Chronic kidney disease (CKD) is one of the most frequent complications associated with type 2 diabetes mellitus (T2DM) and is also an independent risk factor for cardiovascular disease. The mineralocorticoid receptor (MR) is a nuclear receptor expressed in many tissue types, including kidney and heart. Aberrant and long-term activation of MR by aldosterone in patients with T2DM triggers detrimental effects (eg, inflammation and fibrosis) in these tissues. The suppression of aldosterone at the early stage of T2DM has been a therapeutic strategy for patients with T2DM-associated CKD. Although patients have been treated with renin-angiotensin system (RAS) blockers for decades, RAS blockers alone are not sufficient to prevent CKD progression. Steroidal MR antagonists (MRAs) have been used in combination with RAS blockers; however, undesired adverse effects have restricted their usage, prompting the development of nonsteroidal MRAs with better target specificity and safety profiles. Recently conducted studies, Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), have reported that finerenone, a nonsteroidal MRA, improves both renal and cardiovascular outcomes compared with placebo. In this article, we review the history of MRA development and discuss the possibility of its combination with other treatment options, such as sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and potassium binders for patients with T2DM-associated CKD.

UNASSIGNED: Breast cancer (BC) survivors experience an increased burden of long-term comorbidities, including heart failure (HF). However, there is limited understanding of the risk for the development of HF subtypes, such as HF with preserved ejection fraction (HFpEF), in BC survivors.
UNASSIGNED: This study sought to estimate the incidence of HFpEF and HF with reduced ejection fraction (HFrEF) in postmenopausal BC survivors and to identify lifestyle and cardiovascular risk factors associated with HF subtypes.
UNASSIGNED: Within the Women\'s Health Initiative, participants with an adjudicated diagnosis of invasive BC were followed to determine the incidence of hospitalized HF, for which adjudication procedures determined left ventricular ejection fraction. We calculated cumulative incidences of HF, HFpEF, and HFrEF. We estimated HRs for risk factors in relation to HF, HFpEF, and HFrEF using Cox proportional hazards survival models.
UNASSIGNED: In 2,272 BC survivors (28.6% Black and 64.9% White), the cumulative incidences of hospitalized HFpEF and HFrEF were 6.68% and 3.96%, respectively, over a median of 7.2 years (IQR: 3.6-12.3 years). For HFpEF, prior myocardial infarction (HR: 2.83; 95% CI: 1.28-6.28), greater waist circumference (HR: 1.99; 95% CI: 1.14-3.49), and smoking history (HR: 1.65; 95% CI: 1.01-2.67) were the strongest risk factors in multivariable models. With the exception of waist circumference, similar patterns were observed for HFrEF, although none were significant. In relation to those without HF, the risk of overall mortality in BC survivors with hospitalized HFpEF was 5.65 (95% CI: 4.11-7.76), and in those with hospitalized HFrEF, it was 3.77 (95% CI: 2.51-5.66).
UNASSIGNED: In this population of older, racially diverse BC survivors, the incidence of HFpEF, as defined by HF hospitalizations, was higher than HFrEF. HF was also associated with an increased mortality risk. Risk factors for HF were largely similar to the general population with the exception of prior myocardial infarction for HFpEF. Notably, both waist circumference and smoking represent potentially modifiable factors.

Tumor heterogeneity and the unclear metastasis mechanisms are the leading cause for the unavailability of effective targeted therapy for Triple-negative breast cancer (TNBC), a breast cancer (BrCa) subtype characterized by high mortality and high frequency of distant metastasis cases. The identification of prognostic biomarker can improve prognosis and personalized treatment regimes. Herein, we collected gene expression datasets representing TNBC and Non-TNBC BrCa. From the complete dataset, a subset reflecting solely known cancer driver genes was also constructed. Recursive Feature Elimination (RFE) was employed to identify top 20, 25, 30, 35, 40, 45, and 50 gene signatures that differentiate TNBC from the other BrCa subtypes. Five machine learning algorithms were employed on these selected features and on the basis of model performance evaluation, it was found that for the complete and driver dataset, XGBoost performs the best for a subset of 25 and 20 genes, respectively. Out of these 45 genes from the two datasets, 34 genes were found to be differentially regulated. The Kaplan-Meier (KM) analysis for Distant Metastasis Free Survival (DMFS) of these 34 differentially regulated genes revealed four genes, out of which two are novel that could be potential prognostic genes (POU2AF1 and S100B). Finally, interactome and pathway enrichment analyses were carried out to investigate the functional role of the identified potential prognostic genes in TNBC. These genes are associated with MAPK, PI3-AkT, Wnt, TGF-β, and other signal transduction pathways, pivotal in metastasis cascade. These gene signatures can provide novel molecular-level insights into metastasis.

