Reproductive Cancers Research Articles

Glutamine and amino acid metabolism as a prognostic signature and therapeutic target in endometrial cancer.

Endometrial cancer (EC) is the most common female reproductive system cancer in developed countries with growing incidence and associated mortality, which may be due to the growing prevalence of obesity. Metabolism reprogramming including glucose, amino acid, and lipid remodeling is a hallmark of tumors. Glutamine metabolism has been reported to participate in tumor proliferation and development. This study aimed to develop a glutamine metabolism-related prognostic model for EC and explore potential targets for cancer treatment. Transcriptomic data and survival outcome of EC were retrieved from The Cancer Genome Atlas (TCGA). Differentially expressed genes related to glutamine metabolism were recognized and utilized to build a prognostic model by univariate and multivariate Cox regressions. The model was confirmed in the training, testing, and the entire cohort. A nomogram combing prognostic model and clinicopathologic features was established and tested. Moreover, we explored the effect of a key metabolic enzyme, PHGDH, on the biological behavior of EC cell lines and xenograft model. Five glutamine metabolism-related genes, including PHGDH, OTC, ASRGL1, ASNS, and NR1H4, were involved in prognostic model construction. Kaplan-Meier curve suggested that patients recognized as high risk underwent inferior outcomes. The receiver operating characteristic (ROC) curve showed the model was sufficient to predict survival. Enrichment analysis recognized DNA replication and repair dysfunction in high-risk patients whereas immune relevance analysis revealed low immune scores in the high-risk group. Finally, a nomogram integrating the prognostic model and clinical factors was created and verified. Further, knockdown of PHGDH showed cell growth inhibition, increasing apoptosis, and reduced migration. Promisingly, NCT-503, a PHGDH inhibitor, significantly repressed tumor growth in vivo (p = 0.0002). Our work established and validated a glutamine metabolism-related prognostic model that favorably evaluates the prognosis of EC patients. DNA replication and repair may be the crucial point that linked glutamine metabolism, amino acid metabolism, and EC progression. High-risk patients stratified by the model may not be sufficient for immune therapy. PHGDH might be a crucial target that links serine metabolism, glutamine metabolism as well as EC progression.

Cancer risk in polycystic ovary syndrome patients: Common treatments and future perspectives

In women of childbearing age, polycystic ovarian syndrome (PCOS) is the most common endocrine and metabolic condition. Ovulatory dysfunction, clinical symptoms of hyperandrogenism, and multiple cystic ovaries are the hallmarks of PCOS. Women who have PCOS may have irregular insulin activity in addition to other difficulties such as pattern hair loss, acne, obesity, infertility, and hirsutism. An unhealthy lifestyle, hereditary causes, androgen exposures, and neuroendocrine factors are frequently the causes of PCOS. This results in an unbalanced hormonal state, hyperandrogenism, high insulin, and inflammation. Due to the overlapping metabolic and endocrine issues, PCOS patients' cancer risk has been the subject of debate for decades.This review article examines the relationship between PCOS and various types of reproductive cancers, focusing on the possible reasons for cancer in PCOS patients.

Hormone replacement therapy did not increase risk of melanoma in Chinese female with menopausal and postmenopausal disorders: A population-based retrospective cohort study in Taiwan.

Hormone replacement therapy (HRT) is widely used to relieve symptoms of menopause with proven efficacy. However, there has been significant controversy surrounding the use of HRT because of its potential link with an increased risk of cancer, particularly female reproductive organ cancers. That HRT increases the risk of melanoma is also disputed, and several cohort studies have produced variable results. To delineate the association between HRT and melanoma in Taiwan, we conducted a population-based retrospective cohort study on 14 291 patients who had received HRT and 57 164 population controls in Taiwan between 2000 and 2013. Multivariate odds ratios (ORs) were calculated utilizing conditional logistic regression. Overall, the use of HRT was not significantly correlated with a higher risk of developing melanoma in Taiwan (95% confidence interval 0.386-1.099; p = 0.341). The hazard ratio analysis of melanoma and different HRTs showed there was no significant association between melanoma and the use of oral or external estrogens alone, including conjugated estrogens, estradiol, and estriol. Estrogen plus progesterone combined therapy was associated with a lower risk of melanoma. Only one case of melanoma was observed among the 2880 patients in this subgroup.

