SweepCluster: A SNP clustering tool for detecting gene-specific sweeps in prokaryotes.

BACKGROUND: The gene-specific sweep is a selection process where an advantageous mutation along with the nearby neutral sites in a gene region increases the frequency in the population. It has been demonstrated to play important roles in ecological differentiation or phenotypic divergence in microbial populations. Therefore, identifying gene-specific sweeps in microorganisms will not only provide insights into the evolutionary mechanisms, but also unravel potential genetic markers associated with biological phenotypes. However, current methods were mainly developed for detecting selective sweeps in eukaryotic data of sparse genotypes and are not readily applicable to prokaryotic data. Furthermore, some challenges have not been sufficiently addressed by the methods, such as the low spatial resolution of sweep regions and lack of consideration of the spatial distribution of mutations. RESULTS: We proposed a novel gene-centric and spatial-aware approach for identifying gene-specific sweeps in prokaryotes and implemented it in a python tool SweepCluster. Our method searches for gene regions with a high level of spatial clustering of pre-selected polymorphisms in genotype datasets assuming a null distribution model of neutral selection. The pre-selection of polymorphisms is based on their genetic signatures, such as elevated population subdivision, excessive linkage disequilibrium, or significant phenotype association. Performance evaluation using simulation data showed that the sensitivity and specificity of the clustering algorithm in SweepCluster is above 90%. The application of SweepCluster in two real datasets from the bacteria Streptococcus pyogenes and Streptococcus suis showed that the impact of pre-selection was dramatic and significantly reduced the uninformative signals. We validated our method using the genotype data from Vibrio cyclitrophicus, the only available dataset of gene-specific sweeps in bacteria, and obtained a concordance rate of 78%. We noted that the concordance rate could be underestimated due to distinct reference genomes and clustering strategies. The application to the human genotype datasets showed that SweepCluster is also applicable to eukaryotic data and is able to recover 80% of a catalog of known sweep regions. CONCLUSION: SweepCluster is applicable to a broad category of datasets. It will be valuable for detecting gene-specific sweeps in diverse genotypic data and provide novel insights on adaptive evolution.

Pyrotinib plus capecitabine versus lapatinib plus capecitabine for the treatment of HER2-positive metastatic breast cancer (PHOEBE): a multicentre, open-label, randomised, controlled, phase 3 trial.

BACKGROUND: Despite therapeutic advances in HER2-positive metastatic breast cancer, resistance to trastuzumab inevitably develops. In the PHOEBE study, we aimed to assess the efficacy and safety of pyrotinib (an irreversible pan-HER inhibitor) plus capecitabine after previous trastuzumab. METHODS: This is an open-label, randomised, controlled, phase 3 trial done at 29 hospitals in China. Patients with pathologically confirmed HER2-positive metastatic breast cancer, aged 18-70 years, who had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had been previously treated with trastuzumab and taxanes were randomly assigned (1:1) to receive oral pyrotinib 400 mg or lapatinib 1250 mg once daily plus oral capecitabine 1000 mg/m2 twice daily on days 1-14 of each 21-day cycle. Randomisation was done via a centralised interactive web-response system with a block size of four or six and stratified by hormone receptor status and previous lines of chemotherapy for metastatic disease. The primary endpoint was progression-free survival according to masked independent central review. Efficacy and safety were assessed in all patients who received at least one dose of the study drugs. Results presented here are from a prespecified interim analysis. This study is registered with ClinicalTrials.gov, NCT03080805. FINDINGS: Between July 31, 2017, and Oct 30, 2018, 267 patients were enrolled and randomly assigned. 134 patients received pyrotinib plus capecitabine and 132 received lapatinib plus capecitabine. At data cutoff of the interim analysis on March 31, 2019, median progression-free survival was significantly longer with pyrotinib plus capecitabine (12·5 months [95% CI 9·7-not reached]) than with lapatinib plus capecitabine (6·8 months [5·4-8·1]; hazard ratio 0·39 [95% CI 0·27-0·56]; one-sided p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [31%] in the pyrotinib group vs 11 [8%] in the lapatinib group) and hand-foot syndrome (22 [16%] vs 20 [15%]). Serious adverse events were reported for 14 (10%) patients in the pyrotinib group and 11 (8%) patients in the lapatinib group. No treatment-related deaths were reported in the pyrotinib group and one sudden death in the lapatinib group was considered treatment related. INTERPRETATION: Pyrotinib plus capecitabine significantly improved progression-free survival compared with that for lapatinib plus capecitabine, with manageable toxicity, and can be considered an alternative treatment option for patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. FUNDING: Jiangsu Hengrui Medicine and National Key R&D Program of China. TRANSLATIONS: For the Chinese translation of the abstract see Supplementary Materials section.

