Case report: Successful treatment of a rare HER2-positive advanced breast squamous cell carcinoma.

Background: Breast squamous cell carcinoma (SCC) is an uncommon and highly aggressive variant of metaplastic breast cancer. Despite its rarity, there is currently no consensus on treatment guidelines for this specific subtype. Previous studies have demonstrated that chemotherapy alone has limited efficacy in treating breast SCC. However, the potential for targeted therapy in combination with chemotherapy holds promise for future treatment options. Case presentation: In this case report, we present a patient with advanced HER2-positive breast SCC, exhibiting a prominent breast mass, localized ulcers, and metastases in the lungs and brain. Our treatment approach involved the administration of HER2-targeted drugs in conjunction with paclitaxel, resulting in a sustained control of tumor growth. Conclusion: This case represents a rare occurrence of HER2-positive breast SCC, with limited available data on the efficacy of previous HER2-targeted drugs in treating such patients. Our study presents the first application of HER2-targeted drugs in this particular case, offering novel therapeutic insights for future considerations. Additionally, it is imperative to conduct further investigations to assess the feasibility of treatment options in a larger cohort of patients.

"Listen to your heart": A novel interoceptive strategy for real-time fMRI neurofeedback training of anterior insula activity.

Real-time fMRI (rt-fMRI) neurofeedback (NF) training is a novel non-invasive technique for volitional brain modulation. Given the important role of the anterior insula (AI) in human cognitive and affective processes, it has become one of the most investigated regions in rt-fMRI studies. Most rt-fMRI insula studies employed emotional recall/imagery as the regulation strategy, which may be less effective for psychiatric disorders characterized by altered emotional processing. The present study thus aimed to examine the feasibility of a novel interoceptive strategy based on heartbeat detection in rt-fMRI guided AI regulation and its associated behavioral changes using a randomized double-blind, sham feedback-controlled between-subject design. 66 participants were recruited and randomly assigned to receive either NF from the left AI (LAI) or sham feedback from a control region while using the interoceptive strategy. N = 57 participants were included in the final data analyses. Empathic and interoceptive pre-post training changes were collected as behavioral measures of NF training effects. Results showed that participants in the NF group exhibited stronger LAI activity than the control group with LAI activity being positively correlated with interoceptive accuracy following NF training, although there were no significant increases of LAI activity over training sessions. Importantly, ability of LAI regulation could be maintained in a transfer session without feedback. Successful LAI regulation was associated with strengthened functional connectivity of the LAI with cognitive control, memory and learning, and salience/interoceptive networks. The present study demonstrated for the first time the efficacy of a novel regulation strategy based on interoceptive processing in up-regulating LAI activity. Our findings also provide proof of concept for the translational potential of this strategy in rt-fMRI AI regulation of psychiatric disorders characterized by altered emotional processing.

Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis.

BACKGROUND: Chronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer. METHODS: Breast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry. RESULTS: Breast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases. CONCLUSIONS: Chronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

Brain-derived neurotrophic factor blood levels after electroconvulsive therapy in patients with mental disorders: A systematic review and meta-analysis.

OBJECTIVE: Multiple studies have indicated that electroconvulsive therapy (ECT) could increase brain-derived neurotrophic factor (BDNF) concentrations in patients with different mental disorders. The aim of this synthesis was to evaluate post-ECT BDNF concentrations in patients with various mental disorders. METHODS: The Embase, PubMed and Web of Science databases were systematically searched for studies in English comparing BDNF concentrations before and after ECT through 11/2022. We extracted the pertinent information from the included studies and evaluated their quality. The standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated to quantify BDNF concentration differences. RESULTS: In total, 35 studies assessed BDNF concentrations in 868 and 859 patients pre and post-ECT treatment, respectively. Post-ECT-treatment BDNF concentrations were significantly higher than the pretreatment concentrations (Hedges'g = -0.50, 95% CI (-0.70, -0.30), heterogeneity I2 = 74%, p < 0.001). The analysis that combined both ECT responders and non-responders demonstrated a marked increase in total BDNF levels subsequent to ECT treatment (Hedges'g = -0.27, 95% CI (-0.42, -0.11), heterogeneity I2 = 40%, p = 0.0007). CONCLUSION: Irrespective of the effectiveness of ECT, Our study shows that peripheral BDNF concentrations increase significantly after the entire course of ECT, which may enhance our comprehension of the interplay between ECT treatment and BDNF levels. However, BDNF concentrations were not associated with the effectiveness of ECT, and abnormal concentrations of BDNF may be linked to the pathophysiological process of mental illness, necessitating more future research.

