The role of non-genomic actions of progesterone and its membrane receptor agonist in ovarian cancer cell death.

BACKGROUND: Progesterone therapy is a relatively inexpensive treatment option for endometrial and breast cancers, with few side effects. Two signaling pathways usually mediate the physiological effects of progesterone, namely genomic and non-genomic actions. Genomic action occurs slowly via the nuclear progesterone receptor (PR), whereas the membrane progesterone receptor (mPR) induces rapid non-genomic action. AIMS: We investigated the effects of progesterone and various PR agonists on ovarian cancer cells. METHODS AND RESULTS: PR expression of six serous ovarian cancer cell lines was examined by western blotting, and mPR expression was examined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). PR-negative and mPR-positive ovarian cancer cells were exposed to progesterone and seven types of PR agonists (medroxyprogesterone acetate [MPA], dehydroepiandrosterone, dienogest, levonorgestrel, drospirenone, pregnenolone, and allopregnanolone) at 10-400 µM, and viable cell counts after exposure for 30 min were measured using the water-soluble tetrazolium (WST-1) assay. Ovarian cancer cell lines were exposed to 100 µM progesterone, and the expression of BAX, a pro-apoptotic protein, after 1-5 min was examined by western blotting. Western blotting detected no PR expression in the six serous ovarian cancer cell lines. In contrast, RT-qPCR detected mPR expression in all six serous ovarian cancer cell lines. Progesterone and MPA-induced cell death in all tested ovarian cancer cell lines in a concentration-dependent manner, whereas no effect was observed for other PR agonists. Western blotting revealed that pro-apoptotic protein BAX expression occurred 1 min after exposure to progesterone, suggesting that the cytocidal effects are mediated by rapid non-genomic action. CONCLUSION: Progesterone and MPA exhibited a rapid cytocidal effect on PR-negative ovarian cancer cells through non-genomic action. Progesterone and MPA could be novel adjuvant therapies for ovarian cancer.

Increase in creatinine levels associated with niraparib maintenance therapy in ovarian cancer.

AIM: In Japan, Niraparib maintenance therapy for primary and recurrent ovarian cancer was approved in September 2020 and is expected to improve the prognosis of ovarian cancer. However, the safety of niraparib maintenance therapy in Japanese patients has not been fully evaluated. METHODS: Patients with ovarian cancer (including fallopian tube and peritoneal cancer) treated with niraparib at Jichi Medical University Hospital from September 2020 to August 2022 were enrolled in this study. Patient background, starting dose, rates of interruption, reduction, or discontinuation, adverse events (AEs) during treatment, and estimated glomerular filtration rate (eGFR) trends were retrospectively analyzed. RESULTS: Twenty-nine patients received niraparib maintenance therapy during the study period, including 21 with primary cancer and 8 patients with recurrent cancer. Seventeen patients (58.6%) required dose interruptions and 16 patients (55.2%) required dose reductions. Only two patients (6.9%) discontinued treatment due to fatigue and nausea. The most frequent AE was creatinine increases in 18 patients (62.1%, all grades). Although eGFR levels decreased significantly after niraparib therapy compared to before niraparib therapy (59.3 vs. 50.3 mL/min/1.73 m2 , p < 0.001), the levels returned to pre-niraparib initiation levels after discontinuation of niraparib (64.6 vs. 64.6 mL/min/1.73 m2 , p = 0.96). Multivariate regression analysis showed that diabetes was independently associated with decreased eGFR (p = 0.013). CONCLUSIONS: Niraparib maintenance therapy frequently increased serum creatinine, but the change was reversible. Further studies are needed to determine the effects of niraparib on renal function in Japanese patients.

Attenuated Total Reflection Infrared and Far-Infrared, and Raman Spectroscopy Studies of Minerals, Rocks, and Biogenic Minerals.

