The miR-17-92 cluster in cardiac health and disease.

MicroRNAs (miRs) are small noncoding RNAs that play important roles in both physiological and pathological processes through post-transcriptional regulation. The miR-17-92 cluster includes six individual members: miR-17, miR-18a, miR-19a, miR-19b-1, miR-20a, and miR-92a-1. The miR-17-92 cluster has been extensively studied and reported to broadly function in cancer biology, immunology, neurology, pulmonology, and cardiology. This review focuses on its roles in heart development and cardiac diseases. We briefly introduce the nature of the miR-17-92 cluster and its crucial roles in both normal development and the pathogenesis of various diseases. We summarize the recent progress in understanding the versatile roles of miR-17-92 during cardiac development, regeneration, and aging. Additionally, we highlight the indispensable roles of the miR-17-92 cluster in pathogenesis and therapeutic potential in cardiac birth defects and adult cardiac diseases.

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

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

Emerging Signaling Regulation of Sinoatrial Node Dysfunction.

PURPOSE OF REVIEW: The sinoatrial node (SAN), the natural pacemaker of the heart, is responsible for generating electrical impulses and initiating each heartbeat. Sinoatrial node dysfunction (SND) causes various arrhythmias such as sinus arrest, SAN block, and tachycardia/bradycardia syndrome. Unraveling the underlying mechanisms of SND is of paramount importance in the pursuit of developing effective therapeutic strategies for patients with SND. This review provides a concise summary of the most recent progress in the signaling regulation of SND. RECENT FINDINGS: Recent studies indicate that SND can be caused by abnormal intercellular and intracellular signaling, various forms of heart failure (HF), and diabetes. These discoveries provide novel insights into the underlying mechanisms SND, advancing our understanding of its pathogenesis. SND can cause severe cardiac arrhythmias associated with syncope and an increased risk of sudden death. In addition to ion channels, the SAN is susceptible to the influence of various signalings including Hippo, AMP-activated protein kinase (AMPK), mechanical force, and natriuretic peptide receptors. New cellular and molecular mechanisms related to SND are also deciphered in systemic diseases such as HF and diabetes. Progress in these studies contributes to the development of potential therapeutics for SND.

DeepMiceTL: a deep transfer learning based prediction of mice cardiac conduction diseases using early electrocardiograms.

Cardiac conduction disease is a major cause of morbidity and mortality worldwide. There is considerable clinical significance and an emerging need of early detection of these diseases for preventive treatment success before more severe arrhythmias occur. However, developing such early screening tools is challenging due to the lack of early electrocardiograms (ECGs) before symptoms occur in patients. Mouse models are widely used in cardiac arrhythmia research. The goal of this paper is to develop deep learning models to predict cardiac conduction diseases in mice using their early ECGs. We hypothesize that mutant mice present subtle abnormalities in their early ECGs before severe arrhythmias present. These subtle patterns can be detected by deep learning though they are hard to be identified by human eyes. We propose a deep transfer learning model, DeepMiceTL, which leverages knowledge from human ECGs to learn mouse ECG patterns. We further apply the Bayesian optimization and $k$-fold cross validation methods to tune the hyperparameters of the DeepMiceTL. Our results show that DeepMiceTL achieves a promising performance (F1-score: 83.8%, accuracy: 84.8%) in predicting the occurrence of cardiac conduction diseases using early mouse ECGs. This study is among the first efforts that use state-of-the-art deep transfer learning to identify ECG patterns during the early course of cardiac conduction disease in mice. Our approach not only could help in cardiac conduction disease research in mice, but also suggest a feasibility for early clinical diagnosis of human cardiac conduction diseases and other types of cardiac arrythmias using deep transfer learning in the future.

Exploring the role of sphingolipid-related genes in clinical outcomes of breast cancer.

