Effects of microplastics on typical macrobenthos in sargassum ecosystems.

Recently, microplastics (MPs) have attracted extensive attention to their wide distribution and potential toxicity in ecosystems. However, there was a lack of research focused on MPs in seaweed bed ecosystems. This study investigated the distribution and toxicity of MPs in macrobenthos in Sargassum ecosystem. According to the in-situ investigation results, the abundance of MPs in the sediment was 0.9-2.3 items/g, the indoor microcosmic experiment was constructed. After exposure to MPs (0, 2, and 20 items/g) for 30 days, the abundance of MPs in macrobenthos exhibits a concentration-dependent increase. However, there was no significant bioaccumulation of MPs at the trophic level. The indoor toxicity test revealed that MPs induced oxidative stress and altered intestinal microflora composition in macrobenthos, even at actual environmental concentrations (2 items/g). It may result in a perturbation of the organism's homeostatic equilibrium. High-concentration (20 items/g) MPs had a greater impact on alkaline phosphatase (AKP) in Mollusks. The increase in AKP activity could be indicative of an adaptive mechanism in some macrobenthos while the decline in AKP activity might signal a decrease in their survival. These results elucidated the fate of MPs in ecosystem and the ecological risks of MPs to large benthic animals on model environmental conditions.

DUSP4 enhances therapeutic sensitivity in HER2-positive breast cancer by inhibiting the G6PD pathway and ROS metabolism by interacting with ALDOB.

BACKGROUND: Breast cancer (BC) poses a global threat, with HER2-positive BC being a particularly hazardous subtype. Despite the promise shown by neoadjuvant therapy (NAT) in improving prognosis, resistance in HER2-positive BC persists despite emerging targeted therapies. The objective of this study is to identify markers that promote therapeutic sensitivity and unravel the underlying mechanisms. METHODS: We conducted an analysis of 86 HER2-positive BC biopsy samples pre-NAT using RNA-seq. Validation was carried out using TCGA, Kaplan‒Meier Plotter, and Oncomine databases. Phenotype verification utilized IC50 assays, and prognostic validation involved IHC on tissue microarrays. RNA-seq was performed on wild-type/DUSP4-KO cells, while RT‒qPCR assessed ROS pathway regulation. Mechanistic insights were obtained through IP and MS assays. RESULTS: Our findings reveal that DUSP4 enhances therapeutic efficacy in HER2-positive BC by inhibiting the ROS pathway. Elevated DUSP4 levels correlate with increased sensitivity to HER2-targeted therapies and improved clinical outcomes. DUSP4 independently predicts disease-free survival (DFS) and overall survival (OS) in HER2-positive BC. Moreover, DUSP4 hinders G6PD activity via ALDOB dephosphorylation, with a noteworthy association with heightened ROS levels. CONCLUSIONS: In summary, our study unveils a metabolic reprogramming paradigm in BC, highlighting DUSP4's role in enhancing therapeutic sensitivity in HER2-positive BC cells. DUSP4 interacts with ALDOB, inhibiting G6PD activity and the ROS pathway, establishing it as an independent prognostic predictor for HER2-positive BC patients.

Patient-Reported Outcomes and Complication Profiles of Implant-Based Breast Reconstruction in Patients With Postmastectomy Radiation Therapy.

OBJECTIVE: This study aims to investigate the patient-reported outcomes (PROs) and complications of distinct implant-based breast reconstruction modality for patients with postmastectomy radiation therapy (PMRT). METHODS: A retrospective review was conducted on breast cancer patients with stage II-III disease who performed implant-based breast reconstruction following with PMRT between September 2016 and April 2022. The patients were categorized into two matched groups: (1) patients receiving prepectoral breast reconstruction (PBR) or (2) subpectoral breast reconstruction (SBR) followed by PMRT. Following reconstruction, the patients were further compared for PMRT with the tissue expander (PMRT-TE) versus PMRT with permanent implant (PMRT-PI). PROs were measured with BREAST-Q questionnaire. Early and late complications were recorded and analyzed. RESULTS: A total of 55 eligible patients were recruited. Patients who underwent PBR reported significantly higher satisfaction with breasts scores (P = 0.003) compared with the SBR group. The PMRT-TE group had higher satisfaction with breasts (P = 0.001) but lower physical well-being (P = 0.029) scores compared with PMRT-PI group. Moreover, patients in SBR cohort had a higher risk of capsular contracture (Baker grade III or IV) (20.5% vs 6.3%) and implant dislocation (48.7% vs 12.5%) than patients in PBR cohort. Patients in PMRT-PI group had a slightly higher rate of capsular contracture (Baker grade III or IV) than PMRT-TE group (20.8% vs 12.9%). CONCLUSIONS: PBR was associated with lower rates of late complications, especially for implant dislocation, and higher satisfaction with breasts scores compared to SBR. In addition, compared to PMRT-TE with PMRT-PI, patients in PMRT-TE cohort reported superior PROs of satisfaction with breasts.