The incidence of adenocarcinoma of the cervix in pregnancy is exceptionally rare, and thus there is no consensus on its management. Here, we report two cases of adenocarcinoma of the cervix diagnosed in the context of pregnancy. In our first case, a patient referred to colposcopy for atypical glandular cells of undetermined significance was subsequently diagnosed with well differentiated endocervical adenocarcinoma on cone biopsy. Just prior to the cone biopsy, she was incidentally found to have a first trimester pregnancy loss. The patient subsequently underwent a radical hysterectomy and bilateral sentinel lymph node dissection. Final pathology revealed a stage 1B1 (FIGO 2009) well differentiated adenocarcinoma of the cervix. Interestingly, the tumour was positive for estrogen receptor, which is unusual for cervical adenocarcinoma. In our second case, a patient presented with a pedunculated, exophytic cervical neoplasm at 31 weeks GA with self-limiting antepartum hemorrhage. The primary lesion measured 52 mm in diameter on MRI and was amputated at the base during the patient\'s elective repeat cesarean section. Final pathology revealed a stage IB2 (FIGO 2009) mucinous adenocarcinoma of the cervix. The patient subsequently underwent a radical hysterectomy and bilateral pelvic lymph node dissection 17 weeks after initial presentation. The depth of invasion was 2.2 mm, restricted to the inner third of the cervical wall, and there was no lymphovascular space invasion in the surgical specimen. Surgical margins, parametria, and lymph nodes were all negative for adenocarcinoma. This tumour was also found to be estrogen receptor/progesterone receptor (ER/PR) positive, again unusual for cervical adenocarcinoma. P16 was strongly positive and HPV DNA studies were also positive for human papilloma virus 18. The patient received adjuvant external beam radiotherapy to the pelvis and currently remains in remission.

BACKGROUND: Despite widespread use of repeated doses of potent bone-targeting agents (BTA) in oncology patients, relatively little is known about their in vivo effects on bone homeostasis, bone quality, and bone architecture. Traditionally bone quality has been assessed using a trans-iliac bone biopsy with a 7 mm \"Bordier\" core needle. We examined the feasibility of using a 2 mm \"Jamshidi™\" core needle as a more practical and less invasive technique.
METHODS: Patients with metastatic breast cancer on BTAs were divided according to the extent of bone metastases. They were given 2 courses of tetracycline labeling and then underwent a posterior trans-iliac trephine biopsy and bone marrow aspirate. Samples were analyzed for the extent of tumor invasion and parameters of bone turnover and bone formation by histomorphometry.
RESULTS: Twelve patients were accrued, 1 had no bone metastases, 3 had limited bone metastases (LSM) (<3 lesions) and 7 had extensive bone metastases (ESM) (>3 lesions). Most of the primary tumors were estrogen receptor (ER)/progesterone receptor (PR) positive. The procedure was well tolerated. The sample quality was sufficient to analyze bone trabecular structure and bone turnover by histomorphometry in 11 out of 12 patients. There was a good correlation between imaging data and morphometric analysis of tumor invasion. Patients with no evidence or minimal bone metastases had no evidence of tumor invasion. Most had suppressed bone turnover and no detectable bone formation when treated with BTA. In contrast, 6 out of 7 patients with extensive bone invasion by imaging and evidence of tumor cells in the marrow had intense osteoclastic activity as measured by the number of osteoclasts. Of these 7 patients with ESM, 6 were treated with BTA with 5 showing resistance to BTA as demonstrated by the high number of osteoclasts present. 3 of these 6 patients had active bone formation. Based on osteoblast activity and bone formation, 3 out of 6 patients with ESM responded to BTA compared to all 3 with LSM. Compared to untreated patients, all patients treated with BTA showed a trend towards suppression of bone formation, as measured by tetracycline labelling. There was also a trend towards a significant difference between ESM and LSM treated with BTA, highly suggestive of resistance although limited by the small sample size.
CONCLUSIONS: Our results indicate that trans-iliac bone biopsy using a 2 mm trephine shows excellent correlation between imaging assessment of tumor invasion and tumor burden by morphometric analysis of bone tissues. In addition, our approach provides additional mechanistic information on therapeutic response to BTA supporting the current clinical understanding that the majority of patients with extensive bone involvement eventually fail to suppress bone turnover (Petrut B, et al. 2008). This suggests that antiresorptive therapies become less effective as disease progresses.