Effect of Capecitabine Maintenance Therapy Using Lower Dosage and Higher Frequency vs Observation on Disease-Free Survival Among Patients With Early-Stage Triple-Negative Breast Cancer Who Had Received Standard Treatment: The SYSUCC-001 Randomized Clinical Trial.

Importance: Among all subtypes of breast cancer, triple-negative breast cancer has a relatively high relapse rate and poor outcome after standard treatment. Effective strategies to reduce the risk of relapse and death are needed. Objective: To evaluate the efficacy and adverse effects of low-dose capecitabine maintenance after standard adjuvant chemotherapy in early-stage triple-negative breast cancer. Design, Setting, and Participants: Randomized clinical trial conducted at 13 academic centers and clinical sites in China from April 2010 to December 2016 and final date of follow-up was April 30, 2020. Patients (n = 443) had early-stage triple-negative breast cancer and had completed standard adjuvant chemotherapy. Interventions: Eligible patients were randomized 1:1 to receive capecitabine (n = 222) at a dose of 650 mg/m2 twice a day by mouth for 1 year without interruption or to observation (n = 221) after completion of standard adjuvant chemotherapy. Main Outcomes and Measures: The primary end point was disease-free survival. Secondary end points included distant disease-free survival, overall survival, locoregional recurrence-free survival, and adverse events. Results: Among 443 women who were randomized, 434 were included in the full analysis set (mean [SD] age, 46 [9.9] years; T1/T2 stage, 93.1%; node-negative, 61.8%) (98.0% completed the trial). After a median follow-up of 61 months (interquartile range, 44-82), 94 events were observed, including 38 events (37 recurrences and 32 deaths) in the capecitabine group and 56 events (56 recurrences and 40 deaths) in the observation group. The estimated 5-year disease-free survival was 82.8% in the capecitabine group and 73.0% in the observation group (hazard ratio [HR] for risk of recurrence or death, 0.64 [95% CI, 0.42-0.95]; P = .03). In the capecitabine group vs the observation group, the estimated 5-year distant disease-free survival was 85.8% vs 75.8% (HR for risk of distant metastasis or death, 0.60 [95% CI, 0.38-0.92]; P = .02), the estimated 5-year overall survival was 85.5% vs 81.3% (HR for risk of death, 0.75 [95% CI, 0.47-1.19]; P = .22), and the estimated 5-year locoregional recurrence-free survival was 85.0% vs 80.8% (HR for risk of locoregional recurrence or death, 0.72 [95% CI, 0.46-1.13]; P = .15). The most common capecitabine-related adverse event was hand-foot syndrome (45.2%), with 7.7% of patients experiencing a grade 3 event. Conclusions and Relevance: Among women with early-stage triple-negative breast cancer who received standard adjuvant treatment, low-dose capecitabine maintenance therapy for 1 year, compared with observation, resulted in significantly improved 5-year disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01112826.

Physicians' attitudes towards reproduction in young patients with early breast cancer in China.