The Effect of Ultrahigh Altitude on the Mental Health of Civil Servants in Western China Based on Propensity Score Matching.

Wang, Luyao, Bo Zhou, Chenghui Yang, Shuya Pan, Yulan Huang, and Jinyu Wang. The effect of ultrahigh altitude on the mental health of civil servants in western China based on propensity score matching. High Alt Med Biol. 24:193-200, 2023. Objective: This study aims to analyze the net effect of ultrahigh altitude on the mental health of civil servants in western China after adjusting for sociodemographic factors. Methods: A cross-sectional study was performed to survey the mental health of 2,939 civil servants working at an altitude of more than 1,500 m in 13 areas of the Tibetan Qiang Autonomous Prefecture of Ngawa using the Insomnia Severity Index Questionnaire, 7-item Generalized Anxiety Disorder Scale, and Patient Health Questionnaire-9. Ultrahigh altitude refers to an area above 3,500 m above sea level, which may have an impact on the sleep and mood of residents. Therefore, our research was divided into two groups based on altitude (ultrahigh altitude >3,500 m; high altitude = 1,500-3,400 m). Propensity score matching (PSM) was used to control for sociodemographic factors and compare the differences in mental health between the two groups. Results: After kernel matching, the mean bias of the covariates was reduced from 21.6 to 1.8. The severity of insomnia, depression, and anxiety in civil servants at ultrahigh altitudes was still significantly greater than that in civil servants at high altitudes after controlling for sociodemographic factors, and the average treatment effects on the treated were 1.39, 1.35, and 0.80, respectively; the results were significant (α < 0.01). PSM regression analysis further showed that for every 100 m increase in altitude, the severity of anxiety, depression, and insomnia increased by 0.042 points (p < 0.001), 0.063 points (p < 0.001), and 0.070 points (p < 0.001), respectively, all of which were higher than those obtained with ordinary least squares regression. Conclusion: Ultrahigh altitude significantly increases the severity of insomnia, depression, and anxiety after adjusting for sociodemographic factors.

Task-related neural activation abnormalities in patients with remitted major depressive disorder: A coordinate-based meta-analysis.

Major depressive disorder (MDD) patients demonstrate abnormal neural activation even after complete remission. Many task-related functional magnetic resonance imaging (fMRI) studies have focused on changes in brain function in individuals with remitted MDD (rMDD). We conducted a meta-analysis of these studies to explore differences in brain activation between patients with rMDD and healthy controls (HCs). Our meta-analysis included 13 studies, encompassing 18 experiments, 304 rMDD patients and 321 HCs. Patients with rMDD showed increased neural activation in the left inferior parietal gyrus and right fusiform gyrus and decreased neural activation in the left superior frontal gyrus, right middle temporal gyrus and right Heschl gyrus. Meta-regression analysis revealed that patient age and the number of depressive episodes were negatively associated with brain activity in the left superior frontal gyrus. Our findings suggest abnormal brain function, especially in areas involved in cognitive function, emotion regulation and perception, in rMDD patients; alterations of these regions may be the primary or secondary neurophysiological mechanisms underlying MDD and provide potential neuroimaging targets for early screening.