Background: Despite tremendous advances in cancer research, breast cancer (BC) remains a major health concern and is the most common cancer affecting women worldwide. Breast cancer is a highly heterogeneous cancer with potentially aggressive and complex biology, and precision treatment for specific subtypes may improve survival in breast cancer patients. Sphingolipids are important components of lipids that play a key role in the growth and death of tumor cells and are increasingly the subject of new anti-cancer therapies. Key enzymes and intermediates of sphingolipid metabolism (SM) play an important role in regulating tumor cells and further influencing clinical prognosis. Methods: We downloaded BC data from the TCGA database and GEO database, on which we performed in depth single-cell sequencing analysis (scRNA-seq), weighted co-expression network analysis, and transcriptome differential expression analysis. Then seven sphingolipid-related genes (SRGs) were identified using Cox regression, least absolute shrinkage, and selection operator (Lasso) regression analysis to construct a prognostic model for BC patients. Finally, the expression and function of the key gene PGK1 in the model were verified by in vitro experiments. Results: This prognostic model allows for the classification of BC patients into high-risk and low-risk groups, with a statistically significant difference in survival time between the two groups. The model is also able to show high prediction accuracy in both internal and external validation sets. After further analysis of the immune microenvironment and immunotherapy, it was found that this risk grouping could be used as a guide for the immunotherapy of BC. The proliferation, migration, and invasive ability of MDA-MB-231 and MCF-7 cell lines were dramatically reduced after knocking down the key gene PGK1 in the model through cellular experiments. Conclusion: This study suggests that prognostic features based on genes related to SM are associated with clinical outcomes, tumor progression, and immune alterations in BC patients. Our findings may provide insights for the development of new strategies for early intervention and prognostic prediction in BC.

Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer.

Background: Although breast cancer (BC) treatment has entered the era of precision therapy, the prognosis is good in the case of comprehensive multimodal treatment such as neoadjuvant, endocrine, and targeted therapy. However, due to its high heterogeneity, some patients still cannot benefit from conventional treatment and have poor survival prognoses. Amino acids and their metabolites affect tumor development, alter the tumor microenvironment, play an increasingly obvious role in immune response and regulation of immune cell function, and are involved in acquired and innate immune regulation; therefore, amino acid metabolism is receiving increasing attention. Methods: Based on public datasets, we carried out a comprehensive transcriptome and single-cell sequencing investigation. Then we used 2.5 Weighted Co-Expression Network Analysis (WGCNA) and Cox to evaluate glutamine metabolism-related genes (GRGs) in BC and constructed a prognostic model for BC patients. Finally, the expression and function of the signature key gene SNX3 were examined by in vitro experiments. Results: In this study, we constituted a risk signature to predict overall survival (OS) in BC patients by glutamine-related genes. According to our risk signature, BC patients can obtain a Prognostic Risk Signature (PRS), and the response to immunotherapy can be further stratified according to PRS. Compared with traditional clinicopathological features, PRS demonstrated robust prognostic power and accurate survival prediction. In addition, altered pathways and mutational patterns were analyzed in PRS subgroups. Our study sheds some light on the immune status of BC. In in vitro experiments, the knockdown of SNX3, an essential gene in the signature, resulted in a dramatic reduction in proliferation, invasion, and migration of MDA-MB-231 and MCF-7 cell lines. Conclusion: We established a brand-new PRS consisting of genes associated with glutamine metabolism. It expands unique ideas for the diagnosis, treatment, and prognosis of BC.

Hippo-deficient cardiac fibroblasts differentiate into osteochondroprogenitors.

Cardiac fibrosis, a common pathophysiology associated with various heart diseases, occurs from the excess deposition of extracellular matrix (ECM) 1 . Cardiac fibroblasts (CFs) are the primary cells that produce, degrade, and remodel ECM during homeostasis and tissue repair 2 . Upon injury, CFs gain plasticity to differentiate into myofibroblasts 3 and adipocyte-like 4,5 and osteoblast-like 6 cells, promoting fibrosis and impairing heart function 7 . How CFs maintain their cell state during homeostasis and adapt plasticity upon injury are not well defined. Recent studies have shown that Hippo signalling in CFs regulates cardiac fibrosis and inflammation 8-11 . Here, we used single-nucleus RNA sequencing (snRNA-seq) and spatially resolved transcriptomic profiling (ST) to investigate how the cell state was altered in the absence of Hippo signaling and how Hippo-deficient CFs interact with macrophages during cardiac fibrosis. We found that Hippo-deficient CFs differentiate into osteochondroprogenitors (OCPs), suggesting that Hippo restricts CF plasticity. Furthermore, Hippo-deficient CFs colocalized with macrophages, suggesting their intercellular communications. Indeed, we identified several ligand-receptor pairs between the Hippo-deficient CFs and macrophages. Blocking the Hippo-deficient CF-induced CSF1 signaling abolished macrophage expansion. Interestingly, blocking macrophage expansion also reduced OCP differentiation of Hippo-deficient CFs, indicating that macrophages promote CF plasticity.