BACKGROUND: As more young patients with breast cancer undergo treatments and obtain good prognoses, the issue of postoperative reproduction in breast cancer patients has attracted more attention. METHODS: We conducted a prospective, cross-sectional survey of 2000 breast cancer-associated physicians using a 24-items questionnaire adapted from prior guides. Then we used a multivariable linear regression model to confirm independent associations between the propensity of physicians' attitudes toward reproduction and physicians' specific demographic characteristics. RESULTS: A total of 911/1249 (72.93%) eligible physicians completed the questionnaire. Regarding the most concerning topic of whether breast cancer patients could conceive, 65 (7.1%) physicians having low and 457 (50.2%) physicians having high propensity for recommending reproduction. For ductal carcinoma in situ (DCIS) after surgery and radiotherapy, 599 (65.8%) physicians did not agree with the recommendation to conceive. 231 (25.4%) highly agree with the recommendation of reproduction for 2 years after surgery in invasive breast cancer patients with lymph nodes-negative. Only 140 (15.4%) physicians did not agree with the recommendation for 5 years after surgery in invasive breast cancer patients with lymph nodes-positive. A total of 861 (94.5%) physicians stated that they advised the patients to consult experts from other disciplines, such as gynecology, oncology, genetic and psychology disciplines. In multivariable analysis, more positive attitude toward reproduction was significantly associated with male, more than 11 times of participating in academic forum on breast cancer, 1-2 times of consulting about reproduction problems after breast cancer surgery per outpatient service and more than 11 min spending on solving the problem about reproduction in early breast cancer. CONCLUSION: This study showed that attitudes towards reproduction of young breast cancer patients from physicians in China. Physicians had a high propensity for recommending reproduction. Compared with the two reproduction guidelines recommendation when to reproduce in different circumstances for breast cancer patients, physicians from China remained a relatively conservative attitude. Most physicians advised the patients to consult experts from other disciplines, such as gynecology, oncology, genetic and psychology disciplines.

Astragaloside IV enhances taxol chemosensitivity of breast cancer via caveolin-1-targeting oxidant damage.

Accumulating evidence suggests that caveolin-1 (CAV-1) is a stress-related oncotarget and closely correlated to chemoresistance. Targeting CAV-1 might be a promising strategy to improve chemosensitivity for breast cancer treatment. Astragaloside IV (AS-IV), a bioactive compound purified from Astragalus membranaceus, has been shown to exhibit multiple bioactivities, including anticancer. However, the involved molecular targets are still ambiguous. In this study, we investigated the critical role of CAV-1 in mediating the chemosensitizing effects of AS-IV to Taxol on breast cancer. We found that AS-IV could enhance the chemosensitivity of Taxol with minimal direct cytotoxicity on breast cancer cell lines MCF-7 and MDA-MB-231, as well as the nontumor mammary epithelial cell line MCF-10A. AS-IV was further demonstrated to aggravate Taxol-induced apoptosis and G2/M checkpoint arrest. The phosphorylation of mitogen-activated protein kinase (MAPK) signaling extracellular signal-regulated kinase (ERK) and c-Jun N-terminal Kinase (JNK), except p38, was also abrogated by a synergistic interaction between AS-IV and Taxol. Moreover, AS-IV inhibited CAV-1 expression in a dose-dependent manner and reversed CAV-1 upregulation induced by Taxol administration. Mechanism study further demonstrated that AS-IV treatment triggered the eNOS/NO/ONOO- pathway via inhibiting CAV-1, which led to intense oxidant damage. CAV-1 overexpression abolished the chemosensitizing effects of AS-IV to Taxol by inhibiting oxidative stress. In vivo experiments further validated that AS-IV increased Taxol chemosensitivity on breast cancer via inhibiting CAV-1 expression, followed by activation of the eNOS/NO/ONOO- pathway. Taken together, our findings not only suggested the potential of AS-IV as a promising candidate to enhance chemosensitivity, but also highlighted the significance of CAV-1 as the target to reverse cancer drug resistance.

Standardization of Syndrome Differentiation Defined by Traditional Chinese Medicine in Operative Breast Cancer: A Modified Delphi Study.

OBJECTIVE: The aim of this study was to establish the standardization of syndrome differentiation of operative breast cancer treated with Traditional Chinese Medicine (TCM) by the modified Delphi method. METHOD: A literature search for standardization of syndrome differentiation of operative breast cancer was conducted and eligible articles were identified in indexed databases from 1982 to 2013. We carried out two rounds of investigation between March and October 2013 and organized 20 experts who focused on TCM or integrative medicine in breast cancer research. Experts' judgments were collected via posted questionnaires or e-mail. A final evaluation was carried out after the end of both rounds. RESULT: The response ratio of the 1st round investigation reached 100%, and two experts were excluded due to the uncompleted questionnaire. The 2nd round investigation was completed by 18 experts in the 1st round panel board. In both rounds, the experts agreed that the stage of breast cancer defined by TCM could be divided into the perioperation period, the perichemotherapy period, the periradiotherapy period, and the consolidation period. CONCLUSION: We identified the feasibility and reasonability to establish the standardization of syndrome differentiation of operative breast cancer. According to the suggestions from experts in our Delphi study, we preliminarily established the TCM standard of syndrome differentiation based on different treatment stages of operative breast cancer.

