Bimetallic Cu@Ru Core-Shell Structures with Ligand Effects for Endo-Exogenous Stimulation-Mediated Dynamic Oncotherapy.

Dynamic therapies, which induce reactive oxygen species (ROS) production in situ through endogenous and exogenous stimulation, are emerging as attractive options for tumor treatment. However, the complexity of the tumor substantially limits the efficacy of individual stimulus-triggered dynamic therapy. Herein, bimetallic copper and ruthenium (Cu@Ru) core-shell nanoparticles are applied for endo-exogenous stimulation-triggered dynamic therapy. The electronic structure of Cu@Ru is regulated through the ligand effects to improve the adsorption level for small molecules, such as water and oxygen. The core-shell heterojunction interface can rapidly separate electron-hole pairs generated by ultrasound and light stimulation, which initiate reactions with adsorbed small molecules, thus enhancing ROS generation. This synergistically complements tumor treatment together with ROS from endogenous stimulation. In vitro and in vivo experiments demonstrate that Cu@Ru nanoparticles can induce tumor cell apoptosis and ferroptosis through generated ROS. This study provides a new paradigm for endo-exogenous stimulation-based synergistic tumor treatment.

Rational and trial design of FASCINATE-N: a prospective, randomized, precision-based umbrella trial.

Background: With our growing insight into the molecular heterogeneity and biological characteristics of breast cancer, individualized treatment is the future of cancer treatment. In this prospective Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study - neoadjuvant therapy (FASCINATE-N) trial, we classify breast cancer patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. Methods and design: The FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. After enrollment, patients will first be divided into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)-, HER2+, and HR-/HER2-. The HR+/HER2- patients are further stratified using fusion and clustering of similarity network fusion (SNF) algorithm into four subtypes; HER2+ patients are divided into HR+/HER2+ and HR-/HER2+ subtypes; and HR-/HER2- patients are stratified using the Fudan University Shanghai Cancer Center classification. For the assignment of drugs to patients, Bayesian methods of adaptive randomization will be used. The primary endpoint is pathological complete response rate; secondary endpoints include 3-year invasive disease-free survival, overall response rate, and toxicities according to common terminology criteria for adverse events (CTCAE) scale version 4.0 and the ratio of patients with complete cell cycle arrest (Ki67 < 2.7%) in HR+/HER2+ breast cancer. Discussion: The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets, and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients. Trial registration: ClinicalTrials.gov identifier: NCT05582499 (https://classic.clinicaltrials.gov/ct2/show/NCT05582499).

Rational and trial design of FASCINATE-N (Fudan University Shanghai Cancer Center Breast Cancer Precision Platform Series study- neoadjuvant therapy): a prospective, randomized, precision-based umbrella trial Our FASCINATE-N trial is a prospective, randomized, precision-based umbrella trial that plans to enroll 716 women with early breast cancer. We will first divide patients into three groups: hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)−, HER2+, and HR−/HER2−. Then, we will further classify patients using multiomic characteristics into different subtypes to evaluate the efficacy of precision-based targeted therapies compared to standard neoadjuvant chemotherapy. The goal of our trial is to test the efficacy of our subtyping-based treatment in a neoadjuvant setting and to conduct a pilot study into the efficacy of targeted therapies within each precision-based subtype. The precision-based treatment arm can be updated with the refinement of our subtyping method, the discovery of new targets and the development of novel targeted drugs. Our trial offers a unique opportunity to provide patients with individualized neoadjuvant therapy and test promising novel treatments that may further benefit patients.

Optimising first-line subtyping-based therapy in triple-negative breast cancer (FUTURE-SUPER): a multi-cohort, randomised, phase 2 trial.

