Blockade of a novel MAP4K4-LATS2-SASH1-YAP1 cascade inhibits tumorigenesis and metastasis in luminal breast cancer.

Novel components in the noncanonical Hippo pathway that mediate the growth, metastasis, and drug resistance of breast cancer (BC) cells need to be identified. Here, we showed that expression of SAM and SH3 domain-containing protein 1 (SASH1) is negatively correlated with expression of mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) in a subpopulation of patients with luminal-subtype BC. Downregulated SASH1 and upregulated MAP4K4 synergistically regulated the proliferation, migration, and invasion of luminal-subtype BC cells. The expression of LATS2, SASH1, and YAP1 and the phosphorylation of YAP1 were negatively regulated by MAP4K4, and LATS2 then phosphorylated SASH1 to form a novel MAP4K4-LATS2-SASH1-YAP1 cascade. Dephosphorylation of Yes1 associated transcriptional regulator (YAP1), YAP1/TAZ nuclear translocation, and downstream transcriptional regulation of YAP1 were promoted by the combined effects of ectopic MAP4K4 expression and SASH1 silencing. Targeted inhibition of MAP4K4 blocked proliferation, cell migration, and ER signaling both in vitro and in vivo. Our findings reveal a novel MAP4K4-LATS2-SASH1-YAP1 phosphorylation cascade, a noncanonical Hippo pathway that mediates ER signaling, tumorigenesis, and metastasis in breast cancer. Targeted intervention with this noncanonical Hippo pathway may constitute a novel alternative therapeutic approach for endocrine-resistant BC.

Metabolomics assisted by transcriptomics analysis to reveal metabolic characteristics and potential biomarkers associated with treatment response of neoadjuvant therapy with TCbHP regimen in HER2 + breast cancer.

BACKGROUND: This study aimed to explore potential indicators associated with the neoadjuvant efficacy of TCbHP regimen (taxane, carboplatin, trastuzumab, and pertuzumab) in HER2 + breast cancer (BrCa) patients. METHODS: A total of 120 plasma samples from 40 patients with HER2 + BrCa were prospectively collected at three treatment times of neoadjuvant therapy (NAT) with TCbHP regimen. Serum metabolites were analyzed based on LC-MS and GC-MS data. Random forest was used to establish predictive models based on pre-therapeutic differentially expressed metabolites. Time series analysis was used to obtain potential monitors for treatment response. Transcriptome analysis was performed in nine available pre­therapeutic specimens of core needle biopsies. Integrated analyses of metabolomics and transcriptomics were also performed in these nine patients. qRT-PCR was used to detect altered genes in trastuzumab-sensitive and trastuzumab-resistant cell lines. RESULTS: Twenty-one patients achieved pCR, and 19 patients achieved non-pCR. There were significant differences in plasma metabolic profiles before and during treatment. A total of 100 differential metabolites were identified between pCR patients and non-pCR patients at baseline; these metabolites were markedly enriched in 40 metabolic pathways. The area under the curve (AUC) values for discriminating the pCR and non-PCR groups from the NAT of the single potential metabolite [sophorose, N-(2-acetamido) iminodiacetic acid, taurine and 6-hydroxy-2-aminohexanoic acid] or combined panel of these metabolites were greater than 0.910. Eighteen metabolites exhibited potential for monitoring efficacy. Several validated genes might be associated with trastuzumab resistance. Thirty-nine altered pathways were found to be abnormally expressed at both the transcriptional and metabolic levels. CONCLUSION: Serum-metabolomics could be used as a powerful tool for exploring informative biomarkers for predicting or monitoring treatment efficacy. Metabolomics integrated with transcriptomics analysis could assist in obtaining new insights into biochemical pathophysiology and might facilitate the development of new treatment targets for insensitive patients.

Quantification of Hepatic Steatosis on Dual-Energy CT in Comparison With MRI mDIXON-Quant Sequence in Breast Cancer.