P-064 MicroRNAs as potential biomarkers for male infertility related to Testicular Germ Cell Tumors

Abstract Study question Could microRNAs represent efficient biomarkers to evaluate male infertility and the tendency of develop testicular germ cell tumors (TGCTs)? Summary answer The up-regulation of miR-193a-5p, miR-93-5p and let-7c-5p in TGCT patients with impaired spermiogram could represent a molecular signature of male infertility related to TGCTs. What is known already Testicular germ cell tumors (TGCTs) are the most recurrent tumors in young men with the highest incidence between the ages of 20 and 40 years and represent more than 60% of all cancers diagnosed in this age range. Several studies have shown a correlation between TGCTs and infertility, not only because infertility could be a consequence of testicular damage due to TGCTs but also because infertility may represent a risk factor for TGCTs. Therefore, it is important to find valid biomarkers that could be used to specifically identify infertility related to an increased risk of developing TGCTs. Study design, size, duration From March 2021 to January 2023, we collected 44 seminal plasma samples: 17 from TGCT patients who were undergoing sperm cryopreservation prior to chemotherapy, 14 with impaired spermiogram (IS) and 3 with normal spermiogram (NS) and 27 from control patients, 16 with IS and 11 with NS, undergoing assisted fertilization techniques. We evaluated the potential role of miRNAs as non-invasive biomarkers, analyzing the differential expression of 84 miRNAs in relation to cancer, infertility and both. Participants/materials, setting, methods Semen samples were placed 30’/37 °C, seminal plasma was purified using density-gradient centrifugation and stored at -80 °C. RNA was purified by Qiagen miRNeasy Serum/Plasma Kit and analyzed by miRCURY LNA miRNA SYBR®Green PCR_SerumPlasma, 96-well plate. We applied the 2−ΔΔCT method and statistical significance was evaluated by Significance Analysis of Microarrays, screened by p-values ≤ 0.05. We performed a Pearson correlation analysis applying two-sided p-values. miRTarBASE, MIENTURNET and Cytoscape were used for bioinformatics analysis. Main results and the role of chance In the four comparisons, we found 9 differentially expressed microRNAs. In particular, miR-221-3p, miR-222-3p, miR-204-5p and miR-205-5p down regulation would appear to be related to infertility, regardless to the cancer. Conversely, all TGCT patients shown an up-regulation of miR-376c-3p. Interestingly, up-regulation of miR-193a-5p, miR-93-5p and let-7c-5p specifically discriminates the infertile cancer patients vs other categories. Moreover, these three miRNAs showed a significant positive correlation both in cancer patients with impaired spermiogram and in infertile controls. This correlation demonstrates that their expression changes in the same way in the single samples and strongly suggests their role as early biomarkers of TGCT patients with impaired spermiogram. From the KEGG pathway analysis has emerged that DE miRNAs are involved in several signaling pathway, such as MAPK, mTOR, p53, PI3K-Akt, AMPK, FoxO, JAK-STAT, Ras, Estrogen signaling pathways, as well as cell cycle and cellular senescence. Moreover, from the Diseases Ontology analysis we found than those miRNAs are involved in germ cell tumor, male reproductive organ cancer, prostate cancer, male infertility and azoospermia. Limitations, reasons for caution The data must be validated by single assays in higher number of samples. These experiments are currently ongoing. Wider implications of the findings Three of the DE miRNAs are overexpressed in TGCT with impaired spermiogram patients. Specifically, they are over-expressed in TGCT with impaired spermiogram compared to infertile controls, so they may represent specific biomarkers able to discriminate, among the young men with infertility, those with higher risk of develop testicular cancer. Trial registration number Not applicable

A New Type of Endometrial Cancer Models in Mice Revealing the Functional Roles of Genetic Drivers and Exploring their Susceptibilities.