Research on partially coherent spatial light interference microscopy.

Based on partial coherence theory, this study rigorously deduces the principle of spatial light interference microscopy (SLIM) and improves the calculation method of SLIM. The main problem we found with SLIM is that it simply defaults the phase of the direct light to 0. To address this problem, we propose and experimentally demonstrate a double four-step phase shift method. Simulation results show that this method can reduce the relative error of oil-immersed microsphere reconstruction to about 3.7%, and for red blood cell reconstruction, the relative error can be reduced to about 13%.

Luminescence and energy transfer of single-phase white-emitting phosphor Ba2Mg(PO4)2:Ce3+, Eu2+ for white LEDs.

A series of Ba2Mg(PO4)2:Ce3+, Eu2+ phosphors were synthesized by the traditional high temperature solid-state method, and the crystal structures and luminescence properties of the samples were discussed systematically. The energy transfer from Ce3+ to Eu2+ in Ba2Mg(PO4)2 was proved to be of resonant type via a dipole-dipole interaction mechanism. With a precisely controlled relative proportion of Ce3+/Eu2+, the emission color of the samples can vary from blue (0.157, 0.071) to white (0.352, 0.332) and ultimately to yellow (0.452, 0.466) under the 323 nm ultraviolet light radiation excitation. The result reveals that the Ba2Mg(PO4)2:Ce3+, Eu2+ phosphor may have potential application as a single-phased white-emitting phosphor for light emitting diodes.

Hippo-Yap Signaling Maintains Sinoatrial Node Homeostasis.

BACKGROUND: The sinoatrial node (SAN) functions as the pacemaker of the heart, initiating rhythmic heartbeats. Despite its importance, the SAN is one of the most poorly understood cardiac entities because of its small size and complex composition and function. The Hippo signaling pathway is a molecular signaling pathway fundamental to heart development and regeneration. Although abnormalities of the Hippo pathway are associated with cardiac arrhythmias in human patients, the role of this pathway in the SAN is unknown. METHODS: We investigated key regulators of the Hippo pathway in SAN pacemaker cells by conditionally inactivating the Hippo signaling kinases Lats1 and Lats2 using the tamoxifen-inducible, cardiac conduction system-specific Cre driver Hcn4CreERT2 with Lats1 and Lats2 conditional knockout alleles. In addition, the Hippo-signaling effectors Yap and Taz were conditionally inactivated in the SAN. To determine the function of Hippo signaling in the SAN and other cardiac conduction system components, we conducted a series of physiological and molecular experiments, including telemetry ECG recording, echocardiography, Masson Trichrome staining, calcium imaging, immunostaining, RNAscope, cleavage under targets and tagmentation sequencing using antibodies against Yap1 or H3K4me3, quantitative real-time polymerase chain reaction, and Western blotting. We also performed comprehensive bioinformatics analyses of various datasets. RESULTS: We found that Lats1/2 inactivation caused severe sinus node dysfunction. Compared with the controls, Lats1/2 conditional knockout mutants exhibited dysregulated calcium handling and increased fibrosis in the SAN, indicating that Lats1/2 function through both cell-autonomous and non-cell-autonomous mechanisms. It is notable that the Lats1/2 conditional knockout phenotype was rescued by genetic deletion of Yap and Taz in the cardiac conduction system. These rescued mice had normal sinus rhythm and reduced fibrosis of the SAN, indicating that Lats1/2 function through Yap and Taz. Cleavage Under Targets and Tagmentation sequencing data showed that Yap potentially regulates genes critical for calcium homeostasis such as Ryr2 and genes encoding paracrine factors important in intercellular communication and fibrosis induction such as Tgfb1 and Tgfb3. Consistent with this, Lats1/2 conditional knockout mutants had decreased Ryr2 expression and increased Tgfb1 and Tgfb3 expression compared with control mice. CONCLUSIONS: We reveal, for the first time to our knowledge, that the canonical Hippo-Yap pathway plays a pivotal role in maintaining SAN homeostasis.

