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BackgroundWe aimed to assess temporal trends in type 2 diabetes mellitus (T2DM)-related deaths and disability-adjusted life years (DALYs) at global and cross-social demographic index (SDI) levels, using data from the Global Burden of Disease (GBD) in 2021.MethodsWe used geospatial mapping to visualize the global distribution of T2DM-related mortality and DALYs in 2021. Joinpoint regression assessed annual and average percent changes in DALYs and deaths from 1990 to 2021 across SDI regions. Age-period-cohort modeling examined the effects of age, period, and cohort on trends. Decomposition analysis evaluated the impact of population growth, aging, and epidemiological changes on DALY trends. A stratified projection forecasted future T2DM burden by age and sex from 2020 to 2044.ResultsT2DM-related mortality and DALYs were highest in low-SDI regions. Globally, T2DM-related deaths and DALYs have increased, with the most rapid rise in low and low-middle SDI regions, driven by population growth and epidemiological shifts. High-SDI countries showed a slower increase in DALYs, influenced more by aging. Age-period-cohort analysis indicated higher DALY rates in later birth cohorts and recent periods, especially in high-SDI regions. Future projections show a significant increase in the 70-74 age group and a gradual rise in other age groups.ConclusionThe burden of T2DM is projected to continue increasing, especially in low-SDI and low-middle SDI regions, where population growth and epidemiological shifts are the main contributors. This underscores the need for targeted, region-specific healthcare policies, preventive strategies, and age-specific interventions to address the increasing T2DM burden globally.

Abstract Assessing failure pressure is critical in determining pipeline integrity. Current research primarily concerns the buckling performance of pressurized pipelines subjected to a bending load or axial compression force, with some also looking at the failure pressure of corroded pipelines. However, there is currently a lack of limit state models for pressurized pipelines with bending moments and axial forces. In this study, based on the unified yield criterion, we propose a limit state equation for steel pipes under various loads. The most common operating loads on buried pipelines are bending moment, internal pressure, and axial force. The proposed limit state equation for intact pipelines is based on a three-dimensional pipeline stress model with complex load coupling. Using failure data, we investigate the applicability of various yield criteria in assessing the failure pressure of pipelines with complex loads. We show that the evaluation model can be effectively used as a theoretical solution for assessing the failure pressure in such circumstances and for selecting appropriate yield criteria based on load condition differences.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of castration-resistant prostate cancer. It is characterized by low or no expression of the androgen receptor (AR), activation of AR-independent signaling, and increased neuroendocrine phenotype. Most of NEPC is induced by treatment of androgen deprivation therapy and androgen receptor pathway inhibitors (ARPIs). Currently, the treatment of NEPC follows the treatment strategy for small-cell lung cancer, lacking effective drugs and specific treatment options. This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (zeste homolog 2 inhibitors, lysine-specific demethylase 1 inhibitors), aurora kinase A inhibitors, poly-ADP-ribose polymerase inhibitors, delta-like ligand 3 targeted therapies, a combination of immunotherapies, etc. Other promising targets and future directions are also discussed in this review. These novel targets and therapies may provide new opportunities for the treatment of NEPC.

Background: Unhealthy diets significantly contribute to stomach, colorectal and esophageal cancer burden globally. Western diets high in processed and red meats promote carcinogenesis in these gastrointestinal cancers. However, adolescent and young adult (AYA) patients' unique needs regarding these cancers have been neglected. Methods: Data from the 2019 Global Burden of Disease study was used to quantify stomach, colorectal and esophageal cancer burden among AYAs from 1990 to 2040 across 204 countries. Correlations between the burden of these cancers and the Socio-demographic Index were examined. Results: High SDI locations experienced the largest reduction in cancer DALY rate change from 1990 to 2019 (-22% [-12 to -33]), compared to a small increase in low-middle SDI regions. Middle SDI areas saw the largest reduction in DALY rate change from 1990 to 2019 (-62% [-32 to -75]), compared to a small decrease in low-middle SDI locations (-9% [-27 to 10]) in esophageal cancer. From 1990–2019, stomach cancer deaths and DALYs declined across all SDI regions, with the largest reductions in high SDI locations (-61% [-57 to -69]) and smallest in low-middle SDI areas (-25% [-13 to -34]). Colorectal cancer deaths and DALYs rose across all SDI regions except high SDI locations, which showed a slight decrease. Conclusion: This study demonstrates the evolving global burden of stomach, colorectal and esophageal cancers among AYAs. The highest burden was in high-middle and high SDI regions, underscoring the need to prioritize initiatives targeting these gastrointestinal malignancies in youth.