BACKGROUND: Triple-negative breast cancers display heterogeneity in molecular drivers and immune traits. We previously classified triple-negative breast cancers into four subtypes: luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed (BLIS), and mesenchymal-like (MES). Here, we aimed to evaluate the efficacy and safety of subtyping-based therapy in the first-line treatment of triple-negative breast cancer. METHODS: FUTURE-SUPER is an ongoing, open-label, randomised, controlled phase 2 trial being conducted at Fudan University Shanghai Cancer Center (FUSCC), Shanghai, China. Eligible participants were females aged 18-70 years, with an Eastern Cooperative Oncology Group performance status of 0-1, and histologically confirmed, untreated metastatic or recurrent triple-negative breast cancer. After categorising participants into five cohorts according to molecular subtype and genomic biomarkers, participants were randomly assigned (1:1) with a block size of 4, stratified by subtype, to receive, in 28-day cycles, nab-paclitaxel (100 mg/m2, intravenously on days 1, 8, and 15) alone (control group) or with a subtyping-based regimen (subtyping-based group): pyrotinib (400 mg orally daily) for the LAR-HER2mut subtype, everolimus (10 mg orally daily) for the LAR-PI3K/AKTmut and MES-PI3K/AKTmut subtypes, camrelizumab (200 mg intravenously on days 1 and 15) and famitinib (20 mg orally daily) for the immunomodulatory subtype, and bevacizumab (10 mg/kg intravenously on days 1 and 15) for the BLIS/MES-PI3K/AKTWT subtype. The primary endpoint was investigator-assessed progression-free survival for the pooled subtyping-based group versus the control group in the intention-to-treat population (all randomly assigned participants). Safety was analysed in all patients with safety records who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT04395989). FINDINGS: Between July 28, 2020, and Oct 16, 2022, 139 female participants were enrolled and randomly assigned to the subtyping-based group (n=69) or control group (n=70). At the data cutoff (May 31, 2023), the median follow-up was 22·5 months (IQR 15·2-29·0). Median progression-free survival was significantly longer in the pooled subtyping-based group (11·3 months [95% CI 8·6-15·2]) than in the control group (5·8 months [4·0-6·7]; hazard ratio 0·44 [95% CI 0·30-0·65]; p<0·0001). The most common grade 3-4 treatment-related adverse events were neutropenia (21 [30%] of 69 in the pooled subtyping-based group vs 16 [23%] of 70 in the control group), anaemia (five [7%] vs none), and increased alanine aminotransferase (four [6%] vs one [1%]). Treatment-related serious adverse events were reported for seven (10%) of 69 patients in the subtyping-based group and none in the control group. No treatment-related deaths were reported in either group. INTERPRETATION: These findings highlight the potential clinical benefits of using molecular subtype-based treatment optimisation in patients with triple-negative breast cancer, suggesting a path for further clinical investigation. Phase 3 randomised clinical trials assessing the efficacy of subtyping-based regimens are now underway. FUNDING: National Natural Science Foundation of China, Natural Science Foundation of Shanghai, Shanghai Hospital Development Center, and Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Targeting EMSY-mediated methionine metabolism is a potential therapeutic strategy for triple-negative breast cancer.

Cancer stem cells (CSCs) are the most intractable subpopulation of triple-negative breast cancer (TNBC) cells, which have been associated with a high risk of relapse and poor prognosis. However, eradication of CSCs continues to be difficult. Here, we integrate the multiomics data of a TNBC cohort (n = 360) to identify vital markers of CSCs. We discover that EMSY, inducing a BRCAness phenotype, is preferentially expressed in breast CSCs, promotes ALDH+ cells enrichment, and is positively correlated with poor relapse-free survival. Mechanistically, EMSY competitively binds to the Jmjc domain, which is critical for KDM5B enzyme activity, to reshape methionine metabolism, and to promote CSC self-renewal and tumorigenesis in an H3K4 methylation-dependent manner. Moreover, EMSY accumulation in TNBC cells sensitizes them to PARP inhibitors against bulk cells and methionine deprivation against CSCs. These findings indicate that clinically relevant eradication of CSCs could be achieved with a strategy that targets CSC-specific vulnerabilities in amino acid metabolism.

Phase separations in oncogenesis, tumor progressions and metastasis: a glance from hallmarks of cancer.

Liquid-liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches.

Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects.

