The influence of cerebellum on visual selective attention in patients with multiple lacunar cerebral infarction and its neuromodulatory mechanisms.

Objective: This study aims to investigate the influence of the cerebellum on visual selective attention function and its neuromodulatory mechanism in patients with multiple lacunar cerebral infarction (MLCI). Methods: A retrospective analysis was conducted on 210 patients admitted with MLCI from January 2016 to May 2022. Analyzed the electrophysiological characteristics of the P3a and P3b components of vision in both groups, as well as source reconstruction simulations of dipole activation in the brains of the two groups, and analyzed the brain regions with differences in activation strength between the two groups. Results: This study found that there was no significant difference in peak amplitude between the two groups, but compared with the control group, the peak latency of the case group was significantly prolonged. Specifically, the P3a peak latency induced by the novel stimulus was longer than that induced by the target stimulus P3b peak latency. Source reconstruction results showed decreased and increased activation in several brain regions in the case group compared to the control group. Conclusion: The study suggests that the impairment of distracted attention capture is more pronounced in patients with MLCI. The cerebellum indirectly influences the ventral and dorsal frontoparietal attention networks by modulating the levels of excitation and inhibition within the cerebral cortex of the attention network. This may represent a potential mechanism through which the cerebellum regulates visual selective attention information in MLCI patients.

Single-cell sequencing advances in research on mesenchymal stem/stromal cells.

Mesenchymal stem/stromal cells (MSCs), originating from the mesoderm, represent a multifunctional stem cell population capable of differentiating into diverse cell types and exhibiting a wide range of biological functions. Despite more than half a century of research, MSCs continue to be among the most extensively studied cell types in clinical research projects globally. However, their significant heterogeneity and phenotypic instability have significantly hindered their exploration and application. Single-cell sequencing technology emerges as a powerful tool to address these challenges, offering precise dissection of complex cellular samples. It uncovers the genetic structure and gene expression status of individual contained cells on a massive scale and reveals the heterogeneity among these cells. It links the molecular characteristics of MSCs with their clinical applications, contributing to the advancement of regenerative medicine. With the development and cost reduction of single-cell analysis techniques, sequencing technology is now widely applied in fundamental research and clinical trials. This study aimed to review the application of single-cell sequencing in MSC research and assess its prospects.

Endoplasmic reticulum stress and death receptor-mediated apoptosis in the neuronal differentiation of adult adipose-derived stromal cells.

Apoptosis is the primary cause of cell death in the differentiation of Adipose-derived stromal cells (ADSCs) into neurons. However, the relationship between endoplasmic reticulum stress (ERS) and death receptor-mediated apoptosis in ADSC-induced neuronal differentiation is not clear. ADSCs were isolated and induced to differentiate into neurons using ß-mercaptoethanol. The expression of neuron-specific enolase (NSE), GRP94, CHOP, Fas/FasL, TNFR1/TNF-α, DR5/TRAIL, Caspase8, and Caspase3 in ADSCs was examined using immunocytochemistry and Western blotting before induction, during pre-induction, and after induction. Transmission electron microscopy (TEM) was used to observe changes in the morphology of the endoplasmic reticulum (ER), and the MTT assay was employed to measure cell viability in the uninduced and induced groups. Additionally, the number of apoptotic cells during the induction process was measured using flow cytometry with Annexin V/PI. With increasing induction time, the positive expression rates of CHOP, Fas/FasL, Caspase8, Caspase-3, and NSE gradually increased, while the positive expression rate of GRP94 decreased. TNFR1/TNF-α and DR5/TRAIL peaked at 5 h post-induction and then decreased at 8 h. TEM revealed swelling and expansion of the ER, vacuolar changes, and degranulation in cells. The MTT assay showed a gradual decrease in the absorbance of surviving cells in all groups. Flow cytometry indicated an increasing rate of apoptosis in cells. Therefore, ERS in the normal culture and growth of ADSCs, manifesting as enhanced unfolded protein response (UPR), maintains the normal survival of ADSCs. However, in the process of ADSC-induced differentiation into neurons, ERS and death receptor-mediated apoptosis are significant causes of cell death.

