Exploring CYP2D6 polymorphisms and angiotensin receptor blocker response in the Bai hypertensive population.

OBJECTIVE: The CYP2D6 enzyme is crucial for the metabolism and disposition of a variety of drugs. This study was conducted to examine the relationship between CYP2D6 gene polymorphisms and the response to angiotensin receptor blocker (ARB)-based treatment in patients of Chinese Bai ethnicity with hypertension. METHODS: Seventy-two hypertensive adults from the Chinese Bai ethnic group, exhibiting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg, were recruited. Targeted regional sequencing was utilized to genotype single nucleotide polymorphisms in the CYP2D6 gene, aiming to assess their frequency and to evaluate their influence on the therapeutic efficacy of ARB medications. RESULTS: Our research identified nine significant CYP2D6 polymorphisms associated with the efficacy of ARB treatment in the Bai hypertensive cohort. Specifically, patients possessing certain mutant genotype at rs111564371 exhibited substantially greater reductions in SBP and DBP, with P -values of 0.021 and 0.016, respectively, compared to those carrying the wild genotype. Additionally, these mutant genotype at rs111564371 and rs112568578 were linked to approximately 20% higher overall efficacy rates and a 10% increased achievement rate relative to the wild genotype. CONCLUSION: Our research with the Bai hypertensive group shows that certain CYP2D6 polymorphisms significantly influence ARB treatment outcomes. Mutations at rs111564371 led to better blood pressure control ( P -values: 0.021 for SBP, 0.016 for DBP), improving ARB efficacy by appromixately 20% and increasing treatment goal achievement by 10% over the wild-type genotype. STATEMENTS: Our investigation into CYP2D6 polymorphisms within the Bai hypertensive cohort marks a substantial advancement towards personalized healthcare, underscoring the pivotal influence of genetic constitution on the effectiveness of ARB therapy.

Clinical outcome and therapeutic impact on neuroendocrine neoplasms of the breast: a national cancer database study.

PURPOSE: Neuroendocrine neoplasms (NENs) of the breast are rare and not well-studied. NEN are subcategorized as well-differentiated neuroendocrine tumor (NET) and poorly differentiated neuroendocrine carcinoma (NEC). The objectives of the current study were to review the clinicopathologic features of NENs, therapeutic efficacy of current systemic therapy and clinical outcomes of NEN of the breast. METHODS: Between 2004 and 2015, 420 NET, 205 NEC, 146 Adenocarcinoma with NE differentiation (ACNED) and 1,479,520 of invasive carcinoma, not otherwise specified (IC-NOS) of the breast were identified in the National Caner Database. Overall survival was compared among groups using Kaplan-Meier method and Log-rank test. Multivariate analyses were performed to identify prognostic factors. RESULTS: After adjusting for other prognostic factors, both NET and NEC of the breast showed significantly worse OS than IC-NOS (HR (95% CI) = 1.41 (1.17, 1.72), p = 0.005 and HR (95% CI) = 2.11 (1.67, 2.67), p < 0.001, respectively). Both NET and NEC benefited from endocrine therapy if the tumors were hormonal receptor positive (median OS for treated with vs without: 125 vs 57 months in NET, not reached vs 29 months in NEC). NEC also benefited from chemotherapy (median OS for treated with vs without: 42 vs 34 months), but not NET. CONCLUSION: NEN is a unique pathologic and clinical entity, which has worse clinical outcome compared to IC-NOS of the breast. Current therapeutics used in the treatment of IC-NOS improve, but do not fully mitigate, the poorer prognosis of NEN patients. More effective therapy for patients with this unique tumor type are needed.

Clinical Genetic Features and Neoadjuvant Chemotherapy Response in HER2-Low Breast Cancers: A Retrospective, Multicenter Cohort Study.