To provide complementary information and reveal the molecular characteristics and therapeutic insights of HER2-low breast cancer, we performed this multiomics study of hormone receptor-negative (HR-) and HER2-low breast cancer, also known as HER2-low triple-negative breast cancer (TNBC), and identified 3 subgroups: basal-like, receptor tyrosine kinase-relevant (TKR), and mesenchymal stem-like. These 3 subgroups had distinct features and potential therapeutic targets and were validated in external data sets. Interestingly, the TKR subgroup (which exists in both HR+ and HR- breast cancer) had activated HER2 and downstream MAPK signaling. In vitro and in vivo patient-derived xenograft experiments revealed that pretreatment of the TKR subgroup with a tyrosine kinase inhibitor (lapatinib or tucatinib) could inhibit HER2 signaling and induce accumulated expression of nonfunctional HER2, resulting in increased sensitivity to the sequential HER2-targeting, Ab-drug conjugate DS-8201. Our findings identify clinically relevant subgroups and provide potential therapeutic strategies for HER2-low TNBC subtypes.

KLHL29-mediated DDX3X degradation promotes chemosensitivity by abrogating cell cycle checkpoint in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous breast cancer subtype and accounts for approximately 15-20% of breast cancer cases. In this study, we identified KLHL29, which is an understudied member of the Kelch-like gene family, as a crucial tumor suppressor that regulates chemosensitivity in TNBC. KLHL29 expression was significantly downregulated in breast cancer tissues compared with adjacent normal tissues, and low levels of KLHL29 were associated with unfavorable prognoses. Ectopic KLHL29 suppressed, while depleting KLHL29 promoted, the growth, proliferation, migration, and invasion of TNBC. Mechanistically, KLHL29 recruited the CUL3 E3-ligase to the RNA-binding protein DDX3X, leading to the proteasomal degradation of the latter. This downregulation of DDX3X resulted in the destabilization of CCND1 mRNA and the consequent cell cycle arrest at G0/G1 phase. Remarkably, the DDX3X inhibitor RK33 combined with platinum-based chemotherapy can synergistically suppress TNBC that usually expresses low levels of KLHL29 and high levels of DDX3X using cancer cell-derived xenograft and patient-derived organoids models. Altogether, we uncovered the potential role for the KLHL29-DDX3X signaling cascade in the regulation of TNBC progression, thus providing a promising combination strategy for overcoming TNBC chemoresistance.

Chronic stress-induced immune dysregulation in breast cancer: Implications of psychosocial factors.

Chronic stress refers to continuous emotional changes and psychological pressure that individuals experience when they are unable to adjust and stabilize the internal environment over an extended period. It can increase the pressure on endocrine mediators and cytokines in the circulation, as well as tissues throughout the hypothalamic-pituitary-adrenaline (HPA) axis and sympathetic nervous system (SNS); thus, evolving the internal environment of the tumor. This review assesses several key issues, involving psychosocial factors, and integrates clinical, cellular, and molecular studies-as well as the latest research progress-to provide a mechanistic understanding regarding breast oncopsychology. We propose that chronic stress contributes to large individual diferences in the prognosis of breast cancer survivors because they change the basic physiological processes of the endocrine and immune systems, which in turn regulate tumor growth. The study of psychological and physiological reactions of breast cancer patients suggests a new idea for psychological intervention and clinical treatment for breast cancer patients.

Comparison of Computer-Assisted Navigation and 3D Printed Patient-Specific Template for the Iliosacral Screw Placement.

