Prognosis and influencing factors of ER-positive, HER2-low breast cancer patients with residual disease after neoadjuvant chemotherapy: a retrospective study.

Previously, we found that patients with estrogen receptor (ER)-positive, HER2-low breast cancer are resistant to neoadjuvant chemotherapy (NACT) and have worse outcomes than those who achieve pathological complete response (pCR) after NACT. This study aimed to investigate the prognosis and influencing factors in these patients. A total of 618 patients with ER-positive breast cancer who received standard thrice-weekly NACT were enrolled, including 411 patients with ER-positive, HER2-low breast cancer. Data on the clinicopathological features of these patients before and after NACT were collected. Univariate and multivariate Cox regression analyses were used to identify the independent factors affecting 5-year disease-free survival (DFS). Among the ER-positive, HER2-low patients, 49 (11.9%) achieved a pCR after NACT. A significant difference in survival was observed between patients with and without residual disease after NACT. Additionally, changes in immunohistochemical markers and tumor stages before and after NACT were found to be significant. According to univariate and multivariate analyses, cN_stage (P = 0.002), ER (P = 0.002) and Ki67 (P = 0.023) expression before NACT were significantly associated with 5-year DFS, while pT_stage (P = 0.015), pN_stage (P = 0.029), ER (P = 0.020) and Ki67 (P < 0.001) levels after NACT were related to 5-year DFS in ER-positive, HER2-low patients with residual disease. Our study suggested that high proliferation, low ER expression and advanced stage before and after NACT are associated with a poor prognosis, providing useful information for developing long-term treatment strategies for ER-positive, HER2-low breast cancer in patients with residual disease in the future.

KLRG1-expressing CD8+ T cells are exhausted and polyfunctional in patients with chronic hepatitis B.

Killer cell lectin-like receptor G1 (KLRG1) has traditionally been regarded as an inhibitory receptor of T cell exhaustion in chronic infection and inflammation. However, its exact role in hepatitis B virus (HBV) infection remains elusive. CD8+ T cells from 190 patients with chronic hepatitis B were analyzed ex vivo for checkpoint and apoptosis markers, transcription factors, cytokines and subtypes in 190 patients with chronic hepatitis B. KLRG1+ and KLRG1- CD8+ T cells were sorted for transcriptome analysis. The impact of the KLRG1-E-cadherin pathway on the suppression of HBV replication mediated by virus-specific T cells was validated in vitro. As expected, HBV-specific CD8+ T cells expressed higher levels of KLRG1 and showed an exhausted molecular phenotype and function. However, despite being enriched for the inhibitory molecules, thymocyte selection-associated high mobility group box protein (TOX), eomesodermin (EOMES), and Helios, CD8+ T cells expressing KLRG1 produced significant levels of tumour necrosis factor (TNF)-α, interferon (IFN)-γ, perforin, and granzyme B, demonstrating not exhausted but active function. Consistent with the in vitro phenotypic assay results, RNA sequencing (RNA-seq) data showed that signature effector T cell and exhausted T cell genes were enriched in KLRG1+ CD8+ T cells. Furthermore, in vitro testing confirmed that KLRG1-E-cadherin binding inhibits the antiviral efficacy of HBV-specific CD8+ T cells. Based on these findings, we concluded that KLRG1+ CD8+ T cells are not only a terminally exhausted subgroup but also exhibit functional diversity, despite inhibitory signs in HBV infection.

Immunomultiple PCR-based electrochemical and lateral flow strategy for the simultaneous detection of liver cancer tumor markers.

The current use of the single serum biomarker α-fetoprotein (AFP) in clinical practice has limitations in terms of specificity and sensitivity. We propose a strategy that combines antigen capture polymerase chain reaction (AC-PCR), lateral flow assay (LFA), and electrochemical biosensors to detect both AFP and circulating tumor cells (CTCs) in liver cancer serum. First, we used the AC-PCR technique to achieve target separation, purification, signal conversion, and amplification, eliminating target heterogeneity. Then, we achieved rapid results through the LFA and electrochemical biosensor platforms. As a result, the proposed assay has limits of 5 cells/mL for CTCs and 5 µg/L for AFP. The proposed method was applied effectively to simulated blood samples. This method has the potential to play a role in early liver cancer and provide a potential application for the diagnosis and precision treatment of liver cancer.