Attenuated total reflection infrared (ATR-IR, 4000-400 cm-1), ATR-far-IR (ATR-FIR, 400-50 cm-1), and Raman spectra (4000-10 cm-1) were measured for calcium carbonate, three kinds of minerals (calcite, aragonite, and quartz), two kinds of rocks (obsidian and pumice), and four kinds of biogenic minerals, i.e., coral (aragonite), Ruditapes philippinarum (aragonite), Meretrix lusoria (aragonite), and Corbicula japonica (aragonite), to investigate the polymorphism of minerals and biogenic minerals, differences in the crystal structure among aragonite and aragonite biogenic minerals, water in the minerals and biogenic minerals, Boson peaks of obsidian and pumice, very small amounts of carotenoids in the three kinds of shells, and so on. In this study, we put some emphasis on the low-frequency region of IR (FIR) and Raman spectra. ATR-FIR spectra were measured down to 50 cm-1 and Raman spectra were obtained down to 10 cm-1. Second derivative spectra were calculated for the FIR spectra. It has been found from the present study that the FIR spectra are the most powerful for exploring polymorphism and differences in the crystal structure among aragonite and aragonite biogenic minerals. A Boson peak, which is a characteristic low-frequency Raman band for amorphous materials, was observed at around 40 cm-1 in the Raman spectra of obsidian and pumice. The Boson peak of pumice is located at a lower frequency by 12 cm-1 than that of obsidian, indicating that the mean atomic volume of pumice is larger than that of obsidian. The present study has revealed that IR spectra are useful to investigate the amounts and structure of fluid and bound water. Moreover, it has also been found that Raman spectra can detect a very tiny amount of carotenoids in the shells due to the resonance Raman effect.

Late-Onset Ovarian Bleeding After Transvaginal Oocyte Retrieval in a Patient With Suspected Hereditary Hemorrhagic Telangiectasia.

Assisted reproductive technology (ART) requires transvaginal oocyte retrieval (TVOR), and ovarian bleeding after TVOR rarely occurs. We present a case of a 37-year-old woman (0-gravida) who was diagnosed with possible hemorrhagic telangiectasia (HHT) and had a history of three laparotomies for ovarian bleeding and an inclusion cyst adjacent to the right ovary after the third operation. HHT is a hereditary disease characterized by spontaneous hemorrhage of some organs, such as the nose, brain, lungs, gastrointestinal tract, and liver. She desired ART after fertility treatment and then had abdominal pain with ovarian swelling five days after TVOR. Moreover, both the right ovary and inclusion cyst were gradually swollen with hematoma. Finally, abdominal pain and the hemoglobin level deteriorated, necessitating an emergency surgery on the eighth day. We notify reproductive physicians that patients with HHT may readily develop ovarian bleeding with or without inclusion cysts after TVOR, although inclusion cysts may also be associated with late-onset bleeding.

Ovarian vein thrombosis after bilateral adnexectomy in a symptomatic patient with concomitant pulmonary embolism: A case report.

OBJECTIVE: Ovarian vein thrombosis (OVT) after adnexectomy is usually asymptomatic, and pulmonary embolism (PE) has not been reported following this type of OVT. We present the case of a patient with symptomatic OVT after bilateral adnexectomy who experienced PE. CASE REPORT: A 52-year-old woman underwent total laparoscopic hysterectomy and bilateral adnexectomy for early stage endometrial cancer. On the 12th postoperative day, she presented with a fever of 38.7 °C. Computed tomography (CT) revealed bilateral OVT. Anticoagulant and antibacterial therapy was initiated; after five days, the fever subsided. On the 19th postoperative day, CT revealed a decrement in OVT; however, PE was observed. By the 60th postoperative day, PE disappeared. No deep vein thromboses were detected at any time. CONCLUSION: This case highlights that OVT, even after adnexectomy, can cause symptoms and PE can occur after this type of OVT. Anticoagulation therapy may be considered in such cases.

Activated neutrophils inhibit chemotactic migration of activated T lymphocytes to CXCL11 by multiple mechanisms.