According Global Cancer Statistics 2020 GLOBOCAN estimates female breast cancer was found as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), and the fourth leading cause (6.9%) of cancer death among women worldwide. Identification of new diagnostic marker sharply characterize the tumor feature is intensive need. The present work was performed to investigate the involvement of the INF-γ + 874 T/A gene polymorphism in different breast cancer prognostic factors. Polymorphism detection analysis was performed on 163 subjects from breast cancer patients, 79 with inflamed cells of breast patients and 144 controls. The gene polymorphism was detected using the amplification refractory mutation system- polymerase chain reaction method (ARMS-PCR). The distribution of INF-γ T + 874A gene polymorphism shows strong significant association between INF-γ + 874 T/A genotypes TT in BC patients (ORTT: 6.41 [95% CI = 2.72-15.1] P < 0.0001) as well as strong significant association regarding T allele (ORT: 1.99 [95% CI = 1.43-2.76] P < 0.0001) when compared to the healthy control. In ICB group the strong association was noted with INF-γ + 874 T/A genotypes AT genotype (ORAT: 2.28 [95% CI = 1.22-4.29] P = 0.007). From the different histological BC hormonal markers the human epidermal growth factor receptor 2 (HER2) was showing significant association in INF-γ + 874 T/A genotypes TT (P = 0.03) and recessive model (TT versus AA + AT P = 0.03). Concerning different BC prognostic models, the poor prognostic one of luminal B, (ER+ve PR+ve Her2+ve) show significant association in the host INF-γ + 874 T/A genotype (TT, P = 0.03) and recessive model (TT versus AA + AT P = 0.02) when compared to the good prognostic hormonal status luminal A model, (ER+ve PR+ve Her2-ve). It seems that this is the first study that interested in correlate the INF-γ + 874 T/A gene polymorphisms in Egyptian BC patients. T allele, TT genotype and recessive model of the INF-γ + 874 T/A gene variants were documented as risk factors for BC pathogenesis. It may be used as practical biomarker to guide the BC carcinogenesis and risk process.

Transmembrane protein 16A (TMEM16A) is a Ca2+-activated chloride channel that plays a role in cancer cell proliferation, migration, invasion, and metastasis. However, whether TMEM16A contributes to breast cancer metastasis remains unknown.
In this study, we investigated whether TMEM16A channel activation by ROCK1/moesin promotes breast cancer metastasis.
Wound healing assays and transwell migration and invasion assays were performed to study the migration and invasion of MCF-7 and T47D breast cancer cells. Western blotting was performed to evaluate the protein expression, and whole-cell patch clamp recordings were used to record TMEM16A Cl- currents. A mouse model of breast cancer lung metastasis was generated by injecting MCF-7 cells via the tail vein. Metastatic nodules in the lung were assessed by hematoxylin and eosin staining. Lymph node metastasis, overall survival, and metastasis-free survival of breast cancer patients were assessed using immunohistochemistry and The Cancer Genome Atlas dataset.
TMEM16A activation promoted breast cancer cell migration and invasion in vitro as well as breast cancer metastasis in mice. Patients with breast cancer who had higher TMEM16A levels showed greater lymph node metastasis and shorter survival. Mechanistically, TMEM16A promoted migration and invasion by activating EGFR/STAT3/ROCK1 signaling, and the role of the TMEM16A channel activity was important in this respect. ROCK1 activation by RhoA enhanced the TMEM16A channel activity via the phosphorylation of moesin at T558. The cooperative action of TMEM16A and ROCK1 was supported through clinical findings indicating that breast cancer patients with high levels of TMEM16A/ROCK1 expression showed greater lymph node metastasis and poor survival.
Our findings revealed a novel mechanism underlying TMEM16A-mediated breast cancer metastasis, in which ROCK1 increased TMEM16A channel activity via moesin phosphorylation and the increase in TMEM16A channel activities promoted cell migration and invasion. TMEM16A inhibition may be a novel strategy for treating breast cancer metastasis.

