Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression.

Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast cancer. In this study, we have explored the aberrantly active kinases in breast cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast cancer (TNBC) progression. We collected 47 pairs of breast cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xl and Vimentin, and decreased levels of Bad, cleaved caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.

What impacts ecosystem services in tropical coastal tourism cities? A comparative case study of Haikou and Sanya, China.

The ecological environment of tourism-oriented towns is attracting increasing attention. Taking the cities of Haikou and Sanya as examples, we examined changes in six ecosystem services (ES), including water conservation (WC), crop production (CP), soil retention (SR), carbon storage (CS), habitat quality (HQ), and tourism recreation (TR) from 2005 to 2020. From the three perspectives of geographical environment, socioeconomic development, and tourism development force, 14 indicators were chosen to examine the impact on ES. Except for Haikou's TR, the other ES of Haikou and Sanya showed a decreasing trend from 2005 to 2020. The values of six ES were lower in coastal zones than in noncoastal zones, which were more obvious in Sanya. Specifically, the areas of low value in Sanya were concentrated in the coastal region, and the areas with low value in Haikou were primarily distributed in blocks along the coast and in bands or points in the central and southern areas. From the perspective of influencing factors, the natural environmental factors dominate in Haikou, followed by the socio-economic factors and finally the tourism development factors, while the natural environmental factors also dominate in Sanya, followed by the tourism development factors and finally the socio-economic factors. We provided recommendations for sustainable tourism development in Haikou and Sanya. This study has significant implications for both integrated management and scientific decision-making to enhance the ES of tourism destinations.

Sono-activation of food enzymes: From principles to practice.

Over the last decade, sono-activation of enzymes as an emerging research area has received considerable attention from food researchers. This kind of relatively new application of ultrasound has demonstrated promising potential in facilitating the modern food industry by broadening the application of various food enzymes, improving relevant industrial unit operation and productivity, as well as increasing the yield of target products. This review aims to provide insight into the fundamental principles and possible industrialization strategies of the sono-activation of food enzymes to facilitate its commercialization. This review first provides an overview of ultrasound application in the activation of food protease, carbohydrase, and lipase. Then, the recent development on ultrasound activation of food enzymes is discussed on aspects including mechanisms, influencing factors, modification effects, and its applications in real food systems for free and immobilized enzymes. Despite the far fewer studies on sono-activation of immobilized enzymes compared with those on free enzymes, we endeavored to summarize the relevant aspects in three stages: ultrasound pretreatment of free enzyme/carrier, assistance in immobilization process, and modification of the already immobilized enzyme. Lastly, challenges for the scalability of ultrasound in these target areas are discussed and future research prospects are proposed.

LncRNA-p21 suppresses cell proliferation and induces apoptosis in gastric cancer by sponging miR-514b-3p and up-regulating ARHGEF9 expression.

The long non-coding RNA p21 (lncRNA-p21) was a tumor suppressor gene in most cancer types including gastric cancer (GC). We aimed to identify a specific lncRNA-p21-involved pathway in regulating the proliferation and apoptosis of GC cells. A lower lncRNA-p21 expression in tumors was associated with advanced disease stage and predicted worse survival of GC patients. LncRNA-p21 overexpression in GC cell line somatic gastric cancer (SGC)-7901 and human gastric cancer (HGC)-27 suppressed cell proliferation and enhanced apoptosis, while lncRNA-p21 knockdown caused the opposite effects. Through bioinformatics analysis and luciferase-based reporter assays, we identified miR-514b-3p as a sponge target of lncRNA-p21. Cdc42 guanine nucleotide exchange factor 9 (ARHGEF9), functioned as a tumor suppress factor in GC, was found as the downstream target of miR-514-3p, and their expressions were negatively correlated in GC tumor tissues. In addition, like lncRNA-p21 overexpression alone, miR-514-3p inactivation alone also led to decreased proliferation and increased apoptosis in SGC-7901 and HGC-27 cells, which were markedly attenuated by additional ARHGEF9 knockdown. Xenograft SGC-7901 cells with more lncRNA-p21 or ARHGEF9 expressions or with less miR-514-3p expression exhibited obviously slower in vivo growth than the control SGC-7901 cells in nude mice. Our study reveals a novel lncRNA-p21/miR-514b-3p/ARHGEF9 pathway that can be targeted for GC therapy.

