Recent studies have indicated that the expression of ubiquitin-specific protease 51 (USP51), a novel deubiquitinating enzyme (DUB) that mediates protein degradation as part of the ubiquitin‒proteasome system (UPS), is associated with tumor progression and therapeutic resistance in multiple malignancies. However, the underlying mechanisms and signaling networks involved in USP51-mediated regulation of malignant phenotypes remain largely unknown. The present study provides evidence of USP51's functions as the prominent DUB in chemoresistant triple-negative breast cancer (TNBC) cells. At the molecular level, ectopic expression of USP51 stabilized the 78 kDa Glucose-Regulated Protein (GRP78) protein through deubiquitination, thereby increasing its expression and localization on the cell surface. Furthermore, the upregulation of cell surface GRP78 increased the activity of ATP binding cassette subfamily B member 1 (ABCB1), the main efflux pump of doxorubicin (DOX), ultimately decreasing its accumulation in TNBC cells and promoting the development of drug resistance both in vitro and in vivo. Clinically, we found significant correlations among USP51, GRP78, and ABCB1 expression in TNBC patients with chemoresistance. Elevated USP51, GRP78, and ABCB1 levels were also strongly associated with a poor patient prognosis. Importantly, we revealed an alternative intervention for specific pharmacological targeting of USP51 for TNBC cell chemosensitization. In conclusion, these findings collectively indicate that the USP51/GRP78/ABCB1 network is a key contributor to the malignant progression and chemotherapeutic resistance of TNBC cells, underscoring the pivotal role of USP51 as a novel therapeutic target for cancer management.

In the present work, we have identified a proteolysis targeting chimera (PROTAC) molecule that potently and selectively degrades CDK4, CDK6, and CDK9, inhibiting triple-negative breast cancer (TNBC) cell proliferation at low nanomolar concentrations. However, its low bioavailability and significant in vivo toxicity in experimental animals limit clinical translation. To address this challenge, we identified an oral bioavailable and tumor-targeting prodrug that substantially reduces systemic exposure of the PROTAC compound while enabling significant tumor-specific enrichment. This prodrug effectively and safely inhibits TNBC cell proliferation in multiple cell line-derived xenografts (CDX) and patient-derived xenograft (PDX) models, positioning it as a promising candidate for targeted TNBC therapy.

While epithelial-mesenchymal plasticity (EMP) drives cancer metastasis, its regulation by redox dynamics remains poorly understood. Herein, we identified an oxidative stress-responsive CBP/SIRT1 axis that coordinated ZEB1 acetylation at K1108 to promote lung metastasis in triple-negative breast cancer (TNBC). Mechanistically, the biochemical and functional analyses revealed that the dual-acetyltransferase CBP, through stabilization and autoacetylation by oxidative stress, formed a dynamic partnership with SIRT1 to execute precision lysine modification. This post-translational rheostat triggered the functional metamorphosis of ZEB1. During this process, ZEB1 dissociation from the transcriptional corepressor CtBP, while recruiting CBP, converts ZEB1 into a transcriptional activator of epithelial genes. The resulting hybrid epithelial‒mesenchymal phenotype orchestrated dual metastatic competence-maintaining stromal interaction capacity through partial epithelial‒mesenchymal transition (EMT) while establishing NADPH-driven redox supremacy to circumvent ferroptosis. Importantly, this acetyl switch of ZEB1 revealed a metastasis-specific therapeutic vulnerability in TNBC. Our work thus highlighted ZEB1 acetylation as a redox-interpreted mechanism coupling phenotypic plasticity with stress resistance, proposing targeted disruption of this protein post-translational modification (PTM) circuit as a precision strategy against metastatic progression.