Machine learning for the prediction of in-hospital mortality in patients with spontaneous intracerebral hemorrhage in intensive care unit.

This study aimed to develop a machine learning (ML)-based tool for early and accurate prediction of in-hospital mortality risk in patients with spontaneous intracerebral hemorrhage (sICH) in the intensive care unit (ICU). We did a retrospective study in our study and identified cases of sICH from the MIMIC IV (n = 1486) and Zhejiang Hospital databases (n = 110). The model was constructed using features selected through LASSO regression. Among five well-known models, the selection of the best model was based on the area under the curve (AUC) in the validation cohort. We further analyzed calibration and decision curves to assess prediction results and visualized the impact of each variable on the model through SHapley Additive exPlanations. To facilitate accessibility, we also created a visual online calculation page for the model. The XGBoost exhibited high accuracy in both internal validation (AUC = 0.907) and external validation (AUC = 0.787) sets. Calibration curve and decision curve analyses showed that the model had no significant bias as well as being useful for supporting clinical decisions. XGBoost is an effective algorithm for predicting in-hospital mortality in patients with sICH, indicating its potential significance in the development of early warning systems.

Revisiting ovarian function suppression with GnRH agonists for premenopausal women with breast cancer: Who should use and the impact on survival outcomes.

Breast cancer diagnosed in premenopausal women tends to be more aggressive and the benefit of ovarian function suppression (OFS), at least in certain groups of patients, is well known. There is hesitancy in using OFS in some groups of patients who may otherwise benefit from the treatment. For instance, it is clear that in premenopausal patients with hormone receptor-positive (HR+), high-risk, early-stage breast cancer, gonadotropin-releasing hormone agonists (GnRHa) should be given in the adjuvant setting; however, confusion remains whether premenopausal patients with intermediate-risk disease benefit from GnRHa, given the lack of consensus on its definition in guidelines and clinical practice. Most recent evidence on the long-term efficacy of GnRHa, with up to 20-years of follow-up, reinforced its benefits in premenopausal patients with early-stage breast cancer. In this comprehensive review, we reviewed the long-term efficacy in terms of improvement in disease-free survival (DFS) and overall survival (OS) for early-stage HR+ breast cancer and examined evidence from multiple randomized clinical studies to identify the clinicopathological characteristics that correlated with improved DFS and OS with the addition of OFS to adjuvant endocrine therapy. Other aspects of GnRHa, including its efficacy in advanced breast cancer, safety profile, evidence in ovarian function preservation, and the advantages of long-acting formulations were also discussed. By addressing the existing gaps and grey areas regarding the inclusion of OFS as a crucial treatment component for premenopausal breast cancer patients, physicians are more aware of who to administer and the potential impact on survival outcomes.

Laser hemorrhoidoplasty vs. rubber band ligation: a randomized trial comparing 2 mini-invasive treatment for grade II hemorrhoids.