The c-Abl-RACK1-FAK signaling axis promotes renal fibrosis in mice through regulating fibroblast-myofibroblast transition.

BACKGROUND: Renal fibrosis is a prevalent manifestation of chronic kidney disease (CKD), and effective treatments for this disease are currently lacking. Myofibroblasts, which originate from interstitial fibroblasts, aggregate in the renal interstitium, leading to significant accumulation of extracellular matrix and impairment of renal function. The nonreceptor tyrosine kinase c-Abl (encoded by the Abl1 gene) has been implicated in the development of renal fibrosis. However, the precise role of c-Abl in this process and its involvement in fibroblast-myofibroblast transition (FMT) remain poorly understood. METHODS: To investigate the effect of c-Abl in FMT during renal fibrosis, we investigated the expression of c-Abl in fibrotic renal tissues of patients with CKD and mouse models. We studied the phenotypic changes in fibroblast or myofibroblast-specific c-Abl conditional knockout mice. We explored the potential targets of c-Abl in NRK-49F fibroblasts. RESULTS: In this study, fibrotic mouse and cell models demonstrated that c-Abl deficiency in fibroblasts mitigated fibrosis by suppressing fibroblast activation, fibroblast-myofibroblast transition, and extracellular matrix deposition. Mechanistically, c-Abl maintains the stability of the RACK1 protein, which serves as a scaffold for proteins such as c-Abl and focal adhesion kinase at focal adhesions, driving fibroblast activation and differentiation during renal fibrosis. Moreover, specifically targeting c-Abl deletion in renal myofibroblasts could prove beneficial in established kidney fibrosis by reducing RACK1 expression and diminishing the extent of fibrosis. CONCLUSIONS: Our findings suggest that c-Abl plays a pathogenic role in interstitial fibrosis through the regulation of RACK1 protein stabilization and myofibroblast differentiation, suggesting a promising strategy for the treatment of CKD.

Cancer screening in hospitalized ischemic stroke patients: a multicenter study focused on multiparametric analysis to improve management of occult cancers.

Background/aims: The reciprocal promotion of cancer and stroke occurs due to changes in shared risk factors, such as metabolic pathways and molecular targets, creating a "vicious cycle." Cancer plays a direct or indirect role in the pathogenesis of ischemic stroke (IS), along with the reactive medical approach used in the treatment and clinical management of IS patients, resulting in clinical challenges associated with occult cancer in these patients. The lack of reliable and simple tools hinders the effectiveness of the predictive, preventive, and personalized medicine (PPPM/3PM) approach. Therefore, we conducted a multicenter study that focused on multiparametric analysis to facilitate early diagnosis of occult cancer and personalized treatment for stroke associated with cancer. Methods: Admission routine clinical examination indicators of IS patients were retrospectively collated from the electronic medical records. The training dataset comprised 136 IS patients with concurrent cancer, matched at a 1:1 ratio with a control group. The risk of occult cancer in IS patients was assessed through logistic regression and five alternative machine-learning models. Subsequently, select the model with the highest predictive efficacy to create a nomogram, which is a quantitative tool for predicting diagnosis in clinical practice. Internal validation employed a ten-fold cross-validation, while external validation involved 239 IS patients from six centers. Validation encompassed receiver operating characteristic (ROC) curves, calibration curves, decision curve analysis (DCA), and comparison with models from prior research. Results: The ultimate prediction model was based on logistic regression and incorporated the following variables: regions of ischemic lesions, multiple vascular territories, hypertension, D-dimer, fibrinogen (FIB), and hemoglobin (Hb). The area under the ROC curve (AUC) for the nomogram was 0.871 in the training dataset and 0.834 in the external test dataset. Both calibration curves and DCA underscored the nomogram's strong performance. Conclusions: The nomogram enables early occult cancer diagnosis in hospitalized IS patients and helps to accurately identify the cause of IS, while the promotion of IS stratification makes personalized treatment feasible. The online nomogram based on routine clinical examination indicators of IS patients offered a cost-effective platform for secondary care in the framework of PPPM. Supplementary Information: The online version contains supplementary material available at 10.1007/s13167-024-00354-8.