Background: Grading based on histopathologic indicators cannot accurately assess the prognosis of phyllodes tumor (PT) of the breast. This article aimed to investigate the correlation between PT prognosis and clinicopathological features, treatment, and surgical margin. Methods: The clinicopathological data of patients with pathologically confirmed PT at our institution were retrospectively collected. Univariate and multivariate Cox proportional risk models were employed to test the effects of different variables on the prognosis of PT. A nomogram to predict the 1-, 3-, 5-, and 10-year recurrence-free survival (RFS) of PT was proposed, and its discriminative ability and calibration were tested using the concordance index (C-index), area under the curve (AUC), and calibration plots. All statistical analyses were performed using R. Results: A total of 342 PT patients were included, including 242 benign (70.8%), 75 borderline (21.9%) and 25 malignant (7.3%) cases. The median follow-up period was 64.5 months (range, 3-179 months), 66 PT patients had local recurrence (LR), and four patients had distant metastasis. The 1-, 3-, 5-, and 10-year RFS of the PT patients were 90.8%, 81.8%, 78%, and 76.7%, respectively. Age, fibroadenoma (FA) surgery history, treatment, mitotic activity, and surgical margin were selected as the independent factors for PT prognosis. The nomogram showed good discriminative ability and calibration, as indicated by the C-index [0.78, 95% confidence interval (CI): 0.75-0.11]. Conclusions: Independent predictors related to PT prognosis were selected to establish a nomogram for predicting the RFS of PT. This nomogram was able to objectively stratify PT patients into prognostic groups and performed well in the internal validation.

Background: The incidence of bilateral breast cancer (BBC) is low, accounting for 5% of patients with breast cancer. This study aimed to investigate the clinicopathological features and prognosis of synchronous bilateral breast cancer (SBBC) and metachronous bilateral breast cancer (MBBC) in the Chinese population. Methods: Patients with BBC, including SBBC and MBBC, were selected from 6,162 breast cancer patients who underwent surgery at the Chinese People's Liberation Army (PLA) General Hospital between January 2007 and December 2019. Furthermore, patients with unilateral breast cancer (UBC) who underwent surgery at the same time were randomly selected at a ratio of 1:2 as the control group. Clinicopathological features and prognosis were compared between the groups. Results: In all, 123 (2.0%) patients with BBC were enrolled in this study, including 98 (1.6%) SBBC and 25 (0.4%) MBBC patients. A total of 280 patients with UBC were selected for the control group. Compared with patients with UBC, patients with SBBC were more likely to be older and have a family history of breast cancer, non-infiltrative carcinoma, lower pathological tumor-node-metastasis (pTNM) stage, and luminal A type breast cancer as their first tumor. Patients with MBBC were more likely to be postmenopausal and have hormone receptor [estrogen receptor (ER)/progesterone receptor (PR)] negativity, a higher pTNM stage, and a triple-negative first tumor. Patients with UBC with ER/PR (-) were more likely to develop contralateral breast cancer (CBC) than those with ER/PR (+). There was no significant difference in overall survival (OS) and disease-free survival (DFS) between patients with SBBC and patients with UBC. Patients with MBBC had worse DFS than those with UBC, but OS was similar for both types of patients. Patients with MBBC <55 years at first diagnosis had significantly shorter DFS compared to those with SBBC and UBC. A multivariate Cox proportional hazards model revealed that age >= 55 years and ER/PR negativity of the first tumor were independent risk factors for OS. Independent risk factors for DFS included MBBC, age <55 years, family history of other malignant tumors, ER/PR (-), lymphovascular invasion, and N stage >= 2 of the first tumor. Conclusions: The OS and DFS of patients with SBBC and UBC were similar. The MBBC patients, especially those <55 years old at first diagnosis, had shorter DFS than patients with UBC.