BACKGROUND: Meningiomas that are progesterone receptor positive have a low recurrence rate and good prognosis compared to those that are progesterone receptor negative. This study aimed to determine the prevalence of expression of progesterone in meningiomas and its association with clinicopathological characteristics.
METHODS: This was a cross-sectional laboratory-based study that was conducted at Muhimbili National Hospital. The study included 112 formalin-fixed paraffin-embedded tissue blocks of patients who were confirmed to have meningiomas on histological basis from January 2010 to December 2014. Immunohistochemical expression of progesterone receptor was tested using a primary monoclonal progesterone receptor antibody ready to use (IR 068 Dako). The χ2 test was used to determine the association between clinicopathological characteristics and progesterone receptor expression. A 2-tailed P < 0.05 was considered significant.
RESULTS: The mean age of the patients was 45.5 ± 3.601 years, and majority (66.1%, n = 74) were in the age group between 31 and 60 years. Also, majority of the patients (60%, n = 67) in this study were females. Over one-third of the cases (34.8%, n = 39) comprised of meningotheliomatous subtype, and majority of the cases (89.3%, n = 100) were of grade I. The prevalence of progesterone expression was 54.5% (n = 61), and only age was associated with progesterone receptor expression (P = 0.043).
CONCLUSIONS: The finding of high expression of the progesterone receptor for grade I cases in this study indicates that progesterone receptor expression in meningiomas is of prognostic value and may be considered when evaluating patients for management. Lack of expression of progesterone receptor in all the malignant cases is intriguing and needs further studies that can investigate its prognostic role.

Breast cancer arises as a result of multiple interactions between environmental and genetic factors. Conventionally, breast cancer is treated based on histopathological and clinical features. DNA technologies like the human genome microarray are now partially integrated into clinical practice and are used for developing new \"personalized medicines\" and \"pharmacogenetics\" for improving the efficiency and safety of cancer medications. We investigated the effects of four established therapies-for ER+ ductal breast cancer-on the differential gene expression. The therapies included single agent tamoxifen, two-agent docetaxel and capecitabine, or combined three-agents CAF (cyclophosphamide, doxorubicin, and fluorouracil) and CMF (cyclophosphamide, methotrexate, and fluorouracil). Genevestigator 8.1.0 was used to compare five datasets from patients with infiltrating ductal carcinoma, untreated or treated with selected drugs, to those from the healthy control. We identified 74 differentially expressed genes involved in three pathways, i.e., apoptosis (extrinsic and intrinsic), oxidative signaling, and PI3K/Akt signaling. The treatments affected the expression of apoptotic genes (TNFRSF10B [TRAIL], FAS, CASP3/6/7/8, PMAIP1 [NOXA], BNIP3L, BNIP3, BCL2A1, and BCL2), the oxidative stress-related genes (NOX4, XDH, MAOA, GSR, GPX3, and SOD3), and the PI3K/Akt pathway gene (ERBB2 [HER2]). Breast cancer treatments are complex with varying drug responses and efficacy among patients. This necessitates identifying novel biomarkers for predicting the drug response, using available data and new technologies. GSR, NOX4, CASP3, and ERBB2 are potential biomarkers for predicting the treatment response in primary ER+ ductal breast carcinoma.

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