Advances in Medical Sciences

Assessing the predictive response of a simple and sensitive blood-based biomarker between estrogen-negative solid tumors

We investigated N Three-dimensional (3D) spheroids models of ER- and estrogen-receptor-positive (ER+) from breast and ovarian tumor, cultured for 9 weeks, were assayed for cellular levels of inducible nitric oxide synthase (NOS2), nitric oxide (as total nitrite) and l-Arginine, and compared to NOHA in culture medium. Statistical difference was set at p < 0.01. Nine-week in vitro studies showed a progressive NOHA reduction in culture medium by at least 0.4-0.8 fold, and 0.65-0.92 fold only in the ER- breast tumor and ER- ovarian tumor 3D spheroids, respectively; with increases in cellular NOS2 and nitric-oxide levels, by at least 1.0-2.45 fold in both ER- tumor subtype 3D spheroids (p < 0.01; n = 6). Within ER- subtypes, medium NOHA decreased by ≥ 38.9% in ovarian cancer over breast cancer 3D-spheroids, with cellular increases in NOS2 (by ≥ 17.4%), and nitric oxide (by ≥ 18.8%). Cellular l-Arginine to medium NOHA ratio was higher, and by at least 6.5-22.5 fold in ER- breast tumor 3D-spheroids, and at least 10-70 fold in ER- ovarian tumor 3D spheroids, than in ER+ and control conditions; and was ≥48% higher in ER- ovarian cancer than in ER- breast cancer 3D-spheroids. The present study shows NOHA as a sensitive and selective indicator differentiating and distinguishing ER- subtypes based on the tumor grade.

Column chart prediction model for ovarian cancer based on serum ovarian tumor related biomarkers and validation

The aim was to study the predictive model and validate serum ovarian tumor-related biomarkers for ovarian cancer histograms. We randomly selected 181 patients with ovarian tumors and 80 healthy individuals who underwent physical examinations from the hospital's medical record information system as the study participants. Clinical data and detection results of ovarian tumor-related markers such as serum carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125), carbohydrate antigen 19-9 (CA19-9), and human epididymal protein (HE4) were collected from all study participants for analysis. Significant differences were found in serum CEA, CA125, CA19-9, and HE4 levels between healthy controls, benign ovarian tumors, and ovarian cancer (P ​< ​0.05). Dysmenorrhea (present), family history (present), age at menarche, menstrual period, number of pregnancies, natural abortion frequency, number of induced abortions, CEA, CA125, CA19-9, HE4 were all influencing factors for the incidence of ovarian cancer (P ​< ​0.05). The number of induced abortions, CEA, CA125, CA19-9, and HE4 were all independent risk factors for ovarian cancer, while the natural abortion frequency was a protective factor for ovarian cancer (P ​< ​0.05). The constructed column chart prediction model had good discrimination and prediction accuracy for ovarian cancer, good clinical utility, and higher predictive performance for ovarian cancer than traditional ROMA models. The ovarian cancer column chart prediction model based on serum ovarian tumor related markers has good discrimination and prediction accuracy for ovarian cancer, with high clinical utility. Future research may need to incorporate more serum markers related to ovarian cancer to further improve the performance of predictive models.

Novel factors of cisplatin resistance in epithelial ovarian tumours

Ovarian tumours are these days one of the biggest oncogynecological problems. In addition to surgery, the treatment of ovarian cancer includes also chemotherapy in which platinum preparations are one of the most used chemotherapeutic drugs. The principle of antineoplastic effects of cisplatin (cis-diamminedichloroplatinum(II), CDDP) is its binding to the DNA and the formation of adducts. While DNA adducts induce the process of apoptosis, or inhibit the process of DNA replication, which prevents further division of tumour cells, various molecular mechanisms can reverse this process. On the other hand, with increasing scientific knowledge, it is becoming clearer that chemotherapy resistance is a very complex process. In this regard, factors and the amount of their expression may regulate the effect of resistance to chemotherapy. This review focuses on new molecular mechanisms and factors such as mitochondrial dynamics, epithelial-mesenchymal transition (EMT), cluster of differentiation, exosomes and others, that could be involved in the emergence of CDDP resistance.

