Association of immune inflammatory biomarkers with pathological complete response and clinical prognosis in young breast cancer patients undergoing neoadjuvant chemotherapy.

Background: The persistence of inflammatory stimulus has a tight relationship with the development of age-related diseases, ultimately resulting in a gradual escalation in the prevalence of tumors, but this phenomenon is rare in young cancer patients. Breast cancer arising in young women is characterized by larger tumor diameters and more aggressive subtypes, so neoadjuvant chemotherapy (NACT) can be especially appropriate for this population. Immune inflammatory biomarkers have been reportedly linked to the prognosis of some malignant tumor types, with varying results. In this study, we investigated the possible predictive value of blood-based markers in young breast cancer patients undergoing NACT, in addition to the association between the clinicopathological features and prognosis. Methods: From December 2011 to October 2018, a total of 215 young breast cancer patients referred to Harbin Medical University Cancer Hospital received NACT and surgery were registered in this retrospective study. The pretreatment complete blood counts were used to calculate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV). Results: NLR, PLR, MLR, and PIV optimal cut-off values were 1.55, 130.66, 0.24, and 243.19, as determined by receiver operating characteristic analysis. Multivariate analysis revealed that PIV, HR status, HER-2 status, and Ki-67 index were all independent predictive factors for pathological complete response. Subgroup analysis revealed that young breast cancer patients in the population characterized by low PIV and HR negative group were more likely to get pCR (P=0.001). The five-year overall survival (OS) rate was 87.9%, and Cox regression models identified PIV as independently related to OS. Conclusion: In the present study, the pretreatment PIV was found to be a useful prognostic indicator for pCR and long-term survival in young breast cancer patients undergoing NACT. High immune and inflammation levels, MLR and PIV were connected to poor clinical prognosis in young breast cancer patients. PIV is a promising biomarker to guide strategic decisions in treating young breast cancer.

Estrogen receptor-negative/progesterone receptor-positive breast cancer has distinct characteristics and pathologic complete response rate after neoadjuvant chemotherapy.

PURPOSE: The status of hormone receptors (HR) is an independent factor affecting survival and chemotherapy sensitivity in breast cancer (BC) patients, with estrogen receptor (ER) and progesterone receptor (PR) having the most significant effects. The ER-/PR + phenotype has been controversial in BC, and experts will face many challenges in determining treatment strategies. Herein, we systematically analyzed the clinicopathological characteristics of the ER-/PR + phenotype in BC patients and the response to chemotherapy. PATIENTS AND METHODS: We included two cohorts. The first cohort counted the relationship between clinicopathologic data and survival outcomes for 72,666 female patients in the Surveillance, Epidemiology, and End Results (SEER) database. The second cohort analyzed the relationship between clinicopathological data and pathologic complete response (pCR) rate in 879 patients at the Harbin Medical University Cancer Hospital. The classification data were compared by the chi-square test and Fister's exact test of the Logistic regression model, and predictor variables with P < 0.05 in the univariate analysis were included in the multivariate regression analysis. The Kaplan-Meier method evaluated breast cancer-specific survival (BCSS) and overall survival (OS) to investigate the relationship between different HR typing and survival and pCR. RESULTS: In the two cohorts, 704 (0.9%) and 11 (1.3%) patients had the ER-/PR + phenotype, respectively. The clinicopathologic features of patients with the ER-/PR + phenotype are more similar to those of the ER-/PR- phenotype. The ER-/PR + phenotype is more common in younger and premenopausal women, and most ER-/PR + phenotypes exhibit higher histological grades. Survival analysis showed that there were significant differences in OS and BCSS among patients with different HR states (P < 0.001). The survival results of patients with the ER + /PR + phenotype were the best. The prognosis of the ER-/PR + phenotype was similar to that of the ER-/PR- phenotype. On the other hand, we found that HR status was also an independent predictor of post-NAC pCR rate in BC patients. The ER + /PR- and ER-/PR- phenotypes were more sensitive to chemotherapy than the ER + /PR + phenotypes. CONCLUSION: HR status is the main factor affecting BC's survival outcome and pCR rate. Patients with the ER-/PR + phenotype possess more aggressive biological factors and can benefit significantly from chemotherapy. We need to pay more attention to this group and achieve individualized treatment, which will help us treat BC better and provide new targets and blueprints for our clinical treatment.

Recent advances in caspase-3, breast cancer, and traditional Chinese medicine: a review.

