BACKGROUND:Extensive research has highlighted the pivotal roles of extracellular matrix (ECM) mechanics and actin cytoskeleton dynamics in regulating cancer progression and metastasis. Mechanical cues from the ECM govern cell motility, proliferation, and invasiveness through mechanotransduction pathways that translate physical stimuli into biochemical signals. A central downstream response is the reorganization of actin filaments, which controls cell shape, force generation, and migration. OBJECTIVE:This review aims to clarify how ECM stiffness and cellular mechanical properties jointly shape cancer cell behavior, with particular emphasis on motility and mechanotransduction. CONTENT:As tumors progress, a "mechanical paradox" emerges, namely the ECM becomes progressively stiffer, while cancer cells often display reduced stiffness compared with their normal counterparts. Recent studies reinterpret this phenomenon as a form of dynamic reciprocity, in which cancer cells actively remodel their surrounding ECM through bidirectional mechanical feedback loops. These concurrent but opposing mechanical alterations have been linked to metastatic potential, yet their combined impact on the dynamic properties of cancer cells remains poorly understood. This review synthesizes current findings on the influence of ECM stiffness, cellular elasticity, and cytoskeletal remodeling on cancer cell motility and mechanotransduction. CONCLUSION:By integrating insights into ECM mechanics and cellular elasticity, this review highlights how reciprocal mechanical interactions between cancer cells and their microenvironment contribute to metastatic progression. Understanding this interplay will be crucial for developing more accurate mechanobiological models and identifying new mechanotherapeutic strategies.

There is a growing need for non-surgical, fertility-preserving treatments for young patients with cervical cancer. This study explores biomarker-driven non-thermal plasma (NTP) therapy as a localized therapeutic strategy with deep tissue penetration, highlighting its potential for controlled oxidative modulation and targeted drug delivery. Screening of ROS-related molecules revealed an association between sensitivity to NTP and the expression of the antioxidant enzyme superoxide dismutase 1 (SOD1), with human papillomavirus (HPV) oncoprotein E6 and p53 identified as upstream regulators. Additionally, NTP was shown to influence toll-like receptor signaling 9 and induce immunogenic cell death (ICD), enhancing localized immune activation within the tumor microenvironment. In a xenografted animal tumor model, SOD1 was identified as a potential biomarker for NTP, while in a syngeneic tumor model using TC-1 cell lines expressing HPV16-E6 and HPV16-E7, NTP treatment demonstrated both antitumor effects and an increase in tumor-infiltrating lymphocytes. Evaluation of NTP penetration in patient uterine tissues showed that the depth of penetration was significantly greater in the transformation zone, where cervical cancer occurs, than in the squamous zone. Notably, NTP reached a penetration depth of ∼5 mm in cervical cancer tissues, suggesting its potential as a drug delivery enhancer for localized therapeutic applications. These findings suggest that NTP may serve as a novel non-invasive platform for controlled therapeutic delivery in cervical cancer treatment, offering an alternative to conventional surgical approaches.

OBJECTIVES:Inconsistent results are available regarding the association between low estimated glomerular filtration rate (eGFR) and lung cancer risk. We aimed to explore the risk of lung cancer according to eGFR category in the Korean population. METHODS:We included 358,293 adults who underwent health checkups between 2009 and 2010, utilizing data from the National Health Insurance Service-National Sample Cohort. Participants were categorized into 3 groups based on their baseline eGFR, as determined using the Chronic Kidney Disease Epidemiology Collaboration equation: group 1 (eGFR ≥90 mL/min/1.73 m2), group 2 (eGFR ≥60 to <90 mL/min/1.73 m2), and group 3 (eGFR <60 mL/min/1.73 m2). Incidences of lung cancer were identified using the corresponding codes from the International Classification of Diseases, 10th revision. Multivariate Cox proportional hazard models were employed to calculate the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lung cancer incidence up to 2019. RESULTS:In multivariate analysis, group 2 exhibited a 26% higher risk of developing lung cancer than group 1 (HR, 1.26; 95% CI, 1.19 to 1.35). Furthermore, group 3 demonstrated a 72% elevated risk of lung cancer relative to group 1 (HR, 1.72; 95% CI, 1.58 to 1.89). Among participants with dipstick proteinuria of 2+ or greater, group 3 faced a significantly higher risk of lung cancer than group 1 (HR, 2.93; 95% CI, 1.37 to 6.24). CONCLUSIONS:Low eGFR was significantly associated with increased lung cancer risk within the Korean population. A particularly robust association was observed in individuals with severe proteinuria, emphasizing the need for further investigation.