Accumulation of T lymphocytes and neutrophils shows inversed association with the prognosis of cancer patients, suggesting infiltration of neutrophils and T cells might be differently regulated in tumor tissue. In this study, we stimulated neutrophils with PMA or LPS to produce neutrophil extracellular traps (NETs) and examined the effects on chemotactic migration of activated T cells to a representative T cell chemokine, CXCL11. Migration of the activated T cells was totally abrogated by PMA-stimulated neutrophils placed either in upper or lower chamber, which was mostly canceled by pretreatment with Catalase. Although LPS-stimulated neutrophils also inhibited T cell migration, depletion of NETs by ultracentrifugation or degradation of NETs with DNAse I restored T cell migration. Western blots showed that LPS-stimulated neutrophils thoroughly degraded CXCL11 with NETs dependent manner. Activated neutrophils inhibit T cell chemotaxis via multiple mechanisms including the release of H2O2 and chemokine degradation by NETs, which may suppress adaptive immunity.

A proposal of a new automated method for SfM/MVS 3D reconstruction through comparisons of 3D data by SfM/MVS and handheld laser scanners.

SfM/MVS photogrammetry has received increasing attention due to its convenience, broadening the range of its applications into archaeology and anthropology. Because the accuracy of SfM/MVS depends on photography, one important issue is that incorrect or low-density point clouds are found in 3D models due to poor overlapping between images. A systematic way of taking photographs solve these problems, though it has not been well established and the accuracy has not been examined either, with some exceptions. The present study aims to (i) develop an efficient method for recording pottery using an automated turntable and (ii) assess its accuracy through a comparison with 3D models made by laser scanning. We recorded relatively simple pottery manufactured by prehistoric farmers in the Japanese archipelago using SfM/MVS photogrammetry and laser scanning. Further, by measuring the Hausdorff distance between 3D models made using these two methods, we show that their difference is negligibly small, suggesting that our method is sufficiently accurate to record pottery.

Neutrophil extracellular traps (NETs) reduce the diffusion of doxorubicin which may attenuate its ability to induce apoptosis of ovarian cancer cells.

Purpose: Although neutrophil extracellular traps (NETs) are present in various tumors, their roles in tumor biology have not been clarified yet. In this study, we examined how NETs affect the pharmacokinetics and effects of doxorubicin (DOX). Methods: NETs were generated by neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) or lipopolysaccharide (LPS). DOX was added to NETs and their distribution was observed under fluorescein microscopy, and the diffusion of DOX through 3 µM pores from lower to upper chambers was evaluated with a fluorescence-based assay. Ovarian cancer cells, KOC-2S and SKOV3, were embedded in collagen gel droplets and cultured in 3D way and their apoptosis was examined with flow cytometry. Results: DOX was mostly co-localized with NETs. The transfer of DOX to upper chambers increased over time, which was significantly decreased by the presence of neutrophils stimulated with PMA or LPS in the lower chamber. DOX outside of the gel increased the rates of annexin V (+) apoptotic cells, which were significantly reduced by the addition of LPS-stimulated neutrophils in media both in KOC-2S and SKOV3. The reduced diffusion and apoptosis were mostly restored by the destruction of the NETs structure with 1000 u/ml DNAse I. Conclusion: NETs efficiently trap and inhibit the diffusion of DOX which may attenuate its ability to induce apoptosis of ovarian cancer cells. Degradation of NETs with DNAse I may augment the response of ovarian cancer to DOX.

Durable response after the discontinuation of pembrolizumab treatment due to an adverse event in a patient with advanced endometrial cancer: A case report.

The persistence of antitumor effects has been reported after the completion of treatment with immune checkpoint inhibitors (ICIs) for various types of carcinoma, such as malignant melanoma, exhibiting a durable response. A durable response has also been noted after the discontinuation of treatment at an early stage due to adverse events, including in renal pelvic cancer, pancreatic cancer and intrahepatic cholangiocarcinoma; however, to the best of our knowledge, a similar case report has not yet been published in the malignant gynecological tumor field. The present study described a patient with refractory advanced endometrial cancer in whom the administration of pembrolizumab was discontinued after the completion of the 7th course due to renal dysfunction; however, persistent tumor-reducing effects and decreases in the levels of tumor markers were noted for more than 18 months after the cessation of treatment. Pembrolizumab may be continuously administered to some patients for a long period, whereas a durable response is achieved by others even after its discontinuation at an early stage; therefore, difficulties are associated with selecting an appropriate duration of administration. Further studies are required to search for biomarkers that facilitate high-accuracy effect predictions, and to establish an optimal administration period in consideration of specific adverse reactions to ICIs and cost-effectiveness.