[Research on the Necessity and Feasibility of Current Medical Device Supervision Legislation].

This paper studies the necessity of the current legislation on the supervision of medical devices in China from the perspectives of strengthening administration according to law, protecting public health, perfecting the legal system of medicine and promoting the development of the medical device industry. This study analyzes and summarizes the legislative experiences and forms in the field of medical device regulation in the United States, the European Union, Japan and other countries and regions, at present, the conditions of carrying out the legislation of medical device supervision in China are quite mature, and some policy suggestions are put forward for the enactment of the law of medical device management in China.

Ultrasound for pectinase modification: an investigation into potential mechanisms.

BACKGROUND: Today, ultrasound is increasingly utilized in enzyme modification. Strongly dependent on the specific operational conditions, the modification effect brought by ultrasound can be activation and inactivation of enzymes. This work aims to study the ultrasound mechanisms under different conditions, to investigate the respective roles of free radical effect and mechanical effect in pectinase activation and inactivation, and to reveal the influence of pectinase concentration on the ultrasound-modification effect. RESULTS: When ultrasound was introduced to a liquid system, generation of free radicals was positively correlated with ultrasound intensity and treatment duration, but negatively correlated with temperature. Thiourea with a concentration of 4 mmol L-1 was selected as a free radical scavenger to effectively shield ultrasound free radicals. The highest enzyme activity of pectinase solutions at 0.1, 1.0, and 10.0 mg mL-1 was obtained at the same ultrasound intensity of 4.50 W mL-1 and time of 15 min, where the enzyme activity was increased by 68.24%, 20.98% and 18.83%, respectively. Furthermore, the addition of thiourea enhanced the enzyme activity at each tested ultrasound intensity and time, especially those exceeding the best conditions; it also eliminated the redshift phenomenon that was previously presented in the fluorescence spectra of pectinase samples. CONCLUSION: Pectinase concentrations did not change the optimum ultrasound conditions for enzyme modification, but pectinase with a low concentration was more vulnerable to ultrasound treatment. During modification, ultrasound mechanical effects dominated in the pectinase activation, while free radical effects dominated in the inactivation process. © 2020 Society of Chemical Industry.

Downregulation of APE1 potentiates breast cancer cells to olaparib by inhibiting PARP-1 expression.

PURPOSE: Targeting DNA repair mechanisms to induce apoptosis may be a promising strategy for breast cancer treatment. Olaparib is proved to have anticancer effect by inhibiting DNA repairing protein poly (ADP-ribose) polymerase (PARP). However, the cytotoxicity of olaparib is very limited to homologous recombination-proficient cells. This study aims to examine the effect and mechanism of olaparib treatment in breast cancer cell lines. METHODS: We investigated the cytotoxic effect of various doses of olaparib treatment to MCF-7 and ZR-75-1 cells in vitro. mRNA and protein levels of PARP and APE1 were examined by real-time PCR and western blot, respectively. APE1-deficient cell lines were created by RNA interference and used for in vitro cytotoxicity study as well as in vivo study. RESULTS: 2 µM or higher concentrations of olaparib lead to significant cell death and ROS production. Moreover, olaparib treatment not only inhibits PARP1, but also reduces the expression of APE1 in both mRNA and protein levels. Deficiency of APE1 resulted in increased sensitivity of MCF-7 and ZR-75-1 cells to olaparib treatment. In vivo study showed that reduction of APE1 significantly reduced the volume and weight of MCF-7 xenografted tumors when treated with olaparib, which suggests the synergistic function of inhibition of APE1 in promoting antitumor effects of olaparib treatment. CONCLUSION: To acquire better benefits for HR-proficient breast cancer patients, developing chemotherapeutic drugs antagonize APE1 would be an effective strategy to improve the clinical outcome of PARP inhibitors.

Primary drug resistance of mycobacterium tuberculosis in Shandong, China, 2004-2018.

