Exploring cutting-edge strategies for drug repurposing in female cancers - An insight into the tools of the trade.

Female cancers, which include breast and gynaecological cancers, represent a significant global health burden for women. Despite advancements in research pertinent to unearthing crucial pathological characteristics of these cancers, challenges persist in discovering potential therapeutic strategies. This is further exacerbated by economic burdens associated with de novo drug discovery and clinical intricacies such as development of drug resistance and metastasis. Drug repurposing, an innovative approach leveraging existing FDA-approved drugs for new indications, presents a promising avenue to expedite therapeutic development. Computational techniques, including virtual screening and analysis of drug-target-disease relationships, enable the identification of potential candidate drugs. Integration of diverse data types, such as omics and clinical information, enhances the precision and efficacy of drug repurposing strategies. Experimental approaches, including high-throughput screening assays, in vitro, and in vivo models, complement computational methods, facilitating the validation of repurposed drugs. This review highlights various target mining strategies based on analysis of differential gene expression, weighted gene co-expression, protein-protein interaction network, and host-pathogen interaction, among others. To unearth drug candidates, the technicalities of leveraging information from databases such as DrugBank, STITCH, LINCS, and ChEMBL, among others are discussed. Further in silico validation techniques encompassing molecular docking, pharmacophore modelling, molecular dynamic simulations, and ADMET analysis are elaborated. Overall, this review delves into the exploration of individual case studies to offer a wide perspective of the ever-evolving field of drug repurposing, emphasizing the multifaceted approaches and methodologies employed for the same to confront female cancers.

Clinical Significance of TET2 in Female Cancers.

Female cancers refer to malignant tumors of the female reproductive system and breasts, which severely affect the physical and mental health of women. Although emerging experiment-based studies have indicated a potential correlation between ten-eleven translocation methylcytosine dioxygenase (TET2) and female cancers, no comprehensive studies have been conducted. Therefore, this study aimed to summarize the clinical value and underlying oncogenic functions of TET2 in female cancers, such as breast invasive carcinoma (BRCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), ovarian serous cystadenocarcinoma (OV), uterine corpus endometrial carcinoma (UCEC), and uterine carcinosarcoma (UCS), based on the data obtained from The Cancer Genome Atlas. The expression of TET2 was decreased in most female cancers, and its high expression was distinctly associated with the favorable prognosis of most female cancers. Furthermore, CD8+ T-cell infiltration was not correlated with TET2 in OV, UCEC, and UCS, whereas tumor-associated fibroblast infiltration was significantly correlated with TET2 in BRCA, CESC, and OV. TET2 was co-expressed with the immune checkpoint molecules ADORA2A, CD160, CD200, CD200R1, CD44, CD80, NRP1 TNFSF4, and TNFSF15 in most female cancers. Enrichment analysis revealed that some signaling pathways involving TET2 and related genes were related to tumorigenesis. Immunohistochemical and immunofluorescence staining confirmed the results of cancer immune infiltration analysis in BRCA tissues. Therefore, this study provides evidence for the oncogenic functions and clinical value of TET2 in female cancers.

Development and validation of the MARA scale in Spanish to assess knowledge and perceived risks and barriers relating to breast cancer prevention.

OBJECTIVE: The aim of this study was to develop a measurement instrument for assessing knowledge of breast cancer and perceived risk of developing the disease (MARA). METHODS: 641 women with a mean age of 36.19 years (SD = 7.49) participated in the study. Data collection took place during 2019 and included sociodemographic data, data on history of cancer and breast cancer, perceived risk, and feelings of concern about developing breast cancer. Internal consistency, test-retest reliability, convergent validity, and structural validity were tested. RESULTS: The questionnaire items comprise 4 subscales: risk factors (9 items), signs and symptoms (9 items), perceived risk (6 items), barriers (7 items). A factor analysis revealed that the first two subscales had two dimensions each, whereas the other two subscales had one dimension each. Each subscale was shown to have adequate reliability (α = 0.74-0.92) and temporal stability (r = 0.201-0.906), as well as strong evidence of validity in relation to a questionnaire on breast cancer knowledge (r = 0.131-0.434). In addition, the subscales were shown to have high discriminatory power in terms of the presence or absence of a history of cancer or breast cancer, perceived risk, and feelings of concern. CONCLUSION: The MARA questionnaire represents a valid, reliable tool for assessing Spanish women's knowledge, risks, perceptions, and barriers regarding breast cancer.

p38ß - MAPK11 and its role in female cancers.