Circulating sNinj1 as a novel predictor of prognosis and severity in hepatocellular carcinoma.

BACKGROUND: The occurrence and development of HCC are closely associated with cell death. Recently, researchers found that Ninj1 plays a pivotal role in PMR during different types of cell death. However, the importance of Ninj1 in HCC has not been extensively investigated. METHODS: This study included 102 newly diagnosed HCC patients and 102 sex and age-matched NCs. Circulating sNinj1 was assessed by ELISA. Serum LDH and IL-1ß were detected through a chemiluminescence assay. The correlations of these biomarkers with disease severity and their potential as prognostic predictors for HCC were evaluated. The dynamic changes of sNinj1, LDH, and IL-1ß levels before and after treatment were recorded. RESULTS: Serum levels of sNinj1, IL-1ß, and LDH were significantly higher in HCC patients. Our study found that the sNinj1 level was positively correlated with tumor size, metastasis, and staging. ROC analysis indicated that the AUC of sNinj1 in differentiating HCC from NCs was 0.85. As a result of tumor thrombosis and invasion of the hepatic vein, sNinj1's AUCs were 0.71 and 0.73, respectively. After partial resection and TACE treatment, serum sNinj1 and LDH exhibited similar change trends. A one-year follow-up analysis also demonstrated that HCC patients with high sNinj1 had significantly poorer survival than those with low sNinj1. CONCLUSIONS: The serum sNinj1 is another diagnostic biomarker supporting the HCC diagnosis. More importantly, it has been shown that circulating sNinj1 reveals potential as a novel predictor of HCC severity and prognosis.

Development and testing of a random forest-based machine learning model for predicting events among breast cancer patients with a poor response to neoadjuvant chemotherapy.

BACKGROUND: Breast cancer (BC) is the most common malignant tumor around the world. Timely detection of the tumor progression after treatment could improve the survival outcome of patients. This study aimed to develop machine learning models to predict events (defined as either (1) the first tumor relapse locally, regionally, or distantly; (2) a diagnosis of secondary malignant tumor; or (3) death because of any reason.) in BC patients post-treatment. METHODS: The patients with the response of stable disease (SD) and progressive disease (PD) after neoadjuvant chemotherapy (NAC) were selected. The clinicopathological features and the survival data were recorded in 1 year and 5 years, respectively. Patients were randomly divided into the training set and test set in the ratio of 8:2. A random forest (RF) and a logistic regression were established in both of 1-year cohort and the 5-year cohort. The performance was compared between the two models. The models were validated using data from the Surveillance, Epidemiology, and End Results (SEER) database. RESULTS: A total of 315 patients were included. In the 1-year cohort, 197 patients were divided into a training set while 87 were into a test set. The specificity, sensitivity, and AUC were 0.800, 0.833, and 0.810 in the RF model. And 0.520, 0.833, and 0.653 of the logistic regression. In the 5-year cohort, 132 patients were divided into the training set while 33 were into the test set. The specificity, sensitivity, and AUC were 0.882, 0.750, and 0.829 in the RF model. And 0.882, 0.688, and 0.752 of the logistic regression. In the external validation set, of the RF model, the specificity, sensitivity, and AUC were 0.765, 0.812, and 0.779. Of the logistics regression model, the specificity, sensitivity, and AUC were 0.833, 0.376, and 0.619. CONCLUSION: The RF model has a good performance in predicting events among BC patients with SD and PD post-NAC. It may be beneficial to BC patients, assisting in detecting tumor recurrence.

Comparison of the pCR Rate and DFS Among Breast Cancer Patients with Different Hormone Receptor and HER2 Statuses.

