Set7/9 aggravates ischemic brain injury via enhancing glutamine metabolism in a blocking Sirt5 manner.

The aberrant expression of methyltransferase Set7/9 plays a role in various diseases. However, the contribution of Set7/9 in ischemic stroke remains unclear. Here, we show ischemic injury results in a rapid elevation of Set7/9, which is accompanied by the downregulation of Sirt5, a deacetylase reported to protect against injury. Proteomic analysis identifies the decrease of chromobox homolog 1 (Cbx1) in knockdown Set7/9 neurons. Mechanistically, Set7/9 promotes the binding of Cbx1 to H3K9me2/3 and forms a transcription repressor complex at the Sirt5 promoter, ultimately repressing Sirt5 transcription. Thus, the deacetylation of Sirt5 substrate, glutaminase, which catalyzes the hydrolysis of glutamine to glutamate and ammonia, is decreased, promoting glutaminase expression and triggering excitotoxicity. Blocking Set7/9 eliminates H3K9me2/3 from the Sirt5 promoter and normalizes Sirt5 expression and Set7/9 knockout efficiently ameliorates brain ischemic injury by reducing the accumulation of ammonia and glutamate in a Sirt5-dependent manner. Collectively, the Set7/9-Sirt5 axis may be a promising epigenetic therapeutic target.

Development of a nomogram prognostic model for early Grade ≥ 3 infection in newly diagnosed multiple myeloma based on immunoparesis.

BACKGROUND: Infection, a significant cause of death in multiple myeloma (MM) patients, is a common complication and is closely associated with immunoparesis. There exists no clear definition of early infection, so early infection is defined in this paper as the occurrence within 3 months after diagnosis, considering the high incidence of infections within 3 months after diagnosis. This study established a new nomogram model based on immunoparesis to identify MM patients with high-risk early infection. METHODS: A retrospective collection of 430 NDMM patients from June 2013 to June 2022 was conducted, and the patients were further divided into a training cohort and a validation cohort. In the training cohort, the least absolute shrinkage and selection operator (LASSO) was used to select the best variables that can be used to establish a new nomogram prediction model. Validation was performed in the validation and entire cohorts. RESULTS: After diagnosis, 67.7 % of the patients suffered from severe infection within 1 year, and 59.5 % experienced the first severe infection within 3 months. Variables associated with an increased risk of severe infection in the first 3 months included: BMPC, D-dimer, serum ß2 microglobulin, immunoparesis, albumin, and eGFR. The nomogram based on the above six factors achieved a good C-index of 0.754, 0.73, and 0.731 in predicting early infection in the training cohort, validation cohort, and entire cohort, respectively. Finally, the time-dependent receiver operating characteristic (ROC) curve and decision curve analysis (DCA) of the nomogram showed that the model provided superior diagnostic capacity and clinical net benefit. CONCLUSION: In this study, we established a nomogram model to predict early grade ≥ 3 infection in NDMM patients. This model can assist clinicians in identifying NDMM patients with high-risk infections and improve their prognosis through early intervention.

Hematologists' awareness of venous thromboembolism in multiple myeloma: a national survey in China.

BACKGROUND: Venous thromboembolism (VTE) is one of the most common and severe complications of multiple myeloma (MM). The aim of this study was to learn about the current awareness regarding MM-associated VTE among Chinese hematologists. METHODS: A nationwide, online, questionnaire-based survey was sent to the specialized hematologists in mainland China. The questionnaire investigated respondents' demographic and occupational characteristics, their ability to identify VTE risk factors, and their thromboprophylaxis decisions for different anti-MM regimens. Six clinical vignettes were used to evaluate hematologists' awareness of stratified thromboprophylaxis. The data were analyzed using SPSS software. RESULTS: A total of 518 valid questionnaires were received. Of the 518 hematologists investigated, only 23.7% of them could identify VTE-related risk factors correctly. Most hematologists could select appropriate thromboprophylaxis for common anti-MM regimens such as VCd (bortezomib, cyclophosphamide, and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone), but not for uncommon ones such as VTD-PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide) and KRd (carfilzomib, lenalidomide, and dexamethasone). The results from the vignettes suggested that only 19.5% of the hematologists could be defined as the 'stratified thromboprophylaxis' group, and the awareness of stratified thromboprophylaxis depended significantly on physicians' age and working seniority. CONCLUSION: The results of our study showed that a large proportion of Chinese hematologists failed to recognize the VTE risk factors, most of them cannot select appropriate thromboprophylaxis for different MM therapeutic regimens and lack awareness of stratified thromboprophylaxis for MM-associated VTE. A standard VTE prevention guideline is urgently needed for the Chinese myeloma group. Continuous education for new professionals should be encouraged. A VTE collaborative group is supposed to be established in each hospital to enhance the overall medical care for VTE patients.