BACKGROUND: Primary drug-resistant tuberculosis (DR-TB) has contributed to a significant health and economic burden on a global scale, especially in China. we sought to estimate epidemiological characteristics of primary DR-TB in China from 2004 to 2018. METHODS: Eleven thousand four hundred sixty-seven newly diagnosed and 1981 retreated TB cases with drug susceptibility data were included. Chi-Square test for trends, linear regression, a joinpoint regression model and temporal trend in proportions of the different resistance patterns were carried out. RESULTS: The proportion of primary DR-TB and mono-resistant TB (MR-TB) in China had reduced by more than 12% since 2004, and were 21.38%, 13.35% in 2018 respectively. Among primary DR-TB cases (2173,18.95%), the percentage of multiresistant TB (MDR-TB, from 5.41 to 17.46%), male (from 77.03 to 84.13%), cavity (from 13.51 to 43.92%), rifampicin(RFP)-resistant TB (from 8.11 to 26.98%), streptomycin(SM)-resistant TB (from 50.00 to 71.43%) increased significantly (P < 0.05). On the contrary, the proportion of female, non-cavity, isoniazide(INH)-resistant TB (from 55.41 to 48.15%) and MR-TB (from 82.43 to 62.43%) decreased significant (P < 0.05). The primary drug resistance rate among female, cavity, smoking, drinking, 15 to 44 year-old TB subgroups increased by 0.16, 6.24, 20.95, 158.85, 31.49%, respectively. The percentage of primary DR-TB, RFP-resistant TB dropped significantly during 2004-2007 in Joinpoint regression model. CONCLUSION: The total rate of drug resistance among new TB cases showed a downward trend in Shandong, China, from 2004 to 2018. Primary drug resistance patterns were shifting from female, non-cavity, INH-resistant TB, and MR-TB groups to male, cavity, RFP/SM-resistant TB, and MDR-TB groups. Considering the rising drug resistance rate among some special population, future control of primary DR-TB in China may require an increased focus on female, cavity, smoking, drinking, or 15 to 44 year-old TB subgroups.

Time effect on structural and functional properties of whey protein isolate-gum acacia conjugates prepared via Maillard reaction.

BACKGROUND: The functional properties of whey protein isolate (WPI) are sensitive to pH, ionic strength, and temperature. This prevents its application in various food systems and processing technologies. The conjugation of proteins with polysaccharides via the Maillard reaction is an efficient method to improve the functionality of proteins. The purpose of this work was to conjugate gum acacia (GA) with WPI via the dry-heating Maillard reaction and to investigate the effect of reaction time on the physicochemical and functional properties of WPI-GA conjugates. RESULTS: Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and high-performance size exclusion chromatography confirmed the formation of higher molecular weight conjugates. The degrees of glycation for WPI-GA conjugates incubated for 1, 3, 5, and 7 days were 28.14%, 44.98%, 49.50%, and 51.20%, respectively. The glycation reaction reduced the surface hydrophobicity and fluorescence intensity of WPI significantly (P < 0.05). Functional properties of the conjugates, such as solubility, stability against heat-induced insolubility, and emulsion properties were all superior to the control WPI. However, a reaction time longer than a day resulted in a high degree of browning and decreased the functionality of the conjugate significantly (P < 0.05). CONCLUSION: The results indicated that conjugation of WPI with GA can be a promising way to enhance its functional properties. However, the reaction time suitable for producing conjugates with superior functional properties was not necessarily the highest glycation degree that could be reached. © 2019 Society of Chemical Industry.

MicroRNA-1179 suppresses cell growth and invasion by targeting sperm-associated antigen 5-mediated Akt signaling in human non-small cell lung cancer.