BACKGROUND: The p38MAPK family of Mitogen Activated Protein Kinases are a group of signalling molecules involved in cell growth, survival, proliferation and differentiation. The widely studied p38α isoform is ubiquitously expressed and is implicated in a number of cancer pathologies, as are p38γ and p38δ. However, the mechanistic role of the isoform, p38ß, remains fairly elusive. Recent studies suggest a possible role of p38ß in both breast and endometrial cancer with research suggesting involvement in bone metastasis and cancer cell survival. Female tissue specific cancers such as breast, endometrial, uterine and ovary account for over 3,000,000 cancer related incidents annually; advancements in therapeutics and treatment however require a deeper understanding of the molecular aetiology associated with these diseases. This study provides an overview of the MAPK signalling molecule p38ß (MAPK11) in female cancers using an in-silico approach. METHODS: A detailed gene expression and methylation analysis was performed using datasets from cBioportal, CanSar and MEXPRESS. Breast, Uterine Endometrial, Cervical, Ovarian and Uterine Carcinosarcoma TCGA cancer datasets were used and analysed. RESULTS: Data using cBioportal and CanSAR suggest that expression of p38ß is lower in cancers: BRCA, UCEC, UCS, CESC and OV compared to normal tissue. Methylation data from SMART and MEXPRESS indicate significant probe level variation of CpG island methylation status of the gene MAPK11. Analysis of the genes' two CpG islands shows that the gene was hypermethylated in the CpG1 with increased methylation seen in BRCA, CESC and UCEC cancer data sets with a slight increase of expression recorded in cancer samples. CpG2 exhibited hypomethylation with no significant difference between samples and high levels of expression. Further analysis from MEXPRESS revealed no significance between probe methylation and altered levels of expression. In addition, no difference in the expression of BRCA oestrogen/progesterone/HER2 status was seen. CONCLUSION: This data provides an overview of the expression of p38ß in female tissue specific cancers, showing a decrease in expression of the gene in BRCA, UCEC, CESC, UCS and OV, increasing the understanding of p38ß MAPK expression and offering insight for future in-vitro investigation and therapeutic application.

Body composition and bone mineral density in breast cancer survivors and non-cancer controls: A 12- to 15-month follow-up.

While prognosis for breast cancer in women has improved, adverse side effects of treatments may negatively affect body composition and bone mineral density (BMD). This study assessed body composition and BMD changes in breast cancer survivors (BCS) (n = 10, 57.9 ± 5.7 years) and age-matched women (non-cancer, n = 10, 56.5 ± 4.3 years) over a 12- to 15-month period via dual-energy X-ray absorptiometry. No differences were observed between groups at baseline except forearm BMD values were lower in BCS (BCS: 0.462 ± 0.070 g/cm2 ; Control: 0.539 ± 0.052 g/cm2 , p = .012). Body fat increased in both groups compared to baseline (BCS: 38.3-39.6 kg, p = .013; Control: 38.2-39.5 kg, p = .023) at the follow-up. Significant decreases in BMD at the lumbar spine, femoral neck, total femur and ulna were observed in both groups. Breast cancer survivors had a greater decrease in left femoral neck BMD. While BCS demonstrated lower baseline forearm BMD values and a greater decrease in left femoral neck BMD, both groups showed an increase in body fat and decrease in forearm BMD. These findings support the implementation of interventions to improve body composition and BMD in both BCS and women without cancer.

The road less travelled: Australian women's experiences with vulval cancer.

Despite advances in surgical treatments and the availability of more conservative treatment options, women treated for vulval cancer still experience significant complications such as urinary incontinence, lymphoedema, pruritus, sexual and intimacy issues. These issues can profoundly impact a woman's quality of life. The subjective experience of women diagnosed and treated for vulval cancer in the literature is limited, possibly due to its comparable rarity to other gynaecological and female cancers and because it was traditionally seen mainly in the elderly female population. Nonetheless, younger women are also being diagnosed with vulval cancer. This paper reports the findings from a qualitative study about twelve women's experiences with vulval cancer from diagnosis, through treatment and recovery. Women's feelings of isolation, their unmet information and support needs, physical concerns arising from vulval cancer, particularly after surgery, and the consequences for their body image and intimate relationships with partners, were highlighted within the data. The central findings from this study emphasise the need for further research to develop appropriate interventions for women with vulval cancer. It also highlights opportunities to improve clinical practice into the supportive care of women with this isolating disease.