Response to and toxicity of weekly paclitaxel and carboplatin in patients with stage IIIC-IV ovarian cancer and poor general condition.

It has remained elusive whether standard chemotherapy regimens are safe for patients with ovarian cancer and poor general condition. The purpose of the present study was to assess the response to and toxicity of weekly paclitaxel and carboplatin (W-PC) in patients with ovarian cancer and poor general condition. The subjects were patients with ovarian cancer who received W-PC at Jichi Medical University Hospital (Shimotsuke, Japan) between January 2008 and December 2016. Patients who were ≥80 years old and/or had a performance status ≥3 and/or severe complications/underlying diseases were selected. Patients received paclitaxel (60 mg/m2) and carboplatin (area under the curve 2 mg/ml/min) on days 1, 8, and 15 of a 28-day cycle. Their medical records were retrospectively reviewed. A total of 31 patients were included in the study. Grade 3/4 neutropenia, anemia and thrombocytopenia developed in 18 (58%), 5 (16%) and 1 (3%) patients, respectively. Furthermore, three (10%) patients had a complete response (CR), 12 (39%) had a partial response (PR), 5 (16%) had stable disease and 11 (35%) had progressive disease. The overall response rate was 48% (15/31) and the disease control rate was 65% (20/31). The 5-year progression-free survival was 15% and the 5-year overall survival was 15%. A total of 9 patients survived for >40 months, one of whom survived without recurrence for 122 months. Performance status <3, a tumor response of CR or PR and >5 chemotherapy cycles were indicators of favorable prognosis. Only >5 chemotherapy cycles (vs. ≤5; P=0.002) was an independent good prognostic factor according to multivariate analysis. In conclusion, W-PC was tolerable and slightly effective in patients with ovarian cancer and poor general condition. W-PC may be one option for patients who are unable to receive standard chemotherapy regimens.

Prognostic significance of the number of removed lymph nodes according to FIGO stage in ovarian clear cell carcinoma.

A previous study by our group reported that removing a larger number of lymph nodes in patients with stage I ovarian clear cell carcinoma (OCCC) improved progression-free survival (PFS). The present study investigated whether clinical conditions, particularly the number of removed lymph nodes, are independent predictors of progression for stage II or higher OCCC and whether the significance of the number of removed lymph nodes differs according to FIGO stage for OCCC. A total of 113 patients with OCCC who had undergone surgery between January 1993 and December 2015 were retrospectively enrolled and the clinicopathological data were obtained from their medical records. Among patients with stage II or higher OCCC, PFS of those with no residual tumor or no lymph node metastasis was significantly better than that of those with residual tumor (P=0.023) or lymph node metastasis (P=0.035). Multivariate analysis revealed that no residual tumor was the only independent predictor for improved PFS of patients with stage II or higher. Regarding the number of removed lymph nodes, it did not significantly affect the PFS of patients with stage II or higher OCCC, whereas it improved the PFS of those with stage I, being an independent predictor of progression of stage I OCCC. In summary, although the number of removed lymph nodes was an independent predictor of progression for stage I OCCC, it was not for stage II or higher OCCC. The prognostic significance of the number of removed lymph nodes in OCCC may differ depending on the FIGO stage.

Knockout of vasohibin-2 reduces tubulin carboxypeptidase activity and increases paclitaxel sensitivity in ovarian cancer.