OBJECTIVE: The study aimed to evaluate the correlation and diagnostic value of liver fat quantification in unenhanced dual-energy CT (DECT) using quantitative magnetic resonance imaging (MRI) mDIXON-Quant sequence as reference standard in patients with breast cancer. METHODS: Patients with breast cancer were prospectively recruited between June 2018 and April 2020. Each patient underwent liver DECT and MRI mDIXON-Quant examination. The DECT-fat volume fraction (FVF) and liver-spleen attenuation differences were compared with the MRI-proton density fat fraction using scatterplots, Bland-Altman plots, and concordance correlation coefficient. Receiver operating characteristic curves were established to determine the diagnostic accuracy of hepatic steatosis by DECT. RESULTS: A total of 216 patients with breast cancer (mean age, 50.08 ± 9.33 years) were evaluated. The DECT-FVF correlated well with MRI-proton density fat fraction ( r2 = 0.902; P < 0.001), which was higher than the difference in liver-spleen attenuation ( r2 = 0.728; P < 0.001). Bland-Altman analysis revealed slight positive bias; the mean difference was 3.986. The DECT-FVF yielded an average concordance correlation coefficient of 0.677, which was higher than the difference of liver-spleen attenuation (-0.544). The DECT-FVF and the difference in liver-spleen attenuation both lead to mild overestimation of hepatic steatosis. The areas under the curve of DECT-FVF (0.956) were higher than the difference in liver-spleen attenuation (0.807) in identifying hepatic steatosis ( P < 0.001). CONCLUSIONS: Dual-energy CT-FVF may serve as a reliable screening and quantitative tool for hepatic steatosis in patients with breast cancer.

Dalpiciclib plus letrozole or anastrozole versus placebo plus letrozole or anastrozole as first-line treatment in patients with hormone receptor-positive, HER2-negative advanced breast cancer (DAWNA-2): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Adding CDK4/6 inhibitor dalpiciclib to fulvestrant significantly prolonged progression-free survival in patients with hormone receptor-positive, HER2-negative advanced breast cancer progressing after endocrine therapy. We aimed to assess the efficacy and safety of dalpiciclib plus letrozole or anastrozole in patients with hormone receptor-positive, HER2-negative advanced breast cancer who had no previous systemic therapy in the advanced setting. METHODS: DAWNA-2 is a randomised, double-blind, placebo-controlled, phase 3 trial done at 42 hospitals in China. Eligible patients were aged 18-75 years, of any menopausal status, had an ECOG performance status of 0-1, and had pathologically confirmed hormone receptor-positive, HER2-negative untreated advanced breast cancer. Patients were randomly assigned (2:1) to receive oral dalpiciclib (150 mg per day for 3 weeks, followed by 1 week off) or matching placebo. Both groups also received endocrine therapy: either 2·5 mg letrozole or 1 mg anastrozole orally once daily continuously. Randomisation was using an interactive web response system (block size of six) and stratified according to visceral metastasis, previous endocrine therapy in the adjuvant or neoadjuvant setting, and endocrine therapy partner. All investigators, patients, and the funders of the study were masked to group allocation. We present the results of the preplanned interim analyses for the primary endpoint of investigator-assessed progression-free survival, which was assessed in all randomly assigned patients who met the eligibility criteria by intention-to treat. Safety was analysed in all randomly assigned patients who received at least one dose of study treatment. The superiority boundary was calculated as a one-sided p value of 0·0076 or less. This trial is registered with ClinicalTrials.gov, NCT03966898, and is ongoing but closed to recruitment. FINDINGS: Between July 19, 2019, and Dec 25, 2020, 580 patients were screened and 456 were eligible and randomly assigned to the dalpiciclib group (n=303) or placebo group (n=153). At data cutoff (June 1, 2022), median follow-up was 21·6 months (IQR 18·3-25·9), and 103 (34%) of 303 patients in the dalpiciclib group and 83 (54%) of 153 patients in the placebo group had disease progression or died. Median progression-free survival was significantly longer in the dalpiciclib group than in the placebo group (30·6 months [95% CI 30·6-not reached] vs 18·2 months [16·5-22·5]; stratified hazard ratio 0·51 [95% CI 0·38-0·69]; one-sided log-rank p<0·0001). Adverse events of grade 3 or 4 were reported in 271 (90%) of 302 patients in the dalpiciclib group and 18 (12%) of 153 patients in the placebo group. The most common adverse events of grade 3 or 4 were neutropenia (259 [86%] in the dalpiciclib group vs none in the placebo group) and leukopenia (201 [67%] vs none). Serious adverse events were reported for 36 (12%) patients in the dalpiciclib group and ten (7%) patients in the placebo group. Two treatment-related deaths occurred, both in the dalpiciclib group (deaths from unknown causes). INTERPRETATION: Our findings suggest that dalpiciclib plus letrozole or anastrozole could be a novel standard first-line treatment for patients with hormone receptor-positive, HER2-negative advanced breast cancer, and is an alternative option to the current treatment landscape. FUNDING: Jiangsu Hengrui Pharmaceuticals and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A Phase IIb, single arm, multicenter trial of sacituzumab govitecan in Chinese patients with metastatic triple-negative breast cancer who received at least two prior treatments.