Background: Recent studies have investigated the features of breast cancer (BC) with low human epidermal growth factor receptor 2 (HER2) expression or HER2-0 expression. However, the results were inconsistent. In this study, we investigated the differences in the pathological complete response (pCR) rate and disease-free survival (DFS) between HER2-low and HER2-0 BC patients and between subgroups. Methods: HER2-negative BC patients who received neoadjuvant chemotherapy between January 2013 and December 2019 in our hospital were retrospectively reviewed. First, the pCR rate and DFS were compared between HER2-low and HER2-0 patients and among different hormone receptor (HR) and HER2 statuses. Subsequently, DFS was compared between different HER2 status populations with or without pCR. Finally, a Cox regression model was used to identify the prognostic factors. Results: Overall, 693 patients were selected: 561 were HER2-low, and 132 were HER2-0. Between the two groups, there were significant differences in N stage (P = 0.008) and HR status (P = 0.007). No significant difference in the pCR rate (12.12% vs 14.39%, P = 0.468) or DFS was observed, independent of HR status. HR+/HER2-low patients had a significantly worse pCR rate (P < 0.001) and longer DFS (P < 0.001) than HR-/HER2-low or HER2-0 patients. In addition, a longer DFS was found in HER2-low patients versus HER2-0 patients among those who did not achieve pCR. Cox regression showed that N stage and HR status were prognostic factors in the overall and HER2-low populations, while no prognostic factor was found in the HER2-0 group. Conclusion: This study suggested that HER2 status is not associated with the pCR rate or DFS. Longer DFS was found only among patients who did not achieve pCR in the HER2-low versus HER2-0 population. We speculated that the interaction of HR and HER2 might have played a crucial role in this process.

Nomograms for Predicting Disease-Free Survival Based on Core Needle Biopsy and Surgical Specimens in Female Breast Cancer Patients with Non-Pathological Complete Response to Neoadjuvant Chemotherapy.

PURPOSE: While a pathologic complete response (pCR) is regarded as a surrogate endpoint for pos-itive outcomes in breast cancer (BC) patients receiving neoadjuvant chemotherapy (NAC), fore-casting the prognosis of non-pCR patients is still an open issue. This study aimed to create and evaluate nomogram models for estimating the likelihood of disease-free survival (DFS) for non-pCR patients. METHODS: A retrospective analysis of 607 non-pCR BC patients was conducted (2012-2018). After converting continuous variables to categorical variables, variables entering the model were progressively identified by univariate and multivariate Cox regression analyses, and then pre-NAC and post-NAC nomogram models were developed. Regarding their discrimination, ac-curacy, and clinical value, the performance of the models was evaluated by internal and external validation. Two risk assessments were performed for each patient based on two models; patients were separated into different risk groups based on the calculated cut-off values for each model, including low-risk (assessed by the pre-NAC model) to low-risk (assessed by the post-NAC model), high-risk to low-risk, low-risk to high-risk, and high-risk to high-risk groups. The DFS of different groups was assessed using the Kaplan-Meier method. RESULTS: Both pre-NAC and post-NAC nomogram models were built with clinical nodal (cN) status and estrogen receptor (ER), Ki67, and p53 status (all p < 0.05), showing good discrimination and calibration in both internal and external validation. We also assessed the performance of the two models in four subtypes, with the tri-ple-negative subtype showing the best prediction. Patients in the high-risk to high-risk subgroup have significantly poorer survival rates (p < 0.0001). CONCLUSION: Two robust and effective nomo-grams were developed to personalize the prediction of DFS in non-pCR BC patients treated with NAC.

The impact of postmastectomy radiotherapy on cT1-2N1 breast cancer patients with ypN0 after neoadjuvant chemotherapy: a retrospective study based on real-world data.

BACKGROUND: The role of postmastectomy radiation therapy (PMRT) in clinical T1-2N1 breast cancer patients who achieve axillary pathological complete response (ypN0) after neoadjuvant chemotherapy (NAC) is controversial. METHODS: Data from cT1-2N1 breast cancer patients who converted to ypN0 after NAC and subsequent surgery were retrospectively analyzed. Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan‒Meier method. Univariate and multivariate Cox regression models were applied to investigate the correlations between clinical or pathological parameters and survival. RESULTS: From 2012-2019, we identified 116 cases for analysis, including 31 (26.7%) who received PMRT and 85 (73.3%) who did not. At a median follow-up time of 56.4 months, the 5-year DFS and OS rates were 90.2% and 96.7% with PMRT and 93.7% and 97.3% without PMRT, respectively. PMRT did not affect either DFS (p = 0.234) or OS (p = 0.878). On multivariate analyses, no differences in DFS or OS between the two groups were detected, taking into consideration the following factors: age, molecular subtype, Ki67 index, cT stage, and in-breast pathologic complete response (DFS: HR 2.260; 95% CI 0.465-10.982; p = 0.312. OS: HR 1.400; 95% CI 0.138-14.202; p = 0.776). This nonsignificant difference was also consistent in subgroup analyses (all p > 0.05). CONCLUSIONS: PMRT has limited ability to confer DFS or OS benefits for cT1-2N1 breast cancer patients who achieved axillary pathological complete response after NAC and total mastectomy. It is imperative to conduct prospective studies to investigate the safety and feasibility of omitting PMRT. TRIAL REGISTRATION: This research was approved by the Ethics Committee of The First Affiliated Hospital of Chongqing Medical University (ID: No. 2021-442).

