Targeting apoptotic pathways for cancer therapy.

Apoptosis is a form of programmed cell death that is mediated by intrinsic and extrinsic pathways. Dysregulation of and resistance to cell death are hallmarks of cancer. For over three decades, the development of therapies to promote treatment of cancer by inducing various cell death modalities, including apoptosis, has been a main goal of clinical oncology. Apoptosis pathways also interact with other signaling mechanisms, such as the p53 signaling pathway and the integrated stress response (ISR) pathway. In addition to agents directly targeting the intrinsic and extrinsic pathway components, anticancer drugs that target the p53 and ISR signaling pathways are actively being developed. In this Review, we discuss selected and promising anticancer therapies in various stages of development, including drug targets, mechanisms, and resistance to related treatments, focusing especially on B cell lymphoma 2 (BCL-2) inhibitors, TRAIL analogues, DR5 antibodies, and strategies that target p53, mutant p53, and the ISR.

Mechanisms of Concept Verbalization in the Ethnolinguistic Context.

This article investigates the verbalization mechanisms of the 'family' concept within the Kazakh, Russian, and English linguistic cultures. The research aims to examine the verbal representation mechanisms of the 'family' concept within the linguistic worldviews of the aforementioned cultures. The research material comprises dictionary definitions of the primary lexemes as presented in explanatory dictionaries and synonym dictionaries, proverbs and sayings, phraseological units, and data derived from an associative experiment. The employed analysis methods include component analysis, the descriptive method, the experimental method (psycholinguistic experiment), and the statistical method. This article furnishes a thorough analysis of the linguistic representation methods of the 'family' concept, illuminating its intricate and multidimensional nature. The authors endeavored to identify the concept's structure and describe linguistic units via the interpretation of semantic components. Based on the data procured from the psycholinguistic experiment, the components and layers of the 'family' concept, identified during the analysis, substantiate the theory that this concept plays a fundamental role in the shaping of society and individuals.

Response to neoadjuvant chemotherapy in breast cancer: do microRNAs matter?

BACKGROUND: Conventionally, breast cancer (BC) prognosis and prediction of response to therapy are based on TNM staging, histological and molecular subtype, as well as genetic alterations. The role of various epigenetic factors has been elucidated in carcinogenesis. However, it is still unknown to what extent miRNAs affect the response to neoadjuvant chemotherapy (NACT). This pilot study is focused on evaluating the role of miR-34a, miR-124a, miR-155, miR-137 and miR-373 in response to NACT. METHODS: That was a prospective study enrolling 34 patients with histologically confirmed BC of II-III stages. The median age of patients was 53 (47-59.8) years old, 70.6% of whom were HR-positive. MiRs levels were measured in the primary tumor before and after NACT. The response to therapy was assessed after surgery using the Miller-Payne scoring system. To establish the role of miRs in modulating response to NACT the Cox model was applied for analysis. RESULTS: BC demonstrated a great variability of miRs expression before and after NACT with no strong links to tumor stage and molecular subtype. Only miR-124a and miR-373 demonstrated differential expression between malignant and normal breast tissues before and after therapy though these distinctions did not impact response to NACT. Besides miR-124a and miR-137 levels after NACT were found to be dependent on HR status. While miR-124a levels increased (p = 0.021) in the tumor tissue, the expression of miR-137 was downregulated (p = 0.041) after NACT in HR positive BC. CONCLUSIONS: The study revealed differences in miR-124a and miR-373 expression after NACT in primary BC tissues. Although miRs levels did not impact the response to NACT, we found miR-124a and miR-137 levels to be related to hormonal sensitivity of BC.

Predictive factors of pathological response to neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: To identify predictive factors connected with pathologic response in patients with breast cancer (BC) having received neoadjuvant chemotherapy (NACT). METHODS: 49 patients with BC were investigated before and after treatment in this prospective research. Different chemotherapy regimes were administered. The Miller-Payne scoring system was used to assess the tumour response. The nuclear proliferation markers Ki67 and the expression of topoisomerase IIα (Topo IIα) were evaluated. RESULTS: Six patients (12.2 %) achieved pathological complete response (pCR). Noticeable decrease of tumor cellularity was detected in all BC subtypes and pCR in the triple-negative BC (TNBC) group (p=0.007) was observed. Poorly differentiated tumors could be considered as predictive factors of pCR (p=0.07). Ki67 appeared to be a predictive marker of achieving pCR (p<0.001) with a threshold of 28% (AUC=0.89, 95% CI 0.75-0.96). The additional factor of reaching pCR was operable BC (p=0.04). The expression level of Topo IIα (p=0.50) and using different regimens of NACT (p=0.97) did not influence pCR achievement. CONCLUSION: To sum it up, poorly differentiated carcinomas with high cellularity in the primary tumor, TNBC, Ki 67 with a threshold above 28% and operable BC can be considered as early predictors of reaching pCR.