Identification of lactate-related subgroups and prognostic model in triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that exhibits elevated glycolytic capacity. Lactate, as a byproduct of glycolysis, is considered a major oncometabolite that plays an important role in oncogenesis and remodeling of the tumor microenvironment. However, the potential roles of lactate in TNBC are not yet fully understood. In this study, our goal was to identify prognosis-related lactate genes (PLGs) and construct a lactate-related prognostic model (LRPM) for TNBC. METHODS: First, we applied lactate-related genes to classify TNBC samples using a hierarchical clustering algorithm. Then, we performed the log-rank analysis and the least absolute shrinkage and selection operator analysis to screen PLGs and construct the LRPM. The biological functions of the identified PLGs in TNBC were investigated using CCK8 assay and clone formation assay. Finally, we constructed a nomogram based on the lactate-risk score and tumor clinical stage. We used the operating characteristic curve and decision curve analysis to evaluate the predictive capability of the nomogram. RESULTS: Our results showed that the TNBC samples could be classified into two subgroups with different survival probabilities. Three genes (NDUFAF3, CARS2 and FH), which can suppress TNBC cell proliferation, were identified as PLGs. Moreover, the LRPM and nomogram exhibited excellent predictive performance for TNBC patient prognosis. CONCLUSION: We have developed a novel LRPM that enables risk stratification and identification of poor molecular subtypes in TNBC patients, showing great potential in clinical practice.

Banxia Xiexin decoction alleviates AS co-depression disease by regulating the gut microbiome-lipid metabolic axis.

ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic Chinese herbal formulation consisting of 7 herbs including Pinelliae Rhizoma, Scutellariae Radix, Zingiberis Rhizoma, Ginseng Radix, Glycyrrhizae Radix, Coptidis Rhizoma, and Jujubae Fructus, which can exert effects on lowering lipids and alleviating depressive mood disorders via affecting gastrointestinal tract. AIM OF THE STUDY: The pathogenesis of atherosclerosis (AS) co-depression disease has not been well studied, and the current clinical treatment strategies are not satisfactory. As a result, it is critical to find novel methods of treatment. Based on the hypothesis that the gut microbiome may promote the development of AS co-depression disease by regulating host lipid metabolism, this study sought to evaluate the effectiveness and action mechanism of BXD in regulation of the gut microbiome via an intervention in AS co-depression mice. MATERIALS AND METHODS: To determine the primary constituents of BXD, UPLC-Q/TOF-MS analysis was carried out. Sixteen C56BL/6 mice were fed normal chow as a control group; 64 ApoE-/- mice were randomized into four groups (model group and three treatment groups) and fed high-fat chow combined with daily bind stimulation for sixteen weeks to develop the AS co-depression mouse model and were administered saline or low, medium or high concentrations of BXD during the experimental modeling period. The antidepressant efficacy of BXD was examined by weighing, a sucrose preference test, an open field test, and a tail suspension experiment. The effectiveness of BXD as an anti-AS treatment was evaluated by means of biochemical indices, the HE staining method, and the Oil red O staining method. The impacts of BXD on the gut microbiome structure and brain (hippocampus and prefrontal cortex tissue) lipids in mice with the AS co-depression model were examined by 16S rDNA sequencing combined with lipidomics analysis. RESULTS: The main components of BXD include baicalin, berberine, ginsenoside Rb1, and 18 other substances. BXD could improve depression-like behavioral characteristics and AS-related indices in AS co-depression mice; BXD could regulate the abundance of some flora (phylum level: reduced abundance of Proteobacteria and Deferribacteres; genus level: reduced abundance of Clostridium_IV, Helicobacter, and Pseudoflavonifractor, Acetatifactor, Oscillibacter, which were significantly different). The lipidomics analysis showed that the differential lipids between the model and gavaged high-dose BXD (BXH) groups were enriched in glycerophospholipid metabolism, and lysophosphatidylcholine (LPC(20:3)(rep)(rep)) in the hippocampus and LPC(20:4)(rep) in the prefrontal cortex both showed downregulation in BXH. The correlation analysis illustrated that the screened differential lipids were mainly linked to Deferribacteres and Actinobacteria. CONCLUSION: BXD may exert an anti-AS co-depression therapeutic effect by modulating the abundance of some flora and thus intervening in peripheral lipid and brain lipid metabolism (via downregulation of LPC levels).

Abietane diterpenoids with neuroprotective activities from Phlegmariurus carinatus.

Two new abietane diterpenoids, phlecarinatone A (1) and phlecarinatone B (2), along with two known analogues (3 and 4), were isolated from Phlegmariurus carinatus. The structures of 1 - 4 were unambiguously elucidated by comprehensive spectroscopic analyses. Abietane diterpenoids were isolated from the plant for the first time. All isolates were tested for their neuroprotective activities against H2O2-induced SH-SY5Y cells injury, and compound 2 showed moderate effect at the concentrations ranging from 5 ∼ 20 µM in vitro assay.

Metastatic axillary lymph node ratio (LNR) is prognostically superior to pN staging in patients with breast cancer--results for 804 Chinese patients from a single institution.