Identification of CD161 expression as a novel prognostic biomarker in breast cancer correlated with immune infiltration.

Background: CD161 has been identified as a prognostic biomarker in many neoplasms, but its role in breast cancer (BC) has not been fully explained. We aimed to investigate the molecular mechanism and prognostic value of CD161 in BC. Methods: CD161 expression profile was extracted from TIMER, Oncomine, UALCAN databases, and verified by the Gene Expression Omnibus (GEO) database and quantitative real-time polymerase chain reaction (qRT-PCR). The prognostic value of CD161 was assessed via GEPIA, Kaplan-Meier plotter and PrognoScan databases. The Cox regression and nomogram analyses were conducted to further validate the association between CD161 expression and survival. Gene set enrichment analysis (GSEA), Gene Ontology (GO) analysis, and KEGG pathway enrichment analysis were performed to probe the tumor-associated annotations of CD161. CIBERSORT and ssGSEA were employed to investigate the correlation between CD161 expression and immune cell infiltration in BC, and the result was verified by TIMER and TISIDB. Results: Multiple BC cohorts showed that CD161 expression was decreased in BC, and a high CD161 expression was associated with a preferable prognosis. Therefore, we identified the combined model including CD161, age and PR status to predict the survival (C index = 0.78) of BC patients. Functional enrichment analysis indicated that CD161 and its co-expressed genes were closely related to several cancerous and immune signaling pathways, suggesting its involvement in immune response during cancer development. Moreover, immune infiltration analysis revealed that CD161 expression was correlated with immune infiltration. Conclusion: Collectively, our findings revealed that CD161 may serve as a potential biomarker for favorable prognosis and a promising immune therapeutic target in BC.

Yap and Taz promote osteogenesis and prevent chondrogenesis in neural crest cells in vitro and in vivo.

Neural crest cells (NCCs) are multipotent stem cells that can differentiate into multiple cell types, including the osteoblasts and chondrocytes, and constitute most of the craniofacial skeleton. Here, we show through in vitro and in vivo studies that the transcriptional regulators Yap and Taz have redundant functions as key determinants of the specification and differentiation of NCCs into osteoblasts or chondrocytes. Primary and cultured NCCs deficient in Yap and Taz switched from osteogenesis to chondrogenesis, and NCC-specific deficiency for Yap and Taz resulted in bone loss and ectopic cartilage in mice. Yap bound to the regulatory elements of key genes that govern osteogenesis and chondrogenesis in NCCs and directly regulated the expression of these genes, some of which also contained binding sites for the TCF/LEF transcription factors that interact with the Wnt effector ß-catenin. During differentiation of NCCs in vitro and NCC-derived osteogenesis in vivo, Yap and Taz promoted the expression of osteogenic genes such as Runx2 and Sp7 but repressed the expression of chondrogenic genes such as Sox9 and Col2a1. Furthermore, Yap and Taz interacted with ß-catenin in NCCs to coordinately promote osteoblast differentiation and repress chondrogenesis. Together, our data indicate that Yap and Taz promote osteogenesis in NCCs and prevent chondrogenesis, partly through interactions with the Wnt-ß-catenin pathway.

Optimal Selection of Imaging Examination for Lymph Node Detection of Breast Cancer With Different Molecular Subtypes.