Caveolin-1 mediates chemoresistance in breast cancer stem cells via ß-catenin/ABCG2 signaling pathway.

Accumulating evidence has suggested that cancer stem cells (CSCs) are at the root of drug resistance, and recent studies have indicated that caveolin-1, a membrane transporter protein, is involved in the regulation of cancer chemoresistance and stem cell signaling. However, the current understanding of the role of caveolin-1 in breast cancer development remains controversial. Herein, we demonstrate that caveolin-1 expression was upregulated after breast cancer chemotherapy in vitro and in vivo, accompanied by co-overexpression of ß-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Additionally, breast CSCs were enriched for caveolin-1 expression. Caveolin-1 silencing sensitized breast CSCs by limiting their self-renewal ability but promoting the differentiation process. ß-catenin silencing prevented the enhanced chemoresistance of CSCs induced by caveolin-1 overexpression, indicating that ß-catenin is an essential molecule responsible for caveolin-1-mediated action. Further mechanistic investigation revealed that caveolin-1 silencing could downregulate the ß-catenin/ABCG2 pathway through glycogen synthase kinase 3 beta activation and Akt inhibition, resulting in increased ß-catenin phosphorylation and proteasomal degradation. Clinical investigation also revealed a close correlation between caveolin-1 and ß-catenin/ABCG2 signaling in breast cancer samples. Notably, caveolin-1 was highly elevated in triple-negative breast cancer, and caveolin-1 silencing significantly impaired the tumorigenicity and chemoresistance of breast CSCs in in vivo models. Overall, our study not only highlights the role of caveolin-1 in mediating the chemoresistance of breast CSCs via ß-catenin/ABCG2 regulation but also provides novel approaches for future therapies targeting CSCs.

Effect of Huaier granule on prognosis of breast cancer: A single-center propensity score matching retrospective study.

BACKGROUND: Huaier granule is an important medicinal fungus extract widely used in cancer treatment. Previous retrospective studies have reported its effectiveness in breast cancer patients, but the imbalanced baseline characteristics of participants could have biased the results. Therefore, this retrospective study aimed to examine the efficacy of Huaier granule on the prognosis of breast cancer patients. METHODS: In this single-center cohort study, breast cancer patients diagnosed and treated at the Guangdong Provincial Hospital of Chinese Medicine between 2009 and 2017 were selected. The data were retrospectively analyzed and divided into two groups according to whether the patients received Huaier granules. The propensity score matching (PSM) method was used to eliminate selection bias. The disease-free survival (DFS) and overall survival (OS) for these groups were compared using the Kaplan-Meier method and the Cox regression. RESULTS: This study included 214 early invasive breast cancer patients, 107 in the Huaier group and 107 in the control group. In the Kaplan-Meier analysis, the 2-year and 5-year DFS rates were significantly different in the Huaier group and control group (hazard ratio [HR], 0.495; 95% confidence interval [CI], 0.257-0.953; P = 0.023). The 2-year and 5-year OS rates were also significantly different (HR, 0.308; 95% CI, 0.148-0.644; P = 0.001). On multivariable Cox regression, Huaier granule was associated with improved DFS (HR, 0.440; 95% CI, 0.223-0.868; P = 0.018) and OS (HR, 0.236; 95% CI, 0.103-0.540; P = 0.001). CONCLUSION: In this retrospective study, Huaier granules improved the DFS and OS of early invasive breast cancer patients, providing real-world evidence for further prospective studies on treating breast cancer with Huaier granules.

Targeting lipid reprogramming in the tumor microenvironment by traditional Chinese medicines as a potential cancer treatment.

