, the treatment of I3C and Genistein followed by TRAIL showed significant cell death and marked increase in sub-G1 arrest. Three-combination treatment revealed elevated expression of DR4, DR5 and cleaved forms of caspase-3, caspase-8, PARP. The Flip was found down regulated. Moreover, increase in caspase-3 activity and DNA fragmentation indicated the induction of apoptosis. The results indicate that I3C and Genistein with TRAIL synergistically induced apoptosis via death receptor dependent pathway. Our findings might provide a new insight into the development of novel combination therapies against endometrial cancer.

Robotic Single-Site Radical Hysterectomy for Early Cervical Cancer: A Single Center Experience of 5 Years.

BACKGROUND: The mainstay of treatment for early-stage cervical cancer is surgery; we present a 5-year experience of robotic single-site radical hysterectomy (RSRH) focused on surgical and oncologic outcomes. METHODS: This retrospective study included 44 cases of RSRH performed in patients with early-stage cervical cancer. RESULTS: The median follow-up period for the 44 patients was 34 months. The mean total operation time was 156.07 ± 31.77 min, while mean console time was 95.81 ± 24.95 min. Two cases had complications, which required surgical management, while four cases (9.1%) exhibited recurrence. The disease-free survival rate at 5 years was 90.9%. The sub-division analysis showed that Stage Ia2 and stage Ib1 patient sub-group showed better DFS than that of the stage Ib2 patient sub-group. The learning curve analysis showed that the CUSUM-T initially peaks at the sixth case then gradually decreases before rising and peaking at the 24th case. After 24th case, the CUSUM-T gradually decreases and reaches zero. CONCLUSION: The surgical outcomes of RSRH for early-stage cervical cancer treatment were safe and acceptable. However, RSRH could be considered carefully only in well-selected patient groups. Large-scale prospective studies are necessary in the future to validate the results.

In-situ δ18O and 87Sr/86Sr proxies in an unconformable clastic unit at the Ordovician-Silurian transition.

Clastic successions found in the carbonate platform of continental margin during the Ordovician-Silurian Transition (OST) period are archives for interpreting paleo-depositional systems. Here, we report in-situ δ18Oquartz and 87Sr/86Srcarbonate isotope chemo-stratigraphy for an unconformable clastic unit from the Cathaysia terrane that rifted off the Gondwana Supercontinent in the Early Paleozoic Era. Our results suggest a depositional proxy and model for geological events attributed to rapid changes in the sedimentary environment during the OST period. Importantly, these results present crucial clues that infer the influence of Paleo-Tethys Sea opening, global eustatic regression, and rapid sedimentary provenance change. Our study provides insight into paleo-tracer that could be a key method for interpreting depositional system of carbonate platform based on in-situ mineral isotope chemo-stratigraphy that preserves the original value of provenance and geochemical condition.

Production of antibodies with peptide-CpG-DNA-liposome complex without carriers.

BACKGROUND: The screening of peptide-based epitopes has been studied extensively for the purpose of developing therapeutic antibodies and prophylactic vaccines that can be potentially useful for treating cancer and infectious diseases such as influenza virus, malaria, hepatitis B, and HIV. To improve the efficacy of antibody production by epitope-based immunization, researchers evaluated liposomes as a means of delivering vaccines; they also formulated adjuvants such as flagella and CpG-DNA to enhance the magnitude of immune responses. Here, we provide a potent method for peptide-based epitope screening and antibody production without conventional carriers. RESULTS: We present that a particular form of natural phosphodiester bond CpG-DNA encapsulated in a specific liposome complex (Lipoplex(O)) induces potent immunomodulatory activity in humans as well as in mice. Additionally, Lipoplex(O) enhances the production of IgG2a specific to antigenic protein in mice. Most importantly, immunization of mice with several peptides co-encapsulated with Lipoplex(O) without carriers significantly induces each peptide-specific IgG2a production in a TLR9-dependent manner. A peptide-specific monoclonal antibody produced against hepatocellular carcinoma-associated antigen has functional effects on the cancer cells. CONCLUSIONS: Our overall results show that Lipoplex(O) is a potent adjuvant and that complexes of peptide and Lipoplex(O) are extremely useful for B cell epitope screening and antibody production without carriers. Therefore, our strategy may be promptly used for the development of therapeutic antibodies by rapid screening of potent B cell epitopes.

ASB9 interacts with ubiquitous mitochondrial creatine kinase and inhibits mitochondrial function.