Development and Assessment of a Novel Core Biopsy-Based Prediction Model for Pathological Complete Response to Neoadjuvant Chemotherapy in Women with Breast Cancer.

Purpose: Pathological complete response (pCR), the goal of NAC, is considered a surrogate for favorable outcomes in breast cancer (BC) patients administrated neoadjuvant chemotherapy (NAC). This study aimed to develop and assess a novel nomogram model for predicting the probability of pCR based on the core biopsy. Methods: This was a retrospective study involving 920 BC patients administered NAC between January 2012 and December 2018. The patients were divided into a primary cohort (769 patients from January 2012 to December 2017) and a validation cohort (151 patients from January 2017 to December 2018). After converting continuous variables to categorical variables, variables entering the model were sequentially identified via univariate analysis, a multicollinearity test, and binary logistic regression analysis, and then, a nomogram model was developed. The performance of the model was assessed concerning its discrimination, accuracy, and clinical utility. Results: The optimal predictive threshold for estrogen receptor (ER), Ki67, and p53 were 22.5%, 32.5%, and 37.5%, respectively (all p < 0.001). Five variables were selected to develop the model: clinical T staging (cT), clinical nodal (cN) status, ER status, Ki67 status, and p53 status (all p ≤ 0.001). The nomogram showed good discrimination with the area under the curve (AUC) of 0.804 and 0.774 for the primary and validation cohorts, respectively, and good calibration. Decision curve analysis (DCA) showed that the model had practical clinical value. Conclusions: This study constructed a novel nomogram model based on cT, cN, ER status, Ki67 status, and p53 status, which could be applied to personalize the prediction of pCR in BC patients treated with NAC.

Prognostic Signature and Therapeutic Value Based on Membrane Lipid Biosynthesis-Related Genes in Breast Cancer.

There is a need to improve diagnostic and therapeutic approaches to enhance the prognosis of breast cancer, the most common malignancy worldwide. Membrane lipid biosynthesis is a hot biological pathway in current cancer research. It is unclear whether membrane lipid biosynthesis is involved in the prognosis of BRCA. With LASSO regression, a 14-gene prediction model was constructed using data from the TCGA-BRCA cohort. The prediction model includes GPAA1, PIGF, ST3GAL1, ST6GALNAC4, PLPP2, ELOVL1, HACD1, SGPP1, PRKD2, VAPB, CERS2, SGMS2, ALDH3B2, and HACD3. BRCA patients from the TCGA-BRCA cohort were divided into two risk subgroups based on the model. Kaplan-Meier survival curves showed that patients with lower risk scores had significantly improved overall survival (P=2.49e - 09). In addition, risk score, age, stage, and TNM classification were used to predict mortality in BRCA patients. In addition, the 14 genes in the risk model were analyzed for gene variation, methylation level, drug sensitivity, and immune cell infiltration, and the miRNA-mRNA network was constructed. Afterward, the THPA website then analyzed the protein expression of 14 of these risk model genes in normal and pathological BRCA tissues. In conclusion, the membrane lipid biosynthesis-related risk model and nomogram can be used to predict BRCA clinical prognosis.

Association of serum reproductive hormones changes after neoadjuvant chemotherapy with hormone receptors expression alterations and survival outcomes in breast cancer.