A Three-Wavelength Optical Sensor for Measuring the Multi-Particle-Size Channel Mass Concentration of Thermal Power Plant Emissions.

Emissions from thermal power plants have always been the central consideration for environmental protection. Existing optical sensors in thermal power plants usually measure the total mass concentration of the particulate matter (PM) by a single-wavelength laser, bearing intrinsic errors owing to the variation in particle size distribution (PSD). However, the total mass concentration alone cannot characterize all the harmful effects of the air pollution caused by the power plant. Therefore, it is necessary to measure the mass concentration and PSD simultaneously, based on which we can obtain multi-particle-size channel mass concentration. To achieve this, we designed an optical sensor based on the three-wavelength technique and tested its performance in a practical environment. Results showed that the prototype cannot only correctly measure the mass concentration of the emitted PM but also determine the mean diameter and standard deviation of the PSDs. Hence, the mass concentrations of PM10, PM2.5, and PM1 are calculated, and the air pollutants emission by a thermal power plant can be estimated comprehensively.

A convenient and reproducible protocol for acquisition of the hepatocyte phase for liver function-impaired patients in gadoxetic acid disodium-enhanced magnetic resonance imaging.

Background: The hepatocyte phase (HCP) in gadoxetic acid disodium (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) plays an important role in the detection and characterization of liver lesions, treatment planning, and liver function evaluation. However, the imaging protocol is complicated and time-consuming. This cross-sectional study aimed to develop a convenient and reproducible protocol for the HCP acquisition in Gd-EOB-DTPA-enhanced MRI. Methods: A total of 107 patients were prospectively included and assigned to three groups based on Child-Pugh (CP) classification, with 37, 40, and 30 in the non-cirrhosis, CP A, and CP B groups, respectively. Dynamic HCPs were acquired every 5 min after the Gd-EOB-DTPA administration and ended in 25 min in non-cirrhosis patients and 40 min in cirrhotic patients. The HCP acquired 5 min after the initial visualization of the intrahepatic bile duct (IBD) was selected from the dynamic HCPs as the adequate HCP (HCPproposed) and the corresponding acquisition time was recorded as Timeproposed. In addition, according to the 2016 Expert Consensus (EC) on the definition of the adequate HCP from the European Society of Gastrointestinal and Abdominal Radiology (ESGAR), the adequate HCPEC and the corresponding TimeEC were also determined from the dynamic HCPs. The hepatic relative enhancement ratio (RER), the contrast-to-noise ratio (CNR), and signal-to-noise ratio (SNR) of hepatic focal lesions in the HCPEC and HCPproposed images, as well as the TimeEC and Timeproposed were compared by the paired t-test for the three groups, respectively. Inter-observer agreement of the determination of the HCPEC and HCPproposed was compared by the χ2 test. Results: The RER, CNR, and SNR showed no significant difference between the HCPEC and HCPproposed in all three groups (all P>0.05). The paired differences between TimeEC and Timeproposed were 1.08±3.56 min (P=0.07), 2.88±4.22 min (P<0.001), and 5.83±5.27 min (P<0.001) in the three groups, respectively. Inter-observer agreement of the determination of the HCPEC and HCPproposed were 0.804 (86/107) and 0.962 (103/107), respectively (χ²=13.09, P=0.001). Conclusions: The adequate HCP could be acquired 5 min after the initial visualization of the IBD, which could serve as a convenient and reproducible protocol for the HCP imaging.

Associations of type 2 diabetes and the risk of migraine in Chinese populations.

