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El presente estudio investigó si la satisfacción con la vida se predice a partir de la felicidad subjetiva, afectos positivos y negativos, alteración psicológica y emociones de gratitud y si la emoción de gratitud está mediando la relación con la felicidad subjetiva, los afectos y la satisfacción con la vida. Se hicieron correlación de Pearson, pruebas de regresión lineal múltiple y modelos de mediación en una muestra de 1537 adultos españoles, 73.6% mujeres y 26.4% hombres, edad 18-88 años (M = 42.56 años; DT = 16.29). Se halló que las emociones de gratitud median la relación entre felicidad subjetiva y satisfacción con la vida y entre los afectos positivos y la satisfacción con la vida. Los afectos positivos son los que más se relacionan con la satisfacción con la vida, seguidos por la felicidad subjetiva y las emociones de gratitud. Los hombres están más satisfechos con la vida cuando sienten menos afecto negativo. Además, las emociones de gratitud median la relación entre felicidad subjetiva y satisfacción con la vida y entre los afectos positivos y la satisfacción con la vida. La diferencia principal radica en que las emociones de gratitud son más fuertes en las mujeres que en los hombres.(AU)

This study aims to examine the predictability of satisfaction with life on the basis of subjective happiness, positive and negative affect, psy-chological disturbance and emotion of gratitude. It also seeks to assess whether the emotion of gratitude is a mediating variable withsubjective happiness, affect, and satisfaction with life. Statistical analyses of Pearson'scorrelation, multiple linear regression tests, and mediation models were conducted on asample of 1537 Spanish adults, 73.6% were females, 26.4% males, age between 18-88 yearsold (M = 42.56; SD = 16.29). The emo-tions of gratitude were found to mediate therelationship between subjec-tive happiness and satisfaction with life and between positiveaffect and satisfaction with life. Of the variables studied, positive affect is the most related tosatisfaction with life, followed by subjective happiness and emo-tions of gratitude. Maleparticipants are more satisfied with life when they feel the less negative affect. Regardingmediation models, emotions of grat-itude mediate the relationship between subjectivehappiness and satisfac-tion with life and between positive affect and satisfaction with life. Themaindifferenceis thatemotions of gratitudearestronger infemalesthan in males.(AU)

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Purpose: Non-suicidal self-injury (NSSI) is a growing public health concern among college students, with cybervictimization (CV) emerging as a significant contributing factor. Grounded in the experiential avoidance theory, this study investigates the mediating roles of cognitive fusion and negative emotions in the relationship between CV and NSSI, providing new insights into these key variables. Methods: A convenience sample of 457 undergraduate students (29% male; mean age 18.36±0.66 years) from two universities in Fujian Province participated in this study. Data were collected using the Cyberbullying Victimization Scale, Cognitive Fusion Questionnaire, Positive and Negative Affect Schedule, and Non-Suicidal Self-Injury Scale. Descriptive statistics and Pearson correlation analysis were conducted using SPSS 25.0, while the mediating effects were analyzed using Process 3.5. Results: (1) Significant positive correlations were found among CV, cognitive fusion, negative emotions, and NSSI (p < 0.01). (2) CV was directly associated with NSSI (ß = 0.22, p < 0.001) and positively predicted both cognitive fusion (ß = 0.17, p < 0.001) and negative emotions (ß = 0.15, p < 0.01). Additionally, cognitive fusion (ß = 0.16, p < 0.01) and negative emotions (ß = 0.11, p < 0.05) significantly predicted NSSI. (3) Mediation analyses revealed that cognitive fusion and negative emotions mediated the CV-NSSI relationship through three pathways: CV→cognitive fusion→NSSI (mediation effect = 0.026), CV→negative emotions→NSSI (mediation effect = 0.02), and CV→cognitive fusion→negative emotions→NSSI (mediation effect = 0.01). Conclusion: The study confirms that CV influences NSSI indirectly through cognitive fusion and negative emotions, supporting the experiential avoidance model. These findings underscore the importance of addressing cognitive and emotional processes in interventions aimed at reducing NSSI among college students.