Background Information is still controversial in the studies regarding the current optimal surgical management of phyllodes tumors (PTs) of the breast. Local recurrence (LR) may occur with an upgraded in the pathological grade, influencing the prognosis of patients with PT. This systematic review and meta-analysis aimed to investigate the association of LR risk with margin status and margin width which could have significant implications on the surgical management of PT. Methods Independent and comprehensive searches were performed by two authors through five databases including PubMed, Medline, Embase, ScienceDirect and Cochrane Library from January 1990 to October 2021. Studies investigating the association between margin width, margin status and LR rates were considered for inclusion. Study quality was evaluated using the Newcastle-Ottawa Scale (NOS). Meta-analysis was performed using RevMan5.3 software, and statistical heterogeneity was assessed using the Chi-square test and quantified using the I2 statistic. Visual inspection of funnel plots was used to judge publication bias. Results A total of 34 articles were included in this article, all of which with NOS scores above 5. Regardless of the PT grade, positive margin significantly increased the risk of LR [odds ratio (OR) 3.64, 95% confidence interval (CI): 2.60-5.12]. No significant difference was found in the risk of LR between the margins <1 and ≥1 cm (OR 1.39, 95% CI: 0.67-2.92). For benign and borderline PTs, there were no significant differences of the LR risk between breast-conserving surgery (BCS) and mastectomy (benign OR 0.68, 95% CI: 0.12-3.78; borderline OR 1.14, 95% CI: 0.29-4.51). While the LR risk was significantly increased by BCS for malignant PT (OR 2.77, 95% CI: 1.33-5.74). Discussion Different surgical management strategies should be considered for different PT grades. BCS was a feasible option and margins <1 cm was not significantly associated with LR risk for all grade of PT. After BCS, benign PT with positive margin could adopt the "wait and watch" strategy with regular follow-up, while borderline and malignant PTs were expected to underwent re-excision to ensure negative margins. More studies are still needed to clarify and update the existing conclusions and improve the prognosis of PT patients.

Background:Regardless of histological grade, phyllodes tumors (PTs) exhibit the potential of local recurrence. The National Comprehensive Cancer Network (NCCN) recommends wide local excision (WLE) with a 1 cm margin or more for borderline/malignant PTs but excisional biopsy for benign PTs. However, the treatment of benign PTs remains controversial and the clinicopathologic risk factors for the local recurrence is still unclear.Methods:We retrospectively analyzed 238 patients with PTs who underwent surgery at the Chinese PLA General Hospital from January 1, 2006 and April 30, 2020. We stratified our analysis according to histologic grade and explored the clinicopathologic factors to influence local recurrence (LR), including age, histologic grade, history of fibroadenoma, type of surgery [vacuum-assisted biopsy system (VABS), local excision (LE), wide local excision (WLE) and mastectomy].Results:All 238 cases were categorized as benign (171, 71.8%), borderline (38, 16.0%), or malignant (29, 12.2%). The median follow-up was 50.2 months. In multivariate analysis, histologic grade (P<0.01) and history of fibroadenoma (P<0.01) were independent prognostic factors for LR. No difference existed in the recurrence rate of BPT treated with different surgical procedures (P=0.397), whereas a higher recurrence rate was found in VABS and LE subgroups than in WLE and mastectomy subgroups for borderline/malignant tumors (P<0.01).Conclusions:No association found between surgical modalities and LR rate for BPT. We suggested a "wait-and-watch" policy for patients with unexpected benign subtypes, instead of unnecessary re-excision. In addition, VABS or LE can be treated for BPT with small mass, whereas WLE or even mastectomy should be conducted for borderline/malignant PTs with large mass.

BACKGROUND:Triple-negative breast cancer (TNBC) is a malignant subtype of breast cancer, the main treatments for which are chemotherapy and surgery. PIK3CA is an oncogene that encodes the p110α subunit of class IA PI3K to regulate cell proliferation and apoptosis. Some reports have observed neoadjuvant chemotherapy (NAC) to have poor pathological complete response (pCR) rates in TNBC with PIK3CA mutation. This study aimed to explore the mechanism of how mutant PIK3CA alters chemotherapeutic susceptibility in TNBC.METHODS:TNBC cell lines (MDA-MB-231 and MDA-MB-468) with PIK3CA gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for in vivo experiments. Epirubicin was used as the chemotherapeutic agent. Cell viability, cell cycle, apoptosis, and Transwell assays were conducted for phenotype analysis. Western blot, quantitative reverse transcription-polymerase chain reaction, and immunohistochemistry were used to detect gene and protein expression levels. A clinical analysis of 50 patients with TNBC was also performed.RESULTS:Cell viability and Transwell assays showed that PIK3CA mutation promoted TNBC cell growth and conferred an enhanced migratory phenotype. Cell cycle and apoptosis assays showed that PIK3CA mutation moderately improved the proliferation ability of TNBC cells and remarkably inhibited their apoptosis. After epirubicin therapy, the proportion of early apoptotic cells decreased among cells with PIK3CA mutation. Further, xenograft tumors grew faster in NOD/SCID mice injected with mutated cell lines than in control group, suggesting that PIK3CA mutation caused chemotherapy resistance. Importantly, western blot and immunohistochemical analysis showed that cells and mouse tumors in the PIK3CA mutation groups exhibited different expression levels of apoptosis-related markers (Xiap, Bcl-2, and Caspase 3) and proteins associated with the PI3K/AKT/mTOR pathway (p110α, AKT, p-AKT, mTOR, p-mTOR, p-4E-BP1, p-p70S6K, and Pten). Moreover, prognostic analysis of 50 patients with TNBC indicated that PIK3CA mutation might be linked with relapse and death.CONCLUSIONS:PIK3CA mutation confers resistance to chemotherapy in TNBC by inhibiting apoptosis and activating the PI3K/AKT/mTOR signaling pathway.