Refractory or relapsing metastatic triple-negative breast cancer (mTNBC) has a poor prognosis. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate, targeting human trophoblast cell-surface antigen 2 (Trop-2). This is the first report of SG's efficacy and safety in Chinese patients with mTNBC. EVER-132-001 (NCT04454437) was a multicenter, single-arm, Phase IIb study in Chinese patients with mTNBC who failed ≥2 prior chemotherapy regimens. Eligible patients received 10 mg/kg SG on Days 1 and 8 of each 21-day treatment cycle, until disease progression/unacceptable toxicity. The primary endpoint was objective response rate (ORR) assessed by the Independent Review Committee. Secondary endpoints included: duration of response (DOR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS) and safety. Eighty female Chinese patients (median age 47.6 years; range 24-69.9 years) received ≥1 SG dose with a median of 8 treatment cycles by the cutoff date (August 6, 2021). Median number of prior systemic cancer treatments was 4.0 (range 2.0-8.0). ORR and CBR were reported 38.8% (95% confidence interval [CI]: 28.06-50.30) and 43.8% (95% CI, 32.68-55.30) of patients, respectively. The median PFS was 5.55 months (95% CI, 4.14-N/A). SG-related Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 71.3%, the most common were neutrophil count decreased (62.5%), white blood cell count decreased (48.8%) and anemia (21.3%); 6.3% discontinued SG because of TEAEs. SG demonstrated substantial clinical activity in heavily pretreated Chinese patients with mTNBC. The observed safety profile was generally manageable.

Disruption of ZNF334 promotes triple-negative breast carcinoma malignancy through the SFRP1/ Wnt/ß-catenin signaling axis.

Zinc-finger proteins (ZNFs) constitute the largest transcription factor family in the human genome. The family functions in many important biological processes involved in tumorigenesis. In our research, we identified ZNF334 as a novel tumor suppressor of triple-negative breast cancer (TNBC). ZNF334 expression was usually reduced in breast cancerv (BrCa) tissues and TNBC cell lines MDA-MB-231 (MB231) and YCCB1. We observed that promoter hypermethylation of ZNF334 was common in BrCa cell lines and tissues, which was likely responsible for its reduced expression. Ectopic expression of ZNF334 in TNBC cell lines MB231 and YCCB1 could suppress their growth and metastatic capacity both in vitro and in vivo, and as well induce cell cycle arrest at S phase and cell apoptosis. Moreover, re-expression of ZNF334 in TNBC cell lines could rescue Epithelial-Mesenchymal Transition (EMT) process and restrain stemness, due to up-regulation of SFRP1, which is an antagonist of Wnt/ß-catenin signaling. In conclusion, we verified that ZNF334 had a suppressive function of TNBC cell lines by targeting the SFRP1/Wnt/ß-catenin signaling axis, which might have the potentials to become a new biomarker for diagnosis and treatment of TNBC patients.