BACKGROUND: The objective of this work is to reveal differences in clinical and genetic features, as well as neoadjuvant chemotherapy (NAC) response, between HER2-low and HER2-zero or HER2-positive breast cancers. PATIENTS AND METHODS: A total of 245 female patients with breast cancer were retrospectively enrolled from seven hospitals. Core needle biopsy (CNB) samples were collected before NAC and used for next-generation sequencing by a commercial gene panel. Clinical and genetic features, as well as NAC response, were compared between HER2-low and HER2-zero or HER2-positive breast cancers. The nonnegative matrix factorization (NMF) method was applied to cluster the C-Score of enrolled cases to reveal the intrinsic features of each HER2 subgroup. RESULTS: A total of 68 (27.8%) cases are HER2-positive, 117 (47.8%) cases are HER2-low, and 60 (24.5%) cases are HER2-zero. HER2-low breast cancers have a significantly lower pathologic complete response (pCR) rate than HER2-positive and HER2-zero breast cancers (p < 0.050 for all comparisons). Compared with HER2-low breast cancers, HER2-positive cases have higher rates of TP53 mutation, TOP2A amplification, and ERBB2 amplification, as well as lower rates of MAP2K4 mutation, ESR1 amplification, FGFR1 amplification, and MAPK pathway alteration (p < 0.050 for all comparisons). After clustering HER2-low cases by the NMF method, 56/117 (47.9%) are in cluster 1, 51/117 (43.6%) are in cluster 2, and 10/117 (8.5%) are in cluster 3. HER2-low cases in cluster 2 have the lowest pCR rate among the three clusters (p < 0.050). CONCLUSIONS: HER2-low breast cancers have significant genetic differences from HER2-positive cases. Genetic heterogeneity exists in HER2-low breast cancers and impacts on NAC response in this subgroup.

Biomarker profile of invasive lobular carcinoma: pleomorphic versus classic subtypes, clinicopathological characteristics and prognosis analyses.

PURPOSE: To compare the clinicopathologic features and prognosis of pleomorphic invasive lobular carcinoma (P-ILC) and classic ILC (C-ILC) according to the biomarker profile. METHODS: A total of 667 C-ILCs and 133 P-ILCs between 2011 and 2021 were included. Clinicopathologic features and stromal tumor-infiltrating lymphocytes (sTILs) status were evaluated. P-ILCs were divided into subtypes based on ER/PR and HER2 expression. The overall survival and disease-free survival (DFS) of patients were compared among matched P-ILCs, C-ILCs, and invasive ductal carcinomas (IDCs) with biomarker subtypes. RESULTS: Compared to C-ILCs, P-ILCs had greater tumor sizes and stages, fewer ER-positive, more HER2-positive, triple negative (TN), and Ki-67 > 20% tumors (P < 0.05). P-ILCs were subdivided into ER+ (63.1%), HER2+ (21.1%) and TN (15.8%). ER+ P-ILCs were mainly showed trabecular and solid growth patterns. Apocrine and solid features were more strongly associated with HER2+ P-ILCs and TN-P-ILCs, respectively. The prognosis of each biomarker group (ER+, HER2+ and TN) differed by subtype. The P-ILC biomarker subtypes had worse prognosis than the same subtypes in the IDC group, while there was no difference between the P-ILC and the C-ILC counterparts. Solid variants of P-ILC had the worst prognosis. Bone was the most common metastatic site in ER+ P-ILCs and TN-P-ILCs. HER2+ P-ILCs tended to metastasize to the brain and liver. DFS of HER2+ P-ILCs and TN-P-ILCs were worse than that of ER+ P-ILCs. Lacking lobular carcinoma in situ and sTILs ≤ 10% were associated with worse survival of ER+ P-ILCs and TN-P-ILCs, respectively. For HER2+ P-ILCs, Ki-67 > 20% and sTILs ≤ 10% were significant factors for lower DFS. CONCLUSION: P-ILCs is an aggressive subtype of ILCs. Analyzing the prognostic factors of P-ILCs with heterogeneous morphological and biomarker characteristics is helpful for creating an individualized treatment.

Cancer stem cell-targeted therapeutic approaches for overcoming trastuzumab resistance in HER2-positive breast cancer.