Proteinuria is considered as a predictor for cardiovascular complications in diabetes mellitus (DM). However, no study has examined the association between changes in proteinuria and the risk of diabetic microvascular complications. Study participants were 71,825 DM patients who received urine dipstick test for proteinuria both in 2003–2004 and 2006–2007. They were categorized into four groups according to changes in proteinuria over 3 years (negative: negative → negative, resolved: proteinuria ≥ 1+ → negative, incident: negative → proteinuria ≥ 1+, persistent: proteinuria ≥ 1+ → proteinuria ≥ 1+). Cox-proportional hazard model was used in assessing the adjusted hazard ratios (HR) and 95

Cold atmospheric plasma (CAP) has rapidly advanced as a pivotal area in medical research, notably in wound healing and cancer therapy. This review presents an overview of the mechanisms underlying the action of CAP on wound healing and cancer treatment. CAP plays opposing roles in wound healing and cancer treatment. In wound healing, CAP promotes cell migration and proliferation and eradicates pathogens near the wound site. In cancer therapy, CAP has been recognized for its ability to induce cell death through multiple mechanisms. These include activating the mitochondrial pathway, provoking endoplasmic reticulum stress, generating reactive oxygen species (ROS) and reactive nitrogen species (RNS), causing DNA damage, arresting the cell cycle, and modulating signaling pathways. Additionally, CAP's oxidative stress can lead to significant changes in DNA and RNA within the nucleus, further contributing to its anti-cancer properties. These diverse effects underscore CAP's therapeutic potential, though outcomes may differ based on the type of cancer and experimental settings. Furthermore, we compared the CAP application conditions for wound healing and cancer cell treatment. The type and concentration of ROS and RNS depend on plasma generation and treatment conditions. Thus, we aimed to identify the correlations between plasma properties and mechanisms of action by comparing CAP generation and treatment conditions in wound healing and cancer cell treatment.

Objective Polycystic ovarian syndrome is associated with diverse pregnancy related complications and endometrial cancer. However, research on the relationship between pregnancy complications and endometrial cancer in women with polycystic ovarian syndrome is scarce. We aimed to examine the association between gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth and the risk of endometrial cancer in women with polycystic ovarian syndrome. Methods We analyzed data from the National Health Information Database established by the Korean National Health Insurance Service between January 2002 and December 2019. We included women with gestational diabetes mellitus, pregnancy induced hypertension, preterm birth, and endometrial cancer from among the polycystic ovarian syndrome population. All conditions were diagnosed according to the Korean Informative Classification of Diseases, 10th revision codes. Age, area of residence, income, body mass index, waist circumference, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, fasting blood sugar, and creatinine levels were included as covariates in the multiple logistic regression analysis. Results Of 467 221 women with polycystic ovarian syndrome included, 5099 had endometrial cancer. Age, residence, income, body mass index, waist circumference, total cholesterol, high density lipoprotein, low density lipoprotein, triglycerides, fasting blood sugar, and creatinine levels differed significantly between the endometrial cancer and non-endometrial cancer groups (p≤0.001–0.032). Among the polycystic ovarian syndrome population, the odds ratios (ORs) of endometrial cancer were 1.50, 1.43, and 1.23 in women with a history of gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth, respectively, compared with those without a history of these conditions (OR 1.50, 95% confidence interval (CI) 1.32 to 1.69, p<0.001; 1.43, 1.04 to 1.97, p=0.027; and 1.23, 1.05 to 1.45, p=0.011, respectively). Conclusion Our results suggest that a history of pregnancy complications (gestational diabetes mellitus, pregnancy induced hypertension, and preterm birth) increases the risk of endometrial cancer in women with polycystic ovarian syndrome.