BACKGROUND: Iliosacral screw insertion by computer-assisted navigation gradually became the main technique in some hospitals, but the expensive price limited the extensive application. But other techniques such as 3D printed template was used to place iliosacral screw as novel method. This study was to compare the efficiency of percutaneous iliosacral screw placement by using patient-specific template and computer-assisted navigation. METHODS: Total of 58 patients from September 2017 to September 2021 with sacral injury were treated operatively with percutaneous screw technique, which was selected for this retrospective analysis and divided into two groups (template and computer-assisted navigation). There were 31 patients in template group and 27 patients in computer-assisted navigation group. The surgical details (operation time, blood loss, number of screw placements, and number of fluoroscopies), complications, radiographic and clinical results were recorded. The quality of reduction was assessed by the Matta scoring system. T-test and rank-sum test was used in this study. RESULTS: Operation time in template group was less (33.97 ± 16.61 < 60.31 ± 11.46 min, p < 0.01), but the preoperative preparation time was more (6.35 ± 1.60 > 5.41 ± 1.58, p < 0.05). The quality of reduction in both groups was no difference (p = 0.352). A patient was complicated with gluteal vessel injury in operation in navigation group, which was treated with ligation, but the same injury was not observed in template group. The related surgical data of patient with gluteal injury was ignored in statistical analysis. CONCLUSION: Both of the two techniques could improve surgical efficiency, the operation time in template was less than computer-assisted navigation group, but the preoperative preparation time was more.

Both-column Acetabular Fractures with Posterior Wall Involved can be Managed through Single Anterior Approach by Evaluation of Computer-assisted Virtual Surgery Technique.

OBJECTIVE: Posterior wall (PW) fractures were sometimes associated in both-column acetabular fractures. How to evaluate pre-operatively the necessity for the performance of the posterior approach was an issue to be solved. In order to solve this issue, the computer-assisted virtual surgery technique was used to evaluate if the involved PW in both-column acetabular fractures (BACF) should be managed through posterior approach and verify the feasibility of this method. METHODS: Data of a consecutive cohort of 72 patients with both-acetabular fractures from January 2012 to January 2020 was collected for retrospective study, of which 44 patients had concomitant acetabular PW fractures, and patients without PW fractures were labeled as the BCAF group. Computer-assisted virtual surgery technique was performed pre-operatively to evaluate the necessity for performance of posterior approach in 44 patients, and posterior approach was required if more than 3 mm of displacement was still present in the reduced 3D model. The 23 patients without treatment through posterior approach were labeled as the BCAF-PW- group, and the 21 patients with treatment through posterior approach were labeled as the BCAF-PW+ group. Operation-related and post-operative parameters were recorded. The quality of reduction and functional outcomes were assessed by the Matta scoring system and modified Merle d'Aubigné and Postel scoring system. The measurement data were analyzed using the t-test of independent samples and rank-sum test of ranked data between every two groups. Also, the one-way analysis of variance (ANOVA) was used to analyze data between the three groups. RESULTS: Comparing operation-related and post-operative parameters in the three groups, some PW fractures in both-column acetabular fractures could be ignored, and which could be evaluated pre-operatively for necessity of an additional posterior approach. Operative time (271.2 ± 32.8 mins) and intra-operative blood loss (1176.7 ± 211.1 mL) were significantly higher in the BCAF-PW+ group. The excellent/good of reduction (25/28 of the BCAF group, 21/23 of the BCAF-PW- group, 19/21 of the BCAF-PW+ group) and functional outcomes (24/28 of the BCAF group, 18/23 of the BCAF-PW- group, 18/21 of the BCAF-PW+ group) of three groups were similar. The incidence of complications, such as deep vein thrombosis (4/28 of the BCAF group >3/23 of the BCAF-PW- group >1/21 of the BCAF-PW+ group) and injury of lateral femoral cutaneous nerve (3/23 of the BCAF-PW- group >2/28 of the BCAF group >0/21 of the BCAF-PW+ group), was no significant difference. CONCLUSION: The partial both-column acetabular fractures with PW involvement could be managed through a single anterior approach without another posterior approach by evaluation of computer-assisted virtual surgery technique.

Predicting Pathological Complete Response in Breast Cancer After Two Cycles of Neoadjuvant Chemotherapy by Tumor Reduction Rate: A Retrospective Case-Control Study.