Caspases (cysteinyl aspartate-specific proteinases) are a group of structurally similar proteases in the cytoplasm that can be involved in cell differentiation, programmed death, proliferation, and inflammatory generation. Experts have found that caspase-3 can serve as a terminal splicing enzyme in apoptosis and participate in the mechanism by which cytotoxic drugs kill cancer cells. Breast cancer (BC) has become the most common cancer among women worldwide, posing a severe threat to their lives. Finding new therapeutic targets for BC is the primary task of contemporary physicians. Numerous studies have revealed the close association between caspase-3 expression and BC. Caspase-3 is essential in BC's occurrence, invasion, and metastasis. In addition, Caspase-3 exerts anticancer effects by regulating cell death mechanisms. Traditional Chinese medicine acting through caspase-3 expression is increasingly used in clinical treatment. This review summarizes the biological mechanism of caspase-3 and research progress on BC. It introduces a variety of traditional Chinese medicine related to caspase-3 to provide new ideas for the clinical treatment of BC.

Vacuum-assisted biopsy system for breast lesions: a potential therapeutic approach.

Purpose: The primary objective is to optimize the population eligible for Mammotome Minimally Invasive Surgery (MIS) by refining selection criteria. This involves maximizing procedure benefits, minimizing malignancy risk, and reducing the rate of malignant outcomes. Patients and methods: A total of 1158 female patients who came to our hospital from November 2016 to August 2021 for the Mammotome MIS were analyzed retrospectively. Following χ2 tests to screen for risk variables, binary logistic regression analysis was used to determine the independent predictors of malignant lesions. In addition, the correlation between age and lesion diameter was investigated for BI-RADS ultrasound (US) category 4a lesions in order to better understand the relationship between these variables. Results: The malignancy rates of BI-RADS US category 3, category 4a and category 4b patients who underwent the Mammotome MIS were 0.6% (9/1562), 6.4% (37/578) and 8.3% (2/24) respectively. Malignant lesions were more common in patients over the age of 40, have visible blood supply, and BI-RADS category 4 of mammography. In BI-RADS US category 4a lesions, the diameter of malignant tumor was highly correlated with age, and this correlation was strengthened in patients over the age of 40 and with BI-RADS category 4 of mammography. Conclusion: The results of this study demonstrate that the clinical data and imaging results, particularly age, blood supply, and mammography classification, offer valuable insights to optimize patients' surgical options and decrease the incidence of malignant outcomes.

Clinical characteristics and pathologic complete response (pCR) rate after neoadjuvant chemotherapy in postpartum women with breast cancer.

PURPOSE: Breast cancer (BC) is currently the leading cause of death in women worldwide. Studies have confirmed that pregnancy is an independent factor affecting the survival of BC patients. BC found during pregnancy, lactation, or shortly after delivery is what we used to think of as pregnancy-associated breast cancer (PABC). The current expert definition of this concept is not uniform; however, there is growing evidence that postpartum breast cancer (PPBC) differs from other types of BC in terms of both biological features and prognosis, with a slightly different focus on diagnosis and treatment. With the increase of female reproductive age population and changes in fertility policies in China, patients with PPBC are receiving increasing attention. Here, we systematically analyzed the clinicopathological characteristics and chemotherapeutic response of patients with PPBC. We retrospectively analyzed the clinicopathological data, molecular subtypes, chemotherapy regimens, and pathological complete remission (pCR) rates of 1343 patients with non-metastatic BC at Harbin Medical University Cancer Hospital from January 1, 2012 to May 31, 2023. The categorical data were compared by chi-square test and Fisher exact test using logistic regression model. Predictor variables with P < 0.05 in the univariate analysis were included in the multivariate regression analysis to investigate the relationship between different age groups and pCR. RESULTS: A total of 714 patients were eligible for analysis in this study, and 667 patients had a history of pregnancy, 40 (5.6%) of whom were PPBC patients. When diagnosed with BC, patients with PPBC were younger, more likely to undergo breast-conserving surgery (BCS), and more likely to achieve pCR (P < 0.05). In molecular typing, human epidermal growth factor receptor 2 (HER-2)-positive and triple-negative breast cancer (TNBC) were more frequent. In the entire cohort, HER-2 expression and delivery status were independent predictors of pCR rates in BC patients after neoadjuvant chemotherapy (NAC). CONCLUSION: Our findings suggest that postpartum status is an independent predictor of pCR attainment in BC patients. PPBC is more sensitive to chemotherapy than other patients.We need to pay more attention to this group and achieve individualized treatment, which will help us treat BC better and provide new targets and blueprints for our clinical therapy.

Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments.