Early alterations in cortical morphology after neoadjuvant chemotherapy in breast cancer patients: A longitudinal magnetic resonance imaging study.

There is growing evidence that chemotherapy may have a significant impact on the brains of breast cancer patients, causing changes in cortical morphology. However, early morphological alterations induced by chemotherapy in breast cancer patients are unclear. To investigate the patterns of those alterations, we compared female breast cancer patients (n = 45) longitudinally before (time point 0, TP0) and after (time point 1, TP1) the first cycle of neoadjuvant chemotherapy, using voxel-based morphometry (VBM) and surface-based morphometry (SBM). VBM and SBM alteration data underwent correlation analysis. We also compared cognition-related neuropsychological tests in the breast cancer patients between TP0 and TP1. Reductions in gray matter volume, cortical thickness, sulcal depth, and gyrification index were found in most brain areas, while increments were found to be mainly concentrated in and around the hippocampus. Reductions of fractal dimension mainly occurred in the limbic and occipital lobes, while increments mainly occurred in the anterior and posterior central gyrus. Significant correlations were found between altered VBM and altered SBM mainly in the bilateral superior frontal gyrus. We found no significant differences in the cognition-related neuropsychological tests before and after chemotherapy. The altered brain regions are in line with those associated with impaired cognitive domains in previous studies. We conclude that breast cancer patients showed widespread morphological alterations soon after neoadjuvant chemotherapy, despite an absence of cognitive impairments. The affected brain regions may indicate major targets of early brain damage after chemotherapy.

Chemotherapy-associated steatohepatitis was concomitant with epicardial adipose tissue volume increasing in breast cancer patients who received neoadjuvant chemotherapy.

OBJECTIVES: To investigate the prevalence of chemotherapy-associated steatohepatitis, quantitate the epicardial adipose tissue (EAT) volume in breast cancer patients, and explore the mediating effect of liver fat content on EAT volume in breast cancer patients who received neoadjuvant chemotherapy (NAC). METHODS: From October 2018 to April 2020, patients were retrospectively reviewed and divided into breast cancer non-NAC and NAC groups. The prevalence of chemotherapy-associated steatohepatitis was evaluated through quantitative MRI mDIXON-Quant examinations by using defined proton density fat fraction cutoffs of liver fat. The EAT volume was quantified on chest CT by semi-automatic volume analysis software. Bootstrap analysis was used in the breast cancer NAC group to test the significance of the mediating effect of liver fat content on EAT volume. RESULTS: A total of 662 breast cancer patients (non-NAC group: 445 patients; NAC group: 217 patients) were included. The prevalence of chemotherapy-associated steatohepatitis in the NAC group was significantly higher than the prevalence of hepatic steatosis in the non-NAC group (42.8% vs. 33.3%, p < 0.001). EAT volume was measured in 561 of 662 breast cancer patients, and was significantly higher in the NAC group than in the non-NAC group (137.26 ± 53.48 mL vs. 125.14 ± 58.77 mL, p = 0.020). In the breast cancer NAC group, the indirect effect of liver fat content on EAT volume was 2.545 (p < 0.001), and the contribution rate to the effect was 69.1%. CONCLUSIONS: EAT volume was significantly higher in the BC-NAC group than in the BC-non-NAC group. KEY POINTS: • The prevalence of CASH was as high as 42.8% in BC patients. • NAC significantly increased the EAT volume in BC patients. • The liver fat content caused the change of EAT volume through mediating effect.

Axillary masses as clinical manifestations of male sweat gland carcinoma associated with extramammary Paget's disease and accessory breast carcinoma: two cases report and literature review.