The substantial myeloma patient population and extensive use of immunomodulatory drugs indicate that MM-associated VTE deserves more attention in China.The results from our cross-sectional study showed that a significant proportion of Chinese hematologists failed to identify the VTE risk factors, most of them cannot select appropriate thromboprophylaxis for different MM therapeutic regimens and lack awareness of stratified thromboprophylaxis for MM-associated VTE.

MALAT1 regulates network of microRNA-15a/16-VEGFA to promote tumorigenesis and angiogenesis in multiple myeloma.

MALAT1 is one of the most hopeful members implicated in angiogenesis in a variety of non-malignant diseases. In multiple myeloma (MM), MALAT1 is recognized as the most highly expressed long non-coding RNA. However, the functional roles of MALAT1 in angiogenesis and the responsible mechanisms have not yet been explored. Herein, we discovered a novel regulatory network dependent on MALAT1 in relation to MM tumorigenesis and angiogenesis. We observed that MALAT1 was upregulated in MM and significantly associated with poor overall survival. MALAT1 knockdown suppressed MM cell proliferation and promoted apoptosis, while restricting endothelial cells angiogenesis. Moreover, MALAT1 directly targeted microRNA-15a/16, and microRNA-15a/16 suppression partly reverted the effects of MALAT1 deletion on MM cells in vitro as well as tumor growth and angiogenesis in vivo. In addition, further study indicated that MALAT1 functioned as a competing endogenous RNA for microRNA-15a/16 to regulate vascular endothelial growth factor A (VEGFA) expression. Our results suggest that MALAT1 plays an important role in the regulatory axis of microRNA-15a/16-VEGFA to promote tumorigenicity and angiogenesis in MM. Consequently, MALAT1 could serve as a novel promising biomarker and a potential antiangiogenic target against MM.

PARP16-Mediated Stabilization of Amyloid Precursor Protein mRNA Exacerbates Alzheimer's Disease Pathogenesis.

The accumulation and deposition of beta-amyloid (Aß) are key neuropathological hallmarks of Alzheimer's disease (AD). PARP16, a Poly(ADP-ribose) polymerase, is a known tail-anchored endoplasmic reticulum (ER) transmembrane protein that transduces ER stress during pathological processes. Here, we found that PARP16 was significantly increased in the hippocampi and cortices of APPswe/PS1dE9 (APP/PS1) mice and hippocampal neuronal HT22 cells exposed to Aß, suggesting a positive correlation between the progression of AD pathology and the overexpression of PARP16. To define the effect of PARP16 on AD progression, adeno-associated virus mediated-PARP16 knockdown was used in APP/PS1 mice to investigate the role of PARP16 in spatial memory, amyloid burden, and neuroinflammation. Knockdown of PARP16 partly attenuated impaired spatial memory, as indicated by the Morris water maze test, and decreased amyloid deposition, neuronal apoptosis, and the production of inflammatory cytokines in the brains of APP/PS1 mice. In vitro experiments demonstrated that the knockdown of PARP16 expression rescued neuronal damage and ER stress triggered by Aß. Furthermore, we discovered that intracellular PARP16 acts as an RNA-binding protein that regulates the mRNA stability of amyloid precursor protein (APP) and protects targeted APP from degradation, thereby increasing APP levels and AD pathology. Our findings revealed an unanticipated role of PARP16 in the pathogenesis of AD, and at least in part, its association with increased APP mRNA stability.

ADP-ribose transferase PARP16 mediated-unfolded protein response contributes to neuronal cell damage in cerebral ischemia/reperfusion.