Application of the anti-HER2 drug trastuzumab has significantly improved the prognosis of patients with the HER2-positive subtype of breast cancer. However, 50% of patients with HER2 amplification relapse due to trastuzumab resistance. Accumulating evidence indicates that breast cancer is driven by a small subset of cancer-initiating cells or breast cancer stem cells (BCSCs), which have the capacity to self-renew and differentiate to regenerate the tumor cell hierarchy. Increasing data suggest that BCSCs are resistant to conventional therapy, including chemotherapy, radiotherapy, and endocrine therapy, which drives distant metastasis and breast cancer relapse. In recent years, the trastuzumab resistance of breast cancer has been closely related to the prevalence of BCSCs. Here, our primary focus is to discuss the role of epithelial-mesenchymal transition (EMT) of BCSCs in the setting of trastuzumab resistance and approaches of reducing or eradicating BCSCs in HER2-positive breast cancer.

Exosomes derived from human placental mesenchymal stem cells ameliorate myocardial infarction via anti-inflammation and restoring gut dysbiosis.

BACKGROUND: Myocardial infarction (MI) represents a severe cardiovascular disease with limited therapeutic agents. This study was aimed to elucidate the role of the exosomes derived from human placental mesenchymal stem cells (PMSCs-Exos) in MI. METHODS: PMSCs were isolated and cultured in vitro, with identification by both transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). To further investigate the effects of PMSC-Exos on MI, C57BL/6 mice were randomly divided into Sham group, MI group, and PMSC-Exos group. After 4 weeks of the intervention, cardiac function was assessed by cardiac echocardiography, electrocardiogram and masson trichrome staining; lipid indicators were determined by automatic biochemical instrument; inflammatory cytokines were measured by cytometric bead array (CBA); gut microbiota, microbial metabolites short chain fatty acids (SCFAs) as well as lipopolysaccharide (LPS) were separately investigated by 16S rRNA high throughput sequencing, gas chromatography mass spectrometry (GC-MS) and tachypleus amebocyte lysate kit; transcriptome analysis was used to test the transcriptional components (mRNA\miRNA\cirRNA\lncRNA) of PMSC-Exos. RESULTS: We found that human PMSC-Exos were obtained and identified with high purity and uniformity. MI model was successfully established. Compared to MI group, PMSC-Exos treatment ameliorated myocardial fibrosis and left ventricular (LV) remodeling (P < 0.05). Moreover, PMSC-Exos treatment obviously decreased MI molecular markers (AST/BNP/MYO/Tn-I/TC), pro-inflammatory indicators (IL-1ß, IL-6, TNF-α, MCP-1), as well as increased HDL in comparison with MI group (all P < 0.05). Intriguingly, PMSC-Exos intervention notably modulated gut microbial community via increasing the relative abundances of Bacteroidetes, Proteobacteria, Verrucomicrobia, Actinobacteria, Akkermansia, Bacteroides, Bifidobacterium, Thauera and Ruminiclostridium, as well as decreasing Firmicutes (all P < 0.05), compared with MI group. Furthermore, PMSC-Exos supplementation increased gut microbiota metabolites SCFAs (butyric acid, isobutyric acid and valeric acid) and decreased LPS in comparison with MI group (all P < 0.05). Correlation analysis indicated close correlations among gut microbiota, microbial SCFAs and inflammation in MI. CONCLUSIONS: Our study highlighted that PMSC-Exos intervention alleviated MI via modulating gut microbiota and suppressing inflammation.

Correlation between CA12 and TFF3 and their prediction value of neoadjuvant chemotherapy response in breast cancer.