IntroductionAllogeneic hematopoietic cell transplantation (alloHCT) possessed direct cytotoxicity and graft-versus-multiple myeloma effect (GvMM). Growing trials have shown survival benefits of performing alloHCT in both newly diagnosed and relapsed MM.MethodsWe aimed to provide a comprehensive analysis in the recent 10 years to verify the efficacy and survival outcome of alloHCT in MM patients. A total of 61 studies which provide data between 14/04/2013 and 14/04/2023 and a total of 15,294 data from MM patients who had undergone alloSCT were included in our study. The best response rates (CR, VGPR, PR) and survival outcomes (1-, 2-, 3-,5-, and 10-year OS, PFS, NRM) were assessed. We further conducted meta-analysis in the NDMM/frontline setting and RRMM/salvage setting independently.ResultsThe pooled estimate CR, VGPR, and PR rates were 0.45, 0.21, and 0.24, respectively. The pooled estimates of 1-, 2-, 3-, 5-, and 10-year OS were 0.69, 0.57, 0.45, 0.45, and 0.36, respectively; the pooled estimates of 1-, 2-, 3-, 5-, and 10-year PFS were 0.47, 0.35, 0.24, 0.25, and 0.28, respectively; and the pooled estimates of 1-, 2-, 3-, 5-, and 10-year NRM were 0.16, 0.21, 0.16, 0.20, and 0.15, respectively. In the NDMM/upfront setting, the pooled estimate CR rate was 0.54, and those for 5-year OS, PFS, and NRM were 0.69, 0.40, and 0.11, respectively. In a relapsed setting, the pooled estimate CR rate was 0.31, and those for 5-year OS, PFS, and NRM were 0.24, 0.10, and 0.15, respectively.DiscussionOur results showed constant OS, PFS, and NRM from the third year onwards till the 10th year, suggesting that alloSCT has sustained survival benefits. Good response rate and promising survival outcome were observed in the NDMM/ frontline setting.ConclusionAlthough comparing with other treatments, alloSCT had a lower response rate and poorer short-term survival outcome, long-term follow-up could reveal survival benefits of alloSCT in MM patients.

BackgroundThis prospective study aimed to investigate the influence of weight difference between implanted prosthesis and removed bone in cementless total hip arthroplasty (THA) on hip awareness and patient-reported outcomes.MethodsA total of 48 patients (56 hips) who underwent primary THA were prospectively enrolled. Implanted prosthesis and removed bone were weighed intraoperatively. Forgotten Joint Score (FJS) and Western Ontario and McMaster Universities (WOMAC) scores were obtained before and at 1 and 3 months after surgery. Patients were divided into groups A, B, and C according to the percentile of the weight difference.ResultsThe mean weight difference of the implanted prosthesis and removed bone was 117.97 ± 47.35 g. A negative correlation was found among the weight differences of the three groups and 1- and 3-month postoperative FJS (correlation coefficients, −0.331 and −0.734, respectively). A positive correlation was found among the weight difference of the three groups and 3-month postoperative WOMAC (correlation coefficient, 0.403). A significant difference in 3-month postoperative FJS and WOMAC scores was found among the three groups. The mean 3-month postoperative FJS (79.00) of group C was significantly lower than that of group A (93.32) (P