AIM: We aimed to explore the relationship between type 2 diabetes mellitus (T2DM) and the incidence rate of migraine in a Chinese population, and analyze the clinical characteristics of migraine patients with T2DM. METHODS: Data on the study cohort of 9873 individuals were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The incidence rate of migraine from 2015 to 2018 was assessed. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for the relationship between T2DM and the incidence of migraine. In addition, a cross-sectional study including 168 migraine patients was conducted in Xiamen, China. Migraine patients were grouped according to their T2DM status. Multivariable linear regression models were used to estimate ßs and their 95% CIs for the relationship between migraine characteristics and T2DM. RESULTS: The cumulative incidence rate of migraine from 2015 to 2018 in the T2DM group and control group was 7.26% [6.04%.8.65%] and 8.91% [8.27%.9.58%], respectively. The risk of migraine in patients with T2DM was reduced by 21% (HR 0.79 [0.65;0.95]) compared to patients with no T2DM after adjustment for confounders. The cross-sectional study showed that the presence of T2DM significantly reduced migraine frequency and relieved migraine intensity. CONCLUSION: This was the first study to validate that T2DM reduced the risk of migraine in a Chinese population cohort. Patients with migraine and T2DM may experience significant relief from their headache symptoms. Carrying out relevant mechanistic research may help to identify new targets for migraine treatment and contribute to further understanding the impact of T2DM or related metabolic disorders on an individual's health.

Synaptic endocytosis in adult adipose stromal cell-derived neurons.

Synapses are essential for facilitating the transmission of information between neurons and for executing neurophysiological processes. Following the exocytosis of neurotransmitters, the synaptic vesicle may quickly undergo endocytosis to preserve the structural integrity of the synapse. When converting adipose-derived stromal cells (ADSCs) into neurons, the ADSCs have already demonstrated comparable morphology, structure, and electrophysiological characteristics to neurons. Nevertheless, there is currently no published study on the endocytotic function of neurons that are produced from ADSCs. This study aimed to examine synaptic endocytosis in neurons derived from ADSCs by qualitatively and quantitatively analyzing the presence of Ap-2, Clathrin, Endophilin, Dynamin, and Hsc70, which are the key proteins involved in clathrin-mediated endocytosis (CME), as well as by using FM1-43 and cadmium selenide quantum dots (CdSe QDs). Additionally, single-cell RNA sequencing (scRNA-seq) was used to look at the levels of both neuronal markers and markers related to CME at the same time. The results of this study provide evidence that synapses in neurons produced from ADSCs have a role in endocytosis, mainly through the CME route.

Metabolic Risk Profile and Graft Function Deterioration 2 Years After Kidney Transplant.

Importance: Studies exploring the association of body weight and metabolic status with graft function deterioration (GFD) after kidney transplantation have produced inconsistent findings. Few studies have examined whether metabolically healthy overweight or obesity (MHO) may contribute to GFD. Objective: To evaluate associations of overweight or obesity and metabolic disorders with GFD in recipients of kidney transplant. Design, Setting, and Participants: This multicenter retrospective cohort study was conducted from January 1, 2020, through June 30, 2021, with a follow-up period of 2 years after kidney transplantation. Participants included adult recipients of cadaveric kidney transplant in 4 transplantation centers in China. Participants were classified as 4 metabolic phenotypes according to their BMI and metabolic status. Data were analyzed from July to August 2023. Exposures: Overweight and obesity were characterized by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) of 24 or greater. Metabolic disorder was identified by existence of a minimum of 2 of 4 conditions: hypertension, hyperglycemia, increased triglyceride, and decreased high-density lipoprotein cholesterol. Main Outcome and Measures: The main outcome was GFD, defined as a decrease in estimated glomerular filtration rate of at least 25% within 6 months to 2 years after transplant. Results: A total of 1260 adult recipients of cadaveric kidney transplant (mean [SD] age, 43.97 [11.51] years; 755 [59.92%] male) were included in the study, and 127 (10.08%) participants experienced the primary outcome of GFD during follow-up. After accounting for confounding factors in multivariable analyses, overweight or obesity (odds ratio [OR], 1.64; 95% CI, 1.10-2.44; P = .02) and metabolic disorder (OR, 1.71; 95% CI, 1.12-2.63; P = .01) were associated with increased risk of GFD. The MHO subgroup exhibited a greater risk for GFD (OR, 2.37; 95% CI, 1.01-5.57; P = .048) compared with participants who did not have overweight or obesity or metabolic disorder. All components of metabolic disorder, with the exception of elevated triglyceride, were associated with GFD. There was a dose-response association of number of metabolic disorder components (OR per 1 additional condition, 1.40; 95% CI, 1.20-1.63; P < .001) and BMI (OR per 1-unit increase, 1.90; 95% CI, 1.03-1.15; P = .002) with increased risk for GFD. A nonlinear association was observed between BMI and risk of GFD. Conclusions and Relevance: In this cohort study of recipients of cadaveric kidney transplant, individuals with overweight or obesity or metabolic disorder had a significantly higher risk of experiencing GFD. Individuals with MHO had an elevated risk for graft function deterioration. Additional studies with larger sample size and longer follow-up are necessary to validate our findings.

Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

Background: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI). Methods: Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics. Results: CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with the other drugs. The MMF-containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with that of the MMF group, although liver transplantation patients have lower NK cell activity and function. Conclusions: Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

Serum neurofilament light chain levels in migraine patients: a monocentric case-control study in China.

PURPOSE: Serum neurofilament light chain (sNfL) can reflect nerve damage. Whether migraine can cause neurological damage remain unclear. This study assesses sNfL levels in migraine patients and explores whether there is nerve damage in migraine. METHODS: A case-control study was conducted in Xiamen, China. A total of 138 migraine patients and 70 healthy controls were recruited. sNfL (pg/mL) was measured on the single-molecule array platform. Univariate, Pearson correlation and linear regression analysis were used to assess the relationship between migraine and sNfL levels, with further subgroup analysis by migraine characteristics. RESULTS: Overall, 85.10% of the 208 subjects were female, with a median age of 36 years. sNfL levels were higher in the migraine group than in the control group (4.85 (3.49, 6.62) vs. 4.11 (3.22, 5.59)), but the difference was not significant (P = 0.133). The two groups showed an almost consistent trend in which sNfL levels increased significantly with age. Subgroup analysis showed a significant increase in sNfL levels in patients with a migraine course ≥ 10 years (ß = 0.693 (0.168, 1.220), P = 0.010). Regression analysis results show that age and migraine course are independent risk factors for elevated sNfL levels, and there is an interaction between the two factors. Patients aged < 45 years and with a migraine course ≥ 10 years have significantly increased sNfL levels. CONCLUSIONS: This is the first study to evaluate sNfL levels in migraine patients. The sNfL levels significantly increased in patients with a migraine course ≥ 10 years. More attention to nerve damage in young patients with a long course of migraine is required.

CircRBM33 induces endothelial dysfunction by targeting the miR-6838-5p/PDCD4 axis affecting blood-brain barrier in mice with cerebral ischemia-reperfusion injury.

BACKGROUND: circRNAs (circRNAs) are involved in the process of cerebral ischemia-reperfusion injury (CI/RI). Our study aims to explore circRBM33 in the endothelial function of the blood-brain barrier (BBB). METHODS: The mouse middle cerebral artery occlusion model (MCAO) was established and restored to perfusion, and OGD/R-induced endothelial cells were used to simulate CI/RI. circRBM33, miR-6838-5p and PDCD4, as well as Occludin, ZO-1 and Claudin-5 TJs were evaluated by quantitative PCR and Western blot. The ring structure of circRBM33 was verified by RNAse R and actinomycin D experiments. MTT and LDH Cytotoxicity assay determined viability and toxicity, and flow cytometry determined apoptosis rate. Inflammatory cytokines and the number of microglia in brain tissue were measured by ELISA and IHC. The interaction between genes was verified by RIP and dual luciferase reporter assay. RESULTS: circRBM33 was a circrRNA present in the cytoplasm and up-regulated in the brain tissue of MCAO mice and OGD/R-induced endothelial cells. Silenced circRBM33 promoted Occludin, ZO-1, and Claudin-5 expression and cell proliferation, and inhibited cytotoxicity, inflammatory response, and apoptosis. Functionally, circRBM33-absorbed miR-6838-5p was involved in regulating PDCD4, leading to endothelial cell dysfunction, and thus affecting the function of the BBB. CONCLUSIONS: circRBM33 by mediating miR-6838-5p/PDCD4 axis induces endothelial dysfunction, thereby affecting the BBB in mice with CI/RI.