BACKGROUND: Male cases of accessory breast carcinoma and sweat gland carcinoma associated with extramammary Paget's disease of the axilla are uncommon. In clinical diagnosis and treatment, it is necessary to determine the disease carefully and make a reasonable treatment strategy according to the patient's situation. CASE PRESENTATION: We described two male cases of the special tumor with an axillary mass as the first clinical symptom, one of which was diagnosed as accessory breast cancer and the other as sweat gland cancer associated with extramammary Paget's disease. We treated the two diseases individually in the hopes of providing a reference for the diagnosis and management of diseases with axillary nodules as the initial symptom. CONCLUSIONS: The reports of these two cases can provide reference and corresponding thinking for clinical differentiation of axillary lymphadenopathy caused by different causes and subsequent treatment. These two cases may further enrich the database of rare cases and provide some ideas for the treatment of axillary lymphadenopathy caused by different causes.

Additional adjuvant capecitabine in early breast cancer patients: a meta-analysis of randomized controlled trials.

Aims: To assess the efficacy and safety of adjuvant capecitabine in early breast cancer patients. Methods: A literature search of databases was conducted to identify randomized controlled trials reporting the efficacy and toxicity of capecitabine as adjuvant therapy in early breast cancer patients. Results: Six studies were eligible and included a total of 6941 patients. Disease-free survival (hazard ratio = 0.79; 95% CI = 0.71-0.88; p < 0.0001) was significantly improved with additional capecitabine, whereas improvement in overall survival (OS) was not significant. The more pronounced benefits in both disease-free survival and OS were observed among triple-negative breast cancer patients. Conclusion: Additional capecitabine in the adjuvant setting conferred substantial disease-free survival benefit and a tendency toward improved OS. Triple-negative breast cancer patients can benefit from capecitabine irrespective of the administration sequence. Capecitabine may be considered a preferred additional treatment for early-stage triple-negative breast cancer patients, and sequential capecitabine can serve as an alternative choice for patients with poor tolerance.

Lay abstract The authors' meta-analysis focused on the adjuvant role of capecitabine in early-stage breast cancer patients. The authors combined data from different studies to show that disease-free survival was significantly improved with additional capecitabine as adjuvant chemotherapy. The more pronounced survival benefits were observed among triple-negative breast cancer patients irrespective of the administration sequence (concurrent/sequential). Capecitabine may be considered a preferred additional treatment for early-stage triple-negative breast cancer patients, and sequential capecitabine can serve as an alternative choice for patients with poor tolerance.

Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidines inhibit proliferation, promote apoptosis and down-regulation of E6/E7 mRNA in cervical cancer.

The occurrence and development of cervical cancer threaten women's life and health, HPV-induced cervical cancer is a major health issue among women. We synthesized three Rhopaladins' analogue (E)-2-aroyl-4-(4-fluorobenzylidene)-5-oxopyrrolidines via a tandem Ugi 4CC/SN cyclization with pyrrolidone as a core structure. In addition, the cytotoxicity of these new compounds in the cervical cancer cell line CaSki was studied by MTT assay. And then we chose one to research the apoptosis and the expression of E6/E7 mRNA in CaSki cells. The results indicated that the new compound can not only inhibited the proliferation of CaSki in dose-dependent and time-dependent manners but also induced the apoptosis, which may be related to the down-regulation of E6/E7 mRNA expression.

Design, synthesis and biological activity of deuterium-based FFA1 agonists with improved pharmacokinetic profiles.

The free fatty acid receptor 1 (FFA1) is considered as a promising anti-diabetic target based on its function of glucose-stimulated insulin secretion. The previously reported compound 2 is a highly potent FFA1 agonist, but it might be suffered from poor pharmacokinetic properties because the phenylpropanoic acid is vulnerable to ß-oxidation. To identify orally available analogs, we tried to block the route of ß-oxidation by incorporating deuterium at phenylpropionic acid moiety. As expected, the deuterium-based analogs 3 and 4 exhibited better pharmacokinetic properties than parent compound 2. Although the difference of potency between compound 2 and 3 is quite small, the glucose-lowering effect of deuterium analog 3 was better than that of compound 2. Meanwhile, compound 3 docked well into the same binding pocket of TAK-875, and formed almost identical interactions of TAK-875 in binding site. Different from glibenclamide, a lower risk of hypoglycemia was observed in compound 3 even at the high dose of 60 mg/kg.