High lncRNA H19 expression as prognostic indicator: data mining in female cancers and polling analysis in non-female cancers.

Upregulation of lncRNA H19 expression is associated with an unfavorable prognosis in some cancers. However, the prognostic value of H19 in female-specific cancers has remained uncharacterized. In this study, the prognostic power of high H19 expression in female cancer patients from the TCGA datasets was analyzed using Kaplan-Meier survival curves and Cox's proportional hazard modeling. In addition, in a meta-analysis of non-female cancer patients from TCGA datasets and 12 independent studies, hazard ratios (HRs) with 95% confidence interval (CI) for overall survival (OS) and disease-free survival (DFS)/relapse-free survival (RFS)/metastasis-free survival (MFS)/progression-free survival (PFS) were pooled to assess the prognostic value of high H19 expression. Kaplan-Meier analysis revealed that patients with uterine corpus cancer and higher H19 expression had a shorter OS (HR=2.710, p<0.05), while females with cervical cancer and increased H19 expression had a shorter RFS (HR=2.261, p<0.05). Multivariate Cox regression analysis showed that high H19 expression could independently predict a poorer prognosis in cervical cancer patients (HR=4.099, p<0.05). In the meta-analysis, patients with high H19 expression showed a poorer outcome in non-female cancer (p<0.05). These results suggest that high lncRNA H19 expression is predictive of an unfavorable prognosis in two female cancers (uterine corpus endometrioid cancer and cervical cancer) as well as in non-female cancer patients.

A systematic comparison of copy number alterations in four types of female cancer.

BACKGROUND: Detection and localization of genomic alterations and breakpoints are crucial in cancer research. The purpose of this study was to investigate, in a methodological and biological perspective, different female, hormone-dependent cancers to identify common and diverse DNA aberrations, genes, and pathways. METHODS: In this work, we analyzed tissue samples from patients with breast (n = 112), ovarian (n = 74), endometrial (n = 84), or cervical (n = 76) cancer. To identify genomic aberrations, the Circular Binary Segmentation (CBS) and Piecewise Constant Fitting (PCF) algorithms were used and segmentation thresholds optimized. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was applied to the segmented data to identify significantly altered regions and the associated genes were analyzed by Ingenuity Pathway Analysis (IPA) to detect over-represented pathways and functions within the identified gene sets. RESULTS AND DISCUSSION: Analyses of high-resolution copy number alterations in four different female cancer types are presented. For appropriately adjusted segmentation parameters the two segmentation algorithms CBS and PCF performed similarly. We identified one region at 8q24.3 with focal aberrations that was altered at significant frequency across all four cancer types. Considering both, broad regions and focal peaks, three additional regions with gains at significant frequency were revealed at 1p21.1, 8p22, and 13q21.33, respectively. Several of these events involve known cancer-related genes, like PPP2R2A, PSCA, PTP4A3, and PTK2. In the female reproductive system (ovarian, endometrial, and cervix [OEC]), we discovered three common events: copy number gains at 5p15.33 and 15q11.2, further a copy number loss at 8p21.2. Interestingly, as many as 75% of the aberrations (75% amplifications and 86% deletions) identified by GISTIC were specific for just one cancer type and represented distinct molecular pathways. CONCLUSIONS: Our results disclose that some prominent copy number changes are shared in the four examined female, hormone-dependent cancer whereas others are definitive to specific cancer types.

Obstetric Outcomes in Non-Gynecologic Cancer Patients in Remission.

OBJECTIVE: The aim of the present study was to evaluate the obstetric and perinatal outcomes in treated women who were diagnosed with non-gynecologic cancer and to compare these findings with pregnant women with no history of cancer. MATERIALS AND METHODS: This retrospective study was conducted on 21 pregnant women with non-gynecologic cancer who were in remission (study group) and 63 pregnant women with no history of cancer (control group). The women were admitted to the high-risk pregnancy clinic of Zekai Tahir Burak Women's Health Training and Research Hospital with a diagnosis of pregnancy and cancer between January 2010 and January 2015. Obstetric outcomes and demographic characteristics of the patients were recorded. Age, gravida, parity, abortus, body mass index (BMI), gestational week, smoking, mode of delivery, gestational weight, and perinatal outcomes were examined for each woman. RESULTS: The most common cancer types were thyroid (28.5%) and breast cancers (23.8%), which constituted just over half of the non-gynecologic cancer cases during pregnancy. The time elapsed after the diagnosis was 3.8±2.2 (1-9) years. No statistically significant differences were found between the two groups with regard to age, obstetric history, BMI, gestational week, smoking, and obstetric and perinatal outcomes (p>0.05). CONCLUSION: Negative perinatal outcomes in non-gynecologic cancer patients in remission were found to be within acceptable levels.