Genome-Wide Analysis and Expression Profiling of the Phenylalanine Ammonia-Lyase Gene Family in Solanum tuberosum.

Phenylalanine ammonia-lyase is one of the most widely studied enzymes in the plant kingdom. It is a crucial pathway from primary metabolism to significant secondary phenylpropanoid metabolism in plants, and plays an essential role in plant growth, development, and stress defense. Although PAL has been studied in many actual plants, only one report has been reported on potato, one of the five primary staple foods in the world. In this study, 14 StPAL genes were identified in potato for the first time using a genome-wide bioinformatics analysis, and the expression patterns of these genes were further investigated using qRT-PCR. The results showed that the expressions of StPAL1, StPAL6, StPAL8, StPAL12, and StPAL13 were significantly up-regulated under drought and high temperature stress, indicating that they may be involved in the stress defense of potato against high temperature and drought. The expressions of StPAL1, StPAL2, and StPAL6 were significantly up-regulated after MeJa hormone treatment, indicating that these genes are involved in potato chemical defense mechanisms. These three stresses significantly inhibited the expression of StPAL7, StPAL10, and StPAL11, again proving that PAL is a multifunctional gene family, which may give plants resistance to multiple and different stresses. In the future, people may improve critical agronomic traits of crops by introducing other PAL genes. This study aims to deepen the understanding of the versatility of the PAL gene family and provide a valuable reference for further genetic improvement of the potato.

"γδT Cell-IL17A-Neutrophil" Axis Drives Immunosuppression and Confers Breast Cancer Resistance to High-Dose Anti-VEGFR2 Therapy.

Angiogenesis is an essential physiological process and hallmark of cancer. Currently, antiangiogenic therapy, mostly targeting the vascular endothelial growth factor (VEGF)/VEGFR2 signaling axis, is commonly used in the clinic for solid tumors. However, antiangiogenic therapies for breast cancer patients have produced limited survival benefits since cancer cells rapidly resistant to anti-VEGFR2 therapy. We applied the low-dose and high-dose VEGFR2 mAb or VEGFR2-tyrosine kinase inhibitor (TKI) agents in multiple breast cancer mouse models and found that low-dose VEGFR2 mAb or VEGFR2-TKI achieved good effects in controlling cancer progression, while high-dose treatment was not effective. To further investigate the mechanism involved in regulating the drug resistance, we found that high-dose anti-VEGFR2 treatment elicited IL17A expression in γδ T cells via VEGFR1-PI3K-AKT pathway activation and then promoted N2-like neutrophil polarization, thus inducing CD8+ T cell exhaustion to shape an immunosuppressive microenvironment. Combining anti-VEGFR2 therapy with immunotherapy such as IL17A, PD-1 or Ly-6G mAb therapy, which targeting the immunomodulatory axis of "γδT17 cells-N2 neutrophils" in vivo, showed promising therapeutic effects in breast cancer treatment. This study illustrates the potential mechanism of antiangiogenic therapy resistance in breast cancer and provides synergy treatment for cancer.

Aged neutrophils form mitochondria-dependent vital NETs to promote breast cancer lung metastasis.