Accumulating evidence has identified microRNA-1179 (miR-1179) as a novel cancer-related miRNA that is dysregulated in multiple cancers and plays an important role in regulating cancer development and progression. However, little is known about the role of miR-1179 in non-small cell lung cancer (NSCLC). Thus, in the present study, we aimed to investigate the potential biological function and regulatory mechanism of miR-1179 in NSCLC. The results showed that decreased expression of miR-1179 expression was frequently detected in primary NSCLC tissues and cell lines. Overexpression of miR-1179 suppressed the growth and invasion of NSCLC cells in vitro while its inhibition promoted the opposite effect. Sperm-associated antigen 5 (SPAG5) was an identified as a target gene of miR-1179. Moreover, SPAG5 expression was increased in NSCLC cells and showed an inverse correlation with miR-1179 in NSCLC specimens. SPAG5 knockdown inhibited the growth and invasion of NSCLC cells, results that simulated a similar effect to miR-1179 overexpression. Mechanistic investigations showed that miR-1179 overexpression or SPAG5 knockdown significantly downregulated the activation of Akt signaling. Additionally, SPAG5 overexpression partially reversed the antitumor effect of miR-1179. Overall, our results demonstrated that miR-1179 inhibited the growth and invasion of NSCLC cells by targeting SPAG5 and inhibiting Akt, findings that highlight the importance of the miR-1179/SPAG5/Akt axis in the progression of NSCCL.

The effects of chrysophanol on ovalbumin (OVA)-induced chronic lung toxicology by inhibiting Th17 response.

Chrysophanol (CH), extracted from plants of Rheum genus, possesses various pharmacological effects including anti-inflammatory activity. The purpose of the present study was to evaluate the protective effects and the underlying mechanisms of CH on ovalbumin (OVA)-induced asthma in mice. Fifty mice were randomly assigned to five experimental groups: control group, model group, dexamethasone (2 mg/kg) group and CH (5 and 10 mg/kg) groups. The number of eosinophil cells and the production of interleukin-6 (IL-6), IL-1ß, IL-17 A and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF) were measured. In addition, pulmonary histopathology, airway resistance (Raw), T-helper17 (Th17) cells frequency and RORγt expression were evaluated. Our study demonstrated that CH effectively decreased eosinophil count and inflammatory cytokines production in BALF. In addition, treatment with CH significantly inhibited the Raw, Th17 percentage and RORγt expression in OVA-induced animals compared with those in model group. Histological studies also demonstrated that CH significantly suppressed OVA-induced eosinophilia in lung tissue compared with model group. Our findings supported that CH can prevent allergic asthma in the mouse model.

Extracellular UDP and P2Y6 function as a danger signal to protect mice from vesicular stomatitis virus infection through an increase in IFN-ß production.

Extracellular nucleotides that constitute a "danger signal" play an important role in the regulation of immune responses. However, the function and mechanism of extracellular UDP and P2Y6 in antiviral immunity remain unknown. In this study, we demonstrated the in vitro and in vivo protection of UDP/P2Y6 signaling in vesicular stomatitis virus (VSV) infection. First, we demonstrated that VSV-infected cells secrete UDP from the cytoplasm as a danger signal to arouse surrounding cells. Meanwhile, expression of the UDP-specific receptor P2Y6 also was enhanced by VSV. Consequently, UDP protects RAW 264.7 cells, murine embryonic fibroblasts, bone marrow-derived macrophages, and L929 cells from VSV and GFP lentivirus infection. This protection can be blocked by the P2Y6 selective antagonist MRS2578 or IFN-α/ß receptor-blocking Ab. VSV-induced cell death and virus replication were both enhanced significantly by knocking down and knocking out P2Y6 in different cells. Mechanistically, UDP facilitates IFN-ß secretion through the p38/JNK- and ATF-2/c-Jun-signaling pathways, which are crucial in promoting antiviral immunity. Interestingly, UDP was released through a caspase-cleaved pannexin-1 channel in VSV-induced apoptotic cells and protected cells from infection through P2Y6 receptor in an autocrine or paracrine manner. Furthermore, UDP also protected mice from VSV infection through P2Y6 receptors in an acute neurotropic infection mouse model. Taken together, these results demonstrate the important role of extracellular UDP and P2Y6 as a danger signal in antiviral immune responses and suggest a potential therapeutic role for UDP/P2Y6 in preventing and controlling viral diseases.

Induction of apoptosis by total flavonoids from Scutellaria barbata D. Don in human hepatocarcinoma MHCC97-H cells via the mitochondrial pathway.