WHAT IS KNOWN AND OBJECTIVE: Compared with other molecular subtypes, hormone receptor-positive breast cancer often shows worse neoadjuvant chemotherapy efficacy. This study aims to explore the relationship between the oestrogen receptor (ER)-related genes carbonic anhydrase 12 (CA12) and trefoil factor 3 (TFF3) and their predictive value of neoadjuvant chemotherapy for breast cancer. METHODS: We investigated the relationships between CA12, TFF3 and ER status and their predictive value of anthracycline-taxane neoadjuvant chemotherapy in 115 female breast cancer patients via real-time polymerase chain reaction (RT-PCR) and 4 GEO datasets: GSE41998, GSE25065, GSE20194 and GSE20271. Then, the effects of CA12 and TFF3 on the chemotherapy drugs doxorubicin and docetaxel were verified in vitro in the breast cancer cell lines MCF-7 and BT474. RESULTS AND DISCUSSION: The GEO datasets and RT-PCR results showed that the relative expression of both CA12 and TFF3 was higher in oestrogen receptor-positive samples compared with the other samples (p < 0.05). CA12 was significantly correlated with TFF3 (p < 0.05). In MCF-7 cells, inhibition of TFF3 induced downregulation of CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 also downregulated TFF3 and ESR1 (p < 0.05). In BT474 cells, inhibition of TFF3 downregulated CA12 and ESR1 (p < 0.05) at both the mRNA and the protein levels, while inhibition of CA12 led to slight upregulation of TFF3 and ESR1 (p > 0.05). Moreover, GEO datasets and RT-PCR results showed that CA12 and TFF3 were more highly expressed in nonpathological complete response (non-pCR) samples than in pCR samples (p < 0.05). Cell viability assays of MCF-7 and BT474 cells showed that inhibiting CA12 and TFF3 could enhance sensitivity to doxorubicin and docetaxel (p < 0.05). WHAT IS NEW AND CONCLUSION: CA12 and TFF3 were correlated with each other, and their high expression might explain the worse efficacy of neoadjuvant chemotherapy in oestrogen receptor-positive breast cancer patients.

Validation of prognostic significance of the proposed uniform classification framework in neuroendocrine neoplasms of the breast.

PURPOSE: A uniform classification framework for neuroendocrine neoplasms (NENs) in all the organ systems has been recently proposed by an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert panel. Based on the new classification system, the NENs of the breast are divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). This study is aimed to analysis the prognostic differences between NENs and invasive ductal carcinomas of no special type (IDCs-NST). METHODS: The surveillance, epidemiology, and end results (SEER) database released on November 2018 was used for this study. Between 2003 and 2016, 361 NENs (NET = 239, NEC = 122) of the breast and 491,908 of IDCs-NST were identified. Survival analysis was performed for disease-specific survival (DSS) and overall survival (OS). RESULTS: The 5-year DSS of NET, NEC, and IDC-NST was 63.39%, 46.00%, and 89.17%, respectively. And the 5-year OS of NET, NEC, and IDC-NST was 55.66%, 38.87%, and 83.17%, respectively. Within the same clinical stage or grade, NETs and NECs of the breast had worse DSS and OS than corresponding stage or grade IDCs-NST (all P < 0.050). In univariate and multivariate survival analysis, NENs of the breast had significantly worse DSS and OS than IDCs-NST (P < 0.001). CONCLUSION: The universal classification framework for NEN allowed us to further refine the breast carcinoma with neuroendocrine differentiation as a unique pathologic and clinical entity, which has worse clinical outcome compared to IDC-NST.

Prognostic Score-Based Stratification Analysis Reveals Universal Benefits of Radiotherapy on Lowering the Risk of Ipsilateral Breast Event for Ductal Carcinoma In Situ Patients with Different Risk Levels.