BACKGROUND: Neutrophils-linked premetastatic niche plays a key role in tumor metastasis, but not much is known about the heterogeneity and diverse role of neutrophils in niche formation. Our study focuses on the existence and biological function of a rarely delved subset of neutrophils, named as tumor-associated aged neutrophils (Naged, CXCR4+CD62Llow), involved in premetastatic niche formation during breast cancer metastasis. METHODS: We explored the distributions of Naged in 206 patients and mice models (4T1 and MMTV-PyMT) by flow cytometry. The ability of Naged to form neutrophil extracellular traps (NETs) and promote tumor metastasis in patients and mice was determined by polychromatic immunohistochemistry, scanning electron microscopy and real-time video detection. Furthermore, the differences among tumor-associated Naged, Non-Naged and inflammation-associated aged neutrophils were compared by transcriptome, the biological characteristics of Naged were comprehensively analyzed from the perspectives of morphology, the metabolic capacity and mitochondrial function were investigated by Seahorse, co-immunoprecipitation (Co-IP), chromatin immunoprecipitation (ChIP) and transmission electron microscopy (TEM). Finally, 120 patients' sample were applied to confirm the acceleration of Naged formation through secreted NAMPT, and the importance of blocking this pathway in mice was evaluated. RESULTS: We find that Naged accumulate in the lung premetastatic niche at early stage of breast tumorigenesis in multiple mice models and also exist in peripheral blood and metastatic lung of patients with breast cancer. Naged exhibit distinct cell marker and morphological feature of oversegmented nuclei. Further transcriptome reveals that Naged are completely different from those of Non-Aged or inflammation-associated aged neutrophils and illustrates that the key transcription factor SIRT1 in Naged is the core to maintain their lifespan via mitophagy for their function. The responsible mechanism is that SIRT1 can induce the opening of mitochondrial permeability transition pore channels to release mitochondrial DNA and lead to the mitochondria-dependent vital NETs formation, rather than traditional Cit-Histone H3 dependent fatal-NETs. Further mechanically investigation found tumor derived NAMPT could induce Naged formation. Additionally, therapeutic interventions of Naged and its formation-linked pathways could effectively decrease breast cancer lung metastasis. CONCLUSIONS: Naged exerts a vital role in breast cancer lung metastasis, and strategies targeting SIRT1-Naged-NETs axis show promise for translational application.

Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.

Genome-Wide Analysis and Expression Profiling of the Phospholipase D Gene Family in Solanum tuberosum.

Phospholipase D (PLD) is the most important phospholipid hydrolase in plants, which can hydrolyze phospholipids into phosphatidic acid (PA) and choline. When plants encounter low temperature, drought and high salt stress, phospholipase D and its products play an important role in regulating plant growth and development and coping with stress. In this study, 16 members of StPLD gene family were identified in potato genome, which were distributed in α, ß, δ, and ζ subfamilies, and their expression patterns under salt, high temperature, drought, and ABA stress were detected by qRT-PCR method. Gene expression analysis showed that the expression of StPLD genes in potato was upregulated and downregulated to varying degrees under the four stresses, indicating that the PLD gene family is involved in the interaction of potato plant hormones and abiotic stress signals. Chromosome distribution showed that StPLD gene was unevenly distributed on 8 chromosomes, and only one pair of tandem repeat genes was found. All StPLD promoters contain hormone and stress-related cis-regulatory elements to respond to different stresses. Structural analysis showed that StPLD genes in the same subgroup had a similar exon-intron structure. Our study provides a valuable reference for further research of the function and structure of PLD gene.

Comprehensive Analysis and Expression Profiling of PIN, AUX/LAX, and ABCB Auxin Transporter Gene Families in Solanum tuberosum under Phytohormone Stimuli and Abiotic Stresses.

Auxin is the only plant hormone that exhibits transport polarity mediated by three families: auxin resistant (AUX) 1/like AUX1 (LAX) influx carriers, pin-formed (PIN) efflux carriers, and ATP-binding cassette B (ABCB) influx/efflux carriers. Extensive studies about the biological functions of auxin transporter genes have been reported in model plants. Information regarding these genes in potato remains scarce. Here, we conducted a comprehensive analysis of auxin transporter gene families in potato to examine genomic distributions, phylogeny, co-expression analysis, gene structure and subcellular localization, and expression profiling using bioinformatics tools and qRT-PCR analysis. From these analyses, 5 StLAXs, 10 StPINs, and 22 StABCBs were identified in the potato genome and distributed in 10 of 18 gene modules correlating to the development of various tissues. Transient expression experiments indicated that three representative auxin transporters showed plasma membrane localizations. The responsiveness to auxin and auxin transport inhibitors implied their possible roles in mediating intercellular auxin homoeostasis and redistribution. The differential expression under abscisic acid and abiotic stresses indicated their specific adaptive mechanisms regulating tolerance to environmental stimuli. A large number of auxin-responsive and stress-related cis-elements within their promoters could account for their responsiveness to diverse stresses. Our study aimed to understand the biological significance of potato auxin transporters in hormone signaling and tolerance to environmental stresses.

Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis.

Breast cancer lung metastasis has a high mortality rate and lacks effective treatments, for the factors that determine breast cancer lung metastasis are not yet well understood. In this study, data from 1067 primary tumors in four public datasets revealed the distinct microenvironments and immune composition among patients with or without lung metastasis. We used multi-omics data of the TCGA cohort to emphasize the following characteristics that may lead to lung metastasis: more aggressive tumor malignant behaviors, severer genomic instability, higher immunogenicity but showed generalized inhibition of effector functions of immune cells. Furthermore, we found that mast cell fraction can be used as an index for individual lung metastasis status prediction and verified in the 20 human breast cancer samples. The lower mast cell infiltrations correlated with tumors that were more malignant and prone to have lung metastasis. This study is the first comprehensive analysis of the molecular and cellular characteristics and mutation profiles of breast cancer lung metastasis, which may be applicable for prognostic prediction and aid in choosing appropriate medical examinations and therapeutic regimens.

Meta-analysis of the association between CHCHD10 Pro34Ser variant and the risk of amyotrophic lateral sclerosis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS), one of the motor neuron diseases, appears to be caused by genetic and environmental risk factors. However, the influence of Pro34Ser variant of CHCHD10 gene in increasing risk of ALS remains indeterminate. This study conducted a meta-analysis to establish the association between Pro34Ser variant of CHCHD10 gene and risk of ALS. METHODS: PubMed, Web of Science, and Embase databases were systematically searched for genome-wide association studies or case-control studies published up to March 28, 2020, on the association between Pro34Ser variant and risk of ALS. Data from eligible studies were extracted and analyzed. RESULTS: Twelve case-control studies involving 7442 patients with sporadic ALS and 75,371 controls were analyzed. The Pro34Ser variant was not associated with increased risk of ALS disease based on fixed-effects meta-analysis (Pro34Ser-positive vs Pro34Ser-negative: OR 1.23, 95% CI 0.90 to 1.69, P = 0.201). CONCLUSION: Existing evidence suggests that Pro34Ser variant in CHCHD10 is not associated with risk of ALS, particularly in Caucasian participants. However, our results ought to be validated using large, well-designed studies, especially in Asian and African populations.

The effect of a short-term Balint group on the communication ability and self-efficacy of pre-examination and triage nurses during COVID-19.

AIMS AND OBJECTIVES: To investigate the effect of a short-term Balint group on the improvement in communication ability and self-efficacy of pre-examination and triage nurses during coronavirus disease 2019 (COVID-19). BACKGROUND: Working on the front lines of COVID-19 has brought unprecedented psychological stress on pre-examination and triage nurses. Nurse-patient communication ability and the level of self-efficacy are both significant for nurses' psychosomatic health and work input. However, limited empirical evidence exists regarding nurse-patient communication and self-efficacy and specific psychological intervention effects. DESIGN: Cross-sectional research fulfilling the completed checklist of items that should be included in reports of cross-sectional studies (Appendix S1). METHODS: Nurses (n = 41) in the first layer of pre-examination and triage were engaged in a Balint group activity twice a week for two weeks. They were assessed with the General Self-Efficacy Scale (GSES) pre- and postintervention, and a nurse-patient communication survey form was developed for further postintervention evaluation. The sample was recruited from a class A third-grade hospital in Sichuan, China. RESULTS: Most of the subjects reported improvement in nurse-patient communication, increased cooperation between patients and their families, and a decreased missed examination rate after the intervention. Moreover, the total mean score of the GSES of nurses after the intervention was increased, but the difference was not statistically significant. The scores of all items in the GSES were improved, and the scores increase for item 4 (I am confident that I can effectively deal with any unexpected event) was statistically significant. CONCLUSIONS: During the COVID-19 pandemic, a short-term Balint group activity can improve the communication ability and self-efficacy level of front-line nurses to some extent. RELEVANCE TO CLINICAL PRACTICE: This information may provide some theoretical support for the development of early psychological interventions during major epidemic situations.