Introduction Ovarian cancer stem-like cells (CSCs) have been implicated in tumor recurrence, metastasis, and drug resistance. Accumulating evidence has demonstrated the antitumor effect of plasma-activated medium (PAM) in various carcinomas, including ovarian cancer. Thus, PAM represents a novel onco-therapeutic strategy. However, its impact on ovarian CSCs is unclear. Methods In this study, we assessed whether PAM regulates the stemness properties in a CSC-like spheroid model. Furthermore, we investigated the potential enhanced anti-cancer effects of combination treatment with conventional chemotherapeutic agents and PAM using in vitro and in vivo models. Results PAM exhibited synergistic cytotoxicity with cisplatin (CDDP) but not with paclitaxel and doxorubicin. In a peritoneal metastasis xenograft model established via intraperitoneal spheroid injection, PAM intraperitoneal therapy significantly suppressed peritoneal carcinomatosis (tumor size and number), with a more significant decrease observed due to the combined effects of PAM and CDDP with no side effects. Conclusion/Implications We demonstrated the anti-CSC activity of PAM and the synergistic cytotoxic effect of the PAM and CDDP combination therapy on ovarian CSCs. Analysis of intraperitoneal PAM and CDDP combination therapy in a spheroid culture xenograft model of ovarian cancer showed promising results. Further studies are needed to determine the molecular mechanism underlying the synergistic anti-cancer effects of PAM and anti-cancer drugs to enhance their antitumor efficacy against ovarian CSCs and reduce the relevant side effects.

IntroductionCancer stem-like cells (CSCs) are recognized to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a promising target for anticancer therapies, its function in ovarian CSCs remains unknown. We present evidence that WEE1 regulates CSC properties and tumor resistance to carboplatin through a microRNA-dependent mechanism.MethodsPlasmid DNA constructs were transfected into human ovarian cancer cell lines. RNA and protein were extracted from pathologically confirmed tumor tissues. The SKOV3 spheroid tumor model were developed. Immunofluorescence analyses were performed on the xenograft tumors. miR-424 and miR-503 were detected by quantitative real-time PCR and western blot analysis. Spheroid formation assay was performed to investigate the presence and self-renewal ability of CSCs.ResultsWe found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but restoring WEE1 expression reversed this effect. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503- mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer.Conclusion/ImplicationsWe identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Background: Several studies have indicated that prenatal exposure to ambient air pollution is associated with an increased risk of gestational diabetes mellitus, hypertensive disorder during pregnancy, preterm birth, and stillbirth. However, no previous study has focused on the association between the number of pregnancy complications and exposure to ambient air pollution. Objectives: To investigate the association between prenatal exposure to ambient air pollutants and the number of pregnancy complications in high-risk pregnancies. Methods: We collected data on gestational diabetes mellitus, hypertensive disorder during pregnancy, preterm birth, and stillbirth from the National Health Information Databases, provided by the Korean National Health Insurance Service. To assess individual-level exposure to air pollutants, a spatial prediction model and area-averaging approach were used. Results: From 2015 to 2018, data of 789,595 high-risk pregnancies were analyzed. The ratio of gestational diabetes mellitus in the country was the highest, followed by preterm birth, hypertensive disorder during pregnancy, and stillbirth. Approximately 71.7% of pregnant women (566,143) presented with one pregnancy complication in identical pregnancies, 27.5% (216,714) presented with two, and 0.9% (6738) presented with three or more. Multiple logistic regression models with adjustments for age, residence, and income variables indicated that the risk of having two or more pregnancy complications was positively associated with the exposure to higher levels of PM10 (odds ratio [OR], 1.11; 95% confidence interval [CI], 1.09–1.12) and PM2.5 (OR, 1.14; 95% CI, 1.12–1.15). The highest quartile presented higher odds of two or more pregnancy complications compared with the lower three quartiles of PM10, PM2.5, CO, NO2, and SO2 exposures (p < 0.001). Conclusion: The results indicate that the risk of pregnancy complications is positively associated with the exposure to the high concentrations of PM10, PM2.5, CO, NO2, and SO2.

Cancer stem-like cells (CSCs) have been suggested to be responsible for chemoresistance and tumor recurrence owing to their self-renewal capacity and differentiation potential. Although WEE1 is a strong candidate target for anticancer therapies, its role in ovarian CSCs is yet to be elucidated. Here, we show that WEE1 plays a key role in regulating CSC properties and tumor resistance to carboplatin via a microRNA-dependent mechanism. We found that WEE1 expression is upregulated in ovarian cancer spheroids because of the decreased expression of miR-424 and miR-503, which directly target WEE1. The overexpression of miR-424/503 suppressed CSC activity by inhibiting WEE1 expression, but this effect was reversed on the restoration of WEE1 expression. Furthermore, we demonstrated that NANOG modulates the miR-424/503-WEE1 axis that regulates the properties of CSCs. We also demonstrated the pharmacological restoration of the NANOG-miR-424/503-WEE1 axis and attenuation of ovarian CSC characteristics in response to atorvastatin treatment. Lastly, miR-424/503-mediated WEE1 inhibition re-sensitized chemoresistant ovarian cancer cells to carboplatin. Additionally, combined treatment with atorvastatin and carboplatin synergistically reduced tumor growth, chemoresistance, and peritoneal seeding in the intraperitoneal mouse models of ovarian cancer. We identified a novel NANOG-miR-424/503-WEE1 pathway for regulating ovarian CSCs, which has potential therapeutic utility in ovarian cancer treatment.

