Black Phosphorus Nanosheets Protect Neurons by Degrading Aggregative α-syn and Clearing ROS in Parkinson's Disease.

Although evidence indicates that the abnormal accumulation of α-synuclein (α-syn) in dopamine neurons of the substantia nigra is the main pathological feature of Parkinson's disease (PD), no compounds that have both α-syn antiaggregation and α-syn degradation functions have been successful in treating the disease in the clinic. Here, it is shown that black phosphorus nanosheets (BPNSs) interact directly with α-syn fibrils to trigger their disaggregation for PD treatment. Moreover, BPNSs have a specific affinity for α-syn through van der Waals forces. And BPNSs are found to activate autophagy to maintain α-syn homeostasis, improve mitochondrial dysfunction, reduce reactive oxygen species levels, and rescue neuronal death and synaptic loss in PC12 cells. It is also observed that BPNSs penetrate the blood-brain barrier and protect against dopamine neuron loss, alleviating behavioral disorders in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model and hA53T α-syn transgenic mice. Together, the study reveals that BPNSs have the potential as a novel integrated nanomedicine for clinical diagnosis and treatment of neurological diseases.

Unlocking PD-1 antibody resistance: The MUC1 DNA vaccine augments CD8+ T cell infiltration and attenuates tumour suppression.

In light of increasing resistance to PD1 antibody therapy among certain patient populations, there is a critical need for in-depth research. Our study assesses the synergistic effects of a MUC1 DNA vaccine and PD1 antibody for surmounting PD1 resistance, employing a murine CT26/MUC1 colon carcinoma model for this purpose. When given as a standalone treatment, PD1 antibodies showed no impact on tumour growth. Additionally, there was no change observed in the intra-tumoural T-cell ratios or in the functionality of T-cells. In contrast, the sole administration of a MUC1 DNA vaccine markedly boosted the cytotoxicity of CD8+ T cells by elevating IFN-γ and granzyme B production. Our compelling evidence highlights that combination therapy more effectively inhibited tumour growth and prolonged survival compared to either monotherapy, thus mitigating the limitations intrinsic to single-agent therapies. This enhanced efficacy was driven by a significant alteration in the tumour microenvironment, skewing it towards pro-immunogenic conditions. This assertion is backed by a raised CD8+/CD4+ T-cell ratio and a decrease in immunosuppressive MDSC and Treg cell populations. On the mechanistic front, the synergistic therapy amplified expression levels of CXCL13 in tumours, subsequently facilitating T-cell ingress into the tumour setting. In summary, our findings advocate for integrated therapy as a potent mechanism for surmounting PD1 antibody resistance, capitalizing on improved T-cell functionality and infiltration. This investigation affords critical perspectives on enhancing anti-tumour immunity through the application of innovative therapeutic strategies.

AMD1 promotes breast cancer aggressiveness via a spermidine-eIF5A hypusination-TCF4 axis.

BACKGROUND: Basal-like breast cancer (BLBC) is the most aggressive subtype of breast cancer due to its aggressive characteristics and lack of effective therapeutics. However, the mechanism underlying its aggressiveness remains largely unclear. S-adenosylmethionine decarboxylase proenzyme (AMD1) overexpression occurs specifically in BLBC. Here, we explored the potential molecular mechanisms and functions of AMD1 promoting the aggressiveness of BLBC. METHODS: The potential effects of AMD1 on breast cancer cells were tested by western blotting, colony formation, cell proliferation assay, migration and invasion assay. The spermidine level was determined by high performance liquid chromatography. The methylation status of CpG sites within the AMD1 promoter was evaluated by bisulfite sequencing PCR. We elucidated the relationship between AMD1 and Sox10 by ChIP assays and quantitative real-time PCR. The effect of AMD1 expression on breast cancer cells was evaluated by in vitro and in vivo tumorigenesis model. RESULTS: In this study, we showed that AMD1 expression was remarkably elevated in BLBC. AMD1 copy number amplification, hypomethylation of AMD1 promoter and transcription activity of Sox10 contributed to the overexpression of AMD1 in BLBC. AMD1 overexpression enhanced spermidine production, which enhanced eIF5A hypusination, activating translation of TCF4 with multiple conserved Pro-Pro motifs. Our studies showed that AMD1-mediated metabolic system of polyamine in BLBC cells promoted tumor cell proliferation and tumor growth. Clinically, elevated expression of AMD1 was correlated with high grade, metastasis and poor survival, indicating poor prognosis of breast cancer patients. CONCLUSION: Our work reveals the critical association of AMD1-mediated spermidine-eIF5A hypusination-TCF4 axis with BLBC aggressiveness, indicating potential prognostic indicators and therapeutic targets for BLBC.

