Highly expressed lncRNA H19 in endometriosis promotes aerobic glycolysis and histone lactylation.

In brief: Abnormal glucose metabolism may be involved in the pathogenesis of endometriosis. The present study identifies that highly expressed H19 leads to increased aerobic glycolysis and histone lactylation levels in endometriosis. Abstract: Previous studies from our group and others have shown increased IncRNA H19 expression in both the eutopic endometrium and the ectopic endometriosis tissue during endometriosis. In this study, we use immunofluorescence, immunohistochemistry, and protein quantification to determine that levels of aerobic glycolysis and histone lactylation are increased in endometriosis tissues. In human endometrial stromal cells, we found that high H19 expression resulted in abnormal glucose metabolism by examining the levels of glucose, lactate, and ATP and measuring protein levels of enzymes that participate in glycolysis. At the same time, immunofluorescence and western blotting demonstrated increased histone lactylation in H19 overexpressing cells. Altering aerobic glycolysis and histone lactylation levels through the addition of sodium lactate and 2-deoxy-d-glucose demonstrated that increased aerobic glycolysis and histone lactylation levels resulted in enhanced cell proliferation and cell migration, contributing to endometriosis. To validate these findings in vivo, we constructed an endometriosis mouse model, demonstrating similar changes in endometriosis tissues in vivo. Both aerobic glycolysis and histone lactylation levels were elevated in endometriotic lesions. Taken together, these data demonstrate elevated expression levels of H19 in endometriosis patients promote abnormal glucose metabolism and elevated histone lactylation levels in vivo, enhancing cell proliferation and migration and promoting the progression of endometriosis. Our study provides a functional link between H19 expression and histone lactylation and glucose metabolism in endometriosis, providing new insights into disease mechanisms that could result in novel therapeutic approaches.

Combined Computational and Experimental Study Reveals Complex Mechanistic Landscape of Brønsted Acid-Catalyzed Silane-Dependent P═O Reduction.

The reaction mechanism of Brønsted acid-catalyzed silane-dependent P═O reduction has been elucidated through combined computational and experimental methods. Due to its remarkable chemo- and stereoselective nature, the Brønsted acid/silane reduction system has been widely employed in organophosphine-catalyzed transformations involving P(V)/P(III) redox cycle. However, the full mechanistic profile of this type of P═O reduction has yet to be clearly established to date. Supported by both DFT and experimental studies, our research reveals that the reaction likely proceeds through mechanisms other than the widely accepted "dual activation mode by silyl ester" or "acid-mediated direct P═O activation" mechanism. We propose that although the reduction mechanisms may vary with the substitution patterns of silane species, Brønsted acid generally activates the silane rather than the P═O group in transition structures. The proposed activation mode differs significantly from that associated with traditional Brønsted acid-catalyzed C═O reduction. The uniqueness of P═O reduction originates from the dominant Si/O═P orbital interactions in transition structures rather than the P/H-Si interactions. The comprehensive mechanistic landscape provided by us will serve as a guidance for the rational design and development of more efficient P═O reduction systems as well as novel organophosphine-catalyzed reactions involving P(V)/P(III) redox cycle.

Self-Assembled Nanoparticles from the Amphiphilic Prodrug of Resiquimod for Improved Cancer Immunotherapy.

Tumor-associated macrophages (TAMs) usually adopt a tumor-promoting M2-like phenotype, which largely impedes the immune response and therapeutic efficacy of solid tumors. Repolarizing TAMs from M2 to the antitumor M1 phenotype is crucial for reshaping the tumor immunosuppressive microenvironment (TIME). Herein, we developed self-assembled nanoparticles from the polymeric prodrug of resiquimod (R848) to reprogram the TIME for robust cancer immunotherapy. The polymeric prodrug was constructed by conjugating the R848 derivative to terminal amino groups of the linear dendritic polymer composed of linear poly(ethylene glycol) and lysine dendrimer. The amphiphilic prodrug self-assembled into nanoparticles (PLRS) of around 35 nm with a spherical morphology. PLRS nanoparticles could be internalized by antigen-presenting cells (APCs) in vitro and thus efficiently repolarized macrophages from M2 to M1 and facilitated the maturation of APCs. In addition, PLRS significantly inhibited tumor growth in the 4T1 orthotopic breast cancer model with much lower systemic side effects. Mechanistic studies suggested that PLRS significantly stimulated the TIME by repolarizing TAMs into the M1 phenotype and increased the infiltration of cytotoxic T cells into the tumor. This study provides an effective polymeric prodrug-based strategy to improve the therapeutic efficacy of R848 in cancer immunotherapy.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

Chiral Bisphosphine-Catalyzed Asymmetric Staudinger/aza-Wittig Reaction: An Enantioselective Desymmetrizing Approach to Crinine-Type Amaryllidaceae Alkaloids.