Endometrial cancer (EC) is the most common female reproductive tract cancer and its incidence has been continuously increasing in recent years. The underlying mechanisms of EC tumorigenesis remain unclear, and efficient target therapies are lacking, for both of which feasible endometrial cancer animal models are essential but currently limited. Here, an organoid and genome editing-based strategy to generate primary, orthotopic, and driver-defined ECs in mice is reported. These models faithfully recapitulate the molecular and pathohistological characteristics of human diseases. The authors names these models and similar models for other cancers as organoid-initiated precision cancer models (OPCMs). Importantly, this approach can conveniently introduce any driver mutation or a combination of driver mutations. Using these models,it is shown that the mutations in Pik3ca and Pik3r1 cooperate with Pten loss to promote endometrial adenocarcinoma in mice. In contrast, the Kras G12D mutati led to endometrial squamous cell carcinoma. Then, tumor organoids are derived from these mouse EC models and performed high-throughput drug screening and validation. The results reveal distinct vulnerabilities of ECs with different mutations. Taken together, this study develops a multiplexing approach to model EC in mice and demonstrates its value for understanding the pathology of and exploring the potential treatments for this malignancy.

Role of Syndecans in Ovarian Cancer: New Diagnostic and Prognostic Biomarkers and Potential Therapeutic Targets

Ovarian cancer (OC) is the eighth cancer both in prevalence and mortality in women and represents the deadliest female reproductive cancer. Due to generally vague symptoms, OC is frequently diagnosed only at a late and advanced stage, resulting in high mortality. The tumor extracellular matrix and cellular matrix receptors play a key role in the pathogenesis of tumor progression. Syndecans are a family of four transmembrane heparan sulfate proteoglycans (PG), including syndecan-1, -2, -3, and -4, which are dysregulated in a myriad of cancers, including OC. Many clinicopathological studies suggest that these proteins are promising diagnostic and prognostic biomarkers for OC. Furthermore, functions of the syndecan family in the regulation of cellular processes make it an interesting pharmacological target for anticancer therapies.

Exposure to p-dichlorobenzene and prevalent endocrine-related reproductive cancers among US women.

P-dichlorobenzene (p-DCB) is a pest repellent and air deodorant that is commonly found in the household and public buildings. Exposure to p-DCB has been suggested to have potential metabolic and endocrine effects. Little is known about its association with endocrine-related female cancers. In this cross-sectional study, a nationally representative subsample of 4459 women, aged 20years or older, in the 2003-2016 National Health and Nutrition Examination Survey was analyzed for the association between p-DCB exposure, measured as urinary concentrations of 2,5-dichlorophenol (2,5-DCP), the primary metabolite of p-DCB, and prevalent endocrine-related female cancers (defined as breast, ovarian, and uterine cancers) using multivariate logistic regression models, adjusting for potential confounders. Of the study participants, 202 women (weighted prevalence, 4.20%) reported being diagnosed with any of these endocrine-related reproductive cancers. Women with reproductive cancers showed a statistically significant increase in urinary 2,5-DCP concentrations (weighted geometric mean, 7.97 vs. 5.84µg/g creatinine; p < 0.0001), compared to women without these cancers. After adjusting for potential confounders, we found that women in the moderate (1.94- < 28.10µg/g creatinine) and high level (≥ 28.10µg/g creatinine) of 2,5-DCP had significantly increased odds of endocrine-related reproductive cancers (odds ratio of 1.66 (95% CI: 1.02, 2.71) and 1.89 (1.08, 3.29), respectively), as compared with those in the low exposure group (< 1.94µg/g creatinine). This study demonstrates a potential relation between p-DCB exposure and prevalent endocrine-related reproductive cancers in US women. Prospective and mechanistic studies would further explore these interactions and elucidate the pathogenesis of endocrine-related female cancers potentially associated with p-DCB exposure.