BACKGROUND: We aimed to analyze the effects of radiotherapy (RT) on the incidence rate of ipsilateral breast event (IBE) in ductal carcinoma in situ (DCIS) patients with lumpectomy after being stratified by prognostic score. METHODS: We identified DCIS patients who received lumpectomy, from the Surveillance, Epidemiology, and End Results (SEER) database from 1988 to 2015. Cumulative incidence functions for competing risk were used to evaluate the effects of RT on IBE risk over time. Three multivariate regression models (weighted, non-weighted, and Fine-Gray) were applied to compare the IBE risk between the RT and non-RT groups after stratifying patients by prognostic score. RESULTS: Overall, 72,623 DCIS patients were identified from the SEER database and 49,206 (66.8%) patients received RT. During the follow-up period (ranging from 7 to 347 months), the cumulative probability of invasive and in situ IBE was significantly lower in the RT group than in the non-RT group (p < 0.001). After being stratified by prognostic score, the weighted IBE incidence rate increased as the risk level increased (p < 0.050). In multivariate regression models, RT lowered the IBE incidence rate by at least 30% in low-, moderate-, and high-risk DCIS (p < 0.010). In particular, the in situ and invasive IBE incidence rate decreased by over 50% in low-risk DCIS with RT (p < 0.001). CONCLUSIONS: RT is associated with a lowered IBE incidence rate in DCIS patients, regardless of the assigned risk levels for patients. The significant reduction in the IBE incidence rate in low-risk DCIS patients also indicates the potential benefits for recommending RT to such a patient population in clinical practice.

Hyperhomocysteinemia induces vascular calcification by activating the transcription factor RUNX2 via Krüppel-like factor 4 up-regulation in mice.

One of the main characteristics of atherosclerosis is vascular calcification, which is linked to adverse cardiovascular events. Increased homocysteine (Hcy), a feature of hyperhomocysteinemia, is correlated with advanced vascular calcification and phenotypic switching of vascular smooth muscle cells (VSMCs). Oxidative stress and high phosphate levels also induce VSMC calcification, suggesting that the Krüppel-like factor 4 (KLF4) signaling pathway may also contribute to vascular calcification. In this study, we investigated this possibility and the role and mechanisms of Hcy in vascular calcification. We found that in atherosclerotic apolipoprotein E-deficient (ApoE-/-) mice, Hcy significantly increases vascular calcification in vivo, as well as VSMC calcification in vitro Of note, the Hcy-induced VSMC calcification was correlated with elevated KLF4 levels. Hcy promoted KLF4 expression in calcified atherosclerotic lesions in vivo and in calcified VSMCs in vitro shRNA-mediated KLF4 knockdown blocked the Hcy-induced up-regulation of runt-related transcription factor 2 (RUNX2) and VSMC calcification. RUNX2 inhibition abolished Hcy-induced VSMC calcification. Using ChIP analysis, we demonstrate that KLF4 interacts with RUNX2, an interaction promoted by Hcy stimulation. Our experiments also revealed that the KLF4 knockdown attenuates Hcy-induced RUNX2 transactivity, indicating that KLF4 is important in modulating RUNX2 transactivity. These findings support a role for Hcy in regulating vascular calcification through a KLF4-RUNX2 interaction and indicate that Hcy-induced, enhanced RUNX2 transactivity increases VSMC calcification. These insights reveal possible opportunities for developing interventions that prevent or manage vascular calcification.

Prognostic value of systemic inflammatory factors NLR, LMR, PLR and LDH in penile cancer.

BACKGROUND: Penile squamous cell carcinoma (PSCC) represents an important public health problem for developing countries. The major prognostic factors in PSCC are pathological subtype, perineural invasion, lymphovascular invasion, depth of invasion and grade, which are hard to obtain precisely before the operation. Besides, micro-metastases will be detected in about 30% of intermediate-risk patients with clinically non-palpable inguinal lymph nodes after inguinal lymph node dissection (ILND). It means approximately 70% of patients are unable to benefit from ILND who might suffered from the complications of surgery. We hope some biomarkers could be found which are able to predict the outcome before surgery and reflect the inguinal lymph nodes metastasis. METHODS: A total of 349 consecutive patients of penile cancer in Yunnan cancer hospital in China between October 2002 and December2017. Two hundred twenty-five was succeed to follow-up. The association between NLR, LMR, PLR, LDH and Overall survival (OS), progression free survival (PFS), inguinal lymph node (N stage) was analyzed with K-M analysis, univariable, multivariable logistic regression and Kendall's tau-b correlation coefficient. RESULTS: Multivariable analysis reveal that only PLR was significant independent factor which is associated with inferior OS and PFS; Age and LDH was associated with inferior OS; Lymph node and metastatic status remained significant for OS and PFS as NCCN and EAU Guidelines indicated; the tumor type, initial treatment and NLR LMR were not significant in predicting both OS and PFS. NLR, LMR and PLR were corresponded to N stage, while LDH was not associated with the N stage based on logistic regression model analysis. NLR, LMR and PLR were found weakly related to N stage through an application of Kendall's tau-b correlation coefficient. CONCLUSIONS: PLR was significant independent factors for OS and PFS, Age and LDH was significant independent factors for OS. NLR, LMR, PLR was corresponded to N stage.