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PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive breast cancer histological type that is predictive of poor outcomes, shorter remission periods and reduced survival. TNBC is treated with surgery and neo/adjuvant chemotherapy, with evidence of association between longer periods from surgery to adjuvant chemotherapy (time to chemotherapy, TTC) and poorer survival outcomes. This study investigated regional differences in TTC period between regions and ethnic groups to evaluate equity of care in the English TNBC population. Time from neoadjuvant chemotherapy to surgery (time to surgery, TTS) was also compared between groups. METHODS: This retrospective cohort study compared TTC and TTS periods in TNBC patients in England over a two-year period. TTC and TTS were compared by English region and ethnicity, testing for significant differences in treatment pathway timing by these demographics. RESULTS: 1347 TNBC patients were included in the study. Significant regional differences in TTC were observed, with the longest median period of 50 days (IQR 36, 83) in the Midlands compared to 38 days (IQR 27, 55) in the North West (p < 0.001). No significant differences in TTS were observed between regions. Ethnicity was not significantly associated with timeliness of neo/adjuvant chemotherapy initiation (p > 0.05). CONCLUSION: These findings suggest regional differences in TTC for patients treated with surgery and chemotherapy for TNBC. Given evidence of increased mortality risk as the TTC period increases, the causes of regional disparities warrant further investigation. This study can inform targets for improvement in the delivery of adjuvant chemotherapy in cancer treatment centres in England.

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Modulation of estrogen receptor (ER) and progesterone receptor (PR) expression, as well as their emerging functional crosstalk, remains a potential approach for enhancing the response to hormonal therapy in breast cancer. Aberrant epigenetic alterations induced by histone deacetylases (HDACs) were massively implicated in dysregulating the function of hormone receptors in breast cancer. Although much is known about the regulation of ER signaling by HDAC, the precise role of HDAC in modulating the expression of PR and its impact on the outcomes of hormonal therapy is poorly defined. Here, we demonstrate the involvement of HDAC6 in regulating PR expression in breast cancer cells. The correlation between HDAC6 and hormone receptors was investigated in patients' tissues by immunohistochemistry (n = 80) and publicly available data (n = 3260) from breast cancer patients. We explored the effect of modulating the expression of HDAC6 as well as its catalytic inhibition on the level of hormone receptors by a variety of molecular analyses, including western blot, immunofluorescence, Real-time PCR, RNA-seq analysis and chromatin immunoprecipitation. Based on our in-silico and immunohistochemistry analyses, HDAC6 levels were negatively correlated with PR status in breast cancer tissues. The downregulation of HDAC6 enhanced the expression of PR-B in hormone receptor-positive and triple-negative breast cancer (TNBC) cells. The selective targeting of HDAC6 by tubacin resulted in the enrichment of the H3K9 acetylation mark at the PGR-B gene promoter region and enhanced the expression of PR-B. Additionally, transcriptomic analysis of tubacin-treated cells revealed enhanced activity of acetyltransferase and growth factor signaling pathways, along with the enrichment of transcription factors involved in the transcriptional activity of ER, underscoring the crucial role of HDAC6 in regulating hormone receptors. Notably, the addition of HDAC6 inhibitor potentiated the effects of anti-ER and anti-PR drugs mainly in TNBC cells. Together, these data highlight the role of HDAC6 in regulating PR expression and provide a promising therapeutic approach for boosting breast cancer sensitivity to hormonal therapy.

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Terrestrial enhanced rock weathering (ERW) is a promising carbon dioxide removal technology that consists in applying ground silicate rock such as basalt on agricultural soils. On top of carbon sequestration, ERW has the potential to raise the soil pH and release nutrients, thereby improving soil fertility. Despite these possible co-benefits, concerns such as heavy metal pollution or soil structure damage have also been raised. To our knowledge, these contrasted potential effects of ERW on soil fertility have not yet been simultaneously investigated. This field trial aimed at assessing the impact of ERW on biological, physical, and chemical soil properties in a temperate agricultural context. To do so, three vineyard fields in Switzerland were selected for their distinct geochemical properties and were amended with basaltic rock powder at a dose of 20 tons per hectare (2 kg.m-2). On each field, basaltic rock powder was either applied one year before the sampling campaign, one month before the sampling campaign, or not applied (control) for a total of 27 plots with 9 repetitions of each level. Overall, basaltic rock powder addition had a predominantly positive to neutral effect on soil fertility. Most soil properties showed no significant change either 1 month or 1 year post application. Nevertheless, our study highlighted a significant increase in earthworm abundance (+71 % on average), soil respiration (+50 %) and extractable sodium concentration (+23 %) as early as 1 month post application. The higher soil respiration raises the question of CO2 losses from organic matter mineralization that could limit ERW's efficiency. The increase in sodium raises concerns about a sodification risk potentially damaging soil fertility. These elements now require further investigation before enhanced rock weathering can be considered a viable and secure carbon dioxide removal technology.

