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

Abstract Recently, mesoporous nanomaterials with widespread applications have attracted great interest in the field of drug delivery due to their unique structure and good physiochemical properties. As a biomimetic nanomaterial, mesoporous polydopamine (MPDA) possesses both a superior nature and good compatibility, endowing it with good clinical transformation prospects compared with other inorganic mesoporous nanocarriers. However, the subacute toxicity and underlying mechanisms of biomimetic mesoporous polydopamine nanoparticles remain uncertain. Herein, we prepared MPDAs by a soft template method and evaluated their primary physiochemical properties and metabolite toxicity, as well as potential mechanisms. The results demonstrated that MPDA injection at low (3.61 mg/kg) and medium doses (10.87 mg/kg) did not significantly change the body weight, organ index or routine blood parameters. In contrast, high-dose MPDA injection (78.57 mg/kg) is associated with disturbances in the gut microbiota, activation of inflammatory pathways through the abnormal metabolism of bile acids and unsaturated fatty acids, and potential oxidative stress injury. In sum, the MPDA dose applied should be controlled during the treatment. This study first provides a systematic evaluation of metabolite toxicity and related mechanisms for MPDA-based nanoparticles, filling the gap between their research and clinical transformation as a drug delivery nanoplatform.

Using detailed data on U.S. households' locations, employment, and financial portfolios, we document that individuals employed in locally clustered industries are more likely to invest in risky assets. This pattern is strongest among individuals with high labor income, employed in skilled occupations, and with strong cognitive skills. Our overall evidence suggests the relation between industry clusters and investment decisions is best explained by clusters enhancing human capital among local industry workers, in turn amplifying their effective risk tolerance. Our findings highlight the important role of local labor market composition in generating household portfolio patterns within and across geographies. [ABSTRACT FROM AUTHOR]

VO2 is renowned for its electric transition from an insulating monoclinic (M1) phase, characterized by V–V dimerized structures, to a metallic rutile (R) phase above 340 K. This transition is accompanied by a magnetic change: the M1 phase exhibits a non-magnetic spin-singlet state, while the R phase exhibits a state with local magnetic moments. Simultaneous simulation of the structural, electric, and magnetic properties of this compound is of fundamental importance, but the M1 phase alone has posed a significant challenge to the density functional theory (DFT). In this study, we show none of the commonly used DFT functionals, including those combined with on-site Hubbard U to treat 3d electrons better, can accurately predict the V–V dimer length. The spin-restricted method tends to overestimate the strength of the V–V bonds, resulting in a small V–V bond length. Conversely, the spin-symmetry-breaking method exhibits the opposite trends. Each of these two bond-calculation methods underscores one of the two contentious mechanisms, i.e., Peierls lattice distortion or Mott localization due to electron–electron repulsion, involved in the metal–insulator transition in VO2. To elucidate the challenges encountered in DFT, we also employ an effective Hamiltonian that integrates one-dimensional magnetic sites, thereby revealing the inherent difficulties linked with the DFT computations. [ABSTRACT FROM AUTHOR]

VO2 is renowned for its electric transition from an insulating monoclinic (M1) phase, characterized by V–V dimerized structures, to a metallic rutile (R) phase above 340 K. This transition is accompanied by a magnetic change: the M1 phase exhibits a non-magnetic spin-singlet state, while the R phase exhibits a state with local magnetic moments. Simultaneous simulation of the structural, electric, and magnetic properties of this compound is of fundamental importance, but the M1 phase alone has posed a significant challenge to the density functional theory (DFT). In this study, we show none of the commonly used DFT functionals, including those combined with on-site Hubbard U to treat 3d electrons better, can accurately predict the V–V dimer length. The spin-restricted method tends to overestimate the strength of the V–V bonds, resulting in a small V–V bond length. Conversely, the spin-symmetry-breaking method exhibits the opposite trends. Each of these two bond-calculation methods underscores one of the two contentious mechanisms, i.e., Peierls lattice distortion or Mott localization due to electron–electron repulsion, involved in the metal–insulator transition in VO2. To elucidate the challenges encountered in DFT, we also employ an effective Hamiltonian that integrates one-dimensional magnetic sites, thereby revealing the inherent difficulties linked with the DFT computations. [ABSTRACT FROM AUTHOR]

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 ).