Objective: Axillary lymph node management is an important part of breast cancer surgery and the accuracy of preoperative imaging evaluation can provide adequate information to guide operation. Different molecular subtypes of breast cancer have distinct imaging characteristics. This article was aimed to evaluate the predictive ability of imaging methods in accessing the status of axillary lymph node in different molecular subtypes. Methods: A total of 2,340 patients diagnosed with primary invasive breast cancer after breast surgery from 2013 to 2018 in Jiangsu Breast Disease Center, the First Affiliated Hospital with Nanjing Medical University were included in the study. We collected lymph node assessment results from mammography, ultrasounds, and MRIs, performed receiver operating characteristic (ROC) analysis, and calculated the sensitivity and specificity of each test. The C-statistic among different imaging models were compared in different molecular subtypes to access the predictive abilities of these imaging models in evaluating the lymph node metastasis. Results: In Her-2 + patients, the C-statistic of ultrasound was better than that of MRI (0.6883 vs. 0.5935, p=0.0003). The combination of ultrasound and MRI did not raise the predictability compared to ultrasound alone (p=0.492). In ER/PR+HER2- patients, the C-statistic of ultrasound was similar with that of MRI (0.7489 vs. 0.7650, p=0.5619). Ultrasound+MRI raised the prediction accuracy compared to ultrasound alone (p=0.0001). In ER/PR-HER2- patients, the C-statistics of ultrasound was similar with MRI (0.7432 vs. 0.7194, p=0.5579). Combining ultrasound and MRI showed no improvement in the prediction accuracy compared to ultrasound alone (p=0.0532). Conclusion: From a clinical perspective, for Her-2+ patients, ultrasound was the most recommended examination to assess the status of axillary lymph node metastasis. For ER/PR+HER2- patients, we suggested that the lymph node should be evaluated by ultrasound plus MRI. For ER/PR-Her2- patients, ultrasound or MRI were both optional examinations in lymph node assessment. Furthermore, more new technologies should be explored, especially for Her2+ patients, to further raise the prediction accuracy of lymph node assessment.

Comparative analysis of transient receptor potential channel 5 opposite strand-induced gene expression patterns and protein-protein interactions in triple-negative breast cancer.

In patients with triple-negative breast cancer (TNBC), high tumour mutation burden and aberrant oncogene expression profiles are some of the causes of poor prognosis. Therefore, it is necessary to identify aberrantly expressed oncogenes, since they have the potential to serve as therapeutic targets. Transient receptor potential channel 5 opposite strand (TRPC5OS) has been previously shown to function as a novel tumour inducer. However, the underlying mechanism of TRPC5OS function in TNBC remain to be elucidated. Therefore, in the present study TRPC5OS expression was first measured in tissue samples of patients with TNBC and a panel of breast cancer cell lines (ZR-75-1, MDA-MB-453, SK-BR-3, JIMT-1, BT474 and HCC1937) by using qRT-PCR and Western blotting. Subsequently, the possible effects of TRPC5OS on MDA-MB-231 cells proliferation were determined using Cell Counting Kit-8 and 5-Ethynyl-2'-deoxyuridine assays after Lentiviral transfection of MDA-MB-231. In addition, potential interaction partners of TRPC5OS were explored using liquid chromatography-mass spectrometry (LC-MS)/MS. Gene expression patterns following TRPC5OS overexpression were also detected in MDA-MB-231 cells by using High-throughput sequencing. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) analysis were then used to systematically verify the potential interactions among the TRPC5OS-regulated genes. The potential relationship between TRPC5OS-interacting proteins and gene expression patterns were studied using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) analysis. TRPC5OS expression was found to be significantly higher in TNBC tumour tissues and breast cancer cell lines compared with luminal tumour tissues and ZR-75-1. In addition, the overexpression of TRPC5OS significantly increased cell proliferation. High-throughput sequencing results revealed that 5,256 genes exhibited differential expression following TRPC5OS overexpression, including 3,269 upregulated genes and 1,987 downregulated genes. GO analysis results indicated that the functions of these differentially expressed genes were enriched in the categories of 'cell division' and 'cell proliferation' regulation. KEGG analysis showed that the TRPC5OS-regulated genes were associated with processes of 'homologous recombination' and 'TNF signalling pathways'. Subsequently, 17 TRPC5OS-interacting proteins were found using LC-MS/MS and STRING analysis. The most important protein among interacting proteins was ENO1 which was associated with glycolysis and regulated proliferation of cancer. In summary, data from the present study suggest that TRPC5OS overexpression can increase TNBC cell proliferation and ENO1 may be a potential target protein mediated by TRPC5OS. Therefore, TRPC5OS may serve as a novel therapeutic target for TNBC.