Harnessing the Therapeutic Potential of Antimicrobial peptides for cancers: State of the art.

Despite significant breakthroughs in cancer treatment, cancer remains a serious global health concern that takes thousands of lives each year. Still, drug resistance and adverse effects are the main problems in conventional cancer therapeutic approaches. Thus, the discovery of new anti-cancer agents with distinct mechanisms of action is a critical requirement that offers significant obstacles. Antimicrobial peptides (AMPs), which can be found in various forms of life, are recognized as defensive weapons against infections of microbial pathogens. Surprisingly, they are also capable of killing a variety of cancer cells. These powerful peptides can cause cell death in the gastrointestinal, urinary tract, and reproductive cancer cell lines. To emphasize the anti-cancer properties of AMPs, we summarize the research that examined their impact on cancer cell lines in this review.

Effective prevention of COVID-19 infection in cancer patients receiving antitumor drug therapy: a regional analysis

Background. The results of several multicenter studies indicate a high risk of severe COVID-19 and fatal outcomes in immunocompromised patients, including those with cancer. Effective prevention is critical to saving cancer patients' lives during the pandemic. Additional passive immunization with a combination of monoclonal antibodies to the SARS-CoV-2 S protein in clinical studies showed a significant reduction in the risk of severe disease and death and a decrease in the frequency of hospitalizations. Real clinical practice shows the high efficiency of this approach in patients with oncological diseases receiving immunosuppressive therapy.&#x0D; Aim. To perform a comparative analysis of prevention effectiveness and COVID-19 severity in patients with solid malignant tumors receiving antitumor drug therapy.&#x0D; Materials and methods. The analysis included 100 vaccinated patients aged 22 to 84 with metastatic or inoperable solid tumors who received cytostatic therapy with or without a targeted agent. The median age was 56.5 years in Group 1 and 57.7 years in Group 2. In both groups, 32 (64%) patients had breast cancer, 10 (20%) had gastric, colon, and rectal cancers, 2 (4%) had lung cancer, 4 (8%), and 6 (12%) had reproductive cancers. In addition, Group 1 included 1 patient each with bladder and brain cancer. All were treated with antitumor drug therapy following clinical guidelines according to tumor localization.&#x0D; Results. The median number of received treatment lines of patients in Group 1 was 2.2, and 2.38 in Group 2. In Group 1, 42% of patients got infected, and 64% in Group 2. The combination of tixagevimab 150 mg + cilgavimab 150 mg monoclonal antibodies reduced the incidence of COVID-19 infection in any clinical form by 1.5-fold and hospitalizations by 1.3-fold. In Group 1, the rate of mild COVID-19 was higher; in Group 2, a higher risk of severe course was observed. In Group 1, viral pneumonia was 1.6-fold less common than in Group 2. Overall mortality in Group 1 was 6.5-fold lower than in Group 2. In Group 1, no COVID-19-related deaths were registered; in Group 2, the mortality rate was 8% (n=4). Mortality related to underlying disease in Group 2 was 3.5 times higher, and the risk of dying from the malignant tumor progression was 50% higher. In addition, in Group 2, 15% of deaths were related to cardiovascular diseases.&#x0D; Conclusion. Adding Evusheld to vaccinated patients significantly reduces the burden of COVID-19 infection in individuals with solid neoplasms who are receiving antitumor drug therapy. Patients receiving Evusheld at any stage of the underlying disease are less likely to have COVID-19, including severe infection, which requires hospitalization in an infectious hospital. The reduction in overall mortality in the Evusheld group suggests that COVID-19 affects overall survival in cancer patients. Evusheld reduced the risk of death in cancer patients from any causes: the progression of malignant tumors, COVID-19 infection, and other comorbidities.