PURPOSE: As a minimally invasive procedure, laser hemorrhoidoplasty (LHP) can not only relieve the symptoms of hemorrhoids, but also protect the anal cushion structure. This study aimed to investigate the clinical efficacy of LHP in the treatment of grade II hemorrhoids. METHODS: A total of 70 patients with grade II hemorrhoids were randomly assigned to receive LHP or Rubber Band Ligation (RBL) (n = 35 per group) in 2019 from a single center. The postoperative pain, bleeding, feeling of anal distension(local falling, swelling, foreign body sensation, stool) and postoperative recurrence rate were compared between the two groups. RESULTS: The postoperative pain, bleeding, and feeling of anal distension in the LHP group were improved significantly as compared with the RBL group within 2 weeks after surgery (P < 0.01). Both methods can relieve the symptoms of grade II hemorrhoids. There was no difference in the recurrence rate between the two groups at 1 year after surgery (P > 0.05). The patients in LHP group took less time to return to normal activities (P < 0.001). CONCLUSIONS: As a minimally invasive treatment, LHP is easy and not traumatic and results in mild postoperative pain and few complications. It is an ideal choice for grade II hemorrhoids.

Impact of obesity on sentinel lymph node biopsy outcomes and survival in breast cancer patients: A single-center retrospective study.

BACKGROUND: Sentinel lymph node biopsy (SLNB) is a common choice for axillary surgery in patients with early-stage breast cancer (BC) who have clinically negative lymph nodes. Most research indicates that obesity is a prognostic factor for BC patients, but studies assessing its association with the rate of positive sentinel lymph nodes (SLN) and the prognosis of patients with early BC undergoing SLNB are limited. METHODS: Between 2013 and 2016, 7062 early-stage BC patients from the Shanghai Cancer Center of Fudan University were included. Based on the Chinese Body Mass Index (BMI) classification standards, the patients were divided into three groups as follows: normal weight, overweight, and obese. Propensity score matching analysis was used to balance the baseline characteristics of the participants. Logistic regression analysis was used to determine the association between obesity and positive SLN rate. Cox regression analysis was used to investigate whether obesity was an independent prognostic factor for early-stage BC patients who had undergone SLNB. RESULTS: No significant association was observed between obesity and positive SLN rate in early-stage BC patients who had undergone SLNB. However, multivariate analysis revealed that compared to patients with normal BMI, the overall survival (hazard ratio (HR) 2.240, 95% confidence interval (CI) 1.27-3.95, p = 0.005) and disease-free survival (HR 1.750, 95% CI 1.16-2.62, p = 0.007) were poorer in patients with high BMI. CONCLUSION: Obesity is an independent prognostic factor for early-stage BC patients who undergo SLNB; however, it does not affect the positive SLN rate.

TROPION-Breast03: a randomized phase III global trial of datopotamab deruxtecan ± durvalumab in patients with triple-negative breast cancer and residual invasive disease at surgical resection after neoadjuvant therapy.

Background: Despite advances in the treatment of early triple-negative breast cancer (TNBC), patients with residual invasive disease after neoadjuvant therapy have a high risk of disease recurrence and worse survival outcomes than those who have pathological complete response (pCR). Improving outcomes in early TNBC remains an unmet need requiring new adjuvant treatment approaches. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate comprising a humanized anti-trophoblast cell-surface antigen 2 immunoglobulin G1 (IgG1) monoclonal antibody attached via a plasma-stable, cleavable linker to a potent topoisomerase I inhibitor payload, with activity observed in advanced TNBC. Objectives: TROPION-Breast03 is an ongoing phase III study evaluating the efficacy and safety of Dato-DXd alone or combined with durvalumab versus standard-of-care therapy as adjuvant treatment in patients with stage I-III TNBC with residual invasive disease at surgical resection following neoadjuvant treatment. Methods and design: Eligible patients, aged ⩾18 years, will be randomized in a 2:1:2 ratio to receive Dato-DXd [6 mg/kg intravenously (IV) every 3 weeks (Q3W); eight cycles] and durvalumab (1120 mg IV Q3W; nine cycles), Dato-DXd monotherapy (6 mg/kg IV Q3W), or investigator's choice of therapy (ICT; capecitabine, pembrolizumab, or capecitabine and pembrolizumab). The primary endpoint is invasive disease-free survival (iDFS) for Dato-DXd and durvalumab versus ICT. Key secondary endpoints include safety, distant disease-free survival, and overall survival for Dato-DXd and durvalumab versus ICT and iDFS for Dato-DXd monotherapy versus ICT. Ethics: TROPION-Breast03 will be approved by the independent ethics committees or institutional review boards at each study site. All study participants will provide written informed consent. Discussion: TROPION-Breast03 will help define the potential role of Dato-DXd in the treatment of patients with early-stage TNBC who do not have pCR after neoadjuvant therapy. Trial registration: ClinicalTrials.gov identifier: NCT05629585 (registration date: 29 November 2022).