Abstract Background The Organization for Economic Cooperation and Development emphasizes the importance of complex problem-solving (CPS) skills in the 21st century. CPS skills have been linked to academic performance, career development, and job competency training. Reflective learning, which includes journal writing, peer reflection, selfreflection, and group discussion, has been explored to improve critical thinking and problem-solving abilities. The development of various thinking modes and abilities, such as algorithmic thinking, creativity, and empathic concern, all affect problem-solving skills. However, there is a lack of an overall theory to relate variables to each other, which means that different theories need to be integrated to focus on how CPS skills can be effectively trained and improved. Methods Data from 136 medical students were analyzed using partial least square structural equation modeling (PLSSEM) and fuzzy set qualitative comparative analysis (fsQCA). A hypothesized model examining the associations between the CPS skills and influence factors was constructed. Results The evaluation of the structural model showed that some variables had significant influences on CPS skills, while others did not. After deleting the insignificant pathways, a structural model was built, which showed that mediating effects of empathic concern and critical thinking were observed, while personal distress only had a direct effect on CPS skills. The results of necessity showed that only cooperativity and creativity are necessary conditions for critical thinking. The fsQCA analysis provided clues for each different pathway to the result, with all consistency values being higher than 0.8, and most coverage values being between 0.240 and 0.839. The fsQCA confirmed the validity of the model and provided configurations that enhanced the CPS skills. Conclusions This study provides evidence that reflective learning based on multi-dimensional empathy theory and 21 stcentury skills theory can improve CPS skills in medical students. These results have practical implications for learning and suggest that educators should consider incorporating reflective learning strategies that focus on empathy and 21 stcentury skills to enhance CPS skills in their curricula.

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

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

Breast cancer is the most common malignant tumour in women. Our research on alloimperatorin from Angelica dahurica showed that alloimperatorin inhibited breast cancer cell viability in a concentration-and time-dependent manner; it also showed that apoptosis and ferroptosis inhibitors significantly weakened the antisurvival effect of alloimperatorin. Alloimperatorin clearly induced breast cancer cell apoptosis and increased the activities of caspase-3, caspase-8, caspase-9, and poly (ADP-ribose) polymerase; it also caused significant mitochondrial shrinkage, promoted the accumulation of [Fe.sup.2+], reactive oxygen species, and malondialdehyde, and significantly reduced mRNA and protein expression levels of SLC7A11 and GPX4, indicating that alloimperatorin induces ferroptosis. In addition, alloimperatorin significantly promoted Kelch-like ECH-associated protein 1 (Keap1) expression; although it did not affect the expression of PGAM5 (mitochondrial serine/threonine protein phosphatase) and apoptosis-inducing factor mitochondria associated 1 (AIFM1), it significantly reduced the phosphorylation level of AIFM1. After downregulating the expression of Keap1, PGAM5, or AIFM1, the inhibitory effect of alloimperatorin on cell viability was significantly weakened, indicating that alloimperatorin regulates the Keap1/PGAM5/AIFM1 pathway to promote oxeiptosis. Alloimperatorin significantly inhibited the invasion of breast cancer cells, while Keap1 siRNA or GPX4 overexpression vectors significantly enhanced cell invasion and effectively reversed the anti-invasive effect of alloimperatorin. Therefore, alloimperatorin induces breast cancer cell apoptosis, ferroptosis, and oxeiptosis, thereby inhibiting cell growth and invasion. Key words: breast cancer, traditional Chinese medicine, alloimperatorin, ferroptosis, oxeiptosis Le cancer du sein est la tumeur maligne la plus fréquente chez les femmes. La recherche réalisée par les auteurs sur l'alloimpératorine d'Angelica dahurica a montré que l'alloimpératorine inhibait la viabilité des cellules du cancer du sein de manière dépendante de la concentration et du temps; elle a également montré que les inhibiteurs de l'apoptose et de la ferroptose affaiblissent significativement l'effet anti-survie de l'alloimpératorine. L'alloimpératorine induisait de manière évidente l'apoptose des cellules de cancer du sein et augmentait les activités de la caspase-3, de la caspase-8, de la caspase-9 et de la PARP; elle provoquait également une diminution importante du volume des mitochondries, favorisait l'accumulation de [Fe.sup.2+], d'ERO et de MDA, et réduisait de manière significative les niveaux d'expression de l'ARNm et des protéines SLC7A11 et de GPX4, ce qui indique que l'alloimpératorine induit la ferroptose. En outre, l'alloimpératorine favorisait significativement l'expression de Keap1; bien qu'elle n'ait pas affecté l'expression de PGAM5 et d'AIFM1, elle réduisait significativement le niveau de phosphorylation d'AIFM1. Après avoir régulé à la baisse l'expression de Keap1, PGAM5 ou AIFM1, l'effet inhibiteur de l'alloimpératorine sur la viabilité cellulaire était considérablement affaibli, ce qui indique que l'alloimpératorine régule la voie Keap1/PGAM5/AIFM1 pour promouvoir l'oxeiptose. L'alloimpératorine inhibait de manière significative l'invasion des cellules cancéreuses du sein, tandis qu'un ARNsi de Keap1 ou des vecteurs de surexpression de GPX4 augmentaient de manière significative l'invasion cellulaire et inversaient efficacement l'effet anti-invasif de l'alloimpératorine. Par conséquent, l'alloimpératorine induit l'apoptose, la ferroptose et l'oxeiptose des cellules du cancer du sein, inhibant ainsi la croissance et l'invasion cellulaires. [Traduit par la Rédaction] Mots-clés: cancer du sein, médecine traditionnelle chinoise, alloimpératorine, ferroptose, oxeiptose, Introduction Breast cancer is the most common malignant tumour in women worldwide and the leading cause of cancer-related death in women (Noor et al. 2021; Schick et al. 2021). Early [...]