Ischemic stroke is known to cause the accumulation of misfolded proteins and loss of calcium homeostasis, leading to impairment of endoplasmic reticulum (ER) function and activating the unfolded protein response (UPR). PARP16 is an active (ADP-ribosyl)transferase known tail-anchored ER transmembrane protein with a cytosolic catalytic domain. Here, we find PARP16 is highly expressed in ischemic cerebral hemisphere and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated immortalized hippocampal neuronal cell HT22. Using an adeno-associated virus-mediated PARP16 knockdown approach in mice, we find PARP16 knockdown decreases infarct demarcations and has a better neurological outcome after ischemic stroke. Our data indicate PARP16 knockdown decreases ER stress and neuronal death caused by OGD/R, whereas PARP16 overexpression promotes ER stress-mediated cell damage in primary cortical neurons. Furthermore, PARP16 functions mechanistically as ADP-ribosyltransferase to modulate the level of ADP-ribosylation of the corresponding PERK and IRE1α arm of the UPR, and such modifications mediate activation of PERK and IRE1α. Indeed, pharmacological stimulation of the UPR using Brefeldin A partly counteracts PARP16 knockdown-mediated neuronal protection upon OGD/R treatment. In conclusion, PARP16 plays a crucial role in post-ischemic UPR and PARP16 knockdown alleviates brain injury after ischemic stroke. This study demonstrates the potential of the PARP16-PERK/IRE1α axis as a target for neuronal survival in ischemic stroke.

CCL18 promotes migration and invasion of multiple myeloma cells and is associated with poor prognosis.

CCL18 has recently been implicated in malignancies and is increasingly mentioned as a potential tumoral biomarker and furtherly a molecular target for therapeutic intervention, but its expression and clinical significance in multiple myeloma have not been explored. Serum CCL18 levels were measured by ELISA method in 254 newly diagnosed multiple myeloma (NDMM), 21 monoclonal gammopathy of undetermined significance (MGUS) and 22 healthy adults. The study suggests that the serum CCL18 level in NDMM patients was significantly higher than that in MGUS and healthy adults. High level of CCL18 were associated with advanced ISS and R-ISS stages in MM. Patients with high serum CCL18 displayed a significantly more frequent occurrence of renal impairment and hypercalcemia, while the proportion of achieving complete remission (CR) was lower. More importantly, Cox analysis identified CCL18 and LDH as independent predictors of PFS in MM patients, whereas CCL18, creatinine and LDH were independent predictors of OS. Finally, we show that CCL18 can promote migration and invasion of myeloma cell lines RPMI8226 and MM.1S. CCL18 may play a tumor-promoting role by increasing the migration and invasion abilities of myeloma cells.

Histone methyltransferase Smyd2 contributes to blood-brain barrier breakdown in stroke.

BACKGROUND: The blood-brain barrier (BBB) plays a principal role in the healthy and diseased central nervous systems, and BBB disruption after ischaemic stroke is responsible for increased mortality. Smyd2, a member of the SMYD-methyltransferase family, plays a vital role in disease by methylation of diverse substrates; however, little is known about its role in the pathophysiology of the brain in response to ischaemia-reperfusion injury. METHODS: Using oxygen glucose deprivation and reoxygenation (OGD/R)-induced primary brain microvascular endothelial cells (BMECs) and Smyd2 knockdown mice subjected to middle cerebral artery occlusion, we evaluated the role of Smyd2 in BBB disruption. We performed loss-of-function and gain-of-function studies to investigate the biological function of Smyd2 in ischaemic stroke. RESULTS: We found that Smyd2 was a critical factor for regulating brain endothelial barrier integrity in ischaemia-reperfusion injury. Smyd2 is upregulated in peri-ischaemic brains, leading to BBB disruption via methylation-mediated Sphk/S1PR. Knockdown of Smyd2 in mice reduces BBB permeability and improves functional recovery. Using OGD/R-induced BMECs, we demonstrated that Sphk/S1PR methylation modification by Smyd2 affects ubiquitin-dependent degradation and protein stability, which may disrupt endothelial integrity. Moreover, overexpression of Smyd2 can damage endothelial integrity through Sphk/S1PR signalling. CONCLUSIONS: Overall, these results reveal a novel role for Smyd2 in BBB disruption in ischaemic stroke, suggesting that Smyd2 may represent a new therapeutic target for ischaemic stroke.