In the last ten years, there has been a notable rise in the study of metabolic abnormalities in cancer cells. However, compared to glucose or glutamine metabolism, less attention has been paid to the importance of lipid metabolism in tumorigenesis. Recent developments in lipidomics technologies have allowed for detailed analysis of lipid profiles within cancer cells and other cellular players present within the tumor microenvironment (TME). Traditional Chinese medicine (TCM) and its bioactive components have a long history of use in cancer treatments and are also being studied for their potential role in regulating metabolic reprogramming within TME. This review focuses on four core abnormalities altered by lipid reprogramming in cancer cells: de novo synthesis and exogenous uptake of fatty acids (FAs), upregulated fatty acid oxidation (FAO), cholesterol accumulation, which offer benefits for tumor growth and metastasis. The review also discusses how altered lipid metabolism impacts infiltrating immune cell function and phenotype as these interactions between cancer-stromal become more pronounced during tumor progression. Finally, recent literature is highlighted regarding how cancer cells can be metabolically reprogrammed by specific Chinese herbal components with potential therapeutic benefits related to lipid metabolic and signaling pathways.

Knowledge, Attitude, and Practice About Antibiotic Use and Antimicrobial Resistance Among Nursing Students in China: A Cross Sectional Study.

Purpose: The knowledge, attitude, and practices (KAP) concerning antibiotics by healthcare students have the potential impact on controlling antibiotic abuse and antimicrobial resistance (AMR) growth. This study aims to evaluate the levels and explore the associated factors with KAP on antibiotic use and AMR in Chinese nursing students. Methods: A cross-sectional survey using a self-administered questionnaire consisting of demographics and selected features and KAP on antibiotic use and AMR was conducted to measure KAP levels among nursing students at various universities in Hubei Province, China. The logistic regression analyses were performed to analyze the potential factors associated with the KAP. Results: The survey eventually included a total of 1959 nursing students. The mean scores for KAP were 57.89 ±26.32, 55.00 ±12.50, and 71.88 ±15.63, respectively. Regarding knowledge, 54.3% of participants were unaware that antibiotic was ineffective against viral infections. Regarding attitude, 36% of participants agreed that current antibiotic abuse existed; 96.2% of participants thought it necessary to set up a special course on antibiotics. Regarding practice, only 48.4% of participants usually purchased antibiotics with a prescription. Multivariable analyses indicated that lack of discussion on AMR in school courses was an independent risk factor against KAP, respectively. The main knowledge sources of antibiotic being outside the classroom was an independent risk factor related to knowledge and practice. The average score >80 points was an independent protective factor related to knowledge and practice. Conclusion: The KAP level on antibiotic use and AMR among Hubei nursing students was general and required further strengthening. Nursing students with risk factors should be prioritized in educational interventions. The findings of our study pointed out some directions for tailored interventions to improve the training on antibiotics.

Prevotella copri exhausts intrinsic indole-3-pyruvic acid in the host to promote breast cancer progression: inactivation of AMPK via UHRF1-mediated negative regulation.

Emerging evidence has revealed the novel role of gut microbiota in the development of cancer. The characteristics of function and composition in the gut microbiota of patients with breast cancer patients has been reported, however the detailed causation between gut microbiota and breast cancer remains uncertain. In the present study, 16S rRNA sequencing revealed that Prevotella, particularly the dominant species Prevotella copri, is significantly enriched and prevalent in gut microbiota of breast cancer patients. Prior-oral administration of P. copri could promote breast cancer growth in specific pathogen-free mice and germ-free mice, accompanied with sharp reduction of indole-3-pyruvic acid (IPyA). Mechanistically, the present of excessive P. copri consumed a large amount of tryptophan (Trp), thus hampering the physiological accumulation of IPyA in the host. Our results revealed that IPyA is an intrinsic anti-cancer reagent in the host at physiological level. Briefly, IPyA directly suppressed the transcription of UHRF1, following by the declined UHRF1 and PP2A C in nucleus, thus inhibiting the phosphorylation of AMPK, which is just opposite to the cancer promoting effect of P. copri. Therefore, the exhaustion of IPyA by excessive P. copri strengthens the UHRF1-mediated negative control to inactivated the energy-controlling AMPK signaling pathway to promote tumor growth, which was indicated by the alternation in pattern of protein expression and DNA methylation. Our findings, for the first time, highlighted P. copri as a risk factor for the progression of breast cancer.