Targeting treatment resistance in cervical cancer: A new avenue for senolytic therapies

Cervical cancer poses a significant global health challenge, particularly impacting women in economically developing nations. This disparity stems from a combination of factors, including inadequate screening infrastructure and resource limitations. However, the foremost contributor is the widespread lack of awareness and limited accessibility to Human Papillomavirus (HPV) vaccination, which is a key preventative measure against cervical cancer development. Despite advancements in cervical cancer prevention, treatment resistance remains a major hurdle in achieving improved patient outcomes. Cellular senescence, specifically the senescence-associated secretory phenotype (SASP) and its bidirectional relationship with the immune system, has been implicated in resistance to conventional cervical cancer chemotherapy treatments. The exact mechanisms by which this state of growth arrest and the associated changes in immune regulation contribute to cervical cancer progression and the associated drug resistance are not entirely understood. This underscores the necessity for innovative strategies to address the prevalence of treatment-resistant cervical cancer, with one promising avenue being the utilisation of senolytics. Senolytics are agents that have promising efficacy in clearing senescent cells from tumour tissues, however neither the utilisation of senolytics for addressing senescence-induced treatment resistance nor the potential integration of immunotherapy as senolytic agents in cervical cancer treatment has been explored to date. This review provides a concise overview of the mechanisms underlying senescence induction and the pivotal role of the immune system in this process. Additionally, it explores various senolytic approaches that hold significant potential for advancing cervical cancer research.

Progesterone signaling in uterine leiomyoma biology: Implications for potential targeted therapy

Uterine leiomyomas (ULs) are the most common benign smooth muscle cell steroid-dependent tumors that occur in women of reproductive age. Progesterone (P4) is a major hormone that promotes the ULs development and growth. P4 action in ULs is mediated mainly by its nuclear progesterone receptors (PGRs), although rapid non-genomic responses have also been observed. Data on the membrane progesterone receptors (mPRs) regulated signaling pathways in ULs in the available literature is still very limited. One of the essential characteristics of ULs is the excessive production of extracellular matrix (ECM). P4 has been shown to stimulate ECM production and collagen synthesis in ULs. Recent research demonstrated that, despite their benign nature, ULs may present with abnormal vasculature. P4 has been shown to regulate angiogenesis in ULs through the upregulation of vascular endothelial growth factor (VEGF) and by controlling the secretion of permeability factors. This review summarizes the key findings regarding the role of PGRs and mPRs in ULs, especially highlighting the potential ECM and angiogenesis modulation by P4. An increased understanding of this mechanistic role of nuclear and specifically mPRs in the biology of P4-modulated ECM and angiogenesis in the growth of ULs could turn out to be fundamental for developing effective targeted therapies for ULs.

Identification of novel diagnostic biomarkers in endometrial cancer using targeted metabolomic profiling

Endometrial cancer (EC) is the most common gynecological malignancy with high disease burden especially in advanced stages of the disease. Our study investigated the metabolomic profile of EC patient's serum with the aim of identifying novel diagnostic biomarkers that could be used especially in early disease detection. Using targeted metabolomic serum profiling based on HPLC-TQ/MS, women with EC (n ​= ​15) and controls (n ​= ​21) were examined for 232 endogenous metabolites. Top performing biomarkers included ceramides, acylcarnitines and 1-methyl adenosine. Top 4 biomarkers combined achieved 94% sensitivity with 75% specificity with AUC 92.5% (CI 90.5-94.5%). Individual markers also provided significant predictive values: C16-ceramide achieved sensitivity 73%, specificity 81%, AUC 0.83, C22-ceramide sensitivity 67%, specificity 81%, AUC 0.77, hydroxyhexadecenoylcarnitine sensitivity 60%, specificity 96%, AUC 0.76 and 1-methyladenosine sensitivity 67%, specificity 81%, AUC 0.75. The individual markers, however, did not reach the high sensitivity and specificity of the 4-biomarker combination. Using mass spectrometry targeted metabolomic profiling, ceramides, acylcarnitines and 1-methyladenosine were identified as potential diagnostic biomarkers for EC. Additionally, these identified metabolites may provide additional insight into cancer cell metabolism.