High expression of microRNA20b is associated with malignant clinicopathological features and poor prognosis in breast phyllodes tumor.

BACKGROUND: microRNAs, which expound the transcriptional regulation of gene expression, have been validated as prognostic markers in many tumors. The deregulated expression of microRNAs has been shown to aid classification of tumors and predict outcome in many tumors including breast PTs. The aim of our study is to investigate the clinical significance and prognostic value of microRNAs in PTs to identify a biomarker which has the potential for predicting prognosis and target therapy. METHODS: Quantitative real-time PCR (qRT-PCR) was used to detect the expression level of microRNA20b in 123 breast PTs patients. The correlations between the expression of microRNA20b and clinicopathological parameters were investigated. The prognostic significance of microRNA20b was investigated by the Kaplan-Meier survival and Cox proportional hazards regression model. RESULTS: The expression level of microRNA20b increased with the increase in the tumor grade (p < 0.05). High expression of microRNA20b correlated with stromal overgrowth, marked stromal cellularity, high atypia of stromal cells, infiltrative tumor margin, high mitotic activity, tumor grade, local recurrence and metastasis (p < 0.05). High expression of microRNA20b correlated with the shorter disease-free survival (DFS) (log-rank test, p < 0.001). Multivariate Cox regression analysis showed that microRNA20b was an independent prognostic indicator for breast PTs patients. CONCLUSION: The study demonstrated the promising potential of applying microRNA20b as a prognostic biomarker in PT patients.

Repression of miR-135b-5p promotes metastasis of early-stage breast cancer by regulating downstream target SDCBP.

Metastasis is an essential event for breast cancer (BC) progression even after initial surgery. The identification of patients with a high probability of metastasis at an early stage is particularly important in clinical practice and requires individualized treatment or early prevention. A retrospective study of 242 cases of ductal carcinoma in situ with microinvasion (DCIS-Mi), the first stage of invasive BC, was performed in this follow-up analysis. Of all patients, 8 developed metastases, and they were all included for further mechanistic studies with control group of 24 DCIS-Mi by matched-pair designing. By screening DCIS-Mi with different prognoses, we found that the DCIS-Mi that metastasized had significantly lower miR-135b-5p expression than the DCIS-Mi that did not. The function of miR-135b-5p was studied in vitro and in vivo invasion and metastasis assays. We also validated a novel target gene for miR-135b-5p, syndecan binding protein (SDCBP), and assessed the functional consequences of SDCBP by invasion assays. By checking different BC cell lines, a strong inverse correlation between miR-135b-5p and SDCBP expression was recorded. For the functional study, the inhibition of miR-135b-5p was accompanied by increased BC cell growth, epithelial-mesenchymal transition (EMT), migration and invasion in vitro. Interestingly, silencing SDCBP can reverse miR-135b-5p-dependent EMT and proliferation. In vivo studies demonstrated that the newly revealed miR-135b-5p/SDCBP axis increased cell proliferation, invasion and malignant transformation, as well as promoted metastasis in a xenograft tumor mouse model. Thus, our clinical patient cohort and functional data suggest that miR-135b-5p/SDCBP is a crucial determinant of BC metastasis at a very early stage. Our results may shed light on the importance of miR-135b-5p molecular diagnosis and prognosis, as well as the early prevention of BC for metastasis.