A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer.

Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in patients with IBC, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for cross-talk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.

The features of male breast cancer in China: A real-world study.

BACKGROUND: Male breast cancer (MBC) is a rare disease. Although several large-scale studies have investigated MBC patients in other countries, the features of MBC patients in China have not been fully explored. This study aims to explore the features of Chinese MBC patients comprehensively. METHODS: We retrospectively collected data of MBC patients from 36 centers in China. Overall survival (OS) was evaluated by the Kaplan-Meier method, log-rank test, and Cox regression analyses. Multivariate Cox analyses were used to identify independent prognostic factors of the patients. RESULTS: In total, 1119 patients were included. The mean age at diagnosis was 60.9 years, and a significant extension over time was observed (P < 0.001). The majority of the patients (89.1 %) received mastectomy. Sentinel lymph node biopsy was performed in 7.8 % of the patients diagnosed in 2009 or earlier, and this percentage increased significantly to 38.8 % in 2020 or later (P < 0.001). The five-year OS rate for the population was 85.5 % [95 % confidence interval (CI), 82.8 %-88.4 %]. Multivariate Cox analysis identified taxane-based [T-based, hazard ratio (HR) = 0.32, 95 % CI, 0.13 to 0.78, P = 0.012] and anthracycline plus taxane-based (A + T-based, HR = 0.47, 95 % CI, 0.23 to 0.96, P = 0.037) regimens as independent protective factors for OS. However, the anthracycline-based regimen showed no significance in outcome (P = 0.175). CONCLUSION: As the most extensive MBC study in China, we described the characteristics, treatment and prognosis of Chinese MBC population comprehensively. T-based and A + T-based regimens were protective factors for OS in these patients. More research is required for this population.

Does the Dose of Standard Adjuvant Chemotherapy Affect the Triple-negative Breast Cancer Benefit from Extended Capecitabine Metronomic Therapy? An Exploratory Analysis of the SYSUCC-001 Trial.

Purpose: Results from studies of extended capecitabine after the standard adjuvant chemotherapy in early stage triple-negative breast cancer (TNBC) were inconsistent, and only low-dose capecitabine from the SYSUCC-001 trial improved disease-free survival (DFS). Adjustment of the conventional adjuvant chemotherapy doses affect the prognosis and may affect the efficacy of subsequent treatments. This study investigated whether the survival benefit of the SYSUCC-001 trial was affected by dose adjustment of the standard adjuvant chemotherapy or not. Patients and Methods: We reviewed the adjuvant chemotherapy regimens before the extended capecitabine in the SYSUCC-001 trial. Patients were classified into "consistent" (standard acceptable dose) and "inconsistent" (doses lower than acceptable dose) dose based on the minimum acceptable dose range in the landmark clinical trials. Cox proportional hazards model was used to investigate the impact of dose on the survival outcomes. Results: All 434 patients in SYSUCC-001 trial were enrolled in this study. Most of patients administered the anthracycline-taxane regimen accounted for 88.94%. Among patients in the "inconsistent" dose, 60.8% and 47% received lower doses of anthracycline and taxane separately. In the observation group, the "inconsistent" dose of anthracycline and taxane did not affect DFS compared with the "consistent" dose. Moreover, in the capecitabine group, the "inconsistent" anthracycline dose did not affect DFS compared with the "consistent" dose. However, patients with "consistent" taxane doses benefited significantly from extended capecitabine (P=0.014). The sufficient dose of adjuvant taxane had a positive effect of extended capecitabine (hazard ratio [HR] 2.04; 95% confidence interval [CI] 1.02 to 4.06). Conclusion: This study found the dose reduction of adjuvant taxane might negatively impact the efficacy of capecitabine. Therefore, the reduction of anthracycline dose over paclitaxel should be given priority during conventional adjuvant chemotherapy, if patients need dose reduction and plan for extended capecitabine.

Breast cancer prediction model based on clinical and biochemical characteristics: clinical data from patients with benign and malignant breast tumors from a single center in South China.