Superbinder based phosphoproteomic landscape revealed PRKCD_pY313 mediates the activation of Src and p38 MAPK to promote TNBC progression.

Phosphorylation proteomics is the basis for the study of abnormally activated kinase signaling pathways in breast cancer, which facilitates the discovery of new oncogenic agents and drives the discovery of potential targets for early diagnosis and therapy of breast cancer. In this study, we have explored the aberrantly active kinases in breast cancer development and to elucidate the role of PRKCD_pY313 in triple negative breast cancer (TNBC) progression. We collected 47 pairs of breast cancer and paired far-cancer normal tissues and analyzed phosphorylated tyrosine (pY) peptides by Superbinder resin and further enriched the phosphorylated serine/threonine (pS/pT) peptides using TiO2 columns. We mapped the kinases activity of different subtypes of breast cancer and identified PRKCD_pY313 was upregulated in TNBC cell lines. Gain-of-function assay revealed that PRKCD_pY313 facilitated the proliferation, enhanced invasion, accelerated metastasis, increased the mitochondrial membrane potential and reduced ROS level of TNBC cell lines, while Y313F mutation and low PRKCD_pY313 reversed these effects. Furthermore, PRKCD_pY313 significantly upregulated Src_pY419 and p38_pT180/pY182, while low PRKCD_pY313 and PRKCD_Y313F had opposite effects. Dasatinib significantly inhibited the growth of PRKCD_pY313 overexpression cells, and this effect could be enhanced by Adezmapimod. In nude mice xenograft model, PRKCD_pY313 significantly promoted tumor progression, accompanied by increased levels of Ki-67, Bcl-xl and Vimentin, and decreased levels of Bad, cleaved caspase 3 and ZO1, which was opposite to the trend of Y313F group. Collectively, the heterogeneity of phosphorylation exists in different molecular subtypes of breast cancer. PRKCD_pY313 activates Src and accelerates TNBC progression, which could be inhibited by Dasatinib.

Profiling dynamics of the Southeast Asia's largest lake, Tonle Sap Lake.

Lakes, as vital components of the Earth's ecosystem with crucial roles in global biogeochemical cycles, are experiencing pervasive and irreparable worldwide losses due to natural factors and intensive anthropogenic interferences. In this study, we investigated the long-term dynamic patterns of the Tonle Sap Lake, the largest freshwater lake in the Mekong River Basin, using a series of hydrological data and remote sensing images between 2000 and 2020. Our findings revealed a significant decline in the annual average water level of the lake by approximately 2.1 m over 20 years, accompanied by an annual average reduction in surface area of about 1400 km2. The Tonle Sap Lake exhibited episodic declines in water level and surface area, characterized by the absence of flooding during the flood season and increasing aridity during the dry season. Furthermore, the shoreline of the lake has significantly advanced towards the lake in the northwestern and southern regions during the dry season, primarily due to sedimentation-induced shallowing of the lake edge depth and decreased water levels. In contrast, lake shorelines in the eastern region remained relatively stable due to the constructed embankments for the protection of the cultivated farmland. While the seasonal fluctuations of the Tonle Sap Lake are regulated by regional precipitation in the Mekong River Basin, the prolonged shrinking of the lake can be mainly ascribed to intensive anthropogenic activities. The interception of dams along the upper Mekong River has resulted in a decrease in the inflow to Tonle Sap Lake, exacerbating its shrinkage. Moreover, there are minor impacts from agricultural land expansion and irrigation on the lake. This study highlights the driving forces behind the evolution of Tonle Sap Lake, providing valuable information for lake managers to develop strategies aimed at conserving and restoring the ecological integrity of the Tonle Sap Lake.