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The ever-increasing power consumption in integrated circuits has raised concerns about the relentless doubling of transistor density in chips and cost drop per combinational/sequential circuits. To address the physical limit of thermionic emission carrier transport (i.e., subthreshold swing >60 mV/decade at 300 K), alternative charge-transport mechanisms or the implementation of functional substances have been attempted but without appreciable success. One such choice is to take advantage of negative differential resistance with the activation of localized electrons or migration of atom and oxygen vacancies to extend the capabilities of Si-transistors. However, inconsistency in current during forward/reverse bias sweep is confronted as a notable weak point. This work proposes an eye-catching solution to modulating potential distribution between a resistance switching layer and a transistor by employing charge trapping within a hafnium zirconium oxide layer. This approach introduces features advancing the potential of "More Moore" technologies.

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As a common form of negative interpersonal interaction in childhood, school bullying is closely related to individual negative cognition. Few studies have assessed whether there is an interaction between different kinds of school bullying roles and negative cognition. The present study administered four questionnaire follow-up tests among Chinese children over two years to explore the bidirectional relation and underlying mechanisms between bullying/victimization and negative automatic thoughts (about self/others). A total of 993 children with MT1age = 9.66 ± 0.72 participated in the study, including 647(65.16%) boys and 346(34.84%) girls. Results indicated a bidirectional relation between victimization and negative automatic thoughts (about self/others); negative automatic thoughts (about self/others) predicting bullying; negative automatic thoughts (about self/others) form two vicious cycles with victimization separately, in which victimization plays a mediating role. The findings suggest that considering improving children's negative cognition of self and others is an important pathway to reduce the occurrence of bullying and victimization in children and to stop children from falling into the cycle of victimization, which is crucial for children to have healthy relationships later in adolescence.

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BACKGROUND: Absolute lymphocyte count (ALC) is a predictive and prognostic factor for various tumor types, including breast cancer. Palbociclib is a CDK4/6 inhibitor widely used for the treatment of metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer. However, predictive biomarkers of the efficacy of palbociclib remain unelucidated. We conducted a retrospective study to examine the predictive value of the baseline ALC in patients treated with palbociclib. METHODS: The medical records of patients with ER-positive, HER2-negative breast cancer treated with palbociclib plus hormonal therapy between December 2017 and December 2021 were analyzed retrospectively. The cutoff value of ALC was set at 1800 cells/µL at the initiation of palbociclib treatment. The clinical benefit rate (CBR) was defined as the rate of complete or partial response or stable disease for at least 6 months. Progression-free survival (PFS) rates were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses were performed using Cox proportional hazards regression. RESULTS: All of the 202 patients were women, with a median age of 59 years and a performance status (PS) of ≤ 2. The median numbers of lines of chemotherapy and endocrine therapy before palbociclib treatment were 0 (range, 0-9) and 1 (range, 0-7), respectively. Fifty-one patients had liver metastases. Forty-six patients tested negative for progesterone receptor (PgR) expression. The median follow-up time was 9.1 months. The CBR was significantly higher in the ALC-high group than in the ALC-low group (79% vs. 60%; P = 0.018). The median PFS was significantly longer in the ALC-high group than in the ALC-low group (26.8 months vs. 8.4 moths, respectively; P = 0.000013). ALC, age, PS, PgR status, prior chemotherapy, prior endocrine therapy, and liver metastasis were entered into the multivariate analysis. ALC was identified as an independent factor for PFS (P = 0.00085), along with liver metastasis (P = 0.0020), PS (P = 0.026), and prior endocrine therapy (P = 0.019). CONCLUSION: ALC can serve as a predictor of palbociclib efficacy in patients with metastatic ER-positive, HER2-negative breast cancer.

