An unsupervised learning model based on CT radiomics features accurately predicts axillary lymph node metastasis in breast cancer patients-diagnostic study.

BACKGROUND: The accuracy of traditional clinical methods for assessing the metastatic status of axillary lymph nodes is unsatisfactory. In this study, we propose the use of radiomic technology and three-dimensional (3D) visualization technology to develop an unsupervised learning model for predicting axillary lymph node metastasis in patients with breast cancer, aiming to provide a new method for clinical axillary lymph node assessment in patients with this disease. METHODS: In this study, we retrospectively analyzed the data of 350 patients with invasive breast cancer who underwent lung-enhanced CT and axillary lymph node dissection (ALND) surgery at the Department of Breast Surgery of the XXX Hospital of XXX University. We used 3D visualization technology to create a 3D atlas of axillary lymph nodes and identified the region of interest (ROI) for the lymph nodes. Radiomic features were subsequently extracted and selected, and a prediction model for axillary lymph nodes was constructed using the K-means unsupervised algorithm. To validate the model, we prospectively collected data from 128 breast cancer patients who were clinically evaluated as negative at our center. RESULTS: Using 3D visualization technology, we extracted and selected a total of 36 CT radiomics features. The unsupervised learning model categorized 1737 unlabeled lymph nodes into two groups, and the analysis of the radiomic features between these groups indicated potential differences in lymph node status. Further validation with 1397 labeled lymph nodes demonstrated that the model had good predictive ability for axillary lymph node status, with an area under the curve (AUC) of 0.847 (0.825-0.869). Additionally, the model's excellent predictive performance was confirmed in the 128 axillary clinical assessment negative cohort (cN0) and the 350 clinical assessment positive (cN+) cohort, for which the correct classification rates (CCR) were 86.72% and 87.43%, respectively, which were significantly greater than those of clinical assessment methods. CONCLUSIONS: We created an unsupervised learning model that accurately predicts the status of axillary lymph nodes. This approach offers a novel solution for the precise assessment of axillary lymph nodes in patients with breast cancer.

Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death.

Necroptotic immunogenic cell death (ICD) can activate the human immune system to treat the metastasis and recurrence of triple-negative breast cancer (TNBC). However, developing the necroptotic inducer and precisely delivering it to the tumor site is the key issue. Herein, we reported that the combination of shikonin (SHK) and chitosan silver nanoparticles (Chi-Ag NPs) effectively induced ICD by triggering necroptosis in 4T1 cells. Moreover, to address the lack of selectivity of drugs for in vivo application, we developed an MUC1 aptamer-targeted nanocomplex (MUC1@Chi-Ag@CPB@SHK, abbreviated as MUC1@ACS) for co-delivering SHK and Chi-Ag NPs. The accumulation of MUC1@ACS NPs at the tumor site showed a 6.02-fold increase compared to the free drug. Subsequently, upon reaching the tumor site, the acid-responsive release of SHK and Chi-Ag NPs from MUC1@ACS NPs cooperatively induced necroptosis in tumor cells by upregulating the expression of RIPK3, p-RIPK3, and tetrameric MLKL, thereby effectively triggering ICD. The sequential maturation of dendritic cells (DCs) subsequently enhanced the infiltration of CD8+ and CD4+ T cells in tumors, while inhibiting regulatory T cells (Treg cells), resulting in the effective treatment of primary and distal tumor growth and the inhibition of TNBC metastasis. This work highlights the importance of nanoparticles in mediating drug interactions during necroptotic ICD.

Integrated modelling of flow-sediment transport and power generation in the Three Gorges Reservoir.

Reservoirs play a crucial role in regulating runoff and generating energy. However, they also lead to significant sedimentation in the reservoir area. In this study, we propose an integrated model that combines a 1-D hydro- and sediment dynamic module with a power generation module. The model considers both suspended and bed load transports. This model is applied to the Three Gorges Reservoir (TGR) and evaluate its performance against corresponding measurements. The results demonstrate that:① the proposed model accurately reproduces the processes of flow and sediment transport, bed deformation, and power generation during the hydrological years of 2019 and 2020. The relative errors for average discharge and bed deformation volume are <6 % and 10 %, respectively. Moreover, the calculated total power (982 × 108-1115 × 108 kW·h) closely agree with the measured values (969 × 108-1118 × 108 kW·h); ② the inflows of small tributaries have a noticeable impact on the calculated water discharge in the TGR. This impact will lead to a 16 % increase in average discharge and alter the magnitudes and occurrence times of flood peaks; ③ the flocculation of fine sediment particles significantly affects sediment transport, particularly in the sub-reach close to the dam. This flocculation will result in a 37 %-57 % reduction in average suspended sediment discharge and a 63 %-93 % reduction in peak sediment discharge. This research provides a comprehensive tool for simulating flow and sediment transport as well as power generation, which can support the optimal regulation of the TGR.