Relationship between Psychological States and Coping in Reproductive Cancer Patients in the Context of the Pandemic

Abstract Introduction Cancer is known as a disease caused by an uncontrolled division of abnormal cells with the potential to proliferate and destroy body tissues. While it is not uncommon to observe changes in psychological states among patients with cancer, the pandemic situation has been reported to have an impact more severely. Objective This study attempts to understand the psychological problems of cancer patients, and the process of coping adopted by reproductive cancer patients during the period of the pandemic. Materials and Methods This study uses a correlation research design and the tools used for assessment were the four-dimensional symptom questionnaire and Brief COPE inventory. Through nonrandom sampling, a sample of 120 cancer patients diagnosed with reproductive cancer, both male and female from the regional cancer center and private cancer hospitals in Hyderabad, was recruited for the pandemic period from May 2020 to September 2021. Descriptive statistics, correlation, and regression statistical analysis methods were implemented. Results Significant negative correlation was observed between psychological states and coping. Using multiple linear regression analysis, it was found that distress and depression predict problem-solving coping, distress and anxiety predict emotion-solving coping, and distress predicts adaptive coping. Conclusion This study examines the psychological factors and coping methods in adapting to the dual challenges of illness and potential risk of infection transmission, and emphasizes designing an effective intervention. During the coronavirus disease 2019 crisis, the lack of support through psychological counseling to address their coping mechanisms to face the challenges is also glaring.

Water a major source of endocrine-disrupting chemicals: An overview on the occurrence, implications on human health and bioremediation strategies

Endocrine disrupting chemicals (EDCs) are toxic compounds that occur naturally or are the output of anthropogenic activities that negatively impact both humans and wildlife. A number of diseases are associated with these disruptors, including reproductive disorders, cardiovascular disorders, kidney disease, neurological disorders, autoimmune disorders, and cancer. Due to their integral role in pharmaceuticals and cosmetics, packaging companies, agro-industries, pesticides, and plasticizers, the scientific awareness on natural and artificial EDCs are increasing. As these xenobiotic compounds tend to bioaccumulate in body tissues and may also persist longer in the environment, the concentrations of these organic compounds may increase far from their original point of concentrations. Water remains as the major sources of how humans and animals are exposed to EDCs. However, these toxic compounds cannot be completely biodegraded nor bioremediated from the aqueous medium with conventional treatment strategies thereby requiring much more efficient strategies to combat EDC contamination.Recently, genetically engineered microorganism, genome editing, and the knowledge of protein and metabolic engineering has revolutionized the field of bioremediation thereby helping to breakdown EDCs effectively. This review shed lights on understanding the importance of aquatic mediums as a source of EDCs exposure. Furthermore, the review sheds light on the consequences of these EDCs on human health as well as highlights the importance of different remediation and bioremediation approaches. Particular attention is paid to the recent trends and perspectives in order to attain sustainable approaches to the bioremediation of EDCs. Additionally, rigorous restrictions to preclude the discharge of estrogenic chemicals into the environment should be followed in efforts to combat EDC pollution.

The Application of Nanoparticle-Based Imaging and Phototherapy for Female Reproductive Organs Diseases.

Various female reproductive disorders affect millions of women worldwide and bring many troubles to women's daily life. Let alone, gynecological cancer (such as ovarian cancer and cervical cancer) is a severe threat to most women's lives. Endometriosis, pelvic inflammatory disease, and other chronic diseases-induced pain have significantly harmed women's physical and mental health. Despite recent advances in the female reproductive field, the existing challenges are still enormous such as personalization of disease, difficulty in diagnosing early cancers, antibiotic resistance in infectious diseases, etc. To confront such challenges, nanoparticle-based imaging tools and phototherapies that offer minimally invasive detection and treatment of reproductive tract-associated pathologies are indispensable and innovative. Of late, several clinical trials have also been conducted using nanoparticles for the early detection of female reproductive tract infections and cancers, targeted drug delivery, and cellular therapeutics. However, these nanoparticle trials are still nascent due to the body's delicate and complex female reproductive system. The present review comprehensively focuses on emerging nanoparticle-based imaging and phototherapies applications, which hold enormous promise for improved early diagnosis and effective treatments of various female reproductive organ diseases.