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BACKGROUND: Triple-negative breast cancer (TNBC), known for its aggressiveness and limited treatment options, presents a significant challenge. Adoptive cell transfer, involving the ex vivo generation of antigen-specific T cells from peripheral blood mononuclear cells (PBMCs), emerges as a promising approach. The overexpression of mesothelin (MSLN) and nucleolin (NCL) in TNBC samples underscores their potential as targets for T cell therapy. This study explored the efficacy of multi-peptide pulsing of PBMCs to generate MSLN/NCL-specific T cells targeting MSLN+/NCL+ TNBC cells. METHODS: TNBC patient samples were confirmed for both MSLN and NCL expression via immunohistochemistry. Synthesized MSLN and NCL peptides were combined and administered to activate PBMCs from healthy donors. The cancer-killing ability of the resultant T cells was assessed using crystal violet staining, and their subtypes and cytotoxic cytokines were characterized through flow cytometry and cytokine bead array. RESULTS: Findings showed that 85.3% (127/149) of TNBC cases were positive for either MSLN or NCL, or both; with single positivity rates for MSLN and NCL of 14.1% and 28.9%, respectively. MSLN and NCL peptides, with high binding affinity for HLA-A*02, were combined and introduced to activated PBMCs from healthy donors. The co-pulsed PBMCs significantly induced TEM and TEMRA CD3+/CD8+ T cells and IFN-γ production, compared to single-peptide pulsed or unpulsed conditions. Notably, MSLN/NCL-specific T cells successfully induced cell death in MSLN+/NCL+ MDA-MB-231 cells, releasing key cytotoxic factors such as perforin, granzymes A and B, Fas ligand, IFN-γ, and granulysin. CONCLUSIONS: These findings serve as a proof-of-concept for using multiple immunogenic peptides as a novel therapeutic approach in TNBC patients.

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Background: The identification of compound-protein interactions (CPIs) is crucial for drug discovery and understanding mechanisms of action. Accurate CPI prediction can elucidate drug-target-disease interactions, aiding in the discovery of candidate compounds and effective synergistic drugs, particularly from traditional Chinese medicine (TCM). Existing in silico methods face challenges in prediction accuracy and generalization due to compound and target diversity and the lack of largescale interaction datasets and negative datasets for model learning. Methods: To address these issues, we developed a computational model for CPI prediction by integrating the constructed large-scale bioactivity benchmark dataset with a deep learning (DL) algorithm. To verify the accuracy of our CPI model, we applied it to predict the targets of compounds in TCM. An herb pair of Astragalus membranaceus and Hedyotis diffusaas was used as a model, and the active compounds in this herb pair were collected from various public databases and the literature. The complete targets of these active compounds were predicted by the CPI model, resulting in an expanded target dataset. This dataset was next used for the prediction of synergistic antitumor compound combinations. The predicted multi-compound combinations were subsequently examined through in vitro cellular experiments. Results: Our CPI model demonstrated superior performance over other machine learning models, achieving an area under the Receiver Operating Characteristic curve (AUROC) of 0.98, an area under the precision-recall curve (AUPR) of 0.98, and an accuracy (ACC) of 93.31% on the test set. The model's generalization capability and applicability were further confirmed using external databases. Utilizing this model, we predicted the targets of compounds in the herb pair of Astragalus membranaceus and Hedyotis diffusaas, yielding an expanded target dataset. Then, we integrated this expanded target dataset to predict effective drug combinations using our drug synergy prediction model DeepMDS. Experimental assay on breast cancer cell line MDA-MB-231 proved the efficacy of the best predicted multi-compound combinations: Combination I (Epicatechin, Ursolic acid, Quercetin, Aesculetin and Astragaloside IV) exhibited a half-maximal inhibitory concentration (IC50) value of 19.41 µM, and a combination index (CI) value of 0.682; and Combination II (Epicatechin, Ursolic acid, Quercetin, Vanillic acid and Astragaloside IV) displayed a IC50 value of 23.83 µM and a CI value of 0.805. These results validated the ability of our model to make accurate predictions for novel CPI data outside the training dataset and evaluated the reliability of the predictions, showing good applicability potential in drug discovery and in the elucidation of the bioactive compounds in TCM. Conclusion: Our CPI prediction model can serve as a useful tool for accurately identifying potential CPI for a wide range of proteins, and is expected to facilitate drug research, repurposing and support the understanding of TCM.