The number of axillary lymph nodes involved and retrieved are important prognostic factors in breast cancer. The purpose of our study was to investigate whether the lymph node ratio (LNR) is a better prognostic factor in predicting disease-free survival (DFS) for breast cancer patients as compared with pN staging. The analysis was based on 804 breast cancer patients who had underwent axillary lymph node dissection between 1999 and 2008 in Sun Yat-Sen University Cancer Center. Optimal cutoff points of LNR were calculated using X-tile software and validated by bootstrapping. Patients were then divided into three groups (low-, intermediate-, and high-risk) according to the cutoff points. Predicting risk factors for relapse were performed according to Cox proportional hazards analysis. DFS was estimated using the Kaplan-Meier method and compared by the log-rank test. The 5-year DFS rate decreased significantly with increasing LNRs and pN. Univariate analysis found that the pT , pN, LNR, molecule type, HER2, pTNM stage and radiotherapy well classified patients with significantly different prognosis. By multivariate analysis, only LNR classification was retained as an independent prognostic factor. Furthermore, there was a significant prognostic difference among different LNR categories for pN2 category, but no apparent prognostic difference was seen between different pN categories in any LNR category. Therefore, LNR rather than pN staging is preferable in predicting DFS in node positive breast cancer patients, and routine clinical decision-making should take the LNR into consideration.

Clinical characteristics and survival analysis of breast cancer molecular subtypes with hepatic metastases.

BACKGROUND: The liver is one of the most common metastatic sites of breast cancer, hepatic metastases developing in 6%-25% of patients with breast cancer and being associated with a poor prognosis. The aim of this study was to analyze the survival and clinical characteristics of patients with hepatic metastases from breast cancer of different molecular subtypes and to investigate the prognostic and predictive factors that effect clinical outcome. METHODS: We retrospectively studied the charts of 104 patients with breast cancer hepatic metastases diagnosed at Sun Yat-sen University Cancer Center from December 1990 to June 2009. Subtypes were defined as luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) enriched, triple-negative (TN). Prognostic factor correlations with clinical features and treatment approaches were assessed at the diagnosis of hepatic metastases. RESULTS: The median survival time was 16.0 months, and the one-, two- three-, four-, five- year survival rates were 63.5%, 31.7%, 15.6%, 10.8%, and 5.4%, respectively. Median survival periods after hepatic metastases were 19.3 months (luminal A), 13.3 months (luminal B), 18.9 months (HER2-enriched), and 16.1 months (TN, P=0.11). In multivariate analysis, a 2 year-interval from initial diagnosis to hepatic metastasis, treatment with endocrine therapy, and surgery were independent prognostic factors. Endocrine therapy could improve the survival of luminal subtypes (P=0.004) and was a favorable prognostic factor (median survival 23.4 months vs. 13.8 months, respectively, P=0.011). Luminal A group of patients treated with endocrine therapy did significantly better than the Luminal A group of patients treated without endocrine therapy (median survival of 48.9 vs. 13.8 months, P=0.003). CONCLUSIONS: Breast cancer subtypes were not associated with survival after hepatic metastases. Endocrine therapy was a significantly favorable treatment for patients with luminal subtype.

[Effect of daqingye on EP3 mRNA expression of hypothalamus in IL-1beta-induced rabbits].

AIM: To study the antipyretic effect and mechanism of Daqingye injection (DQYI). METHODS: The IL-1beta-induced febrile New Zealand rabbits were chosen as experimental models and the antipyretic effect of DQYI was observed. The expression of EP3 mRNA was investigated by using in situ hybridization (ISH) in POAH. RESULTS: First, the colonic temperature went up gradually after intravenous(i.v) IL-1beta. The peak value of temperature(deltaT) and thermal response index (TRI(1)) in IL-1beta-treated group were higher than those in control group (P<0.01). The DeltaT and TRI(1) of in DQYI and IL-1beta- treated group were lower than those in IL-1beta-treated group (P<0.05). The temperature of DQYI-treated group showed no distinguished difference compared with that in control group (P>0.05). Second, the expression of EP3 mRNA in the POAH of IL- 1beta-treated group increased markedly compared with that in control group (P<0.01). The expression of EP3 mRNA treated by IL-1beta+DQYI in the POAH decreased strikingly compared with that in IL-1beta group(P<0.05). CONCLUSION: DQYI has distinct antipyretic effect on IL-1beta-induced fever. The mechanism might be the inhibition of EP3 mRNA expression in POAH from rabbits.

Effects of electrical stimulation of ventral septal area on firing rates of pyrogen-treated thermosensitive neurons in preoptic anterior hypothalamus from rabbits.

Although there is considerable evidence supporting that fever evolved as a host defense response, it is important that the rise in body temperature would not be too high. Many endogenous cryogens or antipyretics that limit the rise in body temperature have been identified. Endogenous antipyretics attenuate fever by influencing the thermoregulatory neurons in the preoptic anterior hypothalamus (POAH) and in adjacent septal areas including ventral septal area (VSA). Our previous study showed that intracerebroventricular (I.C.V.) injection of interleukin-1beta (IL-1beta) affected electrophysiological activities of thermosensitive neurons in VSA regions, and electrical stimulation of POAH reversed the effect of IL-1beta. To further investigate the functional electrophysiological connection between POAH and VSA and its mechanisms in thermoregulation, the firing rates of thermosensitive neurons in POAH of forty-seven unit discharge were recorded by using extracellular microelectrode technique in New Zealand white rabbits. Our results show that the firing rates of the warm-sensitive neurons decreased significantly and those of the cold-sensitive neurons increased in POAH when the pyrogen (IL-1beta) was injected I.C.V. The effects of IL-1beta on firing rates in thermosensitive neurons of POAH were reversed by electrical stimulation of VSA. An arginine vasopressin (AVP) V1 antagonist abolished the regulatory effects of VSA on the firing rates in thermosensitive neurons of POAH evoked by IL-1beta. However, an AVP V2 antagonist had no effects. These data indicated that VSA regulates the activities of the thermosensitive neurons of POAH through AVP V1 but not AVP V2 receptor.