PURPOSE: We aimed to identify effectiveness-associated indicators and evaluate the optimal tumor reduction rate (TRR) after two cycles of neoadjuvant chemotherapy (NAC) in patients with invasive breast cancer. METHODS: This retrospective case-control study included patients who underwent at least four cycles of NAC at the Department of Breast Surgery between February 2013 and February 2020. A regression nomogram model for predicting pathological responses was constructed based on potential indicators. RESULTS: A total of 784 patients were included, of whom 170 (21.68%) reported pathological complete response (pCR) after NAC and 614 (78.32%) had residual invasive tumors. The clinical T stage, clinical N stage, molecular subtype, and TRR were identified as independent predictors of pCR. Patients with a TRR > 35% were more likely to achieve pCR (odds ratio, 5.396; 95% confidence interval [CI], 3.299-8.825). The receiver operating characteristic (ROC) curve was plotted using the probability value, and the area under the ROC curve was 0.892 (95% CI, 0.863-0.922). CONCLUSION: TRR > 35% is predictive of pCR after two cycles of NAC, and an early evaluation model using a nomogram based on five indicators, age, clinical T stage, clinical N stage, molecular subtype, and TRR, is applicable in patients with invasive breast cancer.

Neoadjuvant Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) and chemotherapy versus placebo plus chemotherapy in patients with HER2-negative breast cancer: a randomized, controlled, double-blind trial.

Background: According to preclinical experiments, Pseudomonas aeruginosa mannose-sensitive hemagglutinin (PA-MSHA) exerts antiproliferative effects against breast cancer cells. It has been approved by the State Food and Drug Administration in China for complementary cancer treatment, and its safety has been confirmed in previous clinical trials. The present randomized, controlled, double-blind clinical trial was conducted to investigate the efficacy and safety of neoadjuvant PA-MSHA and placebo with chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: Eligible patients aged 18 years or older with previously untreated HER2-negative stage II-III breast cancer were enrolled and randomly assigned at a 1:1 ratio to receive neoadjuvant chemotherapy with PA-MSHA or a placebo. The Response Evaluation Criteria in Solid Tumors (RECIST) was used to assess clinical response every 2 cycles. The primary endpoint was the objective response rate (ORR) based on the clinical response following neoadjuvant chemotherapy. Results: A total of 75 patients were randomly assigned to either the PA-MSHA group (37 patients) or the control group (38 patients). The ORR was found to be significantly higher in the PA-MSHA group compared with the control group [86.5% versus 60.5%; rate difference 26.0; 95% confidence interval (CI): 5.9-43.5%; P=0.011]. The pathological complete response (pCR) and survival outcomes did not differ significantly between the 2 groups. Patients with immune-related adverse events (irAEs) appeared to benefit from the PA-MSHA treatment, with greater disease-free, relapse-free, and overall survival. The application of PA-MSHA to neoadjuvant chemotherapy did not increase the incidence of severe adverse events. Moreover, the addition of PA-MSHA increased serum interferon-γ levels and the percentage of peripheral blood T cells, CD8+/CD4+ T cells, CD8+CD28+ T cells, and natural killer (NK) cells, and decreased serum interleukin 4 levels. Conclusions: The addition of PA-MSHA to neoadjuvant chemotherapy is an effective alternative regimen for HER2-negative breast cancer. Patients with irAEs caused by PA-MSHA may obtain more benefits from this treatment. Trial Registration: Chinese Clinical Trial Registry ChiCTR-TRC-10000794.

A generalized non-linear model predicting efficacy of neoadjuvant therapy in HER2+ breast cancer.

Neoadjuvant therapy (NAT) is currently recommended to patients with human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) that typically exhibit a poor prognosis. The tumor immune microenvironment profoundly affects the efficacy of NAT. However, the correlation between tumor-infiltrating lymphocytes or their specific subpopulations and the response to NAT in HER2+ BC remains largely unknown. In our study, the immune infiltration status of 295 patients was classified as "immune-rich" or "immune-poor" phenotypes. The "immune-rich" phenotype was significantly positively related to pathological complete response (pCR). Ten genes were correlated with both pCR and the immune phenotype based on the results of spline and logistic regression. We constructed a generalized non-linear model combining linear and non-linear gene effects and successfully validated its predictive power using an internal and external validation set (AUC = 0.819, 0.797; respectively) and a clinical set (accuracy = 0.75).