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Objective: Triple-negative breast cancer (TNBC) is a common cancer with high aggressiveness and high mortality in women. Recently, a plenty of studies have indicated that long non-coding RNAs (lncRNAs) exert the crucial function in human cancers, TNBC is included. The carcinogenicity of lncRNA long intergenic non-protein coding RNA 1503 (LINC01503) has been confirmed in several cancers, nevertheless, its function in TNBC still unclear. Therefore, our study aimed to reveal the underlying mechanism of LINC01503 in TNBC. Methods: In our study, RT-qPCR was performed to detect the expression of LINC01503 in TNBC cells. The proliferative, invasive, migratory and apoptotic abilities of TNBC cells were detected by functional assay such as CCK-8, clone formation, EdU staining, transwell, and flow cytometry. RIP, RNA pull down, and luciferase assay revealed interactions between LINC01503, miR-335-5p, and sphingolipid transporter protein 2 (SPNS2). Finally, rescue experiments were performed to validate the previous results. Results: LINC01503 expression was singularly high in TNBC cells. LINC01503 knockdown could restrain cell proliferation, invasion and migration, but accelerated cell apoptosis in TNBC. What's more, miR-335-5p could be sponged by LINC01503 in TNBC. We also found that overexpressed miR-335-5p could inhibit cell proliferation, migration and invasion and facilitates cell apoptosis. Moreover, SPNS2 was the target gene of miR-335-5p and it functioned as an oncogene in TNBC cells. Finally, we found that overexpressed SPNS2 or inhibited miR-335-5p could reverse the suppressive function of silencing LINC01503 on TNBC progression. Conclusion: LINC01503 could facilitate cell proliferation, migration and invasion of TNBC by sponging miR-335-5p to elevate SPNS2 expression.

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Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p = 5.81x10-11) and 4.78 (p = 0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3ß, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kß inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kß did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRß, GSK3ß, STAT3, and STAT6. RNA silencing of PDGFRß in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRß signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.

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Lipooligosaccharides are the most abundant cell surface glycoconjugates on the outer membrane of Gram-negative bacteria. They play important roles in host-microbe interactions. Certain Gram-negative pathogenic bacteria cap their lipooligosaccharides with the sialic acid, N-acetylneuraminic acid (Neu5Ac), to mimic host glycans that among others protects these bacteria from recognition by the hosts immune system. This process of molecular mimicry is not fully understood and remains under investigated. To explore the functional role of sialic acid-capped lipooligosaccharides at the molecular level, it is important to have tools readily available for the detection and manipulation of both Neu5Ac on glycoconjugates and the involved sialyltransferases, preferably in live bacteria. We and others have shown that the native sialyltransferases of some Gram-negative bacteria can incorporate extracellular unnatural sialic acid nucleotides onto their lipooligosaccharides. We here report on the expanded use of native bacterial sialyltransferases to incorporate neuraminic acids analogs with a reporter group into the lipooligosaccharides of a variety of Gram-negative bacteria. We show that this approach offers a quick strategy to screen bacteria for the expression of functional sialyltransferases and the ability to use exogenous CMP-Neu5Ac to decorate their glycoconjugates. For selected bacteria we also show this strategy complements two other glycoengineering techniques, Metabolic Oligosaccharide Engineering and Selective Exo-Enzymatic Labeling, and that together they provide tools to modify, label, detect and visualize sialylation of bacterial lipooligosaccharides.

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BACKGROUND: This study aimed to investigate the role of Jumonji AT Rich Interacting Domain 2 (JARID2) in regulating triple-negative breast cancer (TNBC) stemness and its mechanism. RESEARCH DESIGN AND METHODS: Bioinformatics analysis examined JARID2 expression, prognosis, and transcription factors. Quantitative polymerase chain reaction, western blot, and immunohistochemistry detected expression. Dual luciferase reporter gene and chromatin immunoprecipitation assays verified binding. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay detected viability and proliferation. Sphere formation assay detected the sphere formation efficiency. Flow cytometry detected CD44+/CD24- -marked stem cells. A xenograft tumor model verified the effect of JARID2 in vivo. RESULTS: JARID2 and nuclear transcription factor Y subunit α (NFYA) were upregulated in TNBC tissues and positively correlated. Knockdown of JARID2 or NFYA inhibited cell stemness by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) signaling pathway. Enforced JARID2 expression rescued the suppressive effect of NFYA knockdown on the PI3K/AKT signaling pathway and cell stemness. Knockdown of JARID2 inhibited tumor growth and cell stemness in mice but was alleviated by concurrent overexpression of NFYA. CONCLUSIONS: NFYA promotes TNBC cell stemness by upregulating JARID2 expression and regulating the PI3K/AKT signaling pathway, suggesting JARID2 as a potential target for innovating drugs that target TNBC stem cells.