Association between diabetes status and breast cancer in US adults: findings from the US National Health and Nutrition Examination Survey.

Objectives: The aim of this study was to investigate the association between diabetes status and the risk of breast cancer among adult Americans, exploring the impact of BMI, age, and race on this relationship. Methods: A cross-sectional analysis of 8,249 individuals from the National Health and Nutrition Examination Survey (NHANES) was conducted. Diabetes was categorized as type 2 diabetes and prediabetes, with both conditions diagnosed according to the ADA 2014 guidelines. The association between diabetes status and breast cancer risk was explored using multiple logistic regression analysis. Results: Patients with diabetes had higher odds of breast cancer (OR: 1.51; 95% CI 1.00 to 2.28), Using the two-piecewise linear regression model, it was observed that there is a threshold effect in the risk of breast cancer occurrence at the age of 52 years. Specifically, the risk of breast cancer is relatively low before the age of 52 but increases significantly after this age. Conclusions: This study identified a significant association between diabetes status and breast cancer risk among adult Americans. We also found a threshold effect in breast cancer occurrence at the age of 52. Age was significantly associated with breast cancer risk in both Non-Hispanic White and Non-Hispanic Black individuals. These findings underscore the importance of diabetes management, maintaining a healthy BMI, and age-related risk considerations in reducing breast cancer risk.

Modelling of phosphorus and nonuniform sediment transport in the Middle Yangtze River with the effects of channel erosion , tributary confluence and anthropogenic emission.

Phosphorus (P) transport plays a crucial role in the aquatic ecology of natural rivers. However, our understanding still remains unclear that how P transport is affected in a river-lake connected system downstream of a dam. This system usually undergoes both severe channel degradation and complex exchange of flow-sediment-phosphorus between the mainstem and tributaries. In the current study, a method was proposed firstly to determine the individual contribution of different sources to P recover based on the calculation of phosphorus budget; then an integrated model was developed, covering the modules of flow, nonuniform sediment and phosphorus transport. The application of the proposed method in the 955-km-long Middle Yangtze River (MYR) shows that the type of P transportation was predominantly changed from particulate phosphorus to dissolved phosphorus after the operation of the Three Gorges Project (TGP), but a significant longitudinal recovery of total phosphorus (TP) flux was observed. The TP flux exporting from the MYR was mainly from the Upper Yangtze River (44%), and 12%, 18% and 26% of that were originated from channel erosion, tributary confluence and anthropogenic emission. Moreover, the effects were investigated of nonuniform sediment transport and bed-material coarsening on P transport in the MYR, based on the proposed integrated model. Obtained results show that the TP transport process in the MYR was more reasonable simulated using the nonuniform sediment mode, and it is also confirmed that the process of bed-material coarsening after the TGP operation would lead to the decrease of particulate phosphorus flux in the MYR.

The p23 co-chaperone is a succinate-activated COX-2 transcription factor in lung adenocarcinoma tumorigenesis.

P23, historically known as a heat shock protein 90 (HSP90) co-chaperone, exerts some of its critical functions in an HSP90-independent manner, particularly when it translocates into the nucleus. The molecular nature underlying how this HSP90-independent p23 function is achieved remains as a biological mystery. Here, we found that p23 is a previously unidentified transcription factor of COX-2, and its nuclear localization predicts the poor clinical outcomes. Intratumor succinate promotes p23 succinylation at K7, K33, and K79, which drives its nuclear translocation for COX-2 transcription and consequently fascinates tumor growth. We then identified M16 as a potent p23 succinylation inhibitor from 1.6 million compounds through a combined virtual and biological screening. M16 inhibited p23 succinylation and nuclear translocation, attenuated COX-2 transcription in a p23-dependent manner, and markedly suppressed tumor growth. Therefore, our study defines p23 as a succinate-activated transcription factor in tumor progression and provides a rationale for inhibiting p23 succinylation as an anticancer chemotherapy.

BDE209-promoted Dio2 degradation in H4 glioma cells through the autophagy pathway, resulting in hypothyroidism and leading to neurotoxicity.