Background: The predominant feature of cancer cells during the process of carcinogenesis is the inclination towards glycolytic metabolism rather than mitochondrial oxidative phosphorylation. Nevertheless, there is a scarcity of research investigating the correlation between bladder cancer and mitochondrial energy metabolism. Methods: A qPCR array comprising 90 genes associated with mitochondrial oxidative phosphorylation was employed to discern metabolic disparities between three sets of bladder cancer tissue and adjacent normal tissue. Wound healing and transwell assays were utilized to assess cell migration and invasion capabilities, respectively. Colony formation assays were conducted to ascertain the tumorigenic potential of the cells. The proliferative capacity of the cells was examined through in vitro CCK-8 assays. Additionally, nude mouse models were established to evaluate the impact of bladder tumor cells on in vivo proliferation. The Seahorse XFe96 Analyzer was utilized to quantify mitochondrial oxidative phosphorylation, while the levels of glucose-6-phosphate and pyruvate were assessed to evaluate glycolysis. Results: Examination of qPCR array data demonstrated a noteworthy inhibition of mitochondrial oxidative phosphorylation in bladder cancer tissue, as evidenced by the down-regulation of a majority of genes associated with mitochondrial energy metabolism. Notably, GADD45B may potentially exert a significant influence on bladder cancer development, warranting further investigation. The down-regulation of GADD45B in bladder cancer cells resulted in impaired mitochondrial respiration and elevated levels of glycolysis, thereby enhancing cell migration and invasion. Conversely, up-regulation of GADD45B had the opposite effect. Furthermore, over-expression of GADD45B inhibited tumor proliferation and tumorigenesis in both in vitro and in vivo settings. Conclusion: These findings from our study indicate that the down-regulation of GADD45B promotes the shift of cell mitochondrial oxidative phosphorylation towards glycolysis, thereby facilitating the progression of bladder cancer.

Background and aims: There is an association between cancer and increased ribosome biogenesis. At present, the RPL7L1 (60S Ribosomal Protein L7-Like 1) were less reported by literature search. Study reports that RPL7L1 is associated with mouse embryonic and skeletal muscle. The study of RPL7L1 on tumors has not been reported. Methods: Our team downloaded the pan-cancer dataset that is uniformly normalized from the UCSC database (N=19131). Our study examined the relationship between RPL7L1 expression level and clinical prognosis with methylation, anti-tumour immunity, functional states, MSI, TMB, DNSss, LOH and chemotherapeutic responses in 43 cancer types and subtypes. Results and conclusions: RPL7L1 was overexpressed in nine tumor types. Gene mutation, tumor microenvironment and methylation modification of RPL7L1 plays a key role in patient prognosis. And the high expression of RPL7L1 was associated with TMB, MSI, LOH especially LIHC and HNSC. We experimentally verified that genes can promote the proliferation and migration of tumor cells. Our study suggested that RPL7L1 biomarker can be used for treating cancer, detecting it, and predicting its prognosis.

Optical neural networks (ONNs) have recently attracted extensive interest as potential alternatives to electronic artificial neural networks, owing to their intrinsic capabilities in parallel signal processing with reduced power consumption and low latency. Preliminary confirmation of parallelism in optical computing has been widely performed by applying wavelength division multiplexing (WDM) to the linear transformation of neural networks. However, interchannel crosstalk has obstructed WDM technologies from being deployed in nonlinear activation on ONNs. Here, we propose a universal WDM structure called multiplexed neuron sets (MNS), which applies WDM technologies to optical neurons and enables ONNs to be further compressed. A corresponding backpropagation (BP) training algorithm was proposed to alleviate or even annul the influence of interchannel crosstalk in MNS-based WDM-ONNs. For simplicity, semiconductor optical amplifiers are employed as an example of MNS to construct a WDM-ONN trained using the new algorithm. The results show that the combination of MNS and the corresponding BP training algorithm clearly downsizes the system and improves the energy efficiency by a factor of 10 while providing similar performance to traditional ONNs.