OBJECTIVE: Breast cancer is the most prevalent cancer and is second leading cause of death from malignancy among women worldwide. In addition to tumor factors, the host characteristics of tumors have been paid more and more attention by the medical community. This study aimed to develop a breast cancer prediction model for the Chinese population using clinical and biochemical characteristics. METHODS: This is a retrospective study. From 2012 to 2021, we selected 19,751 patients with breast diseases from the Guangdong Hospital of Traditional Chinese Medicine, which included 5660 patients with breast cancer and 14,091 patients with benign breast diseases-75% of patients were randomly assigned to the training group and 25% to the test group using a total of 34 clinical and biochemical characteristics. Significant clinical signs were investigated, and logistic regression with recursive feature elimination (RFE) model was used to develop a prediction model for distinguishing benign from malignant breast diseases. The prediction model's accuracy, precision, sensitivity, specificity, and area under the ROC curve (AUC) were calculated. RESULTS: Clinical statistics demonstrated that the prediction model comprised 19 clinical characteristics had statistical separability in both the training group and the test group, as well as good sensitivity and prediction. CONCLUSIONS: This model based on biochemical parameters demonstrates a significant predictive effect for breast cancer and may be useful as a reference for invasive tissue biopsy in patients undergoing BI-RADS 3 and 4A breast imaging.

A Delphi Study of Expert Consensus on Chinese Medicine Syndrome Differentiation and Herbal Use for Early Breast Cancer.

OBJECTIVES: Chinese herbal medicine (CHM) is widely used in breast cancer, but there is no consensus on the Chinese medicine (CM) syndromes in the different conventional treatment stages (preoperative, postoperative, chemotherapy, radiation therapy and endocrine therapy) of early breast cancer. This Delphi study aimed to achieve expert consensus on the CM syndromes, signs and symptoms, and the Chinese herbal formulae for early breast cancer. METHODS: Thirty senior CM clinicians with expertise in managing breast cancer were enrolled. The syndromes selected by ≥50% of experts and the corresponding most common Chinese herbal formulae were considered a consensus. Consensus on signs and symptoms was defined as a median score ≥4 (the item was important or very important) and ≥70% of experts rating the sign or symptom as 4 (important) or 5 (very important) on a 5-point Likert scale. RESULTS: Three survey rounds were conducted from 15 October 2021 to 10 March 2022. Consensus was reached with 3 syndromes confirmed for each treatment stage. Several syndromes, such as dual deficiency of qi and Blood, were considered common to multiple treatment stages. Some important signs and symptoms were presented in multiple treatment stages (eg, shortage of qi in the radiation therapy and endocrine therapy stages). CONCLUSIONS: This Delphi study achieved consensus on the most common CM syndromes, corresponding signs and symptoms, and the most common formulae in each treatment stage of early breast cancer, providing an evidence-based approach for future clinical practice.

10-Gingerol Enhances the Effect of Taxol in Triple-Negative Breast Cancer via Targeting ADRB2 Signaling.

Purpose: Although paclitaxel is widely used in cancer treatment, severe side effects and drug resistance limit its clinical use. 10-gingerol (10-G) is a natural compound isolated from ginger, which displays anti-inflammatory, antioxidant, and antiproliferative properties. However, the chemotherapy-sensitization effect of 10-G on triple-negative breast cancer (TNBC) has not been fully clarified. This study is aimed at investigating the effect of 10-G on the paclitaxel sensitivity in TNBC, and its underlying mechanism. Methods: The study was determined through in vitro and in vivo experiments. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8) and colony formation. To detect cell apoptosis, flow cytometry and TUNEL were used. The expression of proteins was detected by Western blotting and immunohistochemistry. The molecular docking and gene knockout were corroborated by interactions between 10-G and adrenoceptor Beta 2 (ADRB2). The body weight of mice, histopathology and organs (kidney and spleen) coefficients were used to monitor the drug toxicities. Results: In vitro, 10-G increased the sensitivity of TNBC cells to paclitaxel, and could synergistically promote the apoptosis of TNBC cells induced by paclitaxel. In combination with molecular docking and lentivirus knockdown studies, ADRB2 was identified as a 10-G binding protein. 10-G inhibited ADRB2 by binding to the active site of ADRB2. Knockdown of ADRB2 reduces the proliferation activity of TNBC cells but also attenuates the sensitizing effects of 10-G to paclitaxel. Western blotting and immunohistochemistry showed that 10-G played an anti-proliferation and chemotherapy-sensitizing role by inhibiting the ADRB2/ERK signal. Toxicity evaluation showed that 10-G would not increase hepatorenal toxicity with paclitaxel. Conclusion: This data suggests that 10-G may be used as a new chemotherapeutic synergist in combination with paclitaxel to enhance anticancer activity. The potential value of ADRB2 as a target for improving chemotherapy sensitivity was also emphasized.