An unprecedented chiral bisphosphine-catalyzed asymmetric Staudinger/aza-Wittig reaction of 2,2-disubstituted cyclohexane-1,3-diones is reported, enabling the facile access of a broad range of cis-3a-arylhydroindoles in high yields with excellent enantioselectivities. The key to the success of this work relies on the first application of chiral bisphosphine DuanPhos to the asymmetric Staudinger/aza-Wittig reaction. An effective reductive system has been established to address the challenging PV═O/PIII redox cycle associated with the chiral bisphosphine catalyst. In addition, comprehensive experimental and computational investigations were carried out to elucidate the mechanism of the asymmetric reaction. Leveraging the newly developed chemistry, the enantioselective total syntheses of several crinine-type Amaryllidaceae alkaloids, including (+)-powelline, (+)-buphanamine, (+)-vittatine, and (+)-crinane, have been accomplished with remarkable conciseness and efficiency.

Transition-state defect structure: A new strategy for TiO2-based porous materials to enhance photodegradation of pollutants.

The aim of this paper is to investigate the derived structure and properties of Zeolitic Imidazolate Framework-8 (ZIF-8), and the effect of residual structural on the catalytic properties after loading with Titanium Dioxide (TiO2). For this purpose, we ingeniously prepare C-ZIF-8@TiO2 with a transition-state defect structure and apply it for efficiently degrading organic dye wastewater represented by Rhodamine B (Rh-B). Thanks to the transition-state defect structure loaded with TiO2 and ZIF-8 self-derived Carbon (C) and Zinc Oxide (ZnO), the catalytic performance of C-ZIF-8@TiO2 is superior to that of TiO2 and normal TiO2/ZIF-8 composites, and it is effective in degrading a variety of antibiotics and dyes. The related characterization also shows good photovoltaic properties and long-term durability for C-ZIF-8@TiO2. The mechanism on free radical action is elucidated and the possible degradation pathway for Rh-B is speculated. Therefore, C-ZIF-8@TiO2 provides a new strategy for the degradation of organic pollutants in water bodies.

Access to Chiral ß-Boryl δ-Lactones via NHC-Catalyzed [4 + 2] Annulation.

We report a carbene-catalyzed [4 + 2] annulation of activated esters and ß-borate enones, providing an efficient method to build enantioenriched organoborones with two consecutive stereogenic centers. It is worth noting that this protocol represents a new organocatalytic manner to generate chiral ß-C-B bonds. Moreover, it also greatly enriches the structural diversity of the chiral organoboron compounds.

Dietary pterostilbene exerts potential protective effects by regulating lipid metabolism and enhancing antioxidant capacity on liver in broilers.

Intensive breeding of broilers met the increasing demands of human for broiler products, but it raised their increased susceptibility to various stressors resulting in the disorder of lipid metabolism. Pterostilbene, the methoxylated analogue of resveratrol, exhibits astonishing functions of antioxidant, anti-inflammatory and glycolipid regulatory. The study aimed to elucidate the protective effects of pterostilbene on broiler liver and to explore the potential mechanisms. A total of 480 one-day-old male Arbor Acres (AA) broilers were randomly divided into four groups: the control group (basal diet) and pterostilbene groups (PT200, PT400, and PT600 feeding with basal diet containing 200, 400 and 600 mg/kg pterostilbene, respectively). The results showed that the dietary pterostilbene supplementation significantly improved the ADG of broilers. Dietary pterostilbene supplementation regulated the expression levels of the genes Sirt1 and AMPK and the downstream genes related to lipid metabolism to protect liver function and reduce lipid accumulation in broilers. Dietary pterostilbene supplementation upregulated the expression levels of the Nrf2 gene and its downstream antioxidant genes (SOD, CAT, HO-1, NQO-1, GPX) and phase II detoxification enzyme-related genes (GST, GCLM, GCLC). Collectively, pterostilbene was confirmed the positive effects as a feed additive on lipid metabolism and antioxidant via regulating Sirt1/AMPK and Nrf2 signalling pathways in broilers.