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The complex heterogeneity of tumor microenvironment (TME) of triple-negative breast cancer (TNBC) presents a significant obstacle to cytotoxic immune response and successful treatment, building up one of the most hostile oncological phenotypes. Among the most abundant TME components, tumor-associated macrophages (TAMs) have pivotal pro-tumoral functions, involving discordant roles for the nuclear factor kappa-B (NF-κB) transcription factors and directing to higher levels of pathway complexity. In both resting macrophages and TAMs, we recently revealed the existence of the uncharacterized NF-κB p65/p52 dimer. In the present study, we demonstrated its enhanced active nuclear localization in TAMs and validated selected immune target genes as directly regulated by dimer binding on DNA sequences. We demonstrated by ChIP-qPCR that p65/p52 enrichment on HSPG2 and CSF-1 regulatory regions is strictly dependent on macrophage polarization and tumor environment. Our data provide novel mechanisms of transcriptional regulation in TAMs, orchestrated by the varied and dynamic nature of NF-κB combinations, which needs to be considered when targeting this pathway in cancer therapies. Our results offer p65/p52, together with identified regulatory regions on genes impacting macrophage behavior and tumor biology, as novel molecular targets for TNBC, aimed at modulating TAMs functions towards anti-tumoral phenotypes and thus improving cancer treatment outcomes.

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OBJECTIVES: Triple-negative breast cancer (TNBC) is the deadliest subtype of breast cancer (BC). Tumor-derived extracellular vesicles (EVs) trigger tumor progression by promoting M2 polarization. Some lncRNAs can be encapsulated into EVs for intercellular communication. Herein, we investigated the mechanism of TNBC-derived EV-shuttled lncRNA MALAT1 on macrophage polarization/tumorigenesis. METHODS: BC-associated targeted EV-derived lncRNAs were screened. Tumor tissues/tissues adjacent to cancer of TNBC patients, and blood samples of all subjects were collected. MALAT1/POSTN mRNA levels in tumor tissues/tissues adjacent to cancer, and MALAT1 expression in EVs and its correlation with TNBC patient overall survival were assessed by RT-qPCR/Kaplan-Meier survival analysis/log-rank test. TNBC patient M2 infiltration was detected by flow cytometry. MALAT1/POSTN levels in EVs/macrophages were regulated by transfection. Hippo/YAP activation was determined by Western blot. Nude mouse xenograft model was established and metastasis was detected by H&E staining. RESULTS: MALAT1/POSTN were up-regulated and correlated with M2 infiltration/poor prognosis in TNBC patients. TNBC-derived EVs induced M2 polarization. MALAT1 was highly expressed in TNBC-derived EVs and could be transferred to macrophages via EVs to induce M2 polarization. POSTN overexpression diminished the inhibitory effect of MALAT1 knockdown on M2 markers. EVs activated the Hippo/YAP pathway in macrophages. The Hippo/YAP pathway inhibition abrogated the effect of POSTN overexpression on M2 marker expression. TNBC-EV-derived MALAT1 facilitated M2 polarization, and thus promoting occurrence and metastasis of TNBC in vitro and in vivo. CONCLUSIONS: TNBC-EV-derived MALAT1 activated the Hippo/YAP axis by up-regulating POSTN, thereby inducing M2 polarization to promote TNBC occurrence and metastasis in vivo.