Decabromodiphenyl ether (BDE209), the homologue with the highest number of brominates in polybrominated diphenyl ethers (PBDEs), is one of the most widespread environmental persistent organic pollutants (POPs) due to its mass production and extensive application in recent decades. BDE209 is neurotoxic, possibly related to its interference with the thyroid hormone (TH) system. However, the underlying molecular mechanisms of BDE209-induced TH interference and neurobehavioral disorders remains unknown. Here, we explored how BDE209 manipulated the major enzyme, human type II iodothyronine deiodinase (Dio2), that is most important in regulating local cerebral TH equilibrium by neuroglial cells, using an in vitro model of human glioma H4 cells. Clonogenic cell survival assay and LC/MS/MS analysis showed that BDE209 could induce chronic neurotoxicity by inducing TH interference. Co-IP assay, RT-qPCR and confocal assay identified that BDE209 destroyed the stability of Dio2 without affecting its expression, and promoted its binding to p62, thereby enhancing its autophagic degradation, thus causing TH metabolism disorder and neurotoxicity. Furthermore, molecular docking studies predicted that BDE209 could effectively suppress Dio2 activity by competing with tetraiodothyronine (T4). Collectively, our study demonstrates that BDE209-induced Dio2 degradation and loss of its enzymatic activity in neuroglial cells are the fundamental pathogenic basis for BDE209-mediated cerebral TH disequilibrium and neurotoxicity, providing a target of interest for further investigation using glial/neuronal cell co-culture system and in vivo models.

MiR-24-3p/Dio3 axis is essential for BDE47 to induce local thyroid hormone disorder and neurotoxicity.

BDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells. BDE47 could induce local TH metabolism disorder in neuronal cells by inhibiting the expression of the main enzyme, human type III iodothyronine deiodinase (Dio3). Further elucidation revealed that BDE47 effectively up-regulating miR-24-3p, which binds to the 3'-UTR of Dio3 and inhibits its expression. In addition, BDE47 could also inhibit the deiodinase activity of Dio3. Collectively, our study demonstrates the molecular mechanism of BDE47 regulating Dio3-induced TH metabolism disorder through inducing miR-24-3p, providing new clues for the role of miRNAs in neurodevelopmental toxicity mediated by environmental pollutants.

Correlation between the expression of CD24 on circulating tumor cells and prognosis in breast cancer.

OBJECTIVE: To investigate the expression of tumor stem cell marker CD24 in peripheral blood circulating tumor cells (CTCs) of breast cancer and the value of CTCs in predicting the prognosis of breast cancer patients. METHODS: Clinical data of 102 breast cancer patients from January 2015 to December 2019 were retrospectively collected. CTC test results, CD24 test results, tumor size, tumor stage, pathological type, molecular type, lymph node metastasis, survival time, and survival status of patients were collected. The correlation between the expression of CD24 in peripheral blood CTCs of breast cancer and the survival time of patients was analyzed. RESULTS: Epithelial-CTCs were closely related to estrogen receptor (ER) expression (P = 0.036) and TNM stage (P = 0.018). Mixed epithelial/mesenchymal-CTCs were closely related to lymph node metastasis in breast cancer patients (P = 0.026). There was no obvious correlation between mesenchymal-CTCs and clinical characteristics (P > 0.05). The positive expression rate of CD24 in CTCs was 58.82% (60/102). The number of CD24-positive CTCs was closely related to TNM stage (P = 0.002), lymph node metastasis (P = 0.020), and tumor size (P = 0.025). The cumulative survival rate of patients with CD24-positive CTCs > 1.5/5 ml (73%) was significantly worse than that of patients with CD24-positive CTCs ≤ 1.5/5 ml (88%) (P < 0.05). There was no significant difference in the cumulative survival rate between patients with mixed-CTCs > 2.5/5 ml (72%) and patients with mixed-CTCs ≤ 2.5/5 ml (87%) (P = 0.336). The cumulative survival rate of patients with CD24-positive mixed-CTCs > 0.5/5 ml (72%) was significantly lower than that of patients with CD24-positive mixed-CTCs ≤ 0.5/5 ml (92%) (P < 0.05). CONCLUSION: The positive expression of CD24 in CTC is closely related to TNM stage, lymph node metastasis, and tumor size in breast cancer patients. The positive expression of CD24 in CTCs, especially in mixed-CTCs, may be one of the prognostic indicators for patients with early and intermediate stage breast cancer.