MatBED_B&C: A 3-dimensional biologically effective dose analytic approach for the retrospective study of gamma knife radiosurgery in a B&C model.

The biological effect of irradiation is not solely determined by the physical dose. Gamma knife radiosurgery may be influenced by dose rate, beam-on-time, numbers of iso-centers, the gap between the individual iso-centers, and the dose‒response of various tissues. The biologically effective dose (BED) for radiosurgery considers these issues. Millions of patients treated with Models B and C provide a vast database to mine BED-related information. This research aims to develop MatBED_B&C, a 3-dimensional (3D) BED analytic approach, to generate a BED for individual voxels in the calculation matrix with related parameters extracted from Gammaplan. This approach calculates the distribution profiles of the BED in radiosurgical targets and organs at risk. A BED calculated on a voxel-by-voxel basis can be used to show the 3D morphology of the iso-BED surface and visualize the BED spatial distribution in the target. A 200 × 200 × 200 matrix can cover a greater range of the organ at risk. The BED calculated by MatBED_B&C can also be used to form BED-volume histograms to generate plan quality metrics, which will be studied in a retrospective study of gamma knife radiosurgery to guide future BED planning.•We develop MatBED_B&C to calculate the 3D BED in radiosurgical targets.•The BED of MatBED_B&C can visualize the BED spatial distribution profiles.•The BED of MatBED_B&C will generate plan quality metrics studied in a retrospective study.

The cerebellum and cognitive neural networks.

Cognitive function represents a complex neurophysiological capacity of the human brain, encompassing a higher level of neural processing and integration. It is widely acknowledged that the cerebrum plays a commanding role in the regulation of cognitive functions. However, the specific role of the cerebellum in cognitive processes has become a subject of considerable scholarly intrigue. In 1998, Schmahmann first proposed the concept of "cognitive affective syndrome (CCAS)," linking cerebellar damage to cognitive and emotional impairments. Since then, a substantial body of literature has emerged, exploring the role of the cerebellum in cognitive neurological function. The cerebellum's adjacency to the cerebral cortex, brainstem, and spinal cord suggests that the cerebral-cerebellar network loops play a crucial role in the cerebellum's participation in cognitive neurological functions. In this review, we comprehensively examine the recent literature on the involvement of the cerebellum in cognitive functions from three perspectives: the cytological basis of the cerebellum and its anatomical functions, the cerebellum and cognitive functions, and Crossed cerebellar diaschisis. Our aim is to shed light on the role and mechanisms of the cerebellum in cognitive neurobrain networks.

Shear wave elastography parameters adds prognostic value to adverse outcome in kidney transplantation recipients.