Advantages with prophylactic PEG-rhG-CSF versus rhG-CSF in breast cancer patients receiving multiple cycles of myelosuppressive chemotherapy: an open-label, randomized, multicenter phase III study.

BACKGROUND: PEG-rhG-CSF reduces neutropenia and improves chemotherapy safety. In China's registration trial (CFDA: 2006L01305), we assessed its efficacy and safety against rhG-CSF, and prospectively explored its value over multiple cycles of chemotherapy. METHODS: In this open-label, randomized, multicenter phase 3 study, breast cancer patients (n = 569) were randomized to receive PEG-rhG-CSF 100 µg/kg, PEG-rhG-CSF 6 mg, or rhG-CSF 5 µg/kg/d after chemotherapy. The primary endpoints were the incidence and duration of grade 3/4 neutropenia during cycle 1. Secondary endpoints included the incidence and duration of grade 3/4 neutropenia during cycles 2-4, the incidence of febrile neutropenia, and the safety. RESULTS: A once-per-cycle PEG-rhG-CSF at either 100 µg/kg or 6 mg was not different from daily injections of rhG-CSF for either incidence or duration of grade 3/4 neutropenia. Interestingly, a substantial difference was noted during cycle 2, and the difference became bigger over cycles 3-4, reaching a statistical significance at cycle 4 in either incidence (P = 0.0309) or duration (P = 0.0289) favoring PEG-rhG-CSF. A significant trend toward a lower incidence of all-grade adverse events was noted at 129 (68.98%), 142 (75.53%), and 160 (82.47%) in the PEG-rhG-CSF 100 µg/kg and 6 mg and rhG-CSF groups, respectively (P = 0.0085). The corresponding incidence of grade 3/4 drug-related adverse events was 2/187 (1.07%), 1/188 (0.53%), and 8/194 (4.12%), respectively (P = 0.0477). Additionally, PFS in metastatic patients preferred PEG-rhG-CSF to rhG-CSF despite no significance observed by Kaplan-Meier analysis (n = 49, P = 0.153). CONCLUSIONS: PEG-rhG-CSF is a more convenient and safe formulation and a more effective prophylactic measure in breast cancer patients receiving multiple cycles of chemotherapy.

Nitric oxide donor-based FFA1 agonists: Design, synthesis and biological evaluation as potential anti-diabetic and anti-thrombotic agents.

The cardiovascular complications were highly prevalent in type 2 diabetes mellitus (T2DM), even at the early stage of T2DM or the state of intensive glycemic control. Thus, there is an urgent need for the intervention of cardiovascular complications in T2DM. Herein, the new hybrids of FFA1 agonist and NO donor were design to obtain dual effects of anti-hyperglycemic and anti-thrombosis. As expected, the induced-fit docking study suggested that it is feasible for our design strategy to hybrid NO donor with compound 1. These hybrids exhibited moderate FFA1 agonistic activities and anti-platelet aggregation activities, and their anti-platelet effects mediated by NO were also confirmed in the presence of NO scavenger. Moreover, compound 3 revealed significantly hypoglycemic effect and even stronger than that of TAK-875 during an oral glucose tolerance test in mice. Potent and multifunctional hybrid, such as compound 3, is expected as a potential candidate with additional cardiovascular benefits for the treatment of T2DM.

Survival benefit of pure dose-dense chemotherapy in breast cancer: a meta-analysis of randomized controlled trials.