METTL3 depletion contributes to tumour progression and drug resistance via N6 methyladenosine-dependent mechanism in HR+HER2-breast cancer.

BACKGROUND: Chemotherapy is an important strategy for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+HER2-) breast cancer (BC), but this subtype has a low response rate to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still important. METHODS: mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction and western blotting, respectively. Cell proliferation was detected by CCK-8 and colony formation assays. Cell cycle progression was assessed by flow cytometry. Cell migration and invasion were analysed by wound healing assays and transwell assays, respectively, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation. RESULTS: Chemotherapy-induced downregulation of the m6A modification is regulated by METTL3 depletion in HR+HER2- BC. METTL3 knockdown in MCF-7/T47D cells decreased the drug sensitivity of HR+HER2- BC cells by promoting tumour proliferation and migration and inhibiting apoptosis. Mechanistically, CDKN1A is a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, a decrease in BAX expression was observed when m6A modification was inhibited with METTL3 knockdown, and apoptosis was inhibited by the reduction of caspase-3/-9/-8. CONCLUSION: METTL3 depletion promotes the proliferation and migration and decreases the drug sensitivity of HR+HER2- BC via regulation of the CDKN1A/EMT and m6A-BAX/caspase-9/-3/-8 signalling pathways, which suggests METTL3 played a tumour-suppressor role and it could be a potential biomarker for predicting the prognosis of patients with HR+HER2- BC.

Hydrologic and geomorphic effects on the reduction of channel discharge capacity in the Middle Yangtze River.

A systematic increase in the occurrence of flood events has been noted in rivers worldwide. However, our understanding remains unclear of how the flood level is affected by the change in channel discharge capacity. Therefore, the reduction of channel discharge capacity was quantified in the Middle Yangtze River (MYR) based on extensive measured data. It is confirmed that the variation in channel discharge capacity is a superposition result of channel-morphology and channel-resistance changes, as well as the change in local base-level at the outlet. Then a series of numerical simulations were carried out to quantitatively identify the contribution of each factor to the reduction of channel discharge capacity in the MYR for the years of 2004 and 2020. Simulated results reveal that channel degradation increased the flow passage area, helping the channel to convey floods, with the effect being weakened along the reach; however, the decline in flood level under the same discharge was not observed, which was primarily attributed to the increases in channel resistance and local base-level at the outlet. These two factors accounted for 16-91 % and 9-84 % of the total impact at four hydrometric stations in the MYR. It should be noted that the dominant factor to influence the discharge capacity varied greatly at different stations, which depended on the degree of bed-material coarsening, the distance from the confluence of lakes, etc. At the stations immediately downstream of the dam, the contribution of the increased movable bed roughness usually played a more essential role; while at the stations close to the outlet with the confluence of large lakes, the increase in local base-level became the main factor that accounted for the rise of high-flood levels under the specified large discharge.

MiR-146b-5p/TRAF6 axis is essential for Ginkgo biloba L. extract GBE to attenuate LPS-induced neuroinflammation.

Background: Neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases, including Alzheimer's disease. The Ginkgo biloba leaf extract (GBE) has been widely used to treat cerebral and peripheral blood circulation disorders. However, its potential targets and underlying mechanisms regarding neuroinflammation have not yet been characterized. Aims: The purpose of this study was to investigate and validate the anti-neuroinflammatory properties of GBE against lipopolysaccharide (LPS)-mediated inflammation and to determine the underlying molecular mechanisms. Methods: The effect of GBE on LPS-induced release of inflammatory cytokines was examined using ELISA and western blot assay. The effects of GBE on NF-κB binding activity and translocation were determined via luciferase, streptavidin-agarose pulldown, and immunofluorescence assays. The potential targets of GBE were screened from the GEO and microRNA databases and further identified via qPCR, luciferase, gene mutation, and western blot assays. Results: GBE significantly inhibited LPS-induced pro-inflammatory responses in BV-2 and U87 cells, with no obvious cytotoxicity. GBE significantly induced miR-146b-5p expression, which negatively regulated TRAF6 expression by targeting its 3'-UTR. Thus, due to TRAF6 suppression, GBE decreases the transcriptional activity of NF-κB and the expression of pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, tumor necrosis factor (TNF)-α, and cyclooxygenase (COX)-2, and finally reverses LPS-induced neuroinflammation. Conclusion: Our study revealed the anti-neuroinflammatory mechanism of GBE through the miR-146b-5p/TRAF6 axis and provided a theoretical basis for its rational clinical application.