Polycystic ovarian syndrome (PCOS) is a common endocrine disorder in women of reproductive age and is associated with an increased risk of obesity, compensatory hyperinsulinemia, dyslipidemia, metabolic syndrome, and endometrial cancer. This study analyzed 544619 women using the Korean Informative Classification of Disease, version 10, codes E28.0-E28.9 in the population-based National Health Information Databases from 2010 to 2019. The age-adjusted incidence and prevalence rates of PCOS over 10 years among Korean women were 2.8% and 4.3%, respectively; and they increased in the late teens, peaked in the 20s, and began to decrease at the age of 30. We also found that the body mass index, levels of fasting blood glucose, and high-density lipoprotein values in the recent two years (2018-2019) were higher in women with PCOS compared to the general population. This is the first study to investigate the prevalence of PCOS in a nationwide population of reproductive-aged Korean women. Further research is needed to examine the short- and long-term health risks and psychological problems associated with PCOS.

Ovarian cancer stem-like cells (CSCs) have been implicated in tumor recurrence, metastasis, and drug resistance. Accumulating evidence has demonstrated the antitumor effect of plasma-activated medium (PAM) in various carcinomas, including ovarian cancer. Thus, PAM represents a novel onco-therapeutic strategy. However, its impact on ovarian CSCs is unclear. Here, we show that ovarian CSCs resistant to high-dose conventional chemotherapeutic agents used for ovarian cancer treatment exhibited dose-dependent sensitivity to PAM. In addition, PAM treatment reduced the expression of stem cell markers and sphere formation, along with the aldehyde dehydrogenase- or CD133-positive cell population. We further investigated the effect of PAM in combination with other chemotherapeutics on ovarian CSCs in vitro. PAM exhibited synergistic cytotoxicity with cisplatin (CDDP) but not with paclitaxel and doxorubicin. In a peritoneal metastasis xenograft model established via intraperitoneal spheroid injection, PAM intraperitoneal therapy significantly suppressed peritoneal carcinomatosis (tumor size and number), with a more significant decrease observed due to the combined effects of PAM and CDDP with no side effects. Taken together, our results indicate that PAM inhibits ovarian CSC traits and exhibits synergetic cytotoxicity with CDDP, demonstrating PAM as a promising intraparietal chemotherapy for enhancing antitumor efficacy and reducing side effects.

Although uterine leiomyomas are the most common benign uterine tumors in women, there is no effective therapy that can also preserve the uterus and maintain fertility. The work aimed to work was to discover a potential natural agent that has pharmacological activities on uterine leiomyomas with fewer adverse effects. We chose Rhus verniciflua Stokes (RVS) as a candidate after primary cytotoxicity testing, and analyzed the RVS components that showed pharmacological activity. Leiomyoma cells and myometrium cells were cultured from uterine tissues obtained from patients, and were treated with RVS at varying concentrations. RVS was cytotoxic in both leiomyoma and myometrium cells; however, the effects were more prominent in the leiomyoma cells. Among the bioactive components of RVS, fisetin showed significant pharmacological effects on leiomyoma cells. Fisetin showed excellent leiomyoma cell cytotoxicity and induced apoptotic cell death with cell cycle arrest. The apoptotic cell death appeared to involve not one specific pathway but multichannel pathways (intrinsic, extrinsic, MARK, and p53-mediated pathways), and autophagy. The multichannel apoptosis pathways were activated with a low concentration of fisetin (IC50). This is the first demonstration to show the pharmacological activities of fisetin on leiomyoma cells. These findings suggest that fisetin may be used for the prevention and treatment of uterine leiomyomas. Since fisetin can be obtained from plants, it may be a safe and effective alternative treatment for uterine leiomyomas.