Vasohibin-1 (VASH1) is a VEGF-inducible endothelium-derived angiogenesis inhibitor, and vasohibin-2 (VASH2), its homolog, exhibits proangiogenic activity. VASH2 is expressed by various cancer cells and accelerates tumor angiogenesis and progression. VASH2 was recently shown to exhibit tubulin carboxypeptidase (TCP) activity related to microtubule functions. Paclitaxel (PTX), an effective chemotherapeutic agent that is widely used to treat ovarian cancer, inhibits microtubule depolymerization and may interact with VASH2. We herein established several VASH2 knockout ovarian cancer cell lines using the CRISPR/Cas9 genome editing system to examine the intracellular tubulin detyrosination status and PTX chemosensitivity. The knockout of VASH2 did not affect the proliferation or sphere-forming activity of ovarian cancer cells in vitro. A Western blot analysis of VASH2 knockout cells revealed the weak expression of detyrosinated tubulin and upregulated expression of cyclin B1. The knockout of VASH2 significantly increased chemosensitivity to PTX, but not to cisplatin in ovarian cancer cell lines. The knockout of VASH2 reduced TCP activity and increased cyclin B1 expression, resulting in increased PTX chemosensitivity in ovarian cancer cells. The inhibition of angiogenesis and regulation of microtubule activity may be achieved in ovarian cancer treatment strategies targeting VASH2.

Efficacy and toxicity of pegylated liposomal doxorubicin as therapy for recurrent ovarian cancer in relation to the number of previous chemotherapy regimens: Comparison with gemcitabine.

AIM: Pegylated liposomal doxorubicin (PLD) is one of the second-line chemotherapy regimens for platinum-resistant recurrent ovarian cancer, but in clinical practice, it is also used for third or subsequent lines of chemotherapy. There is no report on the efficacy and toxicity of PLD in relation to the number of previous chemotherapy regimens. The purpose of this study was to clarify these points and compare with the results of gemcitabine (GEM) therapy we reported previously. METHODS: We retrospectively reviewed the medical records of patients with platinum-resistant recurrent ovarian cancer who underwent two or more cycles of PLD therapy between July 2009 and March 2017 at our institution. We used our reported data of GEM for comparison analysis. RESULTS: Seventy-eight patients were enrolled in this study. The overall response rate was 19.2% and the disease control rate (DCR) was 53.8%. The DCR with 1, 2, 3, and 4 or more previous regimens was 53.8%, 48.6%, 63.6% and 66.7%, respectively. Grade 3/4 neutropenia and anemia developed in 59.0% and 12.8%, respectively. Grade 2 or higher hand -foot syndrome, stomatitis, and liver dysfunction developed in 25.6%, 25.6% and 2.6%, respectively. When the number of previous regimens was 3 or higher, the DCR of PLD was significantly higher than that of GEM (64.7% vs 30.8%, P = 0.037). CONCLUSION: The DCR did not decrease with a greater number of previous regimens. When the number of previous regimens was 3 or higher, PLD therapy had a superior DCR to GEM therapy. Toxicity was tolerable in PLD therapy.

Modelling the emergence of an egalitarian society in the n-player game framework.

Unlike other primates, human foragers have an egalitarian society. Therefore, the evolution of egalitarian behaviour has been the subject of long-standing debate in a wide variety of disciplines. A recent hypothesis states that a social control against potentially dominant individuals played an important role in the emergence of an egalitarian society. In the present study, we modelled this hypothesis based on the n-player game framework, in which the owner, who may attempt to monopolise resources, could be punished by a coalition of other group members. Our results suggest that a potentially despotic payoff structure can promote the evolution of egalitarian behaviour. Besides, large group size, small cost of competition, and variation in the strengths of individuals can promote the evolution of egalitarian behaviour. Our results suggest the importance of both social control against dominant individuals and benefits of a coalition for the evolution of egalitarian behaviour.

Population changes in residential clusters in Japan.

Population dynamics in urban and rural areas are different. Understanding factors that contribute to local population changes has various socioeconomic and political implications. In the present study, we use population census data in Japan to examine contributors to the population growth of residential clusters between years 2005 and 2010. The data set covers the entirety of Japan and has a high spatial resolution of 500 × 500 m2, enabling us to examine population dynamics in various parts of the country (urban and rural) using statistical analysis. We found that, in addition to the area, population density, and age, the shape of the cluster and the spatial distribution of inhabitants within the cluster are significantly related to the population growth rate of a residential cluster. Specifically, the population tends to grow if the cluster is "round" shaped (given the area) and the population is concentrated near the center rather than periphery of the cluster. Combination of the present results and analysis framework with other factors that have been omitted in the present study, such as migration, terrain, and transportation infrastructure, will be fruitful.