Subtyping-based platform guides precision medicine for heavily pretreated metastatic triple-negative breast cancer: The FUTURE phase II umbrella clinical trial.

Triple-negative breast cancer (TNBC) is a heterogeneous disease and lacks effective treatment. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we report the final results of FUTURE, a phase II umbrella trial designed to explore whether the subtyping-based strategy may improve the outcomes in metastatic TNBC patients. A total of 141 patients with a median of three previous lines of therapies in the metastatic setting were enrolled in seven parallel arms. Confirmed objective responses were achieved in 42 patients (29.8%; 95% confidence interval [CI], 22.4-38.1). The median values of progression-free survival and overall survival were 3.4 (95% CI: 2.7-4.2) and 10.7 (95% CI: 9.1-12.3) months, respectively. Given Bayesian predictive probability, efficacy boundaries were achieved in four arms. Furthermore, integrated genomic and clinicopathological profiling illustrated associations of clinical and genomic parameters with treatment efficacy, and the efficacy of novel antibody-drug conjugates was explored in preclinical TNBC models of subtypes for which treatment was futile. In general, the FUTURE strategy recruits patients efficiently and provides promising efficacy with manageable toxicities, outlining a direction for further clinical exploration.

A machine learning model to predict efficacy of neoadjuvant therapy in breast cancer based on dynamic changes in systemic immunity.

OBJECTIVE: Neoadjuvant therapy (NAT) has been widely implemented as an essential treatment to improve therapeutic efficacy in patients with locally-advanced cancer to reduce tumor burden and prolong survival, particularly for human epidermal growth receptor 2-positive and triple-negative breast cancer. The role of peripheral immune components in predicting therapeutic responses has received limited attention. Herein we determined the relationship between dynamic changes in peripheral immune indices and therapeutic responses during NAT administration. METHODS: Peripheral immune index data were collected from 134 patients before and after NAT. Logistic regression and machine learning algorithms were applied to the feature selection and model construction processes, respectively. RESULTS: Peripheral immune status with a greater number of CD3+ T cells before and after NAT, and a greater number of CD8+ T cells, fewer CD4+ T cells, and fewer NK cells after NAT was significantly related to a pathological complete response (P < 0.05). The post-NAT NK cell-to-pre-NAT NK cell ratio was negatively correlated with the response to NAT (HR = 0.13, P = 0.008). Based on the results of logistic regression, 14 reliable features (P < 0.05) were selected to construct the machine learning model. The random forest model exhibited the best power to predict efficacy of NAT among 10 machine learning model approaches (AUC = 0.733). CONCLUSIONS: Statistically significant relationships between several specific immune indices and the efficacy of NAT were revealed. A random forest model based on dynamic changes in peripheral immune indices showed robust performance in predicting NAT efficacy.

Combined Single-Cell and Spatial Transcriptomics Reveal the Metabolic Evolvement of Breast Cancer during Early Dissemination.

Breast cancer is now the most frequently diagnosed malignancy, and metastasis remains the leading cause of death in breast cancer. However, little is known about the dynamic changes during the evolvement of dissemination. In this study, 65 968 cells from four patients with breast cancer and paired metastatic axillary lymph nodes are profiled using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. A disseminated cancer cell cluster with high levels of oxidative phosphorylation (OXPHOS), including the upregulation of cytochrome C oxidase subunit 6C and dehydrogenase/reductase 2, is identified. The transition between glycolysis and OXPHOS when dissemination initiates is noticed. Furthermore, this distinct cell cluster is distributed along the tumor's leading edge. The findings here are verified in three different cohorts of breast cancer patients and an external scRNA-seq dataset, which includes eight patients with breast cancer and paired metastatic axillary lymph nodes. This work describes the dynamic metabolic evolvement of early disseminated breast cancer and reveals a switch between glycolysis and OXPHOS in breast cancer cells as the early event during lymph node metastasis.