FTO promotes multiple myeloma progression by posttranscriptional activation of HSF1 in an m6A-YTHDF2-dependent manner.

N6-methyladenosine (m6A), as the most pervasive internal modification of eukaryotic mRNA, plays a crucial role in various cancers, but its role in multiple myeloma (MM) pathogenesis has not yet been investigated. In this study, we revealed significantly decreased m6A methylation in plasma cells (PCs) from MM patients and showed that the abnormal m6A level resulted mainly from upregulation of the demethylase fat mass and obesity-associated protein (FTO). Gain- and loss-of-function studies demonstrated that FTO plays a tumor-promoting and pro-metastatic role in MM. Combined m6A and RNA sequencing (RNA-seq) and subsequent validation and functional studies identified heat shock factor 1 (HSF1) as a functional target of FTO-mediated m6A modification. FTO significantly promotes MM cell proliferation, migration, and invasion by targeting HSF1/HSPs in a YTHDF2-dependent manner. FTO inhibition, especially when combined with bortezomib (BTZ) treatment, synergistically inhibited myeloma bone tumor formation and extramedullary spread in NOD-Prkdcem26Cd52il2rgem26Cd22/Nju (NCG) mice. We demonstrated the functional importance of m6A demethylase FTO in MM progression, especially in promoting extramedullary myeloma (EMM) formation, and proposed the FTO-HSF1/HSP axis as a potential novel therapeutic target in MM.

Prognostic nomogram incorporating cytokines for overall survival in patients with newly diagnosed multiple myeloma.

OBJECTIVE: The purpose of this study was to explore the relationship between pretreatment cytokine status and overall survival and establish a prognostic nomogram incorporating cytokines in newly diagnosed multiple myeloma (NDMM) patients. METHODS: A total of 121 patients with NDMM from the Wuhan Union Hospital were included in our study. Patient serum levels of cytokines, including macrophage inflammatory protein 1 alpha (MIP-1α), migration inhibitory factor (MIF), tumor necrosis factor-α (TNF-α), vascular endothelial growth factor-α (VEGF-α), monocyte chemoattractant protein-1 (MCP-1) and soluble interleukins IL-17A, IL-6, IL-21 and IL-10 were assessed before treatment. Based on the results of the multivariate Cox proportional hazards model, we developed a prognostic nomogram. We used the concordance index (C-index) and a calibration curve to measure the predictive performance of the nomogram. RESULTS: Three important variables (lactate dehydrogenase, MIP-1α and creatinine) were incorporated in the nomogram using multivariate Cox analysis. The 3-year overall survival (OS) rate and progression-free survival (PFS) rate were 83.8% and 21.8% in the low-risk group of the nomogram and 17.4% and 8.4% in the high-risk group, respectively. The C-index of the nomogram for OS prediction was 0.80 (95% CI: 0.68-0.92), showing superiority over the predictive power of the Durie-Salmon staging system (C-index = 0.58; 95% CI: 0.49-0.67), International Staging System (C-index = 0.70; 95% CI: 0.61-0.79) and Revised-International Staging System (C-index = 0.71; 95% CI: 0.63-0.80). The calibration curve showed that the nomogram accurately predicted the 1-year, 2-year and 3-year OS of NDMM patients. CONCLUSION: The established nomogram provides accurate and individualized OS risk estimation for NDMM patients.

Circulating Plasma Cells as a Biomarker to Predict Newly Diagnosed Multiple Myeloma Prognosis: Developing Nomogram Prognostic Models.

Background: To investigate the prognostic value of circulating plasma cells (CPC) and establish novel nomograms to predict individual progression-free survival (PFS) as well as overall survival (OS) of patients with newly diagnosed multiple myeloma (NDMM). Methods: One hundred ninetyone NDMM patients in Wuhan Union Hospital from 2017.10 to 2020.8 were included in the study. The entire cohort was randomly divided into a training (n = 130) and a validation cohort (n = 61). Univariate and multivariate analyses were performed on the training cohort to establish nomograms for the prediction of survival outcomes, and the nomograms were validated by calibration curves. Results: When the cut-off value was 0.038%, CPC could well distinguish patients with higher tumor burden and lower response rates (P < 0.05), and could be used as an independent predictor of PFS and OS. Nomograms predicting PFS and OS were developed according to CPC, lactate dehydrogenase (LDH) and creatinine. The C-index and the area under receiver operating characteristic curves (AUC) of the nomograms showed excellent individually predictive effects in training cohort, validation cohort or entire cohort. Patients with total points of the nomograms ≤ 60.7 for PFS and 75.8 for OS could be defined as low-risk group and the remaining as high-risk group. The 2-year PFS and OS rates of patients in low-risk group was significantly higher than those in high-risk group (p < 0.001). Conclusions: CPC is an independent prognostic factor for NDMM patients. The proposed nomograms could provide individualized PFS and OS prediction and risk stratification.