Purpose: This study aimed to determine the effect of neoadjuvant chemotherapy (NAC) on circulating levels of reproductive hormones and evaluate the correlation of hormone changes after NAC with hormone receptors expression alterations and relapse-free survival (RFS) outcomes in breast cancer. Methods: Information from 181 breast cancer patients who received NAC was retrospectively analyzed. For hormones parameters, the median and interquartile range (IQR) were provided at baseline and the end of NAC then was compared by Wilcoxon signed-rank test. Categorical variables were represented as numbers and percentages and were compared via two-sided chi-square and Fisher's tests. The RFS outcomes were compared between patients according to hormone changes using the log-rank test. Univariate and multivariate survival analyses with hazard ratios (HR) and 95% confidence intervals (95% CI) were carried out using Cox regression. Results: Sex steroids including estradiol, progesterone, testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels decreased significantly after NAC among both premenopausal and postmenopausal patients (all P < 0.05). Decreased estradiol levels were associated with reduced progesterone receptor (PR) expression (P = 0.030). In multivariate survival analysis, the non-decreased progesterone level was strongly associated with worse RFS (non-decreased vs. decreased, HR = 7.178, 95% CI 2.340-22.019, P = 0.001). Patients with decreased progesterone levels exhibited better 3-year RFS compared with those with non-decreased (87.6% vs. 58.3%, log-rank, P = 0.001). Conclusion: Multiple reproductive hormone levels were influenced by NAC. The change in estradiol level had a positive connection with PR expression alteration. Furthermore, an inverse association between the change in progesterone level and RFS outcomes was found. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer patients.

Breast Metastasis From Rectal Signet-Ring Cell Carcinoma: A Case Report and Review of Literature.

Background: Metastatic rectal cancer (mRC) of the breast is an extremely rare clinical situation. There are few reported cases in domestic or foreign literature. The clinicopathologic characteristics along with the diagnostic and therapeutic strategies of such cases remain relatively unclear. Here, we would like to provide our comprehensive insights into this rare entity. Methods: We present a case that till now is the first reported breast metastasis from rectal cancer pathologically diagnosed as a signet-ring cell carcinoma, and we review the current literature on this rare event. The detailed clinical data, histopathology, management, and follow-up aspects were gathered for analysis. Results: A total of 15 cases were collected including the current case. Breast metastases from rectal cancer present at an average age of 47.7 years (range, 28 to 69 years) and appear with an average interval of 28.4 months (range, 5 months to 18 years) following primary tumor diagnoses. Of the 15 cases, 8 and 5 are pathologically diagnosed as adenocarcinomas and mucinous adenocarcinomas, respectively. Most cases (11/15) are accompanied by extramammary metastases. About half of the breast metastases (7/15) were to the left. In all cases, the main complaints were palpable mass. The average maximum diameter of the metastatic mass is 2.7 cm (range, 1-11 cm). The majority (8/12) of cases with accessible therapy information exclude the option of local surgery. Conclusion: Previous cancer history and accurate immunohistochemistry data play critical roles to distinguish mammary metastasis from a primary neoplasm of the breast. Mastectomy and molecular-targeted drugs should be considered with priority if systemic condition supports them.

Pre-treatment circulating reproductive hormones levels predict pathological and survival outcomes in breast cancer submitted to neoadjuvant chemotherapy.

PURPOSE: This study aimed to evaluate the correlation of pre-treatment circulating reproductive hormones levels with pathological and survival outcomes in breast cancer patients received neoadjuvant chemotherapy (NAC). METHODS: Information from 196 premenopausal and 137 postmenopausal breast cancer patients who received NAC were retrospectively analyzed. Treatment response to NAC, with odds ratios (OR) and 95% confidence intervals (95% CI) was estimated using logistic regression adjusted for key confounders. Survival outcomes with hazard ratios (HR) and 95% CI were estimated using Cox regression adjusted for key confounders. The Kaplan-Meier method was applied in the survival analysis. RESULTS: Premenopausal patients with lower testosterone levels (OR = 0.996, 95% CI 0.992-0.999, P = 0.026), and postmenopausal patients with higher follicle-stimulating hormone (FSH) levels (OR = 1.045, 95% CI 1.014-1.077, P = 0.005) were likely to achieve pathological complete response (pCR). In multivariate survival analysis, the lowest tertile (T) progesterone was associated with worse overall survival (OS) in premenopausal patients (T2 vs T1, HR = 0.113, 95% CI 0.013-0.953, P = 0.045; T3 vs T1, HR = 0.109, 95% CI 0.013-0.916, P = 0.041). Premenopausal patients with the lowest tertile progesterone exhibited worse 3-year OS compared with those with higher tertiles (72.9% vs 97.4%, log-rank, P = 0.007). CONCLUSION: Pre-treatment testosterone and FSH are significant independent predictors for pCR to NAC in premenopausal and postmenopausal patients, respectively. Low progesterone levels are correlated with worse OS in premenopausal patients. These findings may provide a theoretical basis for pre-operative endocrine therapy combined with NAC in breast cancer.