Background Electrosurgical technology is widely used in surgical dissection and hemostasis, but the generated heat creates thermal injury to adjacent tissues and delays wound healing. The plasma blade (PB) applies pulsed radiofrequency (RF) to generate electrical plasma along the edge of a thin, flat, insulated electrode, minimizing collateral tissue damage. This study aimed to evaluate wound healing in swine skin following incision with a new surgical system that applies low-temperature plasma (NTS-100), a foreign PB, conventional electrosurgery (ES), and a scalpel blade. Methods In vitro porcine skin and an in vivo porcine skin model were used in this study. Full-thickness skin incisions 3 cm in length were made on the dorsum of each animal for each of the 5 surgical procedures at 0, 21, 28, 35, and 42 days. The timing of the surgical procedures allowed for wound-healing data points at 1, 2, 3, and 6 weeks accordingly. Local operating temperature and blood loss were quantified. Wounds were harvested at designated time points, tested for wound tensile strength, and examined histologically for scar formation and tissue damage. Results Local operating temperature was reduced significantly with NTS-100 (cut mode 83.12±23.55 °C; coagulation mode 90.07±10.6 °C) compared with PB (cut mode 94.46±11.48 °C; coagulation mode 100.23±6.58 °C, P<0.05) and ES (cut mode 208.99±34.33 °C, P<0.01; coagulation mode 233.37±28.69 °C, P<0.01) in vitro. Acute thermal damage from NTS-100 was significantly less than ES incisions (cut mode: 247.345±42.274 versus 495.295±103.525 µm, P<0.01; coagulation mode: 351.419±127.948 versus 584.516±31.708 µm, P<0.05). Bleeding, histological scoring of injury, and wound strength were equivalent for the NTS-100 and PB incisions. Conclusions The local operating temperature of NTS-100 was lower than PB, and NTS-100 had similarly reliable safety and efficacy.

Bleeding complications can cause significant morbidities and mortalities in both civilian and military conditions. The formation of stable blood clots or hemostasis is essential to prevent major blood loss and death from excessive bleeding. However, the body's self-coagulation process cannot accomplish timely hemostasis without the assistance of hemostatic agents under some conditions. In the past two decades, topical hemostatic materials and devices containing platelets, fibrin, and polysaccharides have been gradually developed and introduced to induce faster or more stable blood clot formation, updating or iterating traditional hemostatic materials. Despite the various forms and functions of topical hemostatic materials that have been developed for different clinical conditions, uncontrolled hemorrhage still causes over 30% of trauma deaths across the world. Therefore, it is important to fabricate fast, efficient, safe, and ready-to-use novel hemostatic materials. It is necessary to understand the coagulation process and the hemostatic mechanism of different materials to develop novel topical hemostatic agents, such as tissue adhesives and sealants from various natural and synthetic materials. This review discusses the structural features of topical hemostatic materials related to the stimulation of hemostasis, summarizes the commercially available products and their applications, and reviews the ongoing clinical trials and recent studies concerning the development of different hemostatic materials.