Curcumin Mitigates Oxidative Damage in Broiler Liver and Ileum Caused by Aflatoxin B1-Contaminated Feed through Nrf2 Signaling Pathway.

This experiment aimed to investigate the mitigating effect of CUR on the growth performance and liver and intestinal health of broilers fed AFB1-contaminated diets. In this study, 320 one-day-old healthy male Arbor Acres (AA) broilers were randomly divided into four groups, including the Control group (fed the basal diet), the AFB1 group (fed the AFB1-contaminated diet containing 1 mg/kg AFB1), the AFB1+CUR group (fed the AFB1-contaminated diet with 500 mg/kg CUR), and the CUR group (fed the basal diet containing 500 mg/kg CUR), with eight replicates of ten animals per group and a 28 d experimental period. In terms of the growth performance, the addition of 500 mg/kg CUR significantly improved AFB1-induced significant reductions in the final body weight on day 28 and mean daily gain (p < 0.05) and increased the ratio of the mean daily feed intake to mean daily weight gain in broilers (p < 0.05). In terms of liver health, significant improvements in liver histological lesions occurred in broilers in the AFB1+CUR group compared to the AFB1 group, with significantly higher glutathione peroxidase (GSH-Px), catalase (CAT), and total superoxide dismutase (T-SOD) activities (p < 0.05) and significantly higher levels of nuclear factor erythroid 2-related factor 2 (Nrf2), Kelch-like ECH-associated protein 1 (Keap-1), heme oxygenase 1 (HO-1), and NAD(P)H quinone oxidoreductase 1 (NQO-1) gene expression (p < 0.05). In terms of intestinal health, CUR addition significantly increased the relative length of ileum (p < 0.05), significantly elevated the height of ileal villi (p < 0.05), significantly reduced D-Lactate (D-LA) and diamine oxidase (DAO) activities in broiler serum (p < 0.05), significantly increased GSH, CAT, and T-SOD activities in ileal tissues (p < 0.05), and significantly elevated the expression of Nrf2, HO-1, and NQO-1 genes (p < 0.05) compared to the AFB1 group. In conclusion, CUR showed a protective effect against damage to the liver and intestine caused by AFB1 in broilers through the Nrf2 signaling pathway, thereby improving the growth performance of broilers exposed to AFB1.

Application of near-infrared-activated and ATP-responsive trifunctional upconversion nano-jelly for in vivo tumor imaging and synergistic therapy.

Upconversion nanoparticles (UCNPs)-mediated in-situ imaging and synergistic therapy may be an effective approach against tumors. However, it remains a challenge to improve therapeutic index and reduce toxicity. Here, we investigated the construction process of a three-layer (core-shell-shell) upconversion nano-jelly hydrogels (UCNJs) coated with stimulus-responsive deoxyribonucleic acid chains, aiming to achieve selective recognition of tumor cells and controlled release of drugs. The UCNJs have a NaYF4: Yb, Er core with an outer silica shell with embedded methylene blue (MB). Then the outer layer was coated with mesoporous silica and loaded with doxorubicin (DOX). Finally, polyacrylamide chains containing anti-adenosine triphosphate (ATP) aptamer sequences were assembled layer-by-layer on the surface of particles to form DNA hydrogels to lock DOX. Under near-infrared irradiation, green light (540 nm) emitted by UCNJs can be used for imaging, while red light (660 nm) is absorbed by MB. The latter generates singlet oxygen, resulting in photodynamic therapy (PDT) effect to inhibit tumor growth. UCNJs also can recognize ATP in tumor cells, leading to hydrogel degradation and DOX release. The hydrogel coating can increase drug-carrying capacity of mesoporous materials and improve biocompatibility. Therefore, the UCNJs has great potential advantages for application in the field of cancer diagnosis and treatment.