INTRODUCTION: The tissue stiffness of donor kidneys in transplantation may increase due to pathological changes such as glomerulosclerosis and interstitial fibrosis, and those changes associate worse outcomes in kidney transplantation recipients. Ultrasound elastography is a noninvasive imaging examination with the ability to quantitatively reflect tissue stiffness. Aim of this study was to evaluate the prognostic value of ultrasound elastography for adverse kidney outcome in kidney transplantation recipients. METHODS: Shear wave elastography (SWE) examinations were performed by two independent operators in kidney transplantation recipients. The primary outcome was a composite of kidney graft deterioration, all-cause re-hospitalization, and all-cause mortality. Survival analysis was calculated by Kaplan-Meier curves with the log-rank test and Cox regression analysis. RESULTS: A total of 161 patients (mean age 46 years, 63.4% men) were followed for a median of 20.1 months. 27 patients (16.77%) reached the primary endpoint. The mean and median tissue stiffness at the medulla (hazard ratio: 1.265 and 1.229, respectively), estimated glomerular filtration rate (eGFR), and serum albumin level were associated with the primary outcome in univariate Cox regression. Adding mean or median medulla SWE to a baseline model containing eGFR and albumin significantly improved its discrimination (C-statistics: 0.736 for the baseline, 0.766 and 0.772 for the model added mean and median medulla SWE, respectively). CONCLUSION: The medullary tissue stiffness of kidney allograft measured by shear wave elastography may provide incremental prognostic value to adverse outcomes in kidney transplantation recipients. Including SWE parameters in kidney transplantation recipients management could be considered to improve risk stratification.

Impact of Influenza and Pneumococcal Polysaccharide Vaccination on Economic Burden from Acute Exacerbations of Chronic Obstructive Pulmonary Disease - Hebei Province, China, November 2018 to November 2020.

What is already known on this topic?: Chronic obstructive pulmonary disease (COPD) exacerbations increase household economic burden, but there is limited evidence from prospective cohort studies in China about the impact of vaccination on economic burden. What is added by this report?: This study demonstrated the economic burden of COPD exacerbations, pneumonia, and hospitalization in COPD patients in China is substantial. Influenza vaccine and 23-valent pneumococcal polysaccharide vaccine (PPSV23), separately or together, were significantly associated with decreased economic burden. What are the implications for public health practice?: Our study supports evidence on recommendations that COPD patients in China are offered both influenza vaccine and PPSV23.

Identification and validation of Birc5 as a novel activated cell cycle program biomarker associated with infiltration of immunosuppressive myeloid-derived suppressor cells in hepatocellular carcinoma.

BACKGROUND: Preclinical studies and clinical trials have demonstrated that tumor-intrinsic activation of the cell cycle program impedes anticancer immunotherapy. Identification of cell cycle-related biomarkers may provide novel therapeutic targets to augment the efficacy of immunotherapy in hepatocellular carcinoma (HCC). METHOD AND RESULTS: Based on the genes related to cell cycle program, two clusters (Cluster 1 and Cluster 2) were detected in HCC patients via non-negative matrix factorization algorithm. Multivariable-adjusted Cox regression analysis indicated that the cell cycle gene-based classification was a significant prognostic factor for predicting the clinical outcome of HCC patients. Cluster 1 showed shorter overall survival time and progression-free interval time was associated with activated cell cycle program, higher infiltration of myeloid-derived suppressor cells (MDSCs) and less sensitivity to immunotherapy. A three-gene prognostic model, including BIRC5, C8G, and SPP1, was constructed to characterize the cell cycle-based classification of HCC, which had strong robustness and a stable predictive performance. Notably, Birc5 was positively correlated with CD11b expression (a MDSC marker) in HCC tissue. Concordant high expression of Birc5 and intratumor infiltration level of MDSCs were correlated with worse prognosis of HCC patients. In vitro, hepatocellular Birc5 overexpression promoted immunosuppressive CD11b+ CD33+ HLA-DR- MDSC expansion from human peripheral blood mononuclear cells. Genetically modified animal model of liver cancer revealed that Birc5 depletion upregulated the genes related to lymphocyte-mediated immunity, natural killer cell-mediated immunity, interferon-gamma production, T-cell activation, and T-cell-mediated cytotoxicity. These results suggest an immunosuppressive function of Birc5 in HCC. CONCLUSION: Birc5 was a potential biomarker and inducer of intratumor infiltration of MDSCs, which led to T cell exclusion or dysfunction in tumor immune microenvironment, consequently resulting in reduced response to ICIs in HCC.

IGF2BP3 promotes adult myocardial regeneration by stabilizing MMP3 mRNA through interaction with m6A modification.