Background: Breast ptosis is directly caused by Cooper's ligament laxity, with the decline of nipple areola complex (NAC) and mammary parenchyma. Breast cancer with ptosis is always a knotty problem that can hardly be repaired by classic breast conservation surgery (BCS) ending up with a pleasing appearance. We analyzed our 12 years' experience of performing inverted-T pattern techniques to treat bilateral breast ptosis, with or without breast cancer. Methods: One hundred forty-eight breasts in 74 patients undergoing inverted-T pattern reduction mammoplasty were included in this study. Information about patients' clinical and surgical characteristics, complications, NAC sensitivity, cosmetic and oncological outcomes were collected and retrospectively analyzed. Results: In the cohort of 57 patients with pure breast ptosis, the mean body mass index (BMI) was 25.2 kg/m2, and the mean weight of resected tissue from the left and right breast reductions were 744.9 and 756.7 g. In the cohort of 17 patients diagnosed as breast cancer with ptosis, the mean BMI was 25.1 kg/m2, and the mean weight of resected tissue were 504.1 g for left and 535.6 g for right side. The majority of repairs were performed for tumors located in the upper outer (58.8%), mostly with inferior or superomedial pedicles (90%). All the upper inner tumors were repaired with inferior pedicles. Minor complications such as seroma (8.1%), NAC epidermolysis (8.1%), delayed wound healing (4.1%) were detected postoperatively. Partial NAC necrosis occurred in one patient (1.4%). 82.4% of all the patients rated "very satisfied" or "satisfied" as the final cosmetic outcomes. NAC sensitivity was "very high" and "high" in 82.4% patients. No local occurrence, distant metastasis and mortality occurred in tumor patients. Conclusions: The inverted-T pattern reduction mammoplasty is a reliable technique to treat bilateral breast ptosis with a low complication rate. For cases with breast cancer, this technique can achieve both satisfying cosmetic outcomes and oncological safety.

预防性乳腺切除术是近年来兴起的一种针对乳腺癌高危女性的降低发病风险的手段,美国女性在过去20多年接受该手术的比例大幅增加,且单侧乳腺癌患者选择对侧乳房预防性切除比高风险健康女性选择双侧乳房预防性切除的接受度更高.高危人群选择手术多基于对癌症的恐惧、对乳房对称性的担忧、随访筛查的负担等多重因素.对于健康高危女性,行双侧预防性乳腺切除术可显著降低患乳腺癌的风险,降低死亡率,延长预期寿命,显示出生存获益;对于单侧乳腺癌患者,行对侧预防性乳腺切除术明显降低对侧乳腺癌的发生风险.预防性乳腺切除术结合乳房重建具有良好的美容学效果且显著缓解高危女性心理压力,术后女性的整体满意度高;但术后组织坏死、感染、出血等并发症的风险增加,并可能影响未达预期女性的生活质量.临床上外科医生需充分平衡高危人群的获益与风险,采用多学科、个体化的方法辅助女性决策.

Background Mammary hamartomas were mostly benign tumors with rare rate of recurrence and malignant transformation. Ultrasound (US)-guided vacuum-assisted breast biopsy (VABB) has been reported sufficiently safe in treating many breast benign tumors but remained undefined in mammary hamartoma for its usual underdiagnosis in US. Thus, this study aims to evaluate the efficiency of US-guided VABB in treating mammary hamartomas. Methods From May 2015 to March 2019, 3,388 lesions of 2,534 patients underwent percutaneous US-guided VABB, among which 31 mammary hamartomas proved by pathology were included in this study. Patients were followed up by US three, six and twelve months later, then at 1-year intervals. Lesions were classified to analyze the possible factors associated with excision rate, bleeding volume and complications. Results Of the 31 patients, recurrence was seen in 1 case in 1 year after the procedure and complete excision rate was 96.8% (30/31). The bleeding volume ranged from 1 to 15 mL (mean number ± standard deviation, 6.5±3.4 mL) and significant statistical differences were detected in patient age and the largest diameter of lesions. The main complications included pain (22.6%), hematomas (9.7%) and ecchymosis (3.2%). Conclusions US-guided VABB ensures an outstanding complete excision rate and provides an alternative solution to treat mammary hamartomas.