Oxidation-induced superelasticity in metallic glass nanotubes.

Although metallic nanostructures have been attracting tremendous research interest in nanoscience and nanotechnologies, it is known that environmental attacks, such as surface oxidation, can easily initiate cracking on the surface of metals, thus deteriorating their overall functional/structural properties1-3. In sharp contrast, here we report that severely oxidized metallic glass nanotubes can attain an ultrahigh recoverable elastic strain of up to ~14% at room temperature, which outperform bulk metallic glasses, metallic glass nanowires and many other superelastic metals hitherto reported. Through in situ experiments and atomistic simulations, we reveal that the physical mechanisms underpinning the observed superelasticity can be attributed to the formation of a percolating oxide network in metallic glass nanotubes, which not only restricts atomic-scale plastic events during loading but also leads to the recovery of elastic rigidity on unloading. Our discovery implies that oxidation in low-dimensional metallic glasses can result in unique properties for applications in nanodevices.

HER2-Low Status Was Associated With Better Breast Cancer-Specific Survival in Early-Stage Triple-Negative Breast Cancer.

BACKGROUND: Based on the association between the hormone receptor and the status of human epidermal growth factor receptor 2 (HER2)-low, we investigated the clinicopathological and prognostic characteristics of the HER2-low status in early-stage triple-negative breast cancer (TNBC). METHODS: We collected the data of patients with TNBC who received treatment at our hospital and compared the pathological complete response (pCR) rate, overall survival (OS), and breast cancer-specific survival (BCSS) between the HER2-0 and HER2-low subtypes. RESULTS: A total of 1445 patients were included in the study, of which 698 patients (48.3%) showed HER2-low status. A similar pCR rate was observed between HER2-0 and HER2-low patients (34.9% vs. 37.4%; P = .549). T staging, N staging, and HER2 status were associated with BCSS, whereas T staging and N staging were associated with OS. Patients with the HER2-low status showed better BCSS than those with the HER2-0 status (96.6% vs. 93.7%; log-rank P = .027). In patients with non-pCR, the BCSS of the HER2-low subgroup was better than that of the HER2-0 subgroup (log-rank P = .047); however, no similar result was observed in patients with pCR. In patients with stage III, the BCSS and OS of the HER2-low subgroup were better than those of the HER2-0 subgroup (BCSS, log-rank P = .010; OS, log-rank P = .047). No similar results were observed in patients with stages I and II. CONCLUSION: The HER2-low expression was associated with better BCSS in TNBC, especially in the high-risk groups, suggesting that HER2-low breast cancer is a potential independent biological subtype.

Virus-Inspired Glucose and Polydopamine (GPDA)-Coating as an Effective Strategy for the Construction of Brain Delivery Platforms.

The ability of drugs to cross the blood-brain barrier (BBB) is crucial for treating central nervous system (CNS) disorders. Inspired by natural viruses, here we report a glucose and polydopamine (GPDA) coating method for the construction of delivery platforms for efficient BBB crossing. Such platforms are composed of nanoparticles (NPs) as the inner core and surface functionalized with glucose-poly(ethylene glycol) (Glu-PEG) and polydopamine (PDA) coating. Glu-PEG provides selective targeting of the NPs to brain capillary endothelial cells (BCECs), while PDA enhances the transcytosis of the NPs. This strategy is applicable to gold NPs (AuNPs), silica, and polymeric NPs, which achieves as high as 1.87% of the injected dose/g of brain in healthy brain tissues. In addition, the GPDA coating manages to deliver NPs into the tumor tissue in the orthotopic glioblastoma model. Our study may provide a universal strategy for the construction of delivery platforms for efficient BBB crossing and brain drug delivery.

A common spectrum underlying brain disorders across lifespan revealed by deep learning on brain networks.

Brain disorders in the early and late life of humans potentially share pathological alterations in brain functions. However, the key neuroimaging evidence remains unrevealed for elucidating such commonness and the relationships among these disorders. To explore this puzzle, we build a restricted single-branch deep learning model, using multi-site functional magnetic resonance imaging data (N = 4,410, 6 sites), for classifying 5 different early- and late-life brain disorders from healthy controls (cognitively unimpaired). Our model achieves 62.6 ± 1.9% overall classification accuracy and thus supports us in detecting a set of commonly affected functional subnetworks, including default mode, executive control, visual, and limbic networks. In the deep-layer representation of data, we observe young and aging patients with disorders are continuously distributed, which is in line with the clinical concept of the "spectrum of disorders." The relationships among brain disorders from the revealed spectrum promote the understanding of disorder comorbidities and time associations in the lifespan.