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

Copy number alterations are pivotal genetic events in triple-negative breast cancer. Here the authors show the amplification of ENSA at the 1q21.3 region promotes the progression of TNBC via up-regulation of cholesterol biosynthesis.

Abstract Background Although long noncoding RNA HLA complex group 18 (lncRNA HCG18) has been suggested to regulate cell growth in several tumours, the function of HCG18 in epithelial ovarian cancer (EOC) and its mechanism are still unclear. Methods shRNAs were applied to reduce HCG18 and related genes. For overexpression of miRNA, a miRNA mimic was transfected into cells. Quantitative real-time PCR (qRT–PCR) was used to detect levels of HCG18, miR-29a/b, and mRNAs. MTT, colony formation, wound healing and Transwell assays were used to evaluate cell proliferation, migration and invasion, respectively. A luciferase reporter assay was utilized to evaluate NF-κB activity and the binding of miRNAs with HCG18 or TRAF4/5. BALB nude mice injected with cells stably expressing shHCG18 or shNC were used for in vivo modelling. Subcutaneous tumour growth was monitored in nude mice, and immunohistochemistry (IHC) was used to determine expression of the proliferation marker Ki67. Results Abnormal expression of HCG18 and miR-29a/b was observed in EOC tissues. Knockdown of HCG18 using shRNA inhibited proliferation, migration, EMT and the proinflammatory pathway in EOC cells. miR-29a/b mimics and TRAF4/5 knockdown exhibited effects similar to HCG18 knockdown. Further experiments suggested that HCG18 directly targets miR-29a/b and upregulates TRAF4/5 expression, which are inhibited by targeting miR-29a/b. Moreover, overexpression of TRAF4/5 antagonized the inhibitory effect of HCG18 knockdown, suggesting that they are involved in HCG18-mediated oncogenic effects. Silencing HCG18 reduced tumour size and levels of Ki67 and TRAF4/5 while increasing miR-29a/b levels in vivo. Conclusions Taken together, our data revealed an oncogenic signalling pathway mediated by HCG18 in ovarian cell lines, which functions as a ceRNA of miR-29a/b and thus derepresses expression levels of TRAF4/5, facilitating NF-κB pathway-mediated promotion of EOC cell proliferation and migration.