A novel pyroptosis-related signature predicts prognosis and response to treatment in breast carcinoma.

BACKGROUND: Pyroptosis is a new form of programmed cell death (PCD), also known as cellular inflammatory necrosis. Its discovery has resulted in a novel approach to the progression and medication resistance of breast cancer (BC). However, there is still a significant gap in the investigation of pyroptosis-related genes in BC. METHODS: The mRNA expression profiles and clinical data of BC patients were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Then, using the TCGA cohort, we created a predictive multigene signature including pyroptosis-related genes and verified it using the two GEO cohorts. A pyroptosis-related gene signature was created by combining several bioinformatics and statistical methodologies to predict patient prognosis and responses to immunotherapy and chemotherapy. Furthermore, a nomogram based on the gene signature and clinicopathological markers was created to better classify the risk and quantify the risk assessment of individual patients. RESULTS: A pyroptosis-related gene signature consisting of 15 genes was established. The pyroptosis-related gene signature classified the patients into two groups: high-risk and low-risk. When combined with clinical variables, the risk score was discovered to be an independent predictor of overall survival (OS) in BC patients. Some immunological pathways and genes were linked to pyroptosis, according to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) evaluations. Patients in the high-risk group had a worse prognosis and were not very sensitive to immunotherapy. However, several chemotherapeutic agents were predicted to have greater potential for patients in the high-risk group. Finally, a nomogram was developed that included a classifier based on the 15 pyroptosis-related genes, tumor stage, age, and histologic grade. This nomogram demonstrated good classification capacity and might help with clinical decision-making in BC.

Efficacy evaluation of neoadjuvant chemotherapy in patients with HER2-low expression breast cancer: A real-world retrospective study.

Background: To characterize the clinicopathological features and evaluate the neoadjuvant chemotherapy (NACT) efficacy of patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer. Methods: A total of 905 breast cancer patients who received 4 cycles of thrice-weekly standard NACT in the First Affiliated Hospital of Chongqing Medical University were retrospectively enrolled, including 685 cases with HER2-low expression and 220 cases with HER2-negative expression. Clinicopathological features were compared between patients with HER2-negative and HER2-low expression. Univariate and multivariate logistic regression analyses were used to find the independent factors of achieving a pathological complete response (pCR) after NACT. Results: There were significant differences in stage_N (P = 0.014), histological grade (P = 0.001), estrogen receptor (ER) status (P < 0.001), progesterone receptor (PgR) status (P < 0.001), NACT regimens (P = 0.032) and NACT efficacy (P = 0.037) between patients with HER2-negative and HER2-low expression breast cancer. In subgroup analysis, histological grade (P = 0.032), ER (P = 0.002), Ki-67 (P < 0.001) and HER2 status (P = 0.025) were independent predictors of achieving a pCR in ER-positive breast cancer. And the nomogram for pCR in ER-positive breast cancer showed great discriminatory ability with an AUC of 0.795. The calibration curve also showed that the predictive ability of the nomogram was a good fit to actual observations. Then, in the analysis of ER-negative breast cancer, only stage_N (P = 0.001) and Ki-67 (P = 0.018) were independent influencing factors of achieving a pCR in ER-negative breast cancer. Conclusion: HER2-low breast cancer was a different disease from HER2-negative breast cancer in clinicopathological features. Moreover, the NACT efficacy of HER2-low breast cancer patients was poorer.

Classification of the mitochondrial ribosomal protein-associated molecular subtypes and identified a serological diagnostic biomarker in hepatocellular carcinoma.