Unlocking the mystery associated with infertility and prostate cancer: an update

Male-specific reproductive disorders and cancers have increased intensely in recent years, making them a significant public health problem. Prostate cancer (PC) is the most often diagnosed cancer in men and is one of the leading causes of cancer-related mortality. Both genetic and epigenetic modifications contribute to the development and progression of PC, even though the exact underlying processes causing this disease have yet to be identified. Male infertility is also a complex and poorly understood phenomenon believed to afflict a significant portion of the male population. Chromosomal abnormalities, compromised DNA repair systems, and Y chromosome alterations are just a few of the proposed explanations. It is becoming widely accepted that infertility shares a link with PC. Much of the link between infertility and PC is probably attributable to common genetic defects. This article provides an overview of PC and spermatogenic abnormalities. This study also investigates the link between male infertility and PC and uncovers the underlying reasons, risk factors, and biological mechanisms contributing to this association.

Targeting activins and inhibins to treat reproductive disorders and cancer cachexia.

Although originally characterised as proteins involved in the control of reproductive function, activins, and to a lesser degree inhibins, are also important regulators of homeostasis in extragonadal tissues. Accordingly, disrupted inhibin/activin expression can have detrimental effects not only for fertility and fecundity, but also for the regulation of muscle, fat and bone mass. Indeed, only recently, two complementary mouse models of inhibin designed to lack bioactivity/responsiveness, revealed that inhibin A/B deficiency during pregnancy, restricts embryo and foetal survival. Conversely, hyper elevated levels of activin A/B, as are frequently observed in patients with advanced cancers, can not only promote gonadal tumour growth but also cancer-cachexia. As such, it is not surprising that inhibin/activin genetic variations or altered circulating levels have been linked to reproductive disorders and cancer. Whilst some of the detrimental health effects associated with disrupted inhibin/activin levels can be attributed to accompanied changes in circulating follicle stimulating hormone (FSH) levels, there is now abundant evidence that activins, in particular, have fundamental FSH-independent tissue homeostatic roles. Increased understanding of inhibin/activin activity, garnered over several decades, has enabled the development of targeted therapies with applications for both reproductive and extra-gonadal tissues. Inhibin- or activin-targeted technologies have been shown not just to enhance fertility and fecundity, but also to reduce disease severity in models of cancer cachexia. Excitingly, these technologies are likely to benefit human medicine and be highly valuable to animal breeding and veterinary programs.

Sexual and reproductive health cancer screening avoidance: The role of body image

The current study examines the relationship of female genital self-image, weight-related cancer screening avoidance, and internalized weight stigma among cisgender women that can provide knowledge about avoidance of life-saving preventative healthcare. This cross-sectional survey included a convenience sample of 384 U.S. cisgender women who were 18+. The sample was primarily white (n = 260, 67.7 %) with a mean age of 33.18 years. 28.4 % reported avoiding a pap smear, 27.1 % avoided a clinical breast exam, and 29.4 % avoided a mammogram. Using multivariate logistic regressions, our results show high internalized weight stigma moderates the relationship of positive genital self-image on weight-related genital and breast cancer screening avoidance. Thus, the odds of avoiding screenings are positive, where the odds of avoidance slightly decreases from the interaction term as female genital body image increases. Interventions to improve female genital body image among cisgender women may lessen the effects of internalized weight stigma on avoiding reproductive cancer screenings. BMI was only a predictor for avoiding pap tests. Further examination is warranted because BMI and sexual health behaviors are not usually associated in body image research. Clinical workforce training is needed to educate providers about the harm of weight stigma and its relationship with healthcare avoidance.