Ropivacaine and lidocaine at clinically relevant concentrations suppress proliferation and migration of ovarian cancer cells and induce morphological alterations

Ovarian cancer ranks as a gynecological malignancy with poor prognosis, specifically if detected late. Primary treatment includes cytoreductive surgery and adjuvant chemotherapy with curative intent. Local anesthetics (LA) administered in the perioperative period may potentially impact patient outcome by several mechanisms. The beneficial impact of LA has been attributed, among other factors, to the drug's inhibitory effect on cancer cells. The primary aim of the study was to evaluate the effect of clinically relevant concentrations of ropivacaine and lidocaine on ovarian cancer cell lines. Three ovarian cancer cell lines (SKOV-3, SW-626 and CA-OV-3) were treated with 1, 10, 100, or 1000 ​μM of the two LAs. Cell function and morphology were assessed in the following ways: cell counting, phase-contrast and holographic microscopy, a conventional MTT assay for dose response testing, wound healing assay for migration, and cancer stem cell (CSC) identification by aldehyde dehydrogenase. Both ropivacaine and lidocaine significantly reduced cell number, altered morphology, suppressed migration, and decreased the population of CSCs in a concentration-dependent manner. LAs exert a direct inhibitory effect on ovarian cancer cell lines in vitro, suggesting their potential benefits in perioperative management for patients undergoing surgery. Clinical studies using LA during ovarian cancer surgery are needed.

The TGFBI gene and protein expression in topotecan resistant ovarian cancer cell lines

The primary limiting factor in achieving cures for patients with cancer, particularly ovarian cancer, is drug resistance. The mechanisms of drug resistance of cancer cells during chemotherapy may include compounds of the extracellular matrix, such as the transforming growth factor-beta-induced protein (TGFBI). In this study, we aimed to analyze the TGFBI gene and protein expression in different sensitive and drug-resistant ovarian cancer cell lines, as well as test if TGFBI can be involved in the response to topotecan (TOP) at the very early stages of treatment. In this study, we conducted a detailed analysis of TGFBI expression in different ovarian cancer cell lines (A2780, A2780TR1, A2780TR2, W1, W1TR, SKOV-3, PEA1, PEA2 and PEO23). The level of TGFBI mRNA (QPCR), intracellular and extracellular protein (Western blot analysis) were assessed in this study. We observed upregulation of TGFBI mRNA in drug-resistant cell lines and estrogen-receptor positive cell lines, which was supported by overexpression of both intracellular and extracellular TGFBI protein. We also showed the TGFBI expression after a short period of treatment of sensitive ovarian cancer cell lines with TOP. The expression of TGFBI in ovarian cancer cell lines suggests its role in the development of drug resistance.

Study on the effect of 5-aminolevulinic acid-mediated photodynamic therapy combined with cisplatin on human ovarian cancer OVCAR-3 ​cells

This article explores the effect of 5-aminolevulinic acid (5-ALA)-mediated photodynamic therapy (PDT) combined with cisplatin (CDDP) on the apoptosis of human ovarian cancer cells and the mechanism of action of the combination therapy. Human ovarian cancer OVCAR-3 ​cells were cultured in vitro and divided into 5-ALA/PDT group, CDDP group and combined treatment group (5-ALA/PDT combined with different concentrations of CDDP). After administration of the corresponding drugs, a CCK-8 assay was used to detect the inhibition rate of cell proliferation. After Rhodamine 123 staining, mitochondrial membrane potential changes were observed under fluorescence microscopy. The apoptosis rate and reactive oxygen species (ROS) content were detected by flow cytometry. Western blotting was used to detect protein expression. The CCK-8 assay showed that CDDP in combination with 5-ALA/PDT significantly enhanced cytotoxicity compared to treatment with CDDP alone and that low doses of CDDP were sufficient to induce these combination effects. The mitochondrial membrane potential in each combination treatment group gradually decreased with increasing CDDP concentration, while the apoptosis rate and reactive oxygen species (ROS) content detected by flow cytometry gradually increased. Western blotting assay showed that the expression of bax, cleaved caspase-9, cleaved caspase-3, and cleaved PARP was increased, while the expression of bcl-2, caspase-9, caspase-3, and PARP was decreased, and the differences were statistically significant (P ​< ​0.05). In summary, 5-ALA/PDT combined with CDDP can effectively inhibit cell proliferation and promote apoptosis, and this combination may induce apoptosis by activating the mitochondrial pathway.