BACKGROUND: Dose-dense chemotherapy is a widely accepted regimen for high-risk breast cancer patients. However, conflicting survival benefits of pure dose-dense chemotherapy have been reported in different randomized controlled trials (RCTs). This meta-analysis aimed to further assess the efficacy and safety of pure dose-dense chemotherapy in breast cancer. METHODS: A literature search of electronic databases and websites was performed to identify phase III RCTs reporting the efficacy and toxicity of pure dose-dense chemotherapy. The endpoints of interest were overall survival (OS), disease-free survival (DFS), and toxicities. The hazard ratios (HRs) of death and recurrence and the odds ratios (ORs) of adverse events were estimated and pooled. RESULTS: Seven studies (five trials) were eligible, encompassing a total of 9851 patients. Patients treated with dose-dense chemotherapy obtained better DFS (HR = 0.83; 95% CI 0.75-0.91; p = 0.0001) than those treated with the conventional schedule, while OS benefit of dose-dense chemotherapy was less impressive (HR = 0.86; 95% CI 0.73-1.02; p = 0.08). However, significant OS benefit was observed in node-positive patients (HR = 0.77; 95% CI 0.66-0.90; p = 0.001). The incidence of anemia, pain, and transaminase elevation was higher in the dose-dense chemotherapy arm. CONCLUSIONS: Dose-dense chemotherapy leads to better prognosis; these findings suggest that it may be a potentially preferred treatment for breast cancer patients, particularly for women with lymph node involvement. However, more RCTs are warranted to better define the best candidates for dose-dense chemotherapy.

The impact of FDI on energy conservation and emission reduction performance: A FDI quality perspective.

According to the climate emission reduction commitment of the Paris Agreement, all countries are actively seeking a new path of energy conservation and emission reduction, and trying to "bend downward" the global greenhouse gas emission curve. For China's carbon peak before 2030 and carbon neutral target before 2060, explore whether FDI can reduce China's energy consumption and carbon emissions. From the new research perspective of FDI quality, this paper explores the potential ways to improve regional energy-carbon emission performance (ECEP), and applied dynamic threshold effect and two-stage least squares for validation. The specific results are as follows: FDI quality improvement can have a significant positive impact on regional ECEP.The development level of renewable energy, the optimization of industrial structure and the enhancement of green innovation ability can positively regulate the impact of FDI on energy-carbon emission performance. At the same time, the results of the dynamic panel threshold model demonstrate that with the economic growth pressure of local governments decreases and the fiscal decentralization increases, the role of FDI quality in promoting the ECEP could be stronger. The influence of FDI quality on ECEP has regional heterogeneity, and the influence of FDI quality on ECEP is regional heterogeneous, and the influence of FDI quality on ECEP is more significant in inland and midwestern regions than in coastal and eastern regions. This study provides experience for FDI to formulate the quality assessment system and formulate foreign investment policy.

MAP3K4 kinase action and dual role in cancer.

It is commonly known that the MAPK pathway is involved in translating environmental inputs, regulating downstream reactions, and maintaining the intrinsic dynamic balance. Numerous essential elements and regulatory processes are included in this pathway, which are essential to its functionality. Among these, MAP3K4, a member of the serine/threonine kinases family, plays vital roles throughout the organism's life cycle, including the regulation of apoptosis and autophagy. Moreover, MAP3K4 can interact with key partners like GADD45, which affects organism's growth and development. Notably, MAP3K4 functions as both a tumor promotor and suppressor, being activated by a variety of factors and triggering diverse downstream pathways that differently influence cancer progression. The aim of this study is to provide a brief overview of physiological functions of MAP3K4 and shed light on its contradictory roles in tumorigenesis.

The role of locoregional surgery in de novo stage IV breast cancer: A meta-analysis of randomized controlled trials.

BACKGROUND: We performed an updated meta-analysis to explore the value of locoregional surgery in de novo stage IV breast cancer patients. METHODS: A literature search was conducted to identify randomized controlled trials comparing primary tumor resection with systemic therapy in de novo stage IV breast cancer. The hazard ratio (HR) of overall survival (OS), local relapse-free survival (LRFS), and distant relapse-free survival (DRFS) were estimated and pooled. RESULTS: Six studies were eligible, including a total of 1368 patients. Both OS (HR = 0.86; 95 %CI: 0.77-0.96; p = 0.01; I2 = 45 %) and LRFS (HR = 0.35; 95 %CI: 0.20-0.62; p = 0.0003; I2 = 83 %) were significantly improved with locoregional surgery compared with systemic therapy alone. There was no significant difference in terms of DRFS (HR = 0.96; 95 %CI: 0.41-2.22; p = 0.92; I2 = 86 %). The OS benefit was more pronounced in hormone receptor-positive patients (HR = 0.79; p = 0.003) and HER2-negative patients (HR = 0.80; p = 0.003). CONCLUSIONS: This study demonstrated that locoregional surgery conferred significant OS and LRFS benefits in de novo stage IV breast cancer patients and may serve as an alternative choice for selected patients.