The malignant tumor is a multi-etiological, systemic and complex disease characterized by uncontrolled cell proliferation and distant metastasis. Anticancer treatments including adjuvant therapies and targeted therapies are effective in eliminating cancer cells but in a limited number of patients. Increasing evidence suggests that the extracellular matrix (ECM) plays an important role in tumor development through changes in macromolecule components, degradation enzymes and stiffness. These variations are under the control of cellular components in tumor tissue via the aberrant activation of signaling pathways, the interaction of the ECM components to multiple surface receptors, and mechanical impact. Additionally, the ECM shaped by cancer regulates immune cells which results in an immune suppressive microenvironment and hinders the efficacy of immunotherapies. Thus, the ECM acts as a barrier to protect cancer from treatments and supports tumor progression. Nevertheless, the profound regulatory network of the ECM remodeling hampers the design of individualized antitumor treatment. Here, we elaborate on the composition of the malignant ECM, and discuss the specific mechanisms of the ECM remodeling. Precisely, we highlight the impact of the ECM remodeling on tumor development, including proliferation, anoikis, metastasis, angiogenesis, lymphangiogenesis, and immune escape. Finally, we emphasize ECM "normalization" as a potential strategy for anti-malignant treatment.

Breast Cancer Exosome-Derived miR-425-5p Induces Cancer-Associated Fibroblast-Like Properties in Human Mammary Fibroblasts by TGFß1/ROS Signaling Pathway.

The connection between the cellular microenvironment and tumor cells is crucial for tumor progression. However, the process by which normal fibroblasts (NFs) become cancer-associated fibroblasts (CAFs) is unknown, and mounting evidence suggests that some microRNAs (miRNAs) have an important role in converting NFs into CAFs. Breast cancer (BC) has been proven to have enhanced miR-425-5p expression in order to support progression. We discovered that human mammary fibroblasts (HMFs) could uptake BC cell line-derived exosomes to change their properties, promoting the switch to the CAF phenotype and increasing cell motility, as evidenced by an increase in CAF activation-related marker protein expression and cell proliferation, invasion, and migration. Transfection of exosomes is obtained from BC cells, and miR-425-5p inhibitors suppressed the aforementioned effects as well as lowered chemokine levels and gene expression related with proliferation and metastasis. By suppressing the expression of its target gene TGFßRII (TGFß1 receptor), miR-425-5p enhanced the transition of HMFs to the CAF phenotype. MDA-MB-231 cells and CAFs stimulated by HMF absorption of MDA-MB-23-derived exosomes showed similar proliferation, invasion, migration, and expression of -SMA, FAP, CXCL1, IL-6, TGFß1, P21, P27, Ki67, vimentin, E-cadherin, N-cadherin, α-catenin, fibronectin, and MMP-2. TGFß1 overexpression enhanced ROS production. Finally, we found that HMFs transiently transfected with miR-425-5p can promote tumor growth in vivo. Finally, these findings provide fresh insight on miR-425-5p as an important mediator of the interaction between BC cells and stroma.

Breast cancer-derived exosomes regulate cell invasion and metastasis in breast cancer via miR-146a to activate cancer associated fibroblasts in tumor microenvironment.

OBJECTIVE: To explore the effects of breast cancer (BC)-derived exosomes on invasion and migration of BC cells. METHODS: Exosomes (Exo-MA, Exo-M7, Exo-M1) were extracted from normal breast epithelial cells (MCF-10A), BC cells (MCF-7/MDA-MB-231) and BC cells with miR-146a overexpression or knockdown using multi-step differential centrifugation. Morphologies and sizes of exosomes were observed by transmission electron microscope (TEM) and particle size analysis respectively. BC mouse models were injected with DIR labeled Exo-MA, Exo-M7 or Exo-M1. The epithelial-mesenchymal transition (EMT) in BC cells was determined by PCR and Western blot. PKH67 labeled Exo-MA, Exo-M7 and Exo-M1 were incubated with NFs or MCF-7 to measure the activation of CAFs. Cell invasion and migration abilities were determined by scratch test and Transwell assay. RESULTS: Exo-MA, Exo-M7, Exo-M1 were successfully extracted with positive expressions of Alix, CD63 and TSG101. Contents of Ki67, N-cadherin, Vimentin and Snail-1 were increased but E-cadherin was decreased, compared to Exo-MA group. Exo-M7 or Exo-M1 could increase BC cell proliferation and enhance EMT in nude mouse. Exo-M7 and Exo-M1 could accelerate the transformation of NFs into CAFs and promote the recruitment of CAFs in MCF-7. Transfection of miR-146a could promote the transformation of NFs into CAFs and promote cell invasion and migration of MCF-7 cells. As a target gene of miR-146a, TXNIP could inhibit the activation of CAFs. miR-146a overexpression or TXNIP silence enhance the activation of Wnt signal pathway. CONCLUSION: BC-derived exosomes promote the activation of CAFs through miR-146a/TXNIP axis to activate Wnt pathway, which in turn enhances invasion and metastasis of BC cells.