CD62Ldim Neutrophils Specifically Migrate to the Lung and Participate in the Formation of the Pre-Metastatic Niche of Breast Cancer.

Lung metastasis is one of the leading causes of death in patients with breast cancer. The mechanism of tumor metastasis remains controversial. Recently, the formation of a pre-metastatic niche has been considered a key factor contributing to breast cancer metastasis, which might also explain the tendency of organ metastasis. Our study initially re-examined the critical time of the niche formation and simultaneously detected a novel subset of neutrophils, CD62Ldim neutrophils, which had not previously been reported in tumor metastasis; the number of these cells progressively increased during breast cancer progression and was closely related to the formation of the pre-metastatic niche. Furthermore, we explored the mechanism of their aggregation in the pre-metastatic niche in the lung and found that they were specifically chemoattracted by the CXCL12-CXCR4 signaling pathway. Compared to the CD62Lhi neutrophils, CD62Ldim neutrophils exhibited stronger adhesion and increased survival. The results provide new insights into the subsequent targeted treatment of breast cancer metastasis.

Cross-talk between the gut microbiota and monocyte-like macrophages mediates an inflammatory response to promote colitis-associated tumourigenesis.

OBJECTIVE: Macrophages are among the most abundant cells in the colon tumour microenvironment, and there is a close relationship among monocytes, macrophages and the gut microbiota. Alterations in the gut microbiota are involved in tumour development, but the underlying mechanisms remain unclear. We aim to elucidate the temporal changes in macrophage subsets and functions, and how these dynamics are regulated by microbial cues in the initiation of colitis-associated cancer. DESIGN: A mouse model of colitis-associated tumourigenesis was established to determine macrophage dynamics. The role of monocyte-like macrophage (MLM) was confirmed by targeting its chemotaxis. The effects of the gut microbiota were assessed by antibiotic treatment and faecal microbiota transplantation. RESULTS: A selective increase in MLMs was observed in the initial stages of colitis-associated cancer, with an enhanced secretion of inflammatory cytokines. MLM accumulation was regulated by CCL2 expression of colonic epithelial cells, which was influenced by bacteria-derived lipopolysaccharide (LPS). LPS further stimulated interleukin 1ß production from MLMs, inducing interleukin-17-producing T-helper cell activation to promote inflammation. These observations were also supported by altered microbial composition associated with human colitis and colorectal cancer, evolving transcriptional signature and immune response during human colitis-associated tumourigenesis. CONCLUSIONS: The gut microbiota uses LPS as a trigger to regulate MLM accumulation in a chemokine-dependent manner and generate a precancerous inflammatory milieu to facilitate tumourigenesis.

Huaier Extractum Promotes Dendritic Cells Maturation and Favors them to Induce Th1 Immune Response: One of the Mechanisms Underlying Its Anti-Tumor Activity.