Single cell electron collectors for highly efficient wiring-up electronic abiotic/biotic interfaces.

By electronically wiring-up living cells with abiotic conductive surfaces, bioelectrochemical systems (BES) harvest energy and synthesize electric-/solar-chemicals with unmatched thermodynamic efficiency. However, the establishment of an efficient electronic interface between living cells and abiotic surfaces is hindered due to the requirement of extremely close contact and high interfacial area, which is quite challenging for cell and material engineering. Herein, we propose a new concept of a single cell electron collector, which is in-situ built with an interconnected intact conductive layer on and cross the individual cell membrane. The single cell electron collector forms intimate contact with the cellular electron transfer machinery and maximizes the interfacial area, achieving record-high interfacial electron transfer efficiency and BES performance. Thus, this single cell electron collector provides a superior tool to wire living cells with abiotic surfaces at the single-cell level and adds new dimensions for abiotic/biotic interface engineering.

Incidence and Mortality Trends and Risk Prediction Nomogram for Extranodal Diffuse Large B-Cell Lymphoma: An Analysis of the Surveillance, Epidemiology, and End Results Database.

Background: DLBCL is the most commonly occurring type of non-Hodgkin's lymphoma, which may be found at various extranodal sites. But little is known about the particular trends of extranodal DLBCL. Methods: A total of 15,882 extranodal DLBCL patients were included in incidence analysis from the Surveillance, Epidemiology, and End Results (SEER) database (1973-2015). The joinpoint regression software was used to calculate the annual percent change (APC) in rates. Nomograms were established by R software to predict overall survival (OS). Results: The extranodal DLBCL incidence continued to rise at a rate of 1.6% (95% CI, 0.4-2.8, p < 0.001) per year over the study period, until it declined around 2003. The incidence-based mortality trend of extranodal DLBCL had a similar pattern, with a decrease happening around 1993. Five-year survival rates improved dramatically from the 1970s to 2010s (44.15 vs. 63.7%), and the most obvious increase occurred in DLBCL patients with primary site in the head/neck. The C-index showed a value for OS of 0.708, which validated the nomograms performed well and were able to forecast the prognosis of patients with extranodal DLBCL. The calibration curves showed satisfactory consistency between true values and predicted values for 1-, 5-, and 10-year overall survival, respectively. Conclusions: The incidence and incidence-based mortality of extranodal DLBCL had been increasing for decades, followed by a promising downward trend in recent years. These findings may help scientists identify disease-related risk factors and better manage the disease. The prediction signature cloud identifies high-risk patients who should receive effective therapies to prevent the fatal nature of this disease, and low-risk patients to reduce over-treatment.

Endogenously enhanced biosurfactant production promotes electricity generation from microbial fuel cells.

Microbial fuel cell (MFC) is considered as a promising green energy source and energy-saving pollutants treatment technology as it integrates pollutant biodegradation with energy extraction. In this work, a facile approach to enhance endogenous biosurfactant production was developed to improve the electron transfer rate and power output of MFC. By overexpression of rhlA, the key gene responsible for rhamnolipids synthesis, over-production of self-synthesized rhamnolipids from Pseudomonas aeruginosa PAO1 was achieved. Strikingly, the increased rhamnolipids production by rhlA overexpression significantly promoted the extracellular electron transfer of P. aeruginosa by enhancing electron shuttle (pyocyanin) production and increasing bacteria attachment on the anode. As a result, the strain with endogenously enhanced rhamnolipids production delivered 2.5 times higher power density output than that of the parent strain. This work substantiated that the enhancement on endogenous biosurfactant production could be a promising approach for improvement on the electricity output of MFC.