TROPION-Breast03: a clinical trial designed to assess the effectiveness and safety of Dato-DXd, alone or in combination with durvalumab, in patients with triple-negative breast cancer who have cancer cells remaining at the time of surgery after initial systemic therapy Triple-negative breast cancer (TNBC), in which cells do not have estrogen or progesterone receptors or high levels of human epidermal growth factor receptor 2, is the most aggressive breast cancer subtype. TNBC is difficult to treat and associated with high risk of recurrence despite standard systemic therapy (treatment targeting the entire body), which can include chemotherapy alone or in combination with immunotherapy (treatment targeting the immune system). To reduce the risk of recurrence, standard systemic treatment is often followed by surgical removal of the patient's tumors and additional systemic treatment. Dato-DXd is an antibody-drug conjugate, which is an anticancer drug (DXd) connected to an antibody (datopotamab) by a stable linker. Datopotamab binds to TROP2, a protein found on breast cancer cells, and is taken into the tumor cell where the linker breaks, releasing DXd to kill the cell. By delivering DXd directly to cancer cells, Dato-DXd reduces exposure in the rest of the body, reducing the risk of side effects. Since Dato-DXd can recruit immune cells to cancer sites, it may work better combined with durvalumab, a drug that blocks the activity of a protein called PD-L1, making cancer cells more susceptible to being killed by immune cells. The TROPION-Breast03 study will compare Dato-DXd, alone or combined with durvalumab, with standard-of-care therapy in patients with TNBC that has not spread to parts of the body away from the original tumor site(s), but with cancer cells remaining at the time of surgery after initial systemic therapy. It will assess how well each treatment works and describe any side effects. We plan to recruit 1,075 eligible adults who will be randomly assigned in a 2:1:2 ratio to: • Dato-DXd + durvalumab • Dato-DXd alone • Standard-of-care therapy • Patients will receive treatment until they complete the planned course of therapy (8 or 9 cycles), their cancer returns, side effects become unacceptable, or they choose to stop.

Giredestrant for Estrogen Receptor-Positive, HER2-Negative, Previously Treated Advanced Breast Cancer: Results From the Randomized, Phase II acelERA Breast Cancer Study.

PURPOSE: To compare giredestrant and physician's choice of endocrine monotherapy (PCET) for estrogen receptor-positive, HER2-negative, advanced breast cancer (BC) in the phase II acelERA BC study (ClinicalTrials.gov identifier: NCT04576455). METHODS: Post-/pre-/perimenopausal women, or men, age 18 years or older with measurable disease/evaluable bone lesions, whose disease progressed after 1-2 lines of systemic therapy (≤1 targeted, ≤1 chemotherapy regimen, prior fulvestrant allowed) were randomly assigned 1:1 to giredestrant (30 mg oral once daily) or fulvestrant/aromatase inhibitor per local guidelines (+luteinizing hormone-releasing hormone agonist in pre-/perimenopausal women, and men) until disease progression/unacceptable toxicity. Stratification was by visceral versus nonvisceral disease, prior cyclin-dependent kinase 4/6 inhibitor, and prior fulvestrant. The primary end point was investigator-assessed progression-free survival (INV-PFS). RESULTS: At clinical cutoff (February 18, 2022; median follow-up: 7.9 months; N = 303), the INV-PFS hazard ratio (HR) was 0.81 (95% CI, 0.60 to 1.10; P = .1757). In the prespecified secondary end point analysis of INV-PFS by ESR1 mutation (m) status in circulating tumor DNA-evaluable patients (n = 232), the HR in patients with a detectable ESR1m (n = 90) was 0.60 (95% CI, 0.35 to 1.03) versus 0.88 (95% CI, 0.54 to 1.42) in patients with no ESR1m detected (n = 142). Related grade 3-4 adverse events (AEs), serious AEs, and discontinuations due to AEs were balanced across arms. CONCLUSION: Although the acelERA BC study did not reach statistical significance for its primary INV-PFS end point, there was a consistent treatment effect with giredestrant across most key subgroups and a trend toward favorable benefit among patients with ESR1-mutated tumors. Giredestrant was well tolerated, with a safety profile comparable to PCET and consistent with known endocrine therapy risks. Overall, these data support the continued investigation of giredestrant in other studies.