Recent advances in structure of progestins and their binding to progesterone receptors.

The role of progesterone in women's cancers as well as the knowledge of the progesterone receptor (PR) structure has prompted the design of different therapies. The aim of this review is to describe the basic structure of PR agonists and antagonists as well as the recent treatments for illness associated with the progesterone receptor. The rational design for potent and effective drugs for the treatment of female cancer must consider the structural changes of the androgen and progestogen skeleton which are an indicator of their activity as progestins or antiprogestins. The presence of a hydroxyl group at C-17 in the progesterone skeleton brings about a loss of progestational activity whereas acetylation induces a progestational effect. The incorporation of an ethynyl functional group to the testosterone framework results in a loss of androgenic activity with a concomitant enhancement of the progestational effect. On the other hand, an ester function at C-3 of dehydroepiandrosterone skeleton induces partial antagonism to the PR.

Estresse psicológico e enfrentamento em mulheres com e sem câncer / Psychological stress and coping in women with and without cancer

Considerando o alto índice de mortes de mulheres por cânceres de mama, útero e ovários e resultados de pesquisas indicando relações entre estresse, enfrentamento e doenças como as oncológicas, este estudo investigou, em 30 mulheres com e 30 mulheres sem câncer, a ocorrência de estresse em suas histórias prévias, a importância atribuída ao mesmo e a avaliação de sua superação, nas áreas de saúde, social/trabalho e familiar. Os resultados indicaram relações entre os modos de avaliar e enfrentar o estresse e o adoecimento, sugerindo que padrões mais otimistas e diretos de lidar com o estresse favoreceram a redução de seu impacto no equilíbrio psicofisiológico. Dada a exposição crescente da mulher ao estresse, indica-se a relevância de programas psicoeducativos redutores de seu impacto na população feminina.(AU)

Considering the high death rate of women for breast, uterus and ovary cancers, and research findings indicating links between stress, coping and oncologic diseases, this study investigated, in 30 women with and 30 women without cancer, the occurrence of stress in their previous history as well as the importance attached to the it, and their evaluation of its resilience in the health care, social/work and family areas. The results indicated links between the ways of evaluating and facing stressful situations and the illness condition, suggesting that more optimistic and direct patterns of dealing with stress can reduce its impact on human psychological/physiological balance. Given the increasing exposure of women to stress, psychological and educational programs for reducing the impact of stress on the female population are indicated.(AU)

Estresse psicológico e enfrentamento em mulheres com e sem câncer / Psychological stress and coping in women with and without cancer

Considerando o alto índice de mortes de mulheres por cânceres de mama, útero e ovários e resultados de pesquisas indicando relações entre estresse, enfrentamento e doenças como as oncológicas, este estudo investigou, em 30 mulheres com e 30 mulheres sem câncer, a ocorrência de estresse em suas histórias prévias, a importância atribuída ao mesmo e a avaliação de sua superação, nas áreas de saúde, social/trabalho e familiar. Os resultados indicaram relações entre os modos de avaliar e enfrentar o estresse e o adoecimento, sugerindo que padrões mais otimistas e diretos de lidar com o estresse favoreceram a redução de seu impacto no equilíbrio psicofisiológico. Dada a exposição crescente da mulher ao estresse, indica-se a relevância de programas psicoeducativos redutores de seu impacto na população feminina.

Considering the high death rate of women for breast, uterus and ovary cancers, and research findings indicating links between stress, coping and oncologic diseases, this study investigated, in 30 women with and 30 women without cancer, the occurrence of stress in their previous history as well as the importance attached to the it, and their evaluation of its resilience in the health care, social/work and family areas. The results indicated links between the ways of evaluating and facing stressful situations and the illness condition, suggesting that more optimistic and direct patterns of dealing with stress can reduce its impact on human psychological/physiological balance. Given the increasing exposure of women to stress, psychological and educational programs for reducing the impact of stress on the female population are indicated.