DjhnRNPA2/B1-like gene is required for planarian regeneration and tissue homeostasis.

The hnRNPs play important roles in physiological processes in eukaryotic organisms by regulation of pre-mRNA after transcription, including pre-mRNA splicing, mRNA stability, DNA replication and repair and telomere maintenance and so on. However, it remains unclear about the specific functions of these genes. In this study, the full-length cDNA sequence of hnRNPA2/B1-like was first cloned from Dugesia japonica, and its roles were investigated by WISH and RNAi. The results showed that: (1) DjhnRNPA2/B1-like was highly conserved during animal evolution; (2) DjhnRNPA2/B1-like mRNA was mainly distributed each side of the body in intact worms and regenerative blastemas, and its expression levels were up-regulated on days 0 and 5 after amputation; (3) the intact and regenerating worms gradually lysed or lost regeneration capacity after DjhnRNPA2/B1-like RNAi; and (4) DjhnRNPA2/B1-like expression is induced by temperature and heavy metal ion stress. The data suggests that DjhnRNPA2/B1-like is a multiple functional gene, it plays important roles in regeneration and homeostatic maintenance and it is also involved in stress responses in planarians. Our work provides basic data for the study of regenerative mechanism and stress responses in freshwater planarians.

Identification and expression analysis of a Spsb gene in planarian Dugesia japonica.

The SPSB family is comprised of four highly conserved proteins, each containing a C-terminal SOCS box motif and a central SPRY domain. Presently, Spsb genes have been found in mammals and in a few invertebrates, however, the specific functions of these genes are still unknown. In this study, we identified a Spsb gene from the planarian Dugesia japonica and termed it DjSpsb. The temporal and spatial expression patterns of DjSpsb were examined in both intact and regenerative animals, and expression levels were also quantified in response to various stressors. The results show that (1) DjSpsb is highly conserved in evolutionary history in metazoans and is at closer relationship to Spsb1, Spsb2 and Spsb4; (2) DjSpsb mRNA is mainly expressed in the head and also throughout head regeneration processes, particularly, its expression up-regulated observably on day 5 after amputation; (3) DjSpsb is also expressed in the testes and yolk glands; (4) DjSpsb expression is induced by high temperature and ethanol but inhibited by high doses of ionic liquids. The date suggests that the DjSpsb gene might be active in central nervous system (CNS) formation and functional recovery during head regeneration, and it is also involved in the development of germ cells and stress responses in the planarians.

The characteristics of sox gene in Dugesia japonica.

Sox genes play important roles in animal developmental processes, including embryogenesis, neural cell stemness, neurogenesis, sex determination, among others. Here, the full length sox gene in planarian Dugesia japonica, named DjsoxB, was cloned using rapid amplification of cDNA ends (RACE). Phylogenetic analysis demonstrates that DjsoxB is highly conserved evolutionarily in metazoans. Whole-mount in situ hybridization found DjsoxB mRNA to be mainly expressed in the head, intestine and mouth in both sexually mature and immature planarians. Moreover, DjsoxB transcripts were detected in the blastema after amputation and throughout the head regeneration processes. The data from real-time PCR showed that the mRNA expression levels of DjsoxB were distinctly up-regulated from 3 to 7days after amputation. These results suggest that DjsoxB gene might be active in CNS formation and functional recovery during head regeneration, maintenance of adult CNS function and the development of other tissues (e.g. intestine) in D. japonica.

Molecular characterization of the glucose-regulated protein 78 (GRP78) gene in planarian Dugesia japonica.

GRP78 (78 kDa glucose-regulated protein) has ubiquitously existed in nearly all organisms from yeast to humans, reflecting the central roles it plays in cell survival. In this report, we isolated and sequenced the full-length cDNA of GRP78 (designated DjGRP78) from the planarian Dugesia japonica. The cDNA is 2121 bp, including an open reading frame (ORF) of 1983 bp encoding a polypeptide of 660 amino acids with three HSP70 family signatures. DjGRP78 contains signal peptides at the N-terminus and a KTEL peptide motif at the C-terminus, which suggests that it localizes in the endoplasmic reticulum (ER). Fluorescent real time RT-PCR was employed to detect the expression pattern of Djgrp78 in response to different stressors. Our results show that heat shock and heavy metals (Hg(2+) and Pb(2+)) induce Djgrp78 expression, but starvation does not. Interestingly, we found that Djgrp78 was up-regulated in planarians with septic tissues, and also verified that it was up-regulated in response to bacterial challenge. Our data indicate that Djgrp78 may be a multifunctional gene, and play important roles in physiological and pathological stress in planarians.