Using Machine Learning Algorithms to Estimate the Compressive Property of High Strength Fiber Reinforced Concrete.

The low tensile strain capacity and brittle nature of high-strength concrete (HSC) can be improved by incorporating steel fibers into it. Steel fibers' addition in HSC results in bridging behavior which improves its post-cracking behavior, provides cracks arresting and stresses transfer in concrete. Using machine learning (ML) techniques, concrete properties prediction is an effective solution to conserve construction time and cost. Therefore, sophisticated ML approaches are applied in this study to predict the compressive strength of steel fiber reinforced HSC (SFRHSC). To fulfil this purpose, a standalone ML model called Multiple-Layer Perceptron Neural Network (MLPNN) and ensembled ML algorithms named Bagging and Adaptive Boosting (AdaBoost) were employed in this study. The considered parameters were cement content, fly ash content, slag content, silica fume content, nano-silica content, limestone powder content, sand content, coarse aggregate content, maximum aggregate size, water content, super-plasticizer content, steel fiber content, steel fiber diameter, steel fiber length, and curing time. The application of statistical checks, i.e., root mean square error (RMSE), determination coefficient (R2), and mean absolute error (MAE), was also performed for the assessment of algorithms' performance. The study demonstrated the suitability of the Bagging technique in the prediction of SFRHSC compressive strength. Compared to other models, the Bagging approach was more accurate as it produced higher, i.e., 0.94, R2, and lower error values. It was revealed from the SHAP analysis that curing time and super-plasticizer content have the most significant influence on the compressive strength of SFRHSC. The outcomes of this study will be beneficial for researchers in civil engineering for the timely and effective evaluation of SFRHSC compressive strength.

Analysis on the Differences of Combination Effects of Science and Technology Innovation Policies.

Science and technology innovation (STI) policy is a strategic principle to guide the whole cause of STI. The study on STI policy and its effect is particularly important. Most of the existing studies on the effect of STI policy focus on the effect of a single policy, and the studies on the effect of policy combination and its differences need to be further enriched and improved. This study proposes a method combining system simulation experiment and analysis of variance (ANOVA) to study the differences of combination effects of STI policies. The results show that there are significant effect differences in the combination of STI policies as a whole, but when it comes to different combinations of STI policies, not all policy combinations have significant differences. This study not only points out whether there are significant differences in a certain effect among which combinations of STI policies but also points out whether there are significant differences in all effects among which combinations of STI policies at the same time. This study has theoretical and practical significance for realizing scientific policy-making and sustainable development.

Characterization of a small-molecule inhibitor targeting NEMO/IKKß to suppress colorectal cancer growth.

NEMO/IKKß complex is a central regulator of NF-κB signaling pathway, its dissociation has been considered to be an attractive therapeutic target. Herein, using a combined strategy of molecular pharmacological phenotyping, proteomics and bioinformatics analysis, Shikonin (SHK) is identified as a potential inhibitor of the IKKß/NEMO complex. It destabilizes IKKß/NEMO complex with IC50 of 174 nM, thereby significantly impairing the proliferation of colorectal cancer cells by suppressing the NF-κB pathway in vitro and in vivo. In addition, we also elucidated the potential target sites of SHK in the NEMO/IKKß complex. Our study provides some new insights for the development of potent small-molecule PPI inhibitors.

Physical modelling of energy losses at surcharged three-way junction manholes in drainage system.

Motivated by the observation that vortex flow structure was evident in the energy loss at the surcharged junction manhole due to changes of hydraulic and geometrical parameters, a physical model was used to calculate energy loss coefficients and investigate the relationship between flow structure and energy loss at the surcharged three-way junction manhole. The effects of the flow discharge ratio, the connected angle between two inflow pipes, the manhole geometry, and the downstream water depth on the energy loss were analyzed based on the quantified energy loss coefficients and the identified flow structure. Moreover, two empirical formulae for head loss coefficients were validated by the experimental data. Results indicate that the effect of flow discharge ratio and connected angle are significant, while the effect of downstream water depth is not obvious. With the increase of the lateral inflow discharge, the flow velocity distribution and vortex structure are both enhanced. It is also found that a circular manhole can reduce local energy loss when compared to a square manhole. In addition, the tested empirical formulae can reproduce the trend of total head loss coefficient.