IMPA2 promotes basal-like breast cancer aggressiveness by a MYC-mediated positive feedback loop.

Basal-like breast cancer (BLBC) is the most aggressive subtype with poor prognosis; however, the mechanisms underlying aggressiveness in BLBC remain poorly understood. In this study, we showed that in contrast to other subtypes, inositol monophosphatase 2 (IMPA2) was dramatically increased in BLBC. Mechanistically, IMPA2 expression was upregulated due to copy number amplification, hypomethylation of IMPA2 promoter and MYC-mediated transcriptional activation. IMPA2 promoted MI-PI cycle and IP3 production, and IP3 then elevated intracellular Ca2+ concentration, leading to efficient activation of NFAT1. In turn, NFAT1 up-regulated MYC expression, thereby fulfilling a positive feedback loop that enhanced aggressiveness of BLBC cells. Knockdown of IMPA2 expression caused the inhibition of tumorigenicity and metastasis of BLBC cells in vitro and in vivo. Clinically, high IMPA2 expression was strongly correlated with large tumor size, high grade, metastasis and poor survival, indicating poor prognosis in breast cancer patients. These findings suggest that IMPA2-mediated MI-PI cycle allows crosstalk between metabolic and oncogenic pathways to promote BLBC progression.

Exploiting innate immunity for cancer immunotherapy.

Immunotherapies have revolutionized the treatment paradigms of various types of cancers. However, most of these immunomodulatory strategies focus on harnessing adaptive immunity, mainly by inhibiting immunosuppressive signaling with immune checkpoint blockade, or enhancing immunostimulatory signaling with bispecific T cell engager and chimeric antigen receptor (CAR)-T cell. Although these agents have already achieved great success, only a tiny percentage of patients could benefit from immunotherapies. Actually, immunotherapy efficacy is determined by multiple components in the tumor microenvironment beyond adaptive immunity. Cells from the innate arm of the immune system, such as macrophages, dendritic cells, myeloid-derived suppressor cells, neutrophils, natural killer cells, and unconventional T cells, also participate in cancer immune evasion and surveillance. Considering that the innate arm is the cornerstone of the antitumor immune response, utilizing innate immunity provides potential therapeutic options for cancer control. Up to now, strategies exploiting innate immunity, such as agonists of stimulator of interferon genes, CAR-macrophage or -natural killer cell therapies, metabolic regulators, and novel immune checkpoint blockade, have exhibited potent antitumor activities in preclinical and clinical studies. Here, we summarize the latest insights into the potential roles of innate cells in antitumor immunity and discuss the advances in innate arm-targeted therapeutic strategies.

Estimates of bladder cancer burden attributable to high fasting plasma glucose: Findings of the Global Burden of Disease Study 2019.

BACKGROUND: High fasting plasma glucose (FPG) has been listed as one of the risk factors for bladder cancer. We here estimated the global, regional, and national levels of bladder cancer burden attributable to high FPG from 1990 to 2019. METHODS: Bladder cancer data attributable to high FPG were extracted from the Global Burden of Disease Study 2019, and analyzed by age, sex, year, and location. Age-standardized rates were utilized to evaluate the burden between different populations. The temporal trend of the burden was estimated through the Joinpoint analysis. RESULTS: In 2019, high FPG contributed to 22,823.33 (95% uncertainty interval [UI], 4694.88-48,962.26) deaths and 399,654.91 (95% UI, 81,609.35-865,890.95) disability-adjusted life years (DALYs) of bladder cancer globally. Since 1990, the global age-standardized death and DALY rates of bladder cancer attributable to high FPG increased apparently by 39.18% and 41.48%, respectively. During the last 30 years, high FPG-related age-standardized death and DALY rates of bladder cancer have increased in all countries. In 2019, Central Europe showed the greatest high FPG-related age-standardized death and DALY rates of bladder cancer, but Andean Latin America had the lowest rates. Nationally, Lebanon showed the greatest high FPG-related age-standardized death and DALY rates of bladder cancer in 2019. High FPG-attributable deaths and DALYs of bladder cancer were more considerable among males and older people. Countries with high SDI showed higher levels of age-standardized death and DALY rates of bladder cancer due to high FPG and presented remarkable upward trends in rates in the last 30 years. CONCLUSIONS: Globally, the high FPG-associated bladder cancer burden has remarkably increased in all countries, and showed a higher level among countries with higher SDI. Monitoring FPG levels among patients with bladder cancer is critical to lower the corresponding burden.