Purpose: The objective of this study was to sort out innovative molecular subtypes associated with mitochondrial ribosomal proteins (MRPs) to predict clinical therapy response and determine the presence of circulating markers in hepatocellular carcinoma (HCC) patients. Methods: Using an unsupervised clustering method, we categorized the relative molecular subtypes of MRPs in HCC patients. The prognosis, biological properties, immune checkpoint inhibitor and chemotherapy response of the patients were clarified. A signature and nomogram were developed to evaluate the prognosis. Enzyme-linked immunosorbent assay (ELISA) measured serum mitochondrial ribosomal protein L9 (MRPL9) levels in liver disease patients and normal individuals. Receiver operating characteristic (ROC) curves were conducted to calculate the diagnostic effect. The Cell Counting Kit 8 was carried out to examine cell proliferation, and flow cytometry was used to investigate the cell cycle. Transwell assay was applied to investigate the potential of cell migration and invasion. Western blot detected corresponding changes of biological markers. Results: Participants were classified into two subtypes according to MRPs expression levels, which were characterized by different prognoses, biological features, and marked differences in response to chemotherapy and immune checkpoint inhibitors. Serum MRPL9 was significantly higher in HCC patients than in normal individuals and the benign liver disease group. ROC curve analysis showed that MRPL9 was superior to AFP and Ferritin in differentiating HCC from healthy and benign patients, or alone. Overexpressed MRPL9 could enhance aggressiveness and facilitate the G1/S progression in HCC cells. Conclusion: We constructed novel molecular subtypes based on MRPs expression in HCC patients, which provided valuable strategies for the prediction of prognosis and clinical personalized treatment. MRPL9 might act as a reliable circulating diagnostic biomarker and therapeutic target for HCC patients.

Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice.

Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from Panax notoginseng as an agonist of TGR5 in vitro. However, the pharmacological effects of Ft1 on diet-induced obese (DIO) mice and the underlying mechanisms are still elusive. Here we show that Ft1 (100 mg/100 diet) increased adipose lipolysis, promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1 (GLP-1) secretion in the ileum of wild type but not Tgr5 -/- obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues. The metabolic benefits of Ft1 were abolished in Cyp27a1 -/- mice which have much lower BA levels. These results identify Ft1 as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.

Plasma fibrinogen acts as a predictive factor for pathological complete response to neoadjuvant chemotherapy in breast cancer: a retrospective study of 1004 Chinese breast cancer patients.

BACKGROUND: The aim of this study was to evaluate the relationship between pre-treatment plasma fibrinogen (Fib) level and pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients and to assess the role of plasma Fib as a predictive factor. METHODS: Data from 1004 consecutive patients with invasive breast cancer who received NAC and subsequent surgery were retrospectively analysed. Both univariate and multivariate analyses based on logistic regression model were performed to identify clinicopathological factors associated with pCR to NAC. Cox regression model was used to determine the correlation between clinical or pathological parameters and recurrence-free survival (RFS). The Kaplan-Meier method and the log-rank test were applied in the survival analysis. RESULTS: The median value of Fib, rather than other plasma coagulation parameters, was significantly increased in non-pCR patients compared with pCR patients (P = 0.002). Based on the cut-off value estimated by the receiver operating characteristic (ROC) curve analysis, patients were divided into low or high Fib groups (Fib < 3.435 g/L or ≥ 3.435 g/L). Low Fib levels were significantly associated with premenopausal or perimenopausal status (P <  0.001), tumour size ≤5 cm (P = 0.002), and positive hormone receptor status (P = 0.002). After adjusted for other clinicopathological factors in the multivariate logistic regression model, low Fib status was strongly associated with pCR to NAC (OR = 3.038, 95% CI 1.667-5.537, P <  0.001). Survival analysis showed that patients with low Fib levels exhibited better 3-year RFS compared with patients with high Fib levels in the tumour size>5 cm group (77.5% vs 58.4%, log-rank, P = 0.0168). CONCLUSIONS: This study demonstrates that low pre-treatment plasma Fib (Fib < 3.435 g/L) is an independent predictive factor for pCR to NAC in breast cancer patients. Moreover, T3-featured breast cancer patients with lower Fib level exhibit better RFS outcomes after NAC compared with high Fib status.