Cervical cancer is the fourth most common cancer in women worldwide. The current approaches still have limitations in predicting the therapy outcome of each individual because of cancer heterogeneity. The goal of this study was to establish a gene expression signature that could help when choosing the right therapeutic method for the treatment of advanced-stage cervical cancer. The 666 patients were collected from four independent datasets. The 70-gene expression signature was established using univariate Cox proportional hazard regression analysis. The 70-gene signature was significantly different between low- and high-risk groups in the training dataset (p = 4.24e-6) and in the combined three validation datasets (p = 4.37e-3). Treatment of advanced-stage cancer patients in the high-risk group with molecular-targeted therapy combined with chemoradiotherapy yielded a better survival rate than with only chemoradiotherapy (p = 0.0746). However, treatment of the patients in the low-risk group with the combined therapy resulted in significantly lower survival (p = 0.00283). Functional classification of 70 genes revealed involvement of the angiogenesis pathway, specifically phosphatidylinositol 3-kinase signaling (p = 0.040), extracellular matrix organization (p = 0.0452), and cell adhesion (p = 0.011). The 70-gene signature could predict the prognosis and indicate an optimal therapeutic modality in molecular-targeted therapy or chemotherapy for advanced-stage cervical cancer.

Introduction/Background The cold atmospheric plasma has been extensively researched as a new cancer treatment technology. We investigated the selective cytotoxic effects of cold atmospheric plasma in cervical cancer cells. Methodology Two human cervical cancer cell lines (HeLa and SiHa) and one human fibroblast (HFB) cell line were treated with cold atmospheric plasma. All cells underwent apoptotic death induced by plasma in a dose-dependent manner. The plasma showed selective inhibition of cell proliferation in cervical cancer cells compared to human fibroblast, control. Results To evaluate the cytotoxic effects of non-thermal micro-DBD plasma in both cervical cancer cells and HFBs, we used microscopy to examine the morphological changes of cells and performed MTT assays. The morphology of HFBs, HeLa and SiHa cells did not change significantly after plasma treatment; however, fragmentation of cells was clearly visible after plasma treatment. The cell density decreased in all cases with plasma treatment; however, the decrease was more obvious in SiHa cells. To examine whether apoptosis induced by cold atmospheric plasma is involved in the activation of caspase, cells were incubated with and without plasma treatment for 3 min (E=33 J), and then caspase-3, -6, -8, and -9 activity was evaluated using a commercial caspase assay kit. The flow cytometry shows that cold atmospheric plasma can arrest the cell cycle at subG0 phase in a cell-type-specific manner. Conclusion Cold atmospheric plasma showed selective apoptotic effects depending on cell type. Plasma treatment was more effective in cervical cancer cells compared to control. In cervical cancer cells, the effects of plasma on SiHa cells were stronger than its effects on HeLa cells. This evidence of selective apoptosis was in agreement with the observed gene expression alterations induced by plasma treatment. Disclosure Nothing to disclose.

Introduction/Background Diagnosis of uterine sarcomais is a challenging task for clinicians because its position is not easily accessible by current conventional techniques. In addition, standardized treatment for uterine sarcoma has not yet been established due to its rarity and heterogeneity. We investigated the apoptotic cell death of uterine sarcoma cells (SK-UT-1B) induced by Gyejibokryunghwan (GBH). GBH, an herbal medicine, has been widely used for gynecological diseases in oriental medicine. Methodology SK-UT-1B cells were treated with GBH of varying concentrations from 0 to 500 µg/ml. The mechanism of cell death was investigated through multiple analysis methods, including flow cytometry, cell cycle, and western blotting. Results Flow cytometric analysis revealed that the number of apoptotic cells increased in a GBH dose-dependent manner. The cell populations of sub-G1 and G0/G1 phases were increased by GBH treatment, indicating apoptosis and cell arrest, while the population of S and G2/M phases decreased. With GBH, the expression levels of cleaved caspase-3, -6, and -9 were upregulated, while the expression levels of pro-caspase-3, -6, and -9 were downregulated in SK-UT-1B cells. Conclusion These results are the first observation of uterine sarcoma cell death induced by GBH and confirmation of the mechanism of cell death, which occurred through the intrinsic apoptotic pathway. Clinically, uterine sarcoma has a poor prognosis with no appropriate treatment. GBH may become a new treatment modality for uterine sarcoma. Disclosure Nothing to disclose