Discovery of YH677 as a cancer stemness inhibitor that suppresses triple-negative breast cancer growth and metastasis by regulating the TGFß signaling pathway.

Triple-negative breast cancer (TNBC) has a poor prognosis due to the lack of specific and highly effective therapeutic agents. Cancer stem cells (CSCs) are one of the main factors contributing to TNBC relapse and metastasis. Therefore, targeting CSCs selectively with small molecules is a novel strategy for drug development. In this study, the natural product harmine (HM) was identified as a hit compound from 2632 natural product monomers based on phenotypic screening of a 2D assay and patient-derived organoid (PDO) model that was established from a patient who had multiple drug resistance and various visceral and contralateral breast metastases. Next, harmine was further modified and optimized to obtain a lead compound (YH677) with a tetrahydro-ß-carboline scaffold. YH677 showed potent antiproliferative and antimigratory activities against several TNBC cell lines in vitro. In addition, YH677 inhibited epithelial mesenchymal transition (EMT) and stem cell marker expression in a dose-dependent manner. More importantly, YH677 suppressed breast cancer growth and metastasis in orthotopic, metastatic xenograft and patient-derived xenograft (PDX) models in vivo. Mechanistic studies showed that YH677 inhibits the expansion of CSCs by regulating the TGFß/Smad signaling pathway. These preclinical data provide a basis for the development of YH677 as a lead compound for TNBC treatment.

Establishment of a lysosome-related prognostic signature in breast cancer to predict immune infiltration and therapy response.

Background: Lysosomes are instrumental in intracellular degradation and recycling, with their functional alterations holding significance in tumor growth. Nevertheless, the precise role of lysosome-related genes (LRGs) in breast cancer (BC) remains elucidated. This study aimed to establish a prognostic model for BC based on LRGs. Methods: Employing The Cancer Genome Atlas (TCGA) BC cohort as a training dataset, this study identified differentially expressed lysosome-related genes (DLRGs) through intersecting LRGs with differential expression genes (DEGs) between tumor and normal samples. A prognostic model of BC was subsequently developed using Cox regression analysis and validated within two Gene Expression Omnibus (GEO) external validation sets. Further analyses explored functional pathways, the immune microenvironment, immunotherapeutic responses, and sensitivity to chemotherapeutic drugs in different risk groups. Additionally, the mRNA and protein expression levels of genes within the risk model were examined by utilizing the Gene Expression Profiling Interactive Analysis (GEPIA) and Human Protein Atlas (HPA) databases. Clinical tissue specimens obtained from patients were gathered to validate the expression of the model genes via Real-Time Polymerase Chain Reaction (RT-PCR). Results: We developed a risk model of BC based on five specific genes (ATP6AP1, SLC7A5, EPDR1, SDC1, and PIGR). The model was validated for overall survival (OS) in two GEO validation sets (p=0.00034 for GSE20685 and p=0.0095 for GSE58812). In addition, the nomogram incorporating clinical factors showed better predictive performance. Compared to the low-risk group, the high-risk group had a higher level of certain immune cell infiltration, including regulatory T cells (Tregs) and type 2 T helper cells (Th2). The high-risk patients appeared to respond less well to general immunotherapy and chemotherapeutic drugs, according to the Tumor Immune Dysfunction and Exclusion (TIDE), Immunophenotype Score (IPS), and drug sensitivity scores. The RT-PCR results validated the expression trends of some prognostic-related genes in agreement with the previous differential expression analysis. Conclusion: Our innovative lysosome-associated signature can predict the prognosis for BC patients, offering insights for guiding subsequent immunotherapeutic and chemotherapeutic interventions. Furthermore, it has the potential to provide a scientific foundation for identifying prospective therapeutic targets.