Knowledge mapping of immunotherapy for breast cancer: A bibliometric analysis from 2013 to 2022.

Breast cancer is the leading cause of cancer-related death among women globally. Immunotherapy has emerged as a major milestone in contemporary oncology. This study aims to conduct a bibliometric analysis in the field of immunotherapy for breast cancer, providing a comprehensive overview of the current research status, identifying trends and hotspots in research topics. We searched and retrieved data from the Web of Science Core Collection, and performed a bibliometric analysis of publications on immunotherapy for breast cancer from 2013 to 2022. Current status and hotspots were evaluated by co-occurrence analysis using VOSviewer. Evolution and bursts of knowledge base were assessed by co-citation analysis using CiteSpace. Thematic evolution by bibliometrix package was used to discover keywords trends. The attribution and collaboration of countries/regions, institutions and authors were also explored. A total of 7,975 publications were included. In co-occurrence analysis of keywords, 6 major clusters were revealed: tumor microenvironment, prognosis biomarker, immune checkpoints, novel drug delivery methods, immune cells and therapeutic approaches. The top three most frequently mentioned keywords were tumor microenvironment, triple-negative breast cancer, and programmed cell death ligand 1. The most productive country, institution and author were the USA (2926 publications), the University of Texas MD Anderson Cancer Center (219 publications), and Sherene Loi (28 publications), respectively. There has been a rapid growth in studies on immunotherapy for breast cancer worldwide. This research area has gained increasing attention from different countries and institutions. With the rising incidence of breast cancer, immunotherapy represents a research field of significant clinical value and potential.

Thoracic aorta injury detected by 4D flow MRI predicts subsequent main adverse cardiovascular events in breast cancer patients receiving anthracyclines: A longitudinal study.

PURPOSE: To investigate longitudinal thoracic aorta injury using 3-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) parameters and to evaluate their value for predicting the subsequent main adverse cardiovascular events (MACEs) in breast cancer patients receiving anthracyclines. METHODS: Between July 2020 and July 2021, eighty-eight female participants with breast cancer scheduled to receive anthracyclines with or without trastuzumab prospectively enrolled. Each subjects underwent 4D flow MRI at baseline, 3 and 6 months in relation to baseline. The diameter, peak velocity (Vpeak), wall shear stress (WSS), pulse wave velocity (PWV), energy loss (EL) and pressure gradient (PG) of thoracic aorta were measured. The association between these parameters and subsequent MACEs was performed by Cox proportional hazard models. RESULTS: Ten participants had subsequently MACEs. The Vpeak and PG gradually decreased and the WSS, PWV and EL progressively increased at 3 and 6 months compared with baseline. Adjusted multivariable analysis showed that the WSS of the proximal, mid- and distal ascending aorta [HR, 1.314 (95% confidence interval (CI): 1.003, 1.898)], [HR, 1.320 (95% CI: 1.002, 1.801)] and [HR, 1.322 (95% CI: 1.001, 1.805)] and PWV of ascending aorta [HR, 2.223 (95% CI: 1.010, 4.653)] at 3 months were associated with subsequent MACEs. Combined WSS and PWV of ascending aorta at 3 months yielded the highest AUC (0.912) for predicting subsequent MACEs. CONCLUSION: Combined WSS and PWV of ascending aorta at 3 months is helpful for predicting the subsequent MACEs in breast cancer patients treated by anthracyclines.