TRPC5OS induces tumorigenesis by increasing ENO1-mediated glucose uptake in breast cancer.

Breast cancer is the most common malignant tumor worldwide and the leading cause of cancer-related deaths in female. Metabolic reprogramming plays critical roles in breast tumorigenesis and induces enhanced glucose uptake and glycolysis. TRPC5OS is encoded by short transient receptor potential channel 5 opposite strand, and predicted to correlate with tumor metabolic reprogramming. Here we aim to elucidate the function of TRPC5OS in aberrant metabolism mediated tumorigenesis. We detected TRPC5OS expression levels in cell lines and tissues by quantitative real-time polymerase chain reaction and immunohistochemistry. Then we assessed the effects of TRPC5OS on proliferation and cell cycle progression in breast cancer cells by cell counting kit-8, colony-formation, EdU-incorporation assays and flow cytometry. Tumor growth in vivo was observed in a mouse xenograft model. Mass spectrum analyses were performed to identify potential interactors of TRPC5OS in tumor cells, and the interaction between TRPC5OS and interactors was validated by co-immunoprecipitation (CO-IP), western blots, and immunofluorescent staining. Glucose uptake was measured by liquid scintillation spectrometry. TRPC5OS highly expresses both in breast tumors and cell lines, and might be an independent prognostic marker for breast cancer patients. Overexpressed TRPC5OS promotes breast cancer cell proliferation, cell cycle progression, and enhances tumor xenograft growth. Mass spectral and CO-IP data showed that TRPC5OS interacts with ENO1. We also demonstrate that TRPC5OS could enhance ENO1/PI3K/Akt-mediated glucose uptake in breast cancer cells. Our study demonstrated that TRPC5OS promotes breast tumorigenesis by ENO1/PI3K/Akt-mediated glucose uptake. TRPC5OS might be an independent prognostic marker and potential therapeutic target for breast cancer patients.

Characteristics of metastasis and survival between male and female breast cancer with different molecular subtypes: A population-based observational study.

OBJECTIVE: Male breast cancer (BC) is a rare disease, having different clinicopathological features and survival outcomes from female patients. The aim of this research was to, combine with molecular subtypes, analyze the metastatic patterns, and prognosis between male and female patients, and to determine whether the gender was the independent prognostic factor for BC. METHODS: Data used in this study were acquired from the SEER database from 2010 to 2016. The clinicopathology features and metastatic patterns were compared by the Chi-square test and Fisher's exact test. Kaplan-Meier method was performed to compare overall survival (OS) and factors correlated with OS were determined by Cox regression models. Competing risk models were used to ascertain factors related to breast cancer-specific death (BCSD). RESULTS: Compared with female BC, the incidence of regional LN (HR 1.849, 95% CI 1.674-2.043, p < 0.001) and distant metastasis (HR 1.421, 95%CI: 1.157-1.744, p < 0.001) was higher in male BC. For regional LN metastasis, hormone receptor (HoR)-/HER2+ subtype occupied the majority in both male (55.56%) and female (36.86%) groups. For distant metastasis, HoR-/HER2- subtype (21.26%), and HoR-/HER2+ (7.67%) were in major in male and female group separately. Male patients shared similar combinations of metastases with female groups as for single-site, bi-site, and tri-site metastasis. Gender was an independent prognostic factor for OS (p < 0.001) but not for BCSD(p = 0.620). In subgroup of patients with HoR+/HER2-(OS: p = 0.003; BCSD: p = 0.606), HoR+/HER2+(OS: p = 0.003; BCSD: p = 0.277), regional LN positive(OS: p = 0.005; BCSD: p = 0.379), or bone metastasis (OS: p = 0.030; BCSD: p = 0.862), the male cohort had poorer OS but similar BCSD with female cohort. CONCLUSIONS: Compared with female patients, male BC had different metastasis patterns and prognostic outcomes, and the affection of breast subtypes on metastasis and survivorship was also different. More attention needs to be paid for specific molecular subtype and more personalized therapeutic strategies should be customized while treating male patients.

HSPA13 facilitates NF-κB-mediated transcription and attenuates cell death responses in TNFα signaling.