Pathological complete response rate and clinical outcome after neoadjuvant therapy of HER2-low breast cancer: A National Cancer Database Analysis.

BACKGROUND: The interest in breast cancer with low HER2 expression as a distinct subtype is increasing. We aimed to explore the differences between HER2-low and HER2-zero breast cancer in their prognosis and rate of pathological complete response (pCR) after neoadjuvant therapy. METHODS: The National Cancer Database (NCDB) was used to select patients with breast cancer who received neoadjuvant therapy from 2004 to 2017. Logistic regression model was constructed for analysis of pCR. Cox proportional hazards regression model and Kaplan-Meier method were used for survival analysis. RESULTS: A total of 41500 breast cancer patients were included, among which 14814 (35.7%) had HER2-zero tumors and 26686 (64.3%) had HER2-low. HER2-low tumors were more commonly HR-positive in comparison with HER2-zero (66.3% versus 47.1%, P < 0.001). A lower rate of pCR was observed in HER2-low tumors than in HER2-zero tumors after neoadjuvant therapy in the total cohort (OR = 0.90; 95% CI [0.86-0.95]; P < 0.001) and in the subset of HR-positive (OR = 0.87; 95% CI [0.81-0.94]; P < 0.001). Patients with HER2-low tumors had a significantly superior survival than those with HER2-zero tumors (HR = 0.90; 95% CI [0.86-0.94]; P < 0.001), regardless of the HR status. Additionally, a marginal survival difference was also observed between HER2 IHC1+ and HER2 IHC2+/ISH-negative (HR = 0.91; 95% CI [0.85-0.97]; P = 0.003) cohorts. CONCLUSION: HER2-low tumors are a clinically relevant breast cancer subtype that is distinct from HER2-zero tumors. These findings may provide clues to appropriate therapeutic strategies for this subtype in the future.

Impacts of land-use change on carbon dynamics in China's coastal wetlands.

The impact of land-use and land-cover change (LULCC) on ecosystem carbon (C) dynamics has been previously documented at local and global scales, but uncertainty persists for coastal wetlands due to geographical variability and field data limitations. Field-based assessments of plant and soil C contents and stocks of various LULCC types were conducted in nine regions along the coastline of China (21°-40°N). These regions cover natural coastal wetlands (NWs, including salt marshes and mangroves) and former wetlands converted to different LULCC types, including reclaimed wetlands (RWs), dry farmlands (DFs), paddy fields (PFs) and aquaculture ponds (APs). The results showed that LULCC generally decreased the C contents and stocks of the plant-soil system by 29.6 % ± 2.5 % and 40.4 % ± 9.2 %, respectively, while it slightly increased the soil inorganic C contents and stocks. Wetlands converted to APs and RWs lost greater ecosystem organic C stocks (EOC, sum of plants and top 30 cm of soil organic C stocks) than other LULCC types. The annual potential CO2 emissions estimated from EOC loss depended on the LULCC type, with an average emission of 7.92 ± 2.94 Mg CO2-eq ha-1 yr-1. The change rate of EOC in all LULCC types showed a significantly deceasing trend with increasing latitude (p < 0.05). The loss of EOC due to LULCC was larger in mangroves than in salt marshes. The results showed that the response of plant and soil C variables to LULCC was mainly related to differences in plant biomass, median grain size, soil water content and soil NH4+-N content. This study emphasized the importance of LULCC in triggering C loss in natural coastal wetlands, which strengthens the greenhouse effect. We suggest that the current land-based climate models and climate mitigation policies must account for specific land-use types and their associated land management practices to achieve more effective emission reduction.

Combination of novel oncolytic herpesvirus with paclitaxel as an efficient strategy for breast cancer therapy.