BACKGROUND: The ankyrin repeat and suppressor of cytokine signalling (SOCS) box proteins (Asbs) are a large protein family implicated in diverse biological processes including regulation of proliferation and differentiation. The SOCS box of Asb proteins is important in a ubiquitination-mediated proteolysis pathway. Here, we aimed to evaluate expression and function of human Asb-9 (ASB9). RESULTS: We found that a variant of ASB9 that lacks the SOCS box (ASB9DeltaSOCS) was naturally detected in human cell lines but not in peripheral blood mononuclear cells or normal hepatocytes. We also identified ubiquitous mitochondrial creatine kinase (uMtCK) as a new target of ASB9 in human embryonic kidney 293 (HEK293) cells. The ankyrin repeat domains of ASB9 can associate with the substrate binding site of uMtCK in a SOCS box-independent manner. The overexpression of ASB9, but not ASB9DeltaSOCS, induces ubiquitination of uMtCK. ASB9 and ASB9DeltaSOCS can interact and colocalise with uMtCK in the mitochondria. However, only expression of ASB9 induced abnormal mitochondrial structure and a decrease of mitochondrial membrane potential. Furthermore, the creatine kinase activities and cell growth were significantly reduced by ASB9 but not by ASB9DeltaSOCS. CONCLUSIONS: ASB9 interacts with the creatine kinase system and negatively regulates cell growth. The differential expression and function of ASB9 and ASB9DeltaSOCS may be a key factor in the growth of human cell lines and primary cells.

Acidic fluids in the Earth's lower crust.

Fluid flux through Earth's surface and its interior causes geochemical cycling of elements in the Earth. Quantification of such process needs accurate knowledge about the composition and properties of the fluids. Knowledge about the fluids in Earth's interior is scarce due to limitations in both experimental methods and thermodynamic modeling in high/ultrahigh pressure-temperature conditions. In this study, we present halogen (Cl, F) measurements in apatite grains from the mafic (metagabbro), and felsic (two-pyroxene granulite, charnockite, hornblende-biotite gneiss) rocks preserved in the Nilgiri Block, southern India. Previous experiments show that it is difficult to incorporate Cl in apatite compared to F at high pressure and temperature conditions. Based on regional trends in Cl and F content in apatite (with highest Cl content 2.95 wt%), we suggest the presence of acidic C-O-H fluids in the lower crust (~20-40 km deep) during the high-grade metamorphism of these rocks. These fluids are capable of causing extreme chemical alterations of minerals, especially refractory ones. They also have significant potential for mass transfer, causing extensive geochemical variations on a regional scale and altering the chemical and isotope records of rocks formed in the early Earth. Our findings have important relevance in understanding speciation triggered by acidic fluids in the lower crust, as well as the role of fluids in deep Earth processes.

Robotic single-site versus multiport radical hysterectomy in early stage cervical cancer: An analysis of 62 cases from a single institution.

BACKGROUND: This study aimed to compare the surgical outcomes and cost of robotic single-site radical hysterectomy (RSSRH) versus robotic multiport radical hysterectomy (RMPRH) with pelvic lymph node dissection in early stage cervical cancer. METHODS: Sixty-two patients with early stage cervical cancer were recruited between November 2011 and July 2017 and underwent RSSRH (20 patients) and RMPRH (42 patients) for early stage cervical cancer using the da Vinci Si Surgical System (Intuitive Surgical). RESULTS: There were no significant difference between the two groups in most of parameters. However, postoperative hospital discharge and total hospital costs for RSSRH were significantly shorter than RMPRH (both p < 0.001). However, lymph node retrieval of RMPRH was significantly higher than RSSRH in (18.0 vs. 9.5, respectively; p < 0.001). CONCLUSIONS: RSSRH has comparable surgical outcomes to the RMPRH method. RSSRH could be considered a surgical option in a well-selected patient group.

Modified Laparoscopic Transabdominal Cervicoisthmic Cerclage for the Surgical Management of Recurrent Pregnancy Loss due to Cervical Factors.

This study aimed evaluate the feasibility of modified laparoscopic transabdominal cervicoisthmic cerclage (LTCC) and its impact on recurrent pregnancy loss (RPL) and is a retrospective observational cohort study of patients who underwent modified LTCC from 2003 to 2018 (n = 299). The surgery was performed at a mean gestational age of 12.5 weeks (range 10.5-17.5 weeks). Of the 299 patients, 190 were reported as having undergone abortion (one abortion: 91 (47.9%), two: 59 (31.1%), three or more: 40 (21.1%)) before the present pregnancy and prior to the surgery. The mean operation time was 47.4 min (range 15-100 min). We followed up with 205 of 299 patients and recorded their obstetric outcomes. There were 176 successful deliveries via cesarean section, and the fetal survival rate was 85.9% (176/205). The results of this study suggest that modified LTCC is a safe and feasible surgical option during pregnancy for patients with a history of RPL due to cervical factors.

Updated clinical guideline for human papillomavirus vaccine: the Korean Society of Gynecologic Oncology guidelines.

Since the human papillomavirus (HPV) vaccine guidelines were developed by the Korean Society of Gynecologic Oncology (KSGO) in 2011, 2016, and 2019, several recent studies on the efficacy and safety of HPV vaccines in middle-aged women and men have been reported. Furthermore, there has been an ongoing debate regarding the efficacy of the HPV vaccine in women with prior HPV infection or who have undergone conization for cervical intraepithelial neoplasia (CIN). We searched and reviewed studies on the efficacy and safety of the HPV vaccine in middle-aged women and men and the efficacy of the HPV vaccine in patients infected with HPV and those who underwent conization for CIN. The KSGO updated their guidelines based on the results of the studies included in this review.