Scutellaria barbata D. Don, a traditional Chinese medicine, reportedly possesses antitumor activity against a variety of tumors. In the present study, we investigated the cytotoxic effect of total flavonoids from S. barbata (TF-SB) on human hepatocarcinoma cells and the underlying molecular mechanisms regarding the effect were explored. TF-SB treatment significantly reduced the cell viability of human HCC MHCC97-H cells in a dose-dependent manner. Further flow cytometric analysis showed that the apoptosis rate of MHCC97-H cells increased and the mitochondrial membrane potential (∆ψm) of MHCC97-H cells decreased after TF-SB treatment. DNA ladder showed that TF-SB induced a significant increase in DNA fragmentation in MHCC97-H cells. Reverse transcription PCR and Western blot analysis revealed that the expression levels of Smac, Apaf-1, Cytochrome c, Caspase-9, and Caspase-3 were upregulated in a dose-dependent manner and after treatment with different concentrations of TF-SB for 48 h. These results suggest that TF-SB induces apoptosis in MHCC97-H cells through the mitochondrial pathway.

Functional promoter -765 G > C variant in COX-2 gene is associated with the susceptibility of breast cancer in Chinese Han women.

BACKGROUND: Cyclooxygenase (COX) is a rate-limiting enzyme in prostaglandins synthesis which exists in two isoforms, COX-1 and COX-2. Over-expression of COX-2 was considered to increase the proliferation and enhance the invasiveness of breast cancer cells. It was suggested that genetic variations in COX-2 could influence its expression. Herein, the present study was aimed to investigate the associations between two mostly studied functional polymorphisms (-765 G > C and 8473 C > T) in COX-2 and breast cancer risk in Chinese Han women. METHODS: In the hospital-based case-control study, 465 breast cancer patients and 799 cancer-free controls were genotyped for the COX-2 -765 G > C and 8473 C > T polymorphisms using TaqMan assay. We estimated odds ratios (ORs) and 95% confidence intervals (95% CIs) using the logistic regression. RESULTS: Compared with the wild genotype of -765 G > C, we found a statistically significant increased risk of breast cancer associated with the variant genotypes [GC/CC vs. GG: OR = 1.56, 95% CI = 1.11-2.21]. In the stratified analysis, the increased risk was more predominant among the subgroups of younger subjects (OR = 1.61, 95% CI = 1.00-2.61). Furthermore, the variant genotypes were associated with large tumor size (OR = 3.01, 95% CI = 1.47-6.12). No significant association was observed for the 8473 C > T polymorphism. CONCLUSIONS: Our results suggest that the functional -765 G > C polymorphism in the promoter of COX-2 may influence the susceptibility and progression of breast cancer in the Chinese Han population.

New progress in the deep understanding of the biocake layer property: Combined effect of neglected protein secondary structure, morphology, and mechanism.

The application of magnetic fields (MFs) and magnetic particles (MPs) in water treatment has attracted widespread attention due to their stability, strong biological compatibility, and less chemical consumption. This study introduced MPs and MFs to GDM and probed their effects on filtration performance. Predeposited large MPs (P-large) and batch-added little MPs (B-little) intervened biocake layer development, forming more open and porous structures, they also reduced biomass secretion, resulting in flux increases of 13 % in P-large and 40 % in B-little than P-little, respectively. Besides, MFs controlled MPs distribution on the biocake layer, resulting in forming of more rough and open structures. A relatively lower magnetic field of 20 mT facilitated biomass secretion, while a higher magnetic field of 50 mT decreased biomass. Furthermore, applying magnetic fields decreased the ratios of α-helix and ß-sheet, and increased random coil percentage. Thus, applying magnetic field mediation would contribute to the flux improvements in I-20 and I-50 by 29 % and 32 % relative to I-0. Economic analysis suggested introducing MPs and MFs to GDM was economically feasible, synergy of MPs and MFs had more economic advantages on the community scale and MPs-assisted GDM had significant economic advantages on both community and household scales. Future works should focus on developing new technologies for the recycling of MPs and membranes. This study provided new insight into the protein secondary structures associated with GDM performance and would encourage new sustainable MFs and MPs-assisted GDM technological developments.

Favorable outcome of neoadjuvant endocrine treatment than surgery-first in female HR-positive/HER2-negative breast cancer patients-A NCDB analysis (2010-2016).