Huaier, a sandy beige mushroom with anti-tumor effects, has been applied into Traditional Chinese Medicine for more than 1600 years. Previous studies showed that Huaier exerted its anti-tumor effects not only by direct action on tumor cells, but also indirectly by modulation of immune function. In the present study, we found that Huaier treatment significantly repressed tumor growth in mice with 4T1 breast cancer and resulted in significant accumulation of CD4+ T cells and mature dendritic cells (DCs) in the tumor microenvironment. In vitro experiments demonstrated that Huaier treatment promoted both DC2.4 and bone marrow derived DCs (BMDCs) to express costimulatory molecules, enhance production of IL-1ß and IL-12p70, while it inhibited their phagocytic activities, suggesting that Huaier treatment promotes maturation of DCs. Furthermore, we found Huaier-treated DCs profoundly stimulated proliferation of alloreactive CD4+ T cells and drove them to differentiate into Th1 subset. Expression of PI3K, Akt, p-Akt, JNK, and p-JNK was up-regulated, while p-p38 MAPK was down-regulated in Huaier-treated BMDCs, suggesting that Huaier promotes maturation of DCs with potent ability to activate Th1 immune response via modulation of MAPK and PI3K/Akt signaling pathways. Our findings provide further evidence for the mechanisms underlying the anti-tumor activity of Huaier.

Tumor-derived HMGB1 induces CD62Ldim neutrophil polarization and promotes lung metastasis in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is highly aggressive, difficult to treat and commonly develops visceral metastasis, including lung metastasis. We observed that High mobility group box 1 protein (HMGB1) was highly expressed in human TNBC and positively correlated with cancer metastasis. The hypoxic tumor environment is known to regulate HMGB1 secretion, but an understanding of the underlying mechanism by which tumor-derived HMGB1 regulates interstitial components and promotes breast cancer lung metastasis has remained elusive. The results of the present study showed that the number of CD62Ldim neutrophils, which have a strong ability to produce neutrophil extracellular traps (NETs), increased significantly in both peripheral blood and lung tissues in a mouse TNBC model and were regulated by tumor-derived HMGB1 through the TLR2 pathway. Furthermore, serum HMGB1 levels were positively correlated with CD62Ldim neutrophils in 86 breast cancer patients. We demonstrated that CD62Ldim neutrophils accelerated lung metastasis and that interventions targeting the "HMGB1-CD62Ldim neutrophil-NETs" axis could inhibit lung metastasis. Our results suggest that the combination of HMGB1 and CD62Ldim neutrophils is a potential marker for breast cancer lung metastasis and is novel target for future prevention and therapy.

Construction of a MicroRNA-Based Nomogram for Prediction of Lung Metastasis in Breast Cancer Patients.

The lung is one of the most common sites of distant metastasis in breast cancer (BC). Identifying ideal biomarkers to construct a more accurate prediction model than conventional clinical parameters is crucial. MicroRNAs (miRNAs) data and clinicopathological data were acquired from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database. miR-663, miR-210, miR-17, miR-301a, miR-135b, miR-451, miR-30a, and miR-199a-5p were screened to be highly relevant to lung metastasis (LM) of BC patients. The miRNA-based risk score was developed based on the logistic coefficient of the individual miRNA. Univariate and multivariate logistic regression selected tumor node metastasis (TNM) stage, age at diagnosis, and miRNA-risk score as independent predictive parameters, which were used to construct a nomogram. The Cancer Genome Atlas (TCGA) database was used to validate the signature and nomogram. The predictive performance of the nomogram was compared to that of the TNM stage. The area under the receiver operating characteristics curve (AUC) of the nomogram was higher than that of the TNM stage in all three cohorts (training cohort: 0.774 vs. 0.727; internal validation cohort: 0.763 vs. 0.583; external validation cohort: 0.925 vs. 0.840). The calibration plot of the nomogram showed good agreement between predicted and observed outcomes. The net reclassification improvement (NRI), integrated discrimination improvement (IDI), and decision-curve analysis (DCA) of the nomogram showed that its performances were better than that of the TNM classification system. Functional enrichment analyses suggested several terms with a specific focus on LM. Subgroup analysis showed that miR-30a, miR-135b, and miR-17 have unique roles in lung metastasis of BC. Pan-cancer analysis indicated the significant importance of eight predictive miRNAs in lung metastasis. This study is the first to establish and validate a comprehensive lung metastasis predictive nomogram based on the METABRIC and TCGA databases, which provides a reliable assessment tool for clinicians and aids in appropriate treatment selection.