CRTAM promotes antitumor immune response in triple negative breast cancer by enhancing CD8+ T cell infiltration.

The immunomodulatory (IM) subtype of triple negative breast cancer (TNBC) exhibits high expression of immune cell signaling genes and is more responsive to immunotherapy. However, the specific mechanism underlying this phenomenon remains unclear. One of the potential key genes appears to be the cytotoxic and regulatory T cell molecule (CRTAM). A cohort of 360 previously untreated TNBC patients from Fudan University Shanghai Cancer Center (FUSCC) underwent RNA sequencing analysis of their primary tumor tissue. Combined with three RNA-seq datasets obtained from the GEO database, a LASSO regression analysis was conducted to identify genes specific to the IM type of TNBC. Our findings revealed elevated CRTAM expression in the IM-type TNBC, which correlated with a favorable overall survival and recurrence-free survival in TNBC patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis indicated a strong association between CRTAM and immune responses as well as immune system processes. Notably, CRTAM overexpression induced STAT1 phosphorylation and upregulation of interferon-stimulated genes. We also found that CRTAM enhanced tumor-associated immune cell infiltration, especially CD8+ T cells, which may be related to the increased expression of MHC class I molecules caused by CRTAM overexpression. These results suggest that CRTAM may serve as a potential biomarker for predicting the efficacy of immunotherapy in TNBC.

Somatic mutations in a multigene panel and impact on prognosis based on TP53 status in Chinese HER2-positive patients undergoing neoadjuvant therapy: A single-institution retrospective cohort.

BACKGROUND: Gene mutations play a crucial role in the occurrence and development of tumors, particularly in breast cancer (BC). Neoadjuvant therapy (NAT) has shown greater clinical benefit in HER2-positive breast cancer. However, further clinical investigation is needed to fully understand the correlation between genetic mutations and NAT efficacy and the long-term prognosis in HER2-positive BC. METHODS: This was a retrospective cohort study of 222 patients receiving NAT between 2017 and 2021 in the Department of Breast Surgery of Fudan University Shanghai Cancer Center. Tumor samples from these patients were subjected to Next Generation Sequencing (NGS) to analyze mutations in 513 cancer-related genes. This study aimed to investigate the association between these genetic mutations and postoperative pathological complete response (pCR), as well as their impact on disease-free survival (DFS). RESULTS: In total, 48.65% patients reached pCR, ER-negative status (p < 0.001), PR-negative status (p < 0.001), Ki67 ≥ 20 (p = 0.011), and dual-targeted therapy (p < 0.001) were all associated with enhanced pCR rates. The frequency of somatic alterations in TP53 (60%), PIK3CA (15%), and ERBB2 (11%) was highest. In the HER2+/HR- cohort, patients who achieved pCR had a significant benefit in prognosis (HR = 3.049, p = 0.0498). KMT2C (p = 0.036) and TP53 (p = 0.037) mutations were significantly increased in patients with DFS events. Moreover, TP53 mutations had prognostic significance in HER2-positive BC patients with HR-negative (HR = 3.712, p = 0.027) and pCR (HR = 6.253, p = 0.027) status and who received herceptin-only targeted therapy (HR = 4.145, p = 0.011). CONCLUSIONS: The genetic mutation profiles of Chinese HER2+ patients who received NAT were discrepant with respect to HR status or DFS events. TP53 mutations have significant prognostic value in patients with NAT for HER2-positive BC and patients benefit differently depending on HR status, the neoadjuvant regimen and response, which highlights the significance of genetic factors in treatment customization based on individual genetic and clinical characteristics.

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.

Enhanced ultraviolet-B radiation alleviates structural damages on rice leaf caused by Magnaporthe oryzae infection.