The association between genetically elevated polyunsaturated fatty acids and risk of cancer

The causal relevance of polyunsaturated fatty acids (PUFAs) for risk of site-specific cancers remains uncertain. Using a Mendelian randomization (MR) framework, we assessed the causal relevance of PUFAs for risk of cancer in European and East Asian ancestry individuals. We defined the primary exposure as PUFA desaturase activity, proxied by rs174546 at the FADS locus. Secondary exposures were defined as omega 3 and omega 6 PUFAs that could be proxied by genetic polymorphisms outside the FADS region. Our study used summary genetic data on 10 PUFAs and 67 cancers, corresponding to 562,871 cases and 1,619,465 controls, collected by the Fatty Acids in Cancer Mendelian Randomization Collaboration. We estimated odds ratios (ORs) for cancer per standard deviation increase in genetically proxied PUFA exposures. Genetically elevated PUFA desaturase activity was associated (P<0.0007) with higher risk (OR [95% confidence interval]) of colorectal cancer (1.09 [1.07-1.11]), esophageal squamous cell carcinoma (1.16 [1.06-1.26]), lung cancer (1.06 [1.03-1.08]) and basal cell carcinoma (1.05 [1.02-1.07]). There was little evidence for associations with reproductive cancers (OR=1.00 [95% CI: 0.99-1.01]; Pheterogeneity=0.25), urinary system cancers (1.03 [0.99-1.06], Pheterogeneity=0.51), nervous system cancers (0.99 [0.95-1.03], Pheterogeneity=0.92) or blood cancers (1.01 [0.98-1.04], Pheterogeneity=0.09). Findings for colorectal cancer and esophageal squamous cell carcinoma remained compatible with causality in sensitivity analyses for violations of assumptions. Secondary MR analyses highlighted higher omega 6 PUFAs (arachidonic acid, gamma-linolenic acid and dihomo-gamma-linolenic acid) as potential mediators. PUFA biosynthesis is known to interact with aspirin, which increases risk of bleeding and inflammatory bowel disease. In a phenome-wide MR study of non-neoplastic diseases, we found that genetic lowering of PUFA desaturase activity, mimicking a hypothetical intervention to reduce cancer risk, was associated (P<0.0006) with increased risk of inflammatory bowel disease but not bleeding. The PUFA biosynthesis pathway may be an intervention target for prevention of colorectal cancer and esophageal squamous cell carcinoma but with potential for increased risk of inflammatory bowel disease. Cancer Resesrch UK (C52724/A20138, C18281/A19169). UK Medical Research Council (MR/P014054/1). National Institute for Health Research (NIHR202411). UK Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4). National Cancer Institute (R00 CA215360). National Institutes of Health (U01 CA164973, R01 CA60987, R01 CA72520, U01 CA74806, R01 CA55874, U01 CA164973 and U01 CA164973).

Familial CCM Genes Might Not Be Main Drivers for Pathogenesis of Sporadic CCMs-Genetic Similarity between Cancers and Vascular Malformations.

Cerebral cavernous malformations (CCMs) are abnormally dilated intracranial capillaries that form cerebrovascular lesions with a high risk of hemorrhagic stroke. Recently, several somatic "activating" gain-of-function (GOF) point mutations in PIK3CA (phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit p110α) were discovered as a dominant mutation in the lesions of sporadic forms of cerebral cavernous malformation (sCCM), raising the possibility that CCMs, like other types of vascular malformations, fall in the PIK3CA-related overgrowth spectrum (PROS). However, this possibility has been challenged with different interpretations. In this review, we will continue our efforts to expound the phenomenon of the coexistence of gain-of-function (GOF) point mutations in the PIK3CA gene and loss-of-function (LOF) mutations in CCM genes in the CCM lesions of sCCM and try to delineate the relationship between mutagenic events with CCM lesions in a temporospatial manner. Since GOF PIK3CA point mutations have been well studied in reproductive cancers, especially breast cancer as a driver oncogene, we will perform a comparative meta-analysis for GOF PIK3CA point mutations in an attempt to demonstrate the genetic similarities shared by both cancers and vascular anomalies.

Involvement in Tumorigenesis and Clinical Significance of CXCL1 in Reproductive Cancers: Breast Cancer, Cervical Cancer, Endometrial Cancer, Ovarian Cancer and Prostate Cancer.