PURPOSE: To assess the efficacy of neoadjuvant endocrine therapy in female HR-positive/HER2-negative breast cancer patients. DATA AND METHODS: We identified female patients aged ≥18 years with cT1-4N0-XM0, HR(+), and HER2(-) breast cancer from the National Cancer Database. The patients who underwent surgery first were categorized as "surgery-first," while those who received NET before surgery were classified as "NET." Propensity score-matching, Cox proportional-hazard model, variance inflation factors, and interaction analysis were employed to estimate the correlation between NET and survival outcomes. RESULTS: Among 432,387 cases, 2914 NET patients and 2914 surgery-first patients were matched. Compared with the surgery-first group, the NET group received less adjuvant chemotherapy (p < 0.001). Furthermore, the NET group exhibited higher survival probabilities compared with the surgery-first group (3 years: 91.4% vs. 82.1%; 5 years: 82.1% vs. 66.8%). Multivariate Cox analysis indicated that NET was associated with improved OS (surgery-first vs. NET: HR 2.17, 95% CI: 1.93-2.44). Age over 55 years old, having public insurance, higher CDCC score, higher NSBR grade, ER(+)PR(-), and advanced clinical stage were related to worse OS (all p < 0.05). There was an interaction between age, race, income, and home and treatment regimen (all p < 0.05). CONCLUSION: NET may be a more effective treatment procedure than surgery-first in female HR-positive/HER2-negative, non-metastatic breast cancer patients. Future clinical studies with more detailed data will provide higher-level evidence-based data.

Construction and Validation of a Nomogram Predicting the Overall Survival Benefit of Unilateral Breast Cancer Patients Undergoing Contralateral Prophylactic Mastectomy.

BACKGROUND: Currently, research on the prognostic factors of unilateral breast cancer (UBC) patients receiving contralateral prophylactic mastectomy (CPM) is limited. This study aimed to construct a new nomogram to predict these patients' overall survival (OS). METHODS: In this retrospective study, 88,477 patients who underwent CPM or unilateral mastectomy (UM) were selected from the Surveillance, Epidemiology, and End Results database. Kaplan-Meier curves and Cox regression analyses were used to determine the difference in the impact of the 2 surgical methods on the prognosis. Multivariate Cox analysis was used to determine the best prognostic variable and construct a nomogram. The concordance index (C-index), receiver operating characteristic (ROC) curve, calibration curve, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI) were used to evaluate the discrimination capability and clinical effectiveness of the nomogram. RESULTS: The prognosis of patients receiving CPM and UM was significantly different. The DCA curves indicated that the nomogram could provide more excellent clinical net benefits for these patients. The NRI and IDI of the nomogram demonstrated that its performance was better than that of the classical tumor-node-metastasis (TNM) staging system. CONCLUSION: This study developed and validated a practical nomogram to predict the OS of UBC patients undergoing CPM, which provided a beneficial tool for clinical decision-making management.

Effect of T Stages on the Choice of Axillary Evaluation Modality in Breast Cancer Patients With 1-2 Sentinel Lymph Node Metastases.

INTRODUCTION: The survival benefit of axillary lymph node dissection (ALND), sentinel lymph node biopsy (SLNB) combined with radiation, and ALND combined with radiation remains unclear in breast cancer (BC) patients with 1-2 metastatic sentinel lymph nodes (SLNs). This study aims to rigorously evaluate the prognostic impact of these axillary evaluation modalities on BC patients with varying T-stages and to construct a survival prediction nomogram. METHODS: Following screening for inclusion and exclusion criteria, data pertaining to BC patients were extracted from the SEER database. Overall survival (OS) and breast cancer-specific survival (BCSS) were assessed using Kaplan-Meier curves and Cox proportional hazards model among patients with different stages who underwent various axillary evaluation modalities. A nomogram was constructed to predict the probability of OS and BCSS. RESULTS: A total of 20,283 patients were included, comprising 9626 who underwent breast-conserving surgery (BCS) and 10,657 who underwent mastectomy. In the T4 stage stratified analysis, both BCS and mastectomy groups exhibited superior OS and BCSS with ALND compared to SLNB combined with radiation. Further, ALND combined with radiation improved OS. However, for T1-3 stages, patients treated with ALND experienced similar or worse survival compared to those treated with SLNB combined with radiation. The calibration curve and C-index (0.746-0.794) of the nomogram demonstrated the efficacy of the survival prediction model. CONCLUSION: In T1-3 BC patients with 1-2 metastatic SLNs, SLNB combined with radiation is a safe alternative to ALND. Conversely, for T4 patients, ALND combined with radiation may offer a preferable choice.