Enhanced ultraviolet-B (UV-B) radiation can change the interaction between crops and pathogens. The effects of single and compound stresses of enhanced UV-B radiation (5.0 kJ·m-2) and Magnaporthe oryzae on the morphology, anatomy, and ultrastructure of rice leaves were investigated. M. oryzae infection decreased the leaf area and thickness, reduced the stomatal area and density, and caused damages to the leaf ultrastructure, such as cytoplasm-cell wall separation, atrophy and sinking of fan-shaped bulliform cells, and chloroplast deformation. The enhanced UV-B radiation supplied before or during M. oryzae infection remarkably decreased the mycelia number of M. oryzae in leaf epidermis, increased the leaf area, leaf thickness, stomatal density, and mastoid number; and alleviated the ultrastructural damages induced by M. oryzae to keep an integral chloroplast. While the UV-B radiation was supplied after M. oryzae infection, its alleviation effects on the damages induced by M. oryzae infection on the morphology and structure of rice leaf were attenuated. Thus, the alleviation of enhanced UV-B radiation on damages induced by M. oryzae infection on rice leaves was related to its application period. The enhanced UV-B radiation supplied before or during M. oryzae infection allowed the rice leaf to resist M. oryzae infection.

HER2-low heterogeneity between primary and paired recurrent/metastatic breast cancer: Implications in treatment and prognosis.

BACKGROUND: With the largest sample size to date, the authors' objective was to investigate the incidence of primary-to-metastatic human epidermal growth factor 2 (HER2) conversion and the predictors for such conversion. Moreover, no previous studies have evaluated the prognosis of patients who have negative HER2 expression (HER2-0) versus low HER2 expression (HER2-low) when HER2 status was assessed based on all recurrent/metastatic lesions. METHODS: The authors included 1299 patients who had available HER2 status of primary breast tumors and paired recurrent/metastatic lesions at Fudan University Shanghai Cancer Center and West China Hospital. RESULTS: In total, 370 patients (28.5%) experienced primary-to-metastatic HER2 conversion. Intrapatient intermetastasis spatial heterogeneity and temporal heterogeneity of HER2 were detected. When assessing HER2 based on recurrent/metastatic tumors, patients who had HER2-0 tumors had significantly shorter overall survival than those who had HER2-low tumors in the overall population and in the estrogen receptor (ER)-negative subgroup. However, when assessing HER2 based on primary tumors, there was no difference in overall survival between patients who had HER2-0 versus HER2-low tumors. Moreover, patients who had tumors that converted from HER2-0 to HER2-low had longer overall survival than those who had consistent HER2-0 status in the ER-negative subgroup. By combining four predictors (ER status, Ki67 index, biopsy site, and disease-free interval), the authors established the first prediction tool to estimate the probability of HER2-0 tumors converting to HER2-low/positive tumors. CONCLUSIONS: Intrapatient primary-to-metastatic and intermetastatic HER2 heterogeneity were observed in this large-scale cohort study. When evaluating HER2 based on recurrent/metastatic tumors, an overall survival difference was observed between patients who had HER2-0 versus HER2-low, recurrent/metastatic breast tumors. The developed prediction tool might help clinicians screen out patients with primary HER2-0 tumors that have a high probability of HER2 status conversion and recommend them for re-biopsy, thus helping to screen out candidate patients for trastuzumab deruxtecan treatment.

A prospective comparison of a modified miniaturised hand-held epifluorescence microscope and touch imprint cytology for evaluation of axillary sentinel lymph nodes intraoperatively in breast cancer patients.