Photosensitive and Conductive Hydrogel Induced Innerved Bone Regeneration for Infected Bone Defect Repair.

Repairing infected bone defects is a challenge in the field of orthopedics because of the limited self-healing capacity of bone tissue and the susceptibility of refractory materials to bacterial activity. Innervation is the initiating factor for bone regeneration and plays a key regulatory role in subsequent vascularization, ossification, and mineralization processes. Infection leads to necrosis of local nerve fibers, impeding the repair of infected bone defects. Herein, a biomaterial that can induce skeletal-associated neural network reconstruction and bone regeneration with high antibacterial activity is proposed for the treatment of infected bone defects. A photosensitive conductive hydrogel is prepared by incorporating magnesium-modified black phosphorus (BP@Mg) into gelatin methacrylate (GelMA). The near-infrared irradiation-based photothermal and photodynamic treatment of black phosphorus endows it with strong antibacterial activity, improving the inflammatory microenvironment and reducing bacteria-induced bone tissue damage. The conductive nanosheets and bioactive ions released from BP@Mg synergistically improve the migration and secretion of Schwann cells, promote neurite outgrowth, and facilitate innerved bone regeneration. In an infected skull defect model, the GelMA-BP@Mg hydrogel shows efficient antibacterial activity and promotes bone and CGRP+ nerve fiber regeneration. The phototherapy conductive hydrogel provides a novel strategy based on skeletal-associated innervation for infected bone defect repair.

Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions.

Antibody-drug conjugates (ADCs) are a rapidly developing therapeutic approach in cancer treatment that has shown remarkable activity in breast cancer. Currently, there are two ADCs approved for the treatment of human epidermal growth factor receptor 2-positive breast cancer, one for triple-negative breast cancer, and multiple investigational ADCs in clinical trials. However, drug resistance has been noticed in clinical use, especially in trastuzumab emtansine. Here, the mechanisms of ADC resistance are summarized into four categories: antibody-mediated resistance, impaired drug trafficking, disrupted lysosomal function, and payload-related resistance. To overcome or prevent resistance to ADCs, innovative development strategies and combination therapy options are being investigated. Analyzing predictive biomarkers for optimal therapy selection may also help to prevent drug resistance.

Both-Column Acetabular Fractures: Should Pelvic Ring Reduction or Acetabulum be Performed First?

OBJECTIVE: Both-column acetabular fracture is a type that accumulates both the pelvis and acetabulum with complex fracture line alignment and has variant fracture fragments. The selection of different reduction landmarks and sequences produces different qualities of reduction. This study aims to compare the operation-related items, quality of reduction, and hip functional outcome by using different reduction landmarks and sequences for management of both-column acetabular fractures (BCAF). METHODS: A consecutive cohort of 42 patients from January 2013 to January 2019 with BCAF were treated operatively with different reduction landmarks and sequences: pelvic ring fractures reduction first (PRFRF group) and acetabular fractures reduction first (AFRF group). Preoperative computer visual surgical procedures were applied. There were 22 patients in PRFRF group and 20 patients in AFRF group. The surgical details, complications, radiographic and clinical results were recorded. The quality of reduction was assessed by the Matta scoring system. The functional outcome was evaluated by the modified Merle d'Aubigné and Postel scoring system. The measurement data were analyzed using the t-test of independent samples and rank-sum test of ranked data. RESULTS: The real reduction sequence in both groups was almost identical to the preoperative surgical procedures. The excellent/good quality of reduction in PRFRF group (21/22) was better than AFRF group (17/20). Operative time (152.3 ± 16.3 mins) and intra-operative blood loss (639.5 ± 109.9ml) were significantly reduced in PRFRF group (p < 0.05). The incidence of deep vein thrombosis in PRFRF group (2/22) was less than AFRF group (4/20), but without statistical signification. CONCLUSION: Selection of an appropriate reduction landmark and sequence could result in better quality of reduction, operative time, and decreased blood loss during treatment of BCAF.