BackgroundLiver cancer is a leading cause of cancer-related deaths worldwide. Lysosomal dysfunction is implicated in cancer progression; however, prognostic prediction models based on lysosome-related genes (LRGs) are lacking in liver cancer. This study aimed to establish an LRG-based model to improve prognosis prediction and explore potential therapeutic targets in liver cancer.MethodsExpression profiles of 61 LRGs were analyzed in The Cancer Genome Atlas liver cancer cohorts. There were 14 LRGs identified, and their association with clinical outcomes was evaluated. Unsupervised clustering, Cox regression, and functional assays were performed.ResultsPatients were classified into high-risk and low-risk subgroups based on the 14 LRGs. The high-risk group had significantly worse overall survival. Aberrant immune infiltration and checkpoint expression were observed in the high-risk group. Furthermore, HPS4 was identified as an independent prognostic indicator. Knockdown of HPS4 suppressed liver cancer cell proliferation and induced apoptosis.ConclusionThis study developed an LRG-based prognostic model to improve risk stratification in liver cancer. The potential value of HPS4 as a therapeutic target and biomarker was demonstrated. Regulation of HPS4 may offer novel strategies for precision treatment in liver cancer patients.

TICRR is a regulatory factor of DNA replication with ToPBP1 interaction. At present, the underlying function and mechanisms of TICRR remain unclear in LIHC. Our objective was to assess the function and prognosis of TICRR in LIHC. We conducted a differential expression analysis, GO/KEGG, and GSEA enrichment analysis of TICRR in LIHC. We also carried out the gene frequency and SCNA of TICRR. We found that TICRR could serve as an independent prognostic marker in LIHC by univariate and multivariate analysis. In addition, we observed that TICRR was related to immune infiltration, and TICRR had positive correlation with PD1/PD-L1 and CTLA-4 in LIHC. The hsa-miR-126-3p/IPO9-AS1 may be the candidate ncRNAs to regulate the expression of TICRR. The high rate of SCNV of TICRR might have critical effect on the function of CTL cells in LIHC. We further demonstrate through a series of experiments that TICRR facilitated the proliferation and metastasis of liver cancer cells in vitro. Altogether, TICRR might be a potential biomarker and therapeutic target in LIHC.

Abstract Background The long-term functional recovery of traumatic brain injury (TBI) is hampered by pathological events, such as parenchymal neuroinflammation, neuronal death, and white matter injury. Krüppel-like transcription factor 11 (KLF 11) belongs to the zinc finger family of transcription factors and actively participates in various pathophysiological processes in neurological disorders. Up to now, the role and molecular mechanisms of KLF11 in regulating the pathogenesis of brain trauma is poorly understood. Methods KLF11 knockout (KO) and wild-type (WT) mice were subjected to experimental TBI, and sensorimotor and cognitive functions were evaluated by rotarod, adhesive tape removal, foot fault, water maze, and passive avoidance tests. Brain tissue loss/neuronal death was examined by MAP2 and NeuN immunostaining, and Cresyl violet staining. White matter injury was assessed by Luxol fast blue staining, and also MBP/SMI32 and Caspr/Nav1.6 immunostaining. Activation of cerebral glial cells and infiltration of blood-borne immune cells were detected by GFAP, Iba-1/CD16/32, Iba-1/CD206, Ly-6B, and F4/80 immunostaining. Brian parenchymal inflammatory cytokines were measured with inflammatory array kits. Results Genetic deletion of KLF11 worsened brain trauma-induced sensorimotor and cognitive deficits, brain tissue loss and neuronal death, and white matter injury in mice. KLF11 genetic deficiency in mice also accelerated post-trauma astrocytic activation, promoted microglial polarization to a pro-inflammatory phenotype, and increased the infiltration of peripheral neutrophils and macrophages into the brain parenchyma. Mechanistically, loss-of-KLF11 function was found to directly increase the expression of pro-inflammatory cytokines in the brains of TBI mice. Conclusion KLF11 acts as a novel protective factor in TBI. KLF11 genetic deficiency in mice aggravated the neuroinflammatory responses, grey and white matter injury, and impaired long-term sensorimotor and cognitive recovery. Elucidating the functional importance of KLF11 in TBI may lead us to discover novel pharmacological targets for the development of effective therapies against brain trauma.