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Purpose: To investigate the inhibitory effect of antimicrobial peptide merecidin on triple-negative breast cancer (TNBC) and the mechanism of inhibiting epithelial-mesenchymal transformation (EMT) by regulating miR-30d-5p/vimentin. Methods: TNBC cell lines (MDA-MB-231, MDA-MB-468) were treated with merecidin to assess proliferation, migration, invasion ability, and EMT. Confocal laser localization was used to examine the role of merecidin and TNBC cells. The relationship between merecidin and miR-30d-5p was determined through RT-qPCR and dual-luciferase reporter gene, and the relationship between merecidin and vimentin was verified through pulling down the experiment. The effects of miR-30d-5p on the migration and invasion ability of TNBC cells were confirmed through scratch and transwell experiments. Vimentin levels, tumor volume, shape, size, and weight were observed in the MDA-MB-231 subcutaneous tumor model in nude mice. Results: merecidin inhibited the proliferation, migration, invasion, and EMT of TNBC cells. merecidin was primarily located in the cytoplasm of TNBC cells, and the expression of miR-30d-5p was low in TNBC cells. merecidin significantly up-regulated the expression of miR-30d-5p. miR-30d-5p negatively regulated vimentin. merecidin could bind to vimentin in vitro. miR-30d-5p inhibited the migration and invasion ability of TNBC cells, while vimentin promoted their migration and invasion ability. Down-regulation of miR-30d-5p or overexpression of vimentin partially counteracted the inhibitory effects of merecidin on TNBC cell migration, invasion ability, and EMT. In nude mouse tumor models, merecidin significantly suppressed tumor growth. Conclusion: Merecidin effectively blocks the EMT process and inhibits the migration and invasion of TNBC cells by regulating miR-30d-5p/vimentin.

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Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.

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BACKGROUND: There is scarce data concerning the relationship between negative life events (NLEs)* and current and new depressive episodes by age. METHODS: Cross-sectional (baseline) and prospective analyses (4-year/8-year follow-ups) were performed in 15,105 civil servants in 6 cities in Brazil classified according to age strata at baseline: 1st(35-44), 2nd(45-54), 3rd(55-64), and 4th(65-74) years. The independent variable was NLEs in the last year (robbery, hospitalization, death of a relative, financial hardship, and rupture of a love relationship) collected at baseline. The dependent variable was depressive episodes assessed at baseline (current), and 4-year/8-year follow-ups (new). We built logistic (Odds Ratio[OR];95 % Confidence Interval[CI]) in the cross-sectional analysis and Poisson regression models (Relative Risk[RR], [CI]) in the prospective analysis. RESULTS: Robbery, hospitalization, financial hardship, rupture of a relationship were associated with current depressive episodes concentrated in the 35-44 age range, while for new depressive episodes, the association of hospitalization, death of a relative, and financial hardship were concentrated in the 45-54 age stratum. Financial hardship was associated with current depressive episodes in all age-strata: 1st: OR, 2.77(CI, 1.83-4.19); 2nd: OR, 1.71(CI, 1.26-2.34); 3rd: OR, 1.68(CI,1.15-2.46); 4th, OR, 4.07(CI, 1.24-13.34), and new depressive episodes: 1st: RR, 1.45(CI, 1.09-1.93); 2nd RR, 1.46(CI: 1.15-1.84); 3rd: RR, 1.97(CI, 1.38-2.82). Rupture of a relationship was associated only with current depressive episode, while death of a relative only with new depressive episode. LIMITATION: We cannot rule out the possibility of recall bias, since NLEs` information was self-reported. CONCLUSION: The association between NLEs with depressive episodes was concentrated in youngers.

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Insufficient energy intake to meet energy expenditure demands of physical activity can result in systemic neuroendocrine and metabolic abnormalities in activity-dependent anorexia and relative energy deficiency in sport (REDs). REDs affects >40% of athletes, yet the lack of underlying molecular changes has been a hurdle to have a better understanding of REDs and its treatment. To assess the molecular changes in response to energy deficiency, we implemented the "exercise-for-food" paradigm, in which food reward size is determined by wheel-running activity. By using this paradigm, we replicated several aspects of REDs in female and male mice with high physical activity and gradually reduced food intake, which results in weight loss, compromised bone health, organ-specific mass changes, and altered rest-activity patterns. By integrating transcriptomics of 19 different organs, we provide a comprehensive dataset that will guide future understanding of REDs and may provide important implications for metabolic health and (athletic) performance.

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