Somatic alterations of TP53, ERBB2, PIK3CA and CCND1 are associated with chemosensitivity for breast cancers.

The correlation of genetic alterations with response to neoadjuvant chemotherapy (NAC) has not been fully revealed. In this study, we enrolled 247 breast cancer patients receiving anthracycline-taxane-based NAC treatment. A next generation sequencing (NGS) panel containing 36 hotspot breast cancer-related genes was used in this study. Two different standards for the extent of pathologic complete response (pCR), ypT0/isypN0 and ypT0/is, were used as indicators for NAC treatment. TP53 mutation (n = 149, 60.3%), PIK3CA mutation (n = 109, 44.1%) and MYC amplification (n = 95, 38.5%) were frequently detected in enrolled cases. TP53 mutation (P = 0.019 for ypT0/isypN0 and P = 0.003 for ypT0/is) and ERBB2 amplification (P < 0.001 for both ypT0/isypN0 and ypT0/is) were related to higher pCR rates. PIK3CA mutation (P = 0.040 for ypT0/isypN0) and CCND2 amplification (P = 0.042 for ypT0/is) showed reduced sensitivity to NAC. Patients with MAPK pathway alteration had low pCR rates (P = 0.043 for ypT0/is). Patients with TP53 mutation (-) PIK3CA mutation (-) ERBB2 amplification (+) CCND1 amplification (-), TP53 mutation (+) PIK3CA mutation (-) ERBB2 amplification (+) CCND1 amplification (-) or TP53 mutation (+) PIK3CA mutation (+) ERBB2 amplification (+) CCND1 amplification (-)had significantly higher pCR rates (P < 0.05 for ypT0/isypN0 and ypT0/is) than wild type genotype tumors. Some cancer genetic alterations as well as pathway alterations were associated with chemosensitivity to NAC treatment. Our study may shed light on the molecular characteristics of breast cancer for prediction of NAC expectations when breast cancer is first diagnosed by biopsy.

Association of metformin use with ovarian cancer incidence and prognosis: a systematic review and meta-analysis.

BACKGROUND: Some clinical and basic research studies have indicated that exposure to metformin might have protective effects against ovarian cancer. However, results from epidemiologic studies have been inconsistent. We performed a meta-analysis to evaluate the effect of metformin use on the risk of ovarian cancer occurrence and mortality. METHODS: Multiple databases were searched to identify studies on the association between use of metformin and risk of ovarian cancer or prognosis, up to August 2018. Relevant information for analysis was extracted. A random-effects model was used to calculate the pooled risk estimate. RESULTS: Thirteen articles were included, of which six articles focused on ovarian cancer incidence and the others focused on prognosis. The pooled OR for ovarian cancer occurrence and mortality comparing metformin use with non-use or use of other hypoglycemic drugs was 0.76 (95% CI 0.62 to 0.93, p = 0.008) and 0.55 (95% CI 0.36 to 0.84, p = 0.006), respectively. Moderate to substantial heterogeneity was observed across included studies. CONCLUSIONS: Our findings demonstrate that use of metformin was significantly associated with a lower incidence and a better prognosis of ovarian cancer in patients with diabetes. Well-designed interventional studies are warranted to confirm our findings.

miR-21 modulates prostaglandin signaling and promotes gastric tumorigenesis by targeting 15-PGDH.

miR-21 is an abundantly expressed miRNA in mammalian cells, and evolutionarily conserved across a wide range of vertebrate species. The previous study found that miR-21 is significantly upregulated in gastric cancer. However, the detail mechanisms remain to be largely unknown. In current study, quantitative real-time PCR was applied to examine the expression of miR-21 in gastric cancer tissue and cell lines. The roles of miR-21 in cell proliferation and cell cycle were analyzed by cck8 cell viability assays, flow cytometry cell cycle assays and clone formation assays. As to detail mechanisms, we investigate the relationship between miR-21 and 15-PGDH in gastric cell lines, AGS and BGC-823 treated with In-miR-21, and found that miR-21 is negatively correlated with 15-PGDH. The reduced 15-PGDH may result in PGE2 accumulation which sustains carcinogenesis and tumor progression. We further found that miR-21 exert its oncogenic role through PGE2/PI3K/Akt/Wnt/ß-catenin axis in gastric cell proliferation. In conclusion, our findings enlarged our knowledge in the roles of miR-21 in the progression of gastric cancer.