BACKGROUND: The management of axillary lymph nodes in early-stage breast cancer patients has changed considerably, with the primary focus shifting from the examination of sentinel lymph nodes (SLNs) to toward the detection of all macro-metastases. However, current methods, such as touch imprint cytology (TIC) and frozen sections, are inadequate for clinical needs. To address this issue, we proposed a novel miniaturised epifluorescence widefield microscope (MEW-M) to assess SLN status intraoperatively for improved diagnostic efficiency. METHODS: A prospective, side-by-side comparison of intraoperative SLN evaluation between MEW-M and TIC was performed. RESULTS: A total of 73 patients with 319 SLNs consecutive enrolled in this study. MEW-M showed significantly superior image quality compared to TIC (median score 3.1 vs 2.1, p < 0.0001) and had a shorter time to issue results (10.3 vs 19.4 min, p < 0.0001). Likelihood ratio analysis illustrated that the positive likelihood ratio value of MEW-M compared with TIC was infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 1 (classifying results into negative/positive), infinitely great vs 52.37 (95% CI, 21.96-124.90) in model 2 (classifying results into macro-metastasis/others, and TIC results followed the same classification as model 1), respectively. Similarly, the negative likelihood ratio values of MEW-M compared with TIC were 0.055 (95% CI, 0.018-0.160) and 0.074 (95% CI, 0.029-0.190) in model 1; and 0.019 (95% CI, 0.003-0.130) vs 0.020 (95% CI, 0.003-0.140) in model 2, respectively. CONCLUSIONS: MEW-M is a promising technique that can be utilised to provide a rapid and accurate intraoperative assessment of SLN in a clinical setting to help improve decision-making in axillary surgery.

Serum Protein-Based Profiles for the Diagnostic Model of Alzheimer's Disease.

BACKGROUND: Determining a non-invasive, serum-based diagnostic panel for early diagnosis of AD will play a significant role in the prevention and treatment of the disease. METHODS: We performed standardized clinical assessments and neuroimaging measurements in 45 patients with AD and an equal number of sex - and age-matched controls. 48 target peptides of 14 identified target proteins were quantitatively analyzed by PRM. RESULTS: 8 protein markers were screened, including SAA4, PPBP, PF4, APOA4, F10, CPB2, C1S and IGHM. An diagnosis panel including 8 proteins and demographic characteristics markers respectively was found to be the robust with a AUC of 92.3%. CONCLUSIONS: Our study developed a new panel including protein and demographic characteristics that could be used to distinguish AD from control candidates.

Impact of dietary plant flavonoids on 7,8-dihydroxyflavone transepithelial transport in human intestinal Caco-2 cells.

7,8-dihydroxyflavone (7,8-DHF) is a biologically active flavone with various physiological activities, including neuroprotection, anti-inflammation, and weight loss. Previous studies have found that the efflux protein P-glycoprotein (P-gp) significantly affects the transepithelial transport of 7,8-DHF in the intestine, resulting in its low oral bioavailability. Based on this, in this study, a Caco-2 monolayer cell model was used to investigate 14 dietary plant flavonoids as potential P-gp inhibitors, and their effects on the transepithelial transport and in vitro digestion of 7,8-DHF were explored. The results showed that among the 14 plant flavonoids, hesperetin, epigallocatechin gallate, fisetin, kaempferol, quercetin, and isoorientin increased and the apparent permeability coefficients (P app) of 7,8-DHF at AP → BL direction and lowered P app value at BL → AP direction to varying degrees, reducing the efflux ratio of 7,8-DHF less than 1.5. In particular, kaempferol and quercetin exhibited the best effect on promoting the transepithelial transport of 7,8-DHF, especially when used at molar concentration ratios of 1:1 and 1:2 with 7,8-DHF. This is beneficial for improving the oral bioavailability of 7,8-DHF. Meanwhile, 7,8-DHF was found to maintain structural stability in simulated saliva, gastric juice, and intestinal juice, and its stability was not affected by the coexistence of quercetin and kaempferol. Overall, this study provided a theoretical basis for seeking natural and safe P-gp inhibitors to improve the oral absorption of natural products.

HNAS-Reg: Hierarchical Neural Architecture Search for Deformable Medical Image Registration.

Convolutional neural networks (CNNs) have been widely used to build deep learning models for medical image registration, but manually designed network architectures are not necessarily optimal. This paper presents a hierarchical NAS framework (HNAS-Reg), consisting of both convolutional operation search and network topology search, to identify the optimal network architecture for deformable medical image registration. To mitigate the computational overhead and memory constraints, a partial channel strategy is utilized without losing optimization quality. Experiments on three datasets, consisting of 636 T1-weighted magnetic resonance images (MRIs), have demonstrated that the proposal method can build a deep learning model with improved image registration accuracy and reduced model size, compared with state-of-the-art image registration approaches, including one representative traditional approach and two unsupervised learning-based approaches.