CDDSA: Contrastive domain disentanglement and style augmentation for generalizable medical image segmentation.

Generalization to previously unseen images with potential domain shifts is essential for clinically applicable medical image segmentation. Disentangling domain-specific and domain-invariant features is key for Domain Generalization (DG). However, existing DG methods struggle to achieve effective disentanglement. To address this problem, we propose an efficient framework called Contrastive Domain Disentanglement and Style Augmentation (CDDSA) for generalizable medical image segmentation. First, a disentangle network decomposes the image into domain-invariant anatomical representation and domain-specific style code, where the former is sent for further segmentation that is not affected by domain shift, and the disentanglement is regularized by a decoder that combines the anatomical representation and style code to reconstruct the original image. Second, to achieve better disentanglement, a contrastive loss is proposed to encourage the style codes from the same domain and different domains to be compact and divergent, respectively. Finally, to further improve generalizability, we propose a style augmentation strategy to synthesize images with various unseen styles in real time while maintaining anatomical information. Comprehensive experiments on a public multi-site fundus image dataset and an in-house multi-site Nasopharyngeal Carcinoma Magnetic Resonance Image (NPC-MRI) dataset show that the proposed CDDSA achieved remarkable generalizability across different domains, and it outperformed several state-of-the-art methods in generalizable segmentation. Code is available at https://github.com/HiLab-git/DAG4MIA.

Nanoparticle-Mediated CD47-SIRPα Blockade and Calreticulin Exposure for Improved Cancer Chemo-Immunotherapy.

Enabling macrophages to phagocytose tumor cells holds great potential for cancer therapy but suffers from tremendous challenges because the tumor cells upregulate antiphagocytosis molecules (such as CD47) on their surface. The blockade of CD47 alone is insufficient to stimulate tumor cell phagocytosis in solid tumors due to the lack of "eat me" signals. Herein, a degradable mesoporous silica nanoparticle (MSN) is reported to simultaneously deliver anti-CD47 antibodies (aCD47) and doxorubicin (DOX) for cancer chemo-immunotherapy. The codelivery nanocarrier aCD47-DMSN was constructed by accommodating DOX within the mesoporous cavity, while adsorbing aCD47 on the surface of MSN. aCD47 blocks the CD47-SIRPα axis to disable the "don't eat me" signal, while DOX induces immunogenic tumor cell death (ICD) for calreticulin exposure as an "eat me" signal. This design facilitated the phagocytosis of tumor cells by macrophages, which enhanced antigen cross-presentation and elicited efficient T cell-mediated immune response. In 4T1 and B16F10 murine tumor models, aCD47-DMSN generated a strong antitumor effect after intravenous injection by increasing tumor-infiltration of CD8+ T cells. Taken together, this study offers a nanoplatform to modulate the phagocytosis of macrophages for efficacious cancer chemo-immunotherapy.

Identification of the cell cycle characteristics of non-small cell lung cancer and its relationship with tumor immune microenvironment, cell death pathways, and metabolic reprogramming.