RIP1 has emerged as a master regulator in TNFα signaling that controls two distinct cellular fates: cell survival versus programmed cell death. Because the default response of most cells to TNFα is NF-κB­mediated inflammation and survival, a specific mechanism must exist to control the divergence of signaling outcome. Here, we identify HSPA13 as a transcription-independent checkpoint to modulate the role of RIP1 in TNFα signaling. Through specific binding to TNFR1 and RIP1, HSPA13 enhances TNFα-induced recruitment of RIP1 to TNFR1, and consequently promotes downstream NF-κB transcriptional responses. Meanwhile, HSPA13 attenuates the participation of RIP1 in cytosolic complex II and prevents cells from programmed death. Loss of HSPA13 shifts the transition of RIP1 from complex I to complex II and promotes both apoptosis and necroptosis. Thus, our study provides compelling evidence for the cellular protective function of HSPA13 in fine-tuning TNFα responses.

Bmp Signaling Regulates Hand1 in a Dose-Dependent Manner during Heart Development.

The bone morphogenetic protein (Bmp) signaling pathway and the basic helix-loop-helix (bHLH) transcription factor Hand1 are known key regulators of cardiac development. In this study, we investigated the Bmp signaling regulation of Hand1 during cardiac outflow tract (OFT) development. In Bmp2 and Bmp4loss-of-function embryos with varying levels of Bmp in the heart, Hand1 is sensitively decreased in response to the dose of Bmp expression. In contrast, Hand1 in the heart is dramatically increased in Bmp4 gain-of-function embryos. We further identified and characterized the Bmp/Smad regulatory elements in Hand1. Combined transfection assays and chromatin immunoprecipitation (ChIP) experiments indicated that Hand1 is directly activated and bound by Smads. In addition, we found that upon the treatment of Bmp2 and Bmp4, P19 cells induced Hand1 expression and favored cardiac differentiation. Together, our data indicated that the Bmp signaling pathway directly regulates Hand1 expression in a dose-dependent manner during heart development.

The Cardiac Neural Crest Cells in Heart Development and Congenital Heart Defects.

The neural crest (NC) is a multipotent and temporarily migratory cell population stemming from the dorsal neural tube during vertebrate embryogenesis. Cardiac neural crest cells (NCCs), a specified subpopulation of the NC, are vital for normal cardiovascular development, as they significantly contribute to the pharyngeal arch arteries, the developing cardiac outflow tract (OFT), cardiac valves, and interventricular septum. Various signaling pathways are shown to orchestrate the proper migration, compaction, and differentiation of cardiac NCCs during cardiovascular development. Any loss or dysregulation of signaling pathways in cardiac NCCs can lead to abnormal cardiovascular development during embryogenesis, resulting in abnormalities categorized as congenital heart defects (CHDs). This review focuses on the contributions of cardiac NCCs to cardiovascular formation, discusses cardiac defects caused by a disruption of various regulatory factors, and summarizes the role of multiple signaling pathways during embryonic development. A better understanding of the cardiac NC and its vast regulatory network will provide a deeper insight into the mechanisms of the associated abnormalities, leading to potential therapeutic advancements.

Crumbs proteins stabilize the cone mosaics of photoreceptors and improve vision in zebrafish.

Although the unique organization of vertebrate cone mosaics was first described long ago, both their underlying molecular basis and physiological significance are largely unknown. Here, we demonstrate that Crumbs proteins, the key regulators of epithelial apical polarity, establish the planar cellular polarity of photoreceptors in zebrafish. Via heterophilic Crb2a-Crb2b interactions, the apicobasal polarity protein Crb2b restricts the asymmetric planar distribution of Crb2a in photoreceptors. The planar polarized Crumbs proteins thus balance intercellular adhesions and tension between photoreceptors, thereby stabilizing the geometric organization of cone mosaics. Notably, loss of Crb2b in zebrafish induces a nearsightedness-like phenotype in zebrafish accompanied by an elongated eye axis and impairs zebrafish visual perception for predation. These data reveal a detailed mechanism for cone mosaic homeostasis via previously undiscovered apical-planar polarity coordination and propose a pathogenic mechanism for nearsightedness.