Myocardial infarction that causes damage to heart muscle can lead to heart failure. The identification of molecular mechanisms promoting myocardial regeneration represents a promising strategy to improve cardiac function. Here we show that IGF2BP3 plays an important role in regulating adult cardiomyocyte proliferation and regeneration in a mouse model of myocardial infarction. IGF2BP3 expression progressively decreases during postnatal development and becomes undetectable in the adult heart. However, it becomes upregulated after cardiac injury. Both gain- and loss-of-function analyses indicate that IGF2BP3 regulates cardiomyocyte proliferation in vitro and in vivo. In particular, IGF2BP3 promotes cardiac regeneration and improves cardiac function after myocardial infarction. Mechanistically, we demonstrate that IGF2BP3 binds to and stabilizes MMP3 mRNA through interaction with N6-methyladenosine modification. The expression of MMP3 protein is also progressively downregulated during postnatal development. Functional analyses indicate that MMP3 acts downstream of IGF2BP3 to regulate cardiomyocyte proliferation. These results suggest that IGF2BP3-mediated post-transcriptional regulation of extracellular matrix and tissue remodeling contributes to cardiomyocyte regeneration. They should help to define therapeutic strategy for ameliorating myocardial infarction by inducing cell proliferation and heart repair.

Gene signature developed for predicting early relapse and survival in early-stage pancreatic cancer.

BACKGROUND: The aim of this study was to construct a predictive signature integrating tumour-mutation- and copy-number-variation-associated features using machine learning to precisely predict early relapse and survival in patients with resected stage I-II pancreatic ductal adenocarcinoma. METHODS: Patients with microscopically confirmed stage I-II pancreatic ductal adenocarcinoma undergoing R0 resection at the Chinese PLA General Hospital between March 2015 and December 2016 were enrolled. Whole exosome sequencing was performed, and genes with different mutation or copy number variation statuses between patients with and without relapse within 1 year were identified using bioinformatics analysis. A support vector machine was used to evaluate the importance of the differential gene features and to develop a signature. Signature validation was performed in an independent cohort. The associations of the support vector machine signature and single gene features with disease-free survival and overall survival were assessed. Biological functions of integrated genes were further analysed. RESULTS: Overall, 30 and 40 patients were included in the training and validation cohorts, respectively. Some 11 genes with differential patterns were first identified; using a support vector machine, four features (mutations of DNAH9, TP53, and TUBGCP6, and copy number variation of TMEM132E) were further selected and integrated to construct a predictive signature (the support vector machine classifier). In the training cohort, the 1-year disease-free survival rates were 88 per cent (95 per cent c.i. 73 to 100) and 7 per cent (95 per cent c.i. 1 to 47) in the low-support vector machine subgroup and the high-support vector machine subgroup respectively (P < 0.001). Multivariable analyses showed that high support vector machine was significantly and independently associated with both worse overall survival (HR 29.20 (95 per cent c.i. 4.48 to 190.21); P < 0.001) and disease-free survival (HR 72.04 (95 per cent c.i. 6.74 to 769.96); P < 0.001). The area under the curve of the support vector machine signature for 1-year disease-free survival (0.900) was significantly larger than the area under the curve values of the mutations of DNAH9 (0.733; P = 0.039), TP53 (0.767; P = 0.024), and TUBGCP6 (0.733; P = 0.023), the copy number variation of TMEM132E (0.700; P = 0.014), TNM stage (0.567; P = 0.002), and differentiation grade (0.633; P = 0.005), suggesting higher predictive accuracy for prognosis. The value of the signature was further validated in the validation cohort. The four genes included in the support vector machine signature (DNAH9, TUBGCP6, and TMEM132E were novel in pancreatic ductal adenocarcinoma) were significantly associated with the tumour immune microenvironment, G protein-coupled receptor binding and signalling, cell-cell adhesion, etc. CONCLUSION: The newly constructed support vector machine signature precisely and powerfully predicted relapse and survival in patients with stage I-II pancreatic ductal adenocarcinoma after R0 resection.