Purpose: Antibiotic-loaded bone cement (ALBC) was usually used to prevent periprosthetic joint infection (PJI) in primary total knee arthroplasty (PTKA), but whether to use ALBC or plain bone cement in PTKA remains unclear. We aimed to compare the occurrence rate of PJI using two different cements, and to investigate the efficacy of different antibiotic types and doses administered in preventing surgical site infection (SSI) with ALBC. Methods: The availability of ALBC for preventing PJI was evaluated by using a systematic review and meta-analysis referring to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Existing articles until December 2021 involving PTKA patients with both ALBC and plain bone cement cohorts were scanned by searching “total knee arthroplasty”, “antibiotic-loaded cement”, “antibiotic prophylaxis”, “antibiotic-impregnated cement” and “antibiotic-laden cement” in the database of PubMed/MEDLINE, Embase, Web of Science and the Cochrane Library. Subgroup analysis included the effectiveness of different antibiotic types and doses in preventing SSI with ALBC. The modified Jadad scale was employed to score the qualities of included articles. Results: Eleven quantitative studies were enrolled, including 34,159 knees undergoing PTKA. The meta-analysis results demonstrated that the use of prophylactic ALBC could significantly reduce the prevalence of deep incisional SSI after PTKA, whereas there was no significant reduction in the rate of superficial incisional SSI. Moreover, gentamicin-loaded cement was effective in preventing deep incisional SSI, and the use of high-dose ALBC significantly reduced the rate of deep incisional SSI after PTKA. Besides, no significant adverse reactions and complications were stated during the use of ALBC in PTKA. Conclusion: The preventive application of ALBC during PTKA could reduce the rates of deep PJI. Furthermore, bone cement containing gentamicin and high-dose ALBC could even better prevent deep infection after PTKA. However, the existing related articles are mostly single-center and retrospective studies, and further high-quality ones are needed for confirmation.

Traumatic brain injury (TBI) is commonly followed by intractable psychiatric disorders and long-term changes in affect, such as anxiety. The present study sought to investigate the effect of repetitive intranasal delivery of interleukin-4 (IL-4) nanoparticles on affective symptoms after TBI in mice. Adult male C57BL/6 J mice (10–12 weeks of age) were subjected to controlled cortical impact (CCI) and assessed by a battery of neurobehavioral tests up to 35 days after CCI. Neuron numbers were counted in multiple limbic structures, and the integrity of limbic white matter tracts was evaluated using ex vivo diffusion tensor imaging (DTI). As STAT6 is a critical mediator of IL-4-specific transcriptional activation, STAT6 knockout mice were used to explore the role of endogenous IL-4/STAT6 signaling axis in TBI-induced affective disorders. We also employed microglia/macrophage (Mi/Mϕ)-specific PPARγ conditional knockout (mKO) mice to test if Mi/Mϕ PPARγ critically contributes to IL-4-afforded beneficial effects. We observed anxiety-like behaviors up to 35 days after CCI, and these measures were exacerbated in STAT6 KO mice but mitigated by repetitive IL-4 delivery. We discovered that IL-4 protected against neuronal loss in limbic structures, such as the hippocampus and the amygdala, and improved the structural integrity of fiber tracts connecting the hippocampus and amygdala. We also observed that IL-4 boosted a beneficial Mi/Mϕ phenotype (CD206+/Arginase 1+/PPARγ+ triple-positive) in the subacute injury phase, and that the numbers of Mi/Mϕ appositions with neurons were robustly correlated with long-term behavioral performances. Remarkably, PPARγ-mKO completely abolished IL-4-afforded protection. Thus, CCI induces long-term anxiety-like behaviors in mice, but these changes in affect can be attenuated by transnasal IL-4 delivery. IL-4 prevents the long-term loss of neuronal somata and fiber tracts in key limbic structures, perhaps due to a shift in Mi/Mϕ phenotype. Exogenous IL-4 therefore holds promise for future clinical management of mood disturbances following TBI.