Can neoadjuvant systemic therapy provide additional benefits for T1 HER2+ breast cancer patients: a subgroup analysis based on different high-risk signatures.

INTRODUCTION: Neoadjuvant systemic therapy (NAST) is vital in the management of HER2-positive (HER2+) breast cancer. Nevertheless, the indications for NAST in tumors <2 cm remain controversial. METHOD: A total of 7961 patients were screened from the Surveillance, Epidemiology, and End Result database. Independent prognostic factors were identified using multivariate Cox analysis. Subgroup analyses and Kaplan-Meier analyses were used to simulate whether NAST would provide a survival benefit with different high-risk characteristics. Nomograms were constructed, and an internal validation cohort was employed. RESULTS: Of the 7961 included patients, 1137 (14.3%) underwent NAST. In the total population, NAST was associated with poorer overall survival (OS) and breast cancer-specific survival (BCSS) (OS: P = 0.00093; BCSS: P  <  0.0001). Multivariate Cox analysis confirmed that NAST markedly affected the prognosis of enrolled patients. Besides, a direct association between T, N, age, subtype, and prognosis was observed. Subgroup analyses yielded in these three subgroups, T1c, hormone receptor-negative, and 61-69 years of age, NAST and AST had comparable OS, while NAST possessed worse BCSS. Notably, even in the N3, we still did not observe any additional benefit of NAST. The calculated C-index of 0.72 and 0.73 confirmed the predictability of the nomograms. The AUCs exhibit consistency in the training and validation cohorts. CONCLUSION: Our findings suggest that NAST does not provide additional benefit to patients with T1 HER2+ breast cancer, even in the presence of lymph node metastasis, T1c, or hormone receptor negativity. This study facilitates the implementation of individualized management strategies.

PIK3CA mutation-driven immune signature as a prognostic marker for evaluating the tumor immune microenvironment and therapeutic response in breast cancer.

PURPOSE: Gene mutations drive tumor immune microenvironment (TIME) heterogeneity, in turn affecting prognosis and immunotherapy efficacy. PIK3CA is the most frequently mutated gene in breast cancer (BC), yet its relevance to BC prognosis remains controversial. Herein, we sought to determine the impact of PIK3CA mutation-driven immune genes (PDIGs) on BC prognosis in relation to TIME heterogeneity. METHODS: PIK3CA mutation characteristics were compared and verified between the TCGA-BRCA dataset and a patient cohort from our hospital. PIK3CA mutation-driven differentially expressed genes were identified for consensus clustering and weighted gene co-expression network analysis to select the modules most relevant to the immune subtype. Thereafter, the two were intersected to obtain PDIGs. Univariate Cox, LASSO, and multivariate Cox regression analyses were sequentially performed on PDIGs to obtain a PIK3CA mutation-driven immune signature (PDIS), which was then validated using the Gene Expression Omnibus (GEO) database. Differences in functional enrichment, mutation landscape, immune infiltration, checkpoint gene expression, and drug response were compared between different risk groups. RESULTS: PIK3CA mutation frequencies in the TCGA and validation cohorts were 34.49% and 40.83%, respectively. PIK3CA mutants were significantly associated with ER, PR, and molecular BC subtypes in our hospital cohort. The PDIS allowed for effective risk stratification and exhibited prognostic power in TCGA and GEO sets. The low-risk patients exhibited greater immune infiltration, higher expression of common immune checkpoint factors, and lower scores for tumor immune dysfunction and exclusion. CONCLUSION: The PDIS can be used as an effective prognostic model for predicting immunotherapy response to guide clinical decision-making.