BACKGROUND: New strategies are needed to improve the treatment of patients with breast cancer (BC). Oncolytic virotherapy is a promising new tool for cancer treatment but still has a limited overall durable antitumor response. A novel replicable recombinant oncolytic herpes simplex virus type 1 called VG161 has been developed and has demonstrated antitumor effects in several cancers. Here, we explored the efficacy and the antitumor immune response of VG161 cotreatment with paclitaxel (PTX) which as a novel oncolytic viral immunotherapy for BC. METHODS: The antitumor effect of VG161 and PTX was confirmed in a BC xenograft mouse model. The immunostimulatory pathways were tested by RNA-seq and the remodeling of tumor microenvironment was detected by Flow cytometry analysis or Immunohistochemistry. Pulmonary lesions were analyzed by the EMT6-Luc BC model. RESULTS: In this report, we demonstrate that VG161 can significantly represses BC growth and elicit a robust antitumor immune response in a mouse model. The effect is amplified when combined with PTX treatment. The antitumor effect is associated with the infiltration of lymphoid cells, including CD4+ T cells, CD8+ T cells, and NK cells (expressing TNF and IFN-γ), and myeloid cells, including macrophages, myeloid-derived suppressor cells, and dendritic cell cells. Additionally, VG161 cotreatment with PTX showed a significant reduction in BC lung metastasis, which may result from the enhanced CD4+ and CD8+ T cell-mediated responses. CONCLUSIONS: The combination of PTX and VG161 is effective for repressing BC growth by inducing proinflammatory changes in the tumor microenvironment and reducing BC pulmonary metastasis. These data will provide a new strategy and valuable insight for oncolytic virus therapy applications in primary solid or metastatic BC tumors.

Induced pluripotent stem cell-derived engineered T cells, natural killer cells, macrophages, and dendritic cells in immunotherapy.

T cells, natural killer (NK) cells, macrophages (Macs), and dendritic cells (DCs) are among the most common sources for immune-cell-based therapies for cancer. Antitumor activity can be enhanced in induced pluripotent stem cell (iPSC)-derived immune cells by using iPSCs as a platform for stable genetic modifications that impact immuno-activating or -suppressive signaling pathways, such as transducing a chimeric antigen receptor (CAR) or deletion of immunosuppressive checkpoint molecules. This review outlines the utility of four iPSC-derived immune-cell-based therapies, highlight the latest progress and future trends in the genome-editing strategies designed to improve efficacy, safety, and universality, and provides perspectives that compare different contexts in which each of these iPSC-derived immune cell types can be most effectively used.

Exploration of prognostic genes and risk signature in breast cancer patients based on RNA binding proteins associated with ferroptosis.

Background: Breast cancer (BRCA) is a life-threatening malignancy in women with an unsatisfactory prognosis. The purpose of this study was to explore the prognostic biomarkers and a risk signature based on ferroptosis-related RNA-binding proteins (FR-RBPs). Methods: FR-RBPs were identified using Spearman correlation analysis. Differentially expressed genes (DEGs) were identified by the "limma" R package. The univariate Cox and multivariate Cox analyses were executed to determine the prognostic genes. The risk signature was constructed and verified with the training set, testing set, and validation set. Mutation analysis, immune checkpoint expression analysis in high- and low-risk groups, and correlation between risk signature and chemotherapeutic agents were conducted using the "maftools" package, "ggplot2" package, and the CellMiner database respectively. The Human Protein Atlas (HPA) database was employed to confirm protein expression trends of prognostic genes in BRCA and normal tissues. The expression of prognostic genes in cell lines was verified by Real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-meier (KM) plotter database analysis was applied to predict the correlation between the expression levels of signature genes and survival statuses. Results: Five prognostic genes (GSPT2, RNASE1, TIPARP, TSEN54, and SAMD4A) to construct an FR-RBPs-related risk signature were identified and the risk signature was validated by the International Cancer Genome Consortium (ICGC) cohort. Univariate and multivariate Cox regression analysis demonstrated the risk score was a robust independent prognostic factor in overall survival prediction. The Tumor Mutational Burden (TMB) analysis implied that the high- and low-risk groups responded differently to immunotherapy. Drug sensitivity analysis suggested that the risk signature may serve as a chemosensitivity predictor. The results of GSEA suggested that five prognostic genes might be related to DNA replication and the immune-related pathways. RT-qPCR results demonstrated that the expression trends of prognostic genes in cell lines were consistent with the results from public databases. KM plotter database analysis suggested that high expression levels of GSPT2, RNASE1, and SAMD4A contributed to poor prognoses. Conclusion: In conclusion, this study identified the FR-RBPs-related prognostic genes and developed an FR-RBPs-related risk signature for the prognosis of BRCA, which will be of great significance in developing new therapeutic targets and prognostic molecular biomarkers for BRCA.