Cytotoxic diterpenoid dimer containing an intricately caged core from Euphorbia fischeriana.

Bislangduoids A and B, a novel class of dimeric diterpenoids based on ent-abietanes tethered by C-17-C-15' bridge, were identified as trace components from a traditional Chinese medicine Euphorbia fischeriana (Langdu). Bislangduoid A features a highly oxidized scaffold incorporating a cage-like pentacyclic core. Their structures were elucidated by extensive spectroscopic techniques, electronic circular dichroism, and NMR calculations. The biosynthetic pathway for the dimeric skeleton and the unique caged moiety via Michael and acetal-formation reactions was proposed. Bislangduoid A showed pronounced cytotoxicity against HepG2 cells through the mitochondria-dependent apoptosis pathway.

Integrated modeling of 2D urban surface and 1D sewer hydrodynamic processes and flood risk assessment of people and vehicles.

In order to accurately simulate the whole urban flooding processes and assess the flood risks to people and vehicles in floodwaters, a 2D-surface and a 1D-sewer integrated hydrodynamic model was proposed in this study, with the module of flood risk assessment of people and vehicles being included. The proposed model was firstly validated by a dual-drainage laboratory experiment on the flood inundation process over a typical urban street, and the relative importance of model parameters and model uncertainties were evaluated using the GSA-GLUE method. Then the model was applied to simulate an actual urban flooding process that occurred in Glasgow, UK, with the influence of the sewer drainage system on flood inundation processes and hazard degree distributions of people and vehicles being comprehensively discussed. The following conclusions are drawn from this study: (i) The proposed model has a high degree of accuracy with the NSE values of key hydraulic variables greater than 0.8 and the GSA indicates that Manning roughness coefficients for surface and sewer flows, inlet weir and orifice discharge coefficients, are the most relevant parameters to influence the simulated results; (ii) vehicles are vulnerable to larger water depths while human stability is significantly influenced by higher flow velocities, with the overall flood risk of people being less than that of vehicles; and (iii) about 88.7% of the total inflow volume was drained to the sewer network, and the sewer drainage system greatly reduced the flood risks to people and vehicles except the local areas with large inundation water depths, where the sewer drainage increased the local flow velocity leading to higher flood risks especially for people.

Efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy regimen in Chinese patients with HER2-positive early breast cancer: a real-world retrospective multi-center cohort study.

Background: Pertuzumab plus trastuzumab combined with chemotherapy has become a standard neoadjuvant therapy option for patients with high-risk human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). There is still not enough evidence for the efficacy and safety of neoadjuvant pertuzumab and trastuzumab plus chemotherapy in HER2-positive BC patients in China, both in clinical trials and real-world settings. This study aimed to assess the efficacy and safety of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy in Chinese patients with HER2-positive BC in real-world clinical application. Methods: We retrospectively collected the data from the electronic medical records of HER2-positive patients treated with neoadjuvant trastuzumab and pertuzumab plus chemotherapy from December 2018 to May 2021 at 21 hospitals located in Hunan Province, China, including age, American Joint Committee on Cancer (AJCC) stage, clinical tumor size, clinical lymph node status, pathological characteristics (before neoadjuvant systemic therapy), treatment approach, adverse events to neoadjuvant therapy, and achievement of pathological complete response (pCR). The primary endpoint was the total rate of pCR, and the secondary endpoints were the rate of pCR of each subgroup and the safety of dual anti-HER2 therapy. Results: A total of 188 patients met the inclusion criteria and were included in the analysis. Of the 188 patients, 119 (63.3%) were diagnosed at stage II and 64 (34.0%) at stage III; 163 (86.7%) were cT2-3; 149 patients (79.3%) were ≥ cN1; 84 patients (44.7%) were hormone receptor (HR)-positive. pCR was observed in 88 of 188 patients (46.8%). The pCR rate of HR-negative patients (54.8%) was higher (P=0.014) than that of HR-positive patients (36.9%). Patients with Ki-67 <15% achieved a higher (P=0.033) pCR rate (68.2%) than those with Ki-67 ≥15% (44.0%). Anemia was the most common adverse event (63.4%), and the most common grade 3-4 adverse event was nausea and vomiting (8.5%). Conclusions: Our study confirmed the benefit of neoadjuvant pertuzumab plus trastuzumab in combination with chemotherapy on pCR with a tolerable safety profile in routine clinical practice in Chinese patients with HER2-positive BC. HR-negativity and Ki-67 <15% were associated with pCR in these patients.