Background: The genes related to the cell cycle progression could be considered the key factors in human cancers. However, the genes involved in cell cycle regulation in non-small cell lung cancer (NSCLC) have not yet been reported. Therefore, it is necessary to evaluate the genes related to the cell cycle in all types of cancers, especially NSCLC. Methods: This study constituted the first pan-cancer landscape of cell cycle signaling. Cluster analysis based on cell cycle signaling was conducted to identify the potential molecular heterogeneity of NSCLC. Further, the discrepancies in the tumor immune microenvironment, metabolic remodeling, and cell death among the three clusters were investigated. Immunohistochemistry was performed to validate the protein levels of the ZWINT gene and examine its relationship with the clinical characteristics. Bioinformatics analyses and experimental validation of the ZWINT gene were also conducted. Results: First, pan-cancer analysis provided an overview of cell cycle signaling and highlighted its crucial role in cancer. A majority of cell cycle regulators play risk roles in lung adenocarcinoma (LUAD); however, some cell cycle genes play protective roles in lung squamous cell carcinoma (LUSC). Cluster analysis revealed three potential subtypes for patients with NSCLC. LUAD patients with high cell cycle activities were associated with worse prognosis; while, LUSC patients with high cell cycle activities were associated with a longer survival time. Moreover, the above three subtypes of NSCLC exhibited distinct immune microenvironments, metabolic remodeling, and cell death pathways. ZWINT, a member of the cell signaling pathway, was observed to be significantly associated with the prognosis of LUAD patients. A series of experiments verified the higher expression levels of ZWINT in NSCLC compared to those in paracancerous tissues. The activation of epithelial-mesenchymal transition (EMT) induced by ZWINT might be responsible for tumor progression. Conclusion: This study revealed the regulatory function of the cell cycle genes in NSCLC, and the molecular classification based on cell cycle-associated genes could evaluate the different prognoses of patients with NSCLC. ZWINT expression was found to be significantly upregulated in NSCLC tissues, which might promote tumor progression via activation of the EMT pathway.

S3R: Shape and Semantics-Based Selective Regularization for Explainable Continual Segmentation Across Multiple Sites.

In clinical practice, it is desirable for medical image segmentation models to be able to continually learn on a sequential data stream from multiple sites, rather than a consolidated dataset, due to storage cost and privacy restrictions. However, when learning on a new site, existing methods struggle with a weak memorizability for previous sites with complex shape and semantic information, and a poor explainability for the memory consolidation process. In this work, we propose a novel Shape and Semantics-based Selective Regularization ( [Formula: see text]) method for explainable cross-site continual segmentation to maintain both shape and semantic knowledge of previously learned sites. Specifically, [Formula: see text] method adopts a selective regularization scheme to penalize changes of parameters with high Joint Shape and Semantics-based Importance (JSSI) weights, which are estimated based on the parameter sensitivity to shape properties and reliable semantics of the segmentation object. This helps to prevent the related shape and semantic knowledge from being forgotten. Moreover, we propose an Importance Activation Mapping (IAM) method for memory interpretation, which indicates the spatial support for important parameters to visualize the memorized content. We have extensively evaluated our method on prostate segmentation and optic cup and disc segmentation tasks. Our method outperforms other comparison methods in reducing model forgetting and increasing explainability. Our code is available at https://github.com/jingyzhang/S3R.

Prognostic Value of the Evolution of HER2-Low Expression after Neoadjuvant Chemotherapy.

PURPOSE: Patients with human epidermal growth factor receptor 2 (HER2)-low advanced breast cancer can benefit from trastuzumab deruxtecan. Given the unclear prognostic characteristics of HER2-low breast cancer, we investigated the prognostic characteristics of HER2-low expression from primary tumor to residual disease after neoadjuvant chemotherapy (NACT). MATERIALS AND METHODS: The data of HER2-negative patients receiving NACT at our center were collected. Pathological complete response (pCR) rate were compared between HER2-0 and HER2-low patients. The evolution of HER2 expression from primary tumor to residual disease and its impact on disease-free survival (DFS) were examined. RESULTS: Of the 690 patients, 494 patients had HER2-low status, of which 72.3% were hormone receptor (HR)-positive (p < 0.001). The pCR rates of HER2-low and HER2-0 patients (14.2% vs. 23.0%) showed no difference in multivariate analysis regardless of HR status. No association was observed between DFS and HER2 status. Of the 564 non-pCR patients, 57 (10.1%) changed to HER2-positive, and 64 of the 150 patients (42.7%) with HER2-0 tumors changed to HER2-low. HER2-low (p=0.004) and HR-positive (p=0.010) tumors before NACT were prone to HER2 gain. HER2 gain patients had a better DFS compared with HER2-negative maintained patients (87.9% vs. 79.5%, p=0.048), and the DFS of targeted therapy group was better than that of no targeted therapy group (92.4% vs. 66.7%, p=0.016). CONCLUSION: Although HER2-low did not affect the pCR rate and DFS, significant evolution of HER2-low expression after NACT creates opportunities for targeted therapy including trastuzumab.