Population Structure, Demographic History, and Adaptation of Giant Honeybees in China Revealed by Population Genomic Data.

There have been many population-based genomic studies on human-managed honeybees (Apis mellifera and Apis cerana), but there has been a notable lack of analysis with regard to wild honeybees, particularly in relation to their evolutionary history. Nevertheless, giant honeybees have been found to occupy distinct habitats and display remarkable characteristics, which are attracting an increased amount of attention. In this study, we de novo sequenced and then assembled the draft genome sequence of the Himalayan giant honeybee, Apis laboriosa. Phylogenetic analysis based on genomic information indicated that A. laboriosa and its tropical sister species Apis dorsata diverged ∼2.61 Ma, which supports the speciation hypothesis that links A. laboriosa to geological changes throughout history. Furthermore, we re-sequenced A. laboriosa and A. dorsata samples from five and six regions, respectively, across their population ranges in China. These analyses highlighted major genetic differences for Tibetan A. laboriosa as well as the Hainan Island A. dorsata. The demographic history of most giant honeybee populations has mirrored glacial cycles. More importantly, contrary to what has occurred among human-managed honeybees, the demographic history of these two wild honeybee species indicates a rapid decline in effective population size in the recent past, reflecting their differences in evolutionary histories. Several genes were found to be subject to selection, which may help giant honeybees to adapt to specific local conditions. In summary, our study sheds light on the evolutionary and adaptational characteristics of two wild giant honeybee species, which was useful for giant honeybee conservation.

Curvature-Regulated Multiphase Patterns in Tori.

Biological functions in living systems are closely related to their geometries and morphologies. Toroidal structures, which widely exist in nature, present interesting features containing positive, zero, and negative Gaussian curvatures within one system. Such varying curvatures would significantly affect the growing or dehydrating morphogenesis, as observed in various intricate patterns in abundant biological structures. To understand the underlying morphoelastic mechanism and to determine the crucial factors that govern the patterning in toroidal structures, we develop a core-shell model and derive a scaling law to characterize growth- or dehydration-induced instability patterns. We find that the eventual patterns are mainly determined by two dimensionless parameters that are composed of stiffness and curvature of the system. Moreover, we construct a phase diagram showing the multiphase wrinkling pattern selection in various toroidal structures in terms of these two parameters, which is confirmed by our experimental observations. Physical insights into the multiphase transitions and existence of bistable modes are further provided by identifying hysteresis loops and the Maxwell equal-energy conditions. The universal law for morphology selection on core shell structures with varying curvatures can fundamentally explain and precisely predict wrinkling patterns of diverse toroidal structures, which may also provide a platform to design morphology-related functional surfaces.

A clustering method for small scRNA-seq data based on subspace and weighted distance.

Background: Identifying the cell types using unsupervised methods is essential for scRNA-seq research. However, conventional similarity measures introduce challenges to single-cell data clustering because of the high dimensional, high noise, and high dropout. Methods: We proposed a clustering method for small ScRNA-seq data based on Subspace and Weighted Distance (SSWD), which follows the assumption that the sets of gene subspace composed of similar density-distributing genes can better distinguish cell groups. To accurately capture the intrinsic relationship among cells or genes, a new distance metric that combines Euclidean and Pearson distance through a weighting strategy was proposed. The relative Calinski-Harabasz (CH) index was used to estimate the cluster numbers instead of the CH index because it is comparable across degrees of freedom. Results: We compared SSWD with seven prevailing methods on eight publicly scRNA-seq datasets. The experimental results show that the SSWD has better clustering accuracy and the partitioning ability of cell groups. SSWD can be downloaded at https://github.com/ningzilan/SSWD.