A Potentially Useful Addition to Predict Spontaneous Resolution of Uterine Artery Pseudoaneurysm: Absence of Diastolic Flow.

Pregnancy-associated uterine artery pseudoaneurysm (UAP) usually requires transarterial embolization (TAE) irrespective of the presence/absence of current bleeding. Some UAP cases spontaneously resolve without TAE; however, such UAP is not well characterized. Here, we suggest that Pulse Wave Doppler may become an addition to predict its spontaneous resolution. A woman underwent 1st-trimester vaginal termination. Vaginal bleeding repeated and, 36 days later, an intrauterine low-echoic mass (24 mm) with swirling blood flow and arterial waveforms (Pulse Wave Doppler) and an enhanced intrauterine sac-like structure without current extravasation were observed, leading to the diagnosis of UAP. Subsequently, the low-echoic mass mostly disappeared but the swirling flow was still observed, with Pulse Wave Doppler revealing arterial flow but the absence of diastolic flow. Finally, the flow disappeared and UAP resolved. This observation reconfirmed spontaneous UAP resolution. The "absent diastolic flow," possibly indicative of decreased intrasac blood flow, may be a candidate for predicting UAP resolution.

Effects of the distant population density on spatial patterns of demographic dynamics.

Spatio-temporal patterns of population changes within and across countries have various implications. Different geographical, demographic and econo-societal factors seem to contribute to migratory decisions made by individual inhabitants. Focusing on internal (i.e. domestic) migration, we ask whether individuals may take into account the information on the population density in distant locations to make migratory decisions. We analyse population census data in Japan recorded with a high spatial resolution (i.e. cells of size 500×500 m) for the entirety of the country, and simulate demographic dynamics induced by the gravity model and its variants. We show that, in the census data, the population growth rate in a cell is positively correlated with the population density in nearby cells up to a distance of 20 km as well as that of the focal cell. The ordinary gravity model does not capture this empirical observation. We then show that the empirical observation is better accounted for by extensions of the gravity model such that individuals are assumed to perceive the attractiveness, approximated by the population density, of the source or destination cell of migration as the spatial average over a circle of radius ≈1 km.

Violence in the prehistoric period of Japan: the spatio-temporal pattern of skeletal evidence for violence in the Jomon period.

Whether man is predisposed to lethal violence, ranging from homicide to warfare, and how that may have impacted human evolution, are among the most controversial topics of debate on human evolution. Although recent studies on the evolution of warfare have been based on various archaeological and ethnographic data, they have reported mixed results: it is unclear whether or not warfare among prehistoric hunter-gatherers was common enough to be a component of human nature and a selective pressure for the evolution of human behaviour. This paper reports the mortality attributable to violence, and the spatio-temporal pattern of violence thus shown among ancient hunter-gatherers using skeletal evidence in prehistoric Japan (the Jomon period: 13 000 cal BC-800 cal BC). Our results suggest that the mortality due to violence was low and spatio-temporally highly restricted in the Jomon period, which implies that violence including warfare in prehistoric Japan was not common.

Laparoscopic Cholecystectomy for a Patient with Left-sided Gallbladder.

A 47-year-old man who presented with epigastric pain after a meal was diagnosed with biliary sludge present in the gallbladder. Endoscopic retrograde cholangiopancreatography showed normal anatomy of the biliary tree. During the exploratory phase of a laparoscopic cholecystectomy using four ports positioned as usual, surgeons observed a left-sided gallbladder. A review of the preoperative imaging by computed tomography confirmed a round ligament connected to the right portal umbilical portion. It also established that the gallbladder was located to the left of the round ligament, and attached to the left lateral segment of the liver. Laparoscopic cholecystectomy was performed successfully in this patient with the usual port site and careful dissection with a normograde approach. The patient was discharged on the second postoperative day with an uneventful course. Prior identification of a left-sided gallbladder is possible with cautious attention. In particular, it is important for the surgeon to be aware of unusual alterations in the portal and biliary anatomy associated with this anomaly to safely complete a laparoscopic cholecystectomy.