C-X-C motif chemokine ligand 1 (CXCL1) is a member of the CXC chemokine subfamily and a ligand for CXCR2. Its main function in the immune system is the chemoattraction of neutrophils. However, there is a lack of comprehensive reviews summarizing the significance of CXCL1 in cancer processes. To fill this gap, this work describes the clinical significance and participation of CXCL1 in cancer processes in the most important reproductive cancers: breast cancer, cervical cancer, endometrial cancer, ovarian cancer, and prostate cancer. The focus is on both clinical aspects and the significance of CXCL1 in molecular cancer processes. We describe the association of CXCL1 with clinical features of tumors, including prognosis, ER, PR and HER2 status, and TNM stage. We present the molecular contribution of CXCL1 to chemoresistance and radioresistance in selected tumors and its influence on the proliferation, migration, and invasion of tumor cells. Additionally, we present the impact of CXCL1 on the microenvironment of reproductive cancers, including its effect on angiogenesis, recruitment, and function of cancer-associated cells (macrophages, neutrophils, MDSC, and Treg). The article concludes by summarizing the significance of introducing drugs targeting CXCL1. This paper also discusses the significance of ACKR1/DARC in reproductive cancers.

The role of GnRH metabolite, GnRH-(1-5), in endometrial cancer.

From the time of its discovery and isolation in the mammalian hypothalamus, the decapeptide, gonadotropin-releasing hormone (GnRH), has also been found to be expressed in non-hypothalamic tissues and can elicit a diverse array of functions both in the brain and periphery. In cancer, past studies have targeted the gonadotropin-releasing hormone receptors (GnRHR) as a way to treat reproductive cancers due to its anti-tumorigenic effects. On the contrary, its metabolite, GnRH-(1-5), behaves divergently from its parental peptide through putative orphan G-protein coupled receptor (oGPCR), GPR101. In this review, we will focus on the potential roles of GnRH-(1-5) in the periphery with an emphasis on its effects on endometrial cancer progression.

Cancer incidence risk of female reproductive organs in the Southern Urals Populations Exposed to Radiation Cohort: 1956-2019

The objective of the study is to obtain direct estimates of the excess relative risk of the reproductive organ cancer in women from the cohort of the Southern Urals population exposed to radiation under chronic exposure in the dose range not exceeding 1 Gy. Materials and Methods: The analytical cohort of the Southern Urals population exposed to radiation of women included 26,076 individuals with a follow-up period of 65 years (1956 to 2019) and 749,053 person-years at risk. The cancer incidence catchment area is limited to five districts of the Chelyabinsk region, the city of Chelyabinsk and the city of Ozyorsk. Over a 65 year-period 601 cases of the reproductive organ cancers have been registered in the incidence catchment area. The average cumulative dose to the uterus for women in the analytical cohort was 42 mGy; the maximum dose was 988 mGy. A regression analysis with a simple parametric model of the excess relative risk was used in the study. The significance of the results was assessed by the maximum likelihood method with 95% probability. Calculations were performed with the statistical software package “Epicure”. Results: The risk analysis revealed a statistically significant linear dependence of the excess relative risk of the cervical cancer incidence and that of all reproductive organ cancers in total on the dose accumulated in the walls of the uterus. The paper assesses the influence of modifying factors available for analysis on the magnitude of the risk. No dependence of either uterine body cancer risk on the dose to the uterus or ovary cancer risk on the dose to the ovaries was revealed. The possibility of obtaining significant risk values of the development of site-specific cancers appeared with an increase in the size of the analyzed population as a result of combining people exposed in the Southern Urals in two radiation accidents into one cohort, which increased the statistical power of the study. Assessment of the excess relative risk of the reproductive organ cancer in this cohort was carried out for the first time. This cohort has a great potential for further research to obtain direct estimates of the radiation risk of cancer and non-cancer diseases due to chronic exposure in the dose range up to 1 Gy.