Loss of bisecting GlcNAcylation on MCAM of bone marrow stoma determined pro-tumoral niche in MDS/AML.

Bone marrow (BM) stroma plays key roles in supporting hematopoietic stem cell (HSC) growth. Glycosylation contributes to the interactions between HSC and surrounding microenvironment. We observed that bisecting N-acetylglucosamine (GlcNAc) structures, in BM stromal cells were significantly lower for MDS/AML patients than for healthy subjects. Malignant clonal cells delivered exosomal miR-188-5p to recipient stromal cells, where it suppressed bisecting GlcNAc by targeting MGAT3 gene. Proteomic analysis revealed reduced GlcNAc structures and enhanced expression of MCAM, a marker of BM niche. We characterized MCAM as a bisecting GlcNAc-bearing target protein, and identified Asn 56 as bisecting GlcNAc modification site on MCAM. MCAM on stromal cell surface with reduced bisecting GlcNAc bound strongly to CD13 on myeloid cells, activated responding ERK signaling, and thereby promoted myeloid cell growth. Our findings, taken together, suggest a novel mechanism whereby MDS/AML clonal cells generate a self-permissive niche by modifying glycosylation level of stromal cells.

Increased expression of ECT2 predicts the poor prognosis of breast cancer patients.

Breast cancer is the most common malignancy and the second leading cause of cancer-related death in women. Recent studies have indicated that aberrant activation of Rho GTPases relates to the malignant properties of breast cancer cells. As the guanine nucleotide exchange factor of Rho GTPases, the role of ECT2 (epithelial cell transforming 2) in breast cancer is still unclear. Tissue microarrays and multiple public databases were utilized to investigate the relationship between ECT2 level and clinical-pathological features of breast cancer patients. Kaplan Meier-plotter online tool and tissue microarray with survival information were used to investigate the predictive value for breast cancer. Here, we found increased ECT2 level was highly associated with advanced TNM stage, poor differentiation, and loss of hormone receptors of breast cancer. Gene expression profile showed that ECT2 level was closely correlated to cell-proliferation-associated pathways. Integration analysis using public databases and tissue microarray indicated that high ECT2 was an adverse prognostic factor for breast cancer patients. We believe the ECT2 level might be a valuable complement for commercially available predictors such as the 21 genes test. Furthermore, ECT2 would be a novel target for drug development for breast cancer.

Use of period analysis to timely assess 5-year relative survival for breast cancer patients from Taizhou, Eastern China.

Objectives: While timely assessment of long-term survival for patients with breast cancer is essential for evaluation on early detection and screening programs, those data are extremely scant in China. We aimed to derive most up-to-date survival estimates and to predict future survival using the cancer registry data from Taizhou city, Eastern China. Methods: Patients diagnosed with breast cancer during 2004-2018 from four cancer registries with high-quality data from Taizhou, Eastern China were included. Period analysis was used to calculate 5-year relative survival (RS) for the overall population and according to the stratification factors sex, age at diagnosis and geographic region. We further predict the upcoming 5-year RS during 2019-2023, using continuous data from three 5-year periods (2004-2008, 2009-2013 and 2014-2018) and a model-based period approach. Results: Overall 6159 patients diagnosed with breast cancer during 2004-2018 were enrolled. The 5-year RS for breast cancer in 2014-2018 reached 88.8%, while women were higher compared to men (90.5% versus 83.7%) and urban areas were higher compared to rural areas (91.9% versus 86.7%). Additionally, we found a clear gradient by age at diagnosis, ranging from 94.8% for age<45 years to 83.3% for age>74 years. Projected overall 5-year RS for the upcoming 2019-2023 could reach 91.5% (84.8% for men and 93.5% for women). Conclusions: We provided, for first time in China, using period analysis, most up-to-date 5-year RS (88.8%) for patients with breast cancer from Taizhou, Eastern China. We also demonstrate the 5-year RS has improved greatly over last 15 years, which has important implications for timely evaluation of early detection and screening programs.