Role of Natural Killer T (NKT) Cells in Type II Diabetes-Induced Vascular Injuries.

BACKGROUND This study investigated the distribution and features of natural killer T (NKT) cells in the peripheral blood of diabetic patients, and their regulatory roles on vascular endothelial cells. MATERIAL AND METHODS Peripheral lymphocytes were isolated from diabetic patients. NKT cell distribution, proportion, and surface and intracellular markers were detected with flow cytometry. Peripheral blood-derived NKT cells were isolated and co-cultured with human umbilical vein endothelial cells (HUVECs). Proliferation and migration of HUVECs were assessed with the CCK-8 assay and the Transwell chamber assay. RESULTS The ratios of CD3-CD56+ NK and CD3+CD56+ NKT cells in the peripheral blood of patients with type II diabetes were significantly elevated. The expression levels of NKp30, NKG2D, and NKp44 on the surface were increased in the CD3+CD56+ NKT cells, while the expression levels of NKG2A and 158b were significantly downregulated. The expression level of granzymes in the peripheral blood-derived NKT cells were not changed in patients with type II diabetes, but the expression levels of IFNg and IL-4 were significantly increased. However, after co-culture with NKT cells derived from the peripheral blood of diabetic patients, the proliferation and migration of HUVECs were significantly inhibited, and was restored by treatment with IL-4 antibody. In addition, the IL-4 stimulus inhibited the proliferation and migration of HUVECs. ls were not changed in patients with type II diabetes, while the expression levels of IFNγ and IL-4 were significantly increased. However, after co-cultured with NKT cells derived from the peripheral blood of diabetic patients, the proliferation and migration of HUVECs were significantly inhibited, which could significantly restored by the treatment of IL-4 antibody. In addition, the IL-4 stimulus could down-regulate the proliferation and migration of HUVECs.  CONCLUSIONS Peripheral blood NKT cells are increased and activated in diabetes. NKT cells inhibit the proliferation and migration of HUVECs by secreting IL-4, thereby inducing vascular injuries.

Clinical significance and prognostic value of receptor conversion in hormone receptor positive breast cancers after neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is widely used in advanced breast cancer patients. However, there is little known about conversion frequency of estrogen receptor (ER) and/or progesterone receptor (PR) status for hormone receptor positive-breast cancer patients after NAC and their correlation with prognosis. METHODS: In this study, 231 breast cancer patients with residual disease after NAC were enrolled and divided into receptor stable group (having no conversion in both ER and PR status pre- and post-NAC) and any receptor conversion group (having any conversion in either ER or PR status). Univariate and multivariate survival analyses were used to compare survival differences between the two groups. RESULTS: Fifty-five patients (23.8%) had ER and/or PR conversion after NAC. Younger patients (≤ 50 years) were more likely to have receptor conversion (P = 0.014). For 213 patients (92.2%) who received adjuvant endocrinotherapy after surgery, the 5-year disease free survival (DFS) estimates for patients in the any receptor conversion group (55.2%) was worse than patients in the receptor stable group (73.7%, Log-rank test, P = 0.015). While the 5-year overall survival estimates for patients with or without receptor conversion were not statistically different (86.0 vs. 82.4%, Log-rank test, P = 0.587). In multivariate Cox proportional hazard analyses, patients with any receptor conversion had worse DFS (hazard ratio, 1.995; 95% confidence interval, 1.130-3.521, P = 0.031). CONCLUSIONS: It is necessary to recommend patients to test biomarkers in residual disease and pay more attention to patients who have any receptor conversion. These patients may need more individual therapy after surgery.