Abstract The blood–brain barrier (BBB) is an essential component of the neurovascular unit that controls the exchanges of various biological substances between the blood and the brain. BBB damage is a common feature of different central nervous systems (CNS) disorders and plays a vital role in the pathogenesis of the diseases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs), are important regulatory RNA molecules that are involved in almost all cellular processes in normal development and various diseases, including CNS diseases. Cumulative evidences have demonstrated ncRNA regulation of BBB functions in different CNS diseases. In this review, we have summarized the miRNAs, lncRNAs, and circRNAs that can be served as diagnostic and prognostic biomarkers for BBB injuries, and demonstrated the involvement and underlying mechanisms of ncRNAs in modulating BBB structure and function in various CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), Alzheimer's disease (AD), vascular cognitive impairment and dementia (VCID), brain tumors, brain infections, diabetes, sepsis-associated encephalopathy (SAE), and others. We have also discussed the pharmaceutical drugs that can regulate BBB functions via ncRNAs-related signaling cascades in CNS disorders, along with the challenges, perspective, and therapeutic potential of ncRNA regulation of BBB functions in CNS diseases.

Abstract Background Periprosthetic joint infection (PJI) is considered to be one of the most challenging complications of joint replacement, which remains unpredictable. As a simple and emerging biomarker, calprotectin (CLP) has been considered to be useful in ruling out PJI in recent years. The purpose of this study was to investigate the accuracy and sensitivity of CLP in the diagnosis of PJI. Methods We searched and screened the publications from PubMed, Web of Science, EMBASE, and Cochrane Library from database establishment to June 2021. Subsequently, Stata version 16.0 software was used to combine the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), operating characteristic curve, and area under the curve (AUC). Heterogeneity across articles was evaluated by the I2 statistics. Finally, sources of heterogeneity were detected by subgroup analysis based on study design, detection method, sample size, and cutoff values. Results A total of 7 studies were included in our study, comprising 525 patients. The pooled sensitivity, specificity, PLR, and NLR of CLP for PJI diagnosis were 0.94(95% CI 0.87–0.98), 0.93(95% CI 0.87–0.96), 13.65(95% CI 6.89–27.08), and 0.06(95% CI 0.02–0.15), respectively, while the DOR and AUC were 222.33(95% CI 52.52–941.11) and 0.98 (95% CI 0.96–0.99), respectively. Conclusion Synovial CLP is a reliable biomarker and can be used as a diagnostic criterion for PJI in the future. However, the uncertainty resulting from the poor study numbers and sample sizes limit our ability to definitely draw conclusions on the basis of our study.

Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies.

BackgroundSpindle and kinetochore-associated complex subunits 1–3 (SKA1–3) stabilize the kinetochore-attached spindle microtubules in metaphase. Due to the dysregulation in multiple cancers, SKA1–3 is considered a predictor for the prognosis of the patients. However, the potential clinical applications of SKA1–3, particularly in hepatocellular carcinoma (HCC) prognosis and progression, have completely unknown yet.MethodsFor the analysis of SKA1–3 expression and applications in clinics in HCC patients, several databases, such as STRING, UALCAN, GEO, and TCGA, were searched. In addition, the underlying mechanisms of SKA for the regulation of HCC occurrence, development, and progression were also explored.ResultsCompared to the normal controls, HCC patients showed dramatically elevated SKA1–3 expression at the mRNA level, and the values of the area under the curve (AUC) were 0.982, 0.887, and 0.973, respectively. Increased SKA1–3 expression levels were associated with the clinical stage, age, body mass index, tumor grade, tissue subtype, and Tp53 mutation status in HCC patients. The analyses of Kyoto Encyclopedia of Genes and Genome (KEGG) and Gene ontology (GO) demonstrated that SKA1–3 are enriched mainly in the Fanconi anemia, homologous recombination, spliceosome, DNA replication, and cell cycle signaling pathways. The hub genes, such as CDK1, CCNB1, CCNA2, TOP2A, BUB1, AURKB, CCNB2, BUB1B, NCAPG, and KIF11, were identified in protein–protein interactions (PPIs). The expression levels of hub genes were increased in HCC patients and predictive of a poor prognosis. Finally, the expression levels of SKA1–3 were determined using the GEO database.ConclusionsSKA1–3 are potential prognostic biomarkers of and targets for HCC. In addition, SKA1–3 may affect HCC prognosis via the Fanconi anemia pathway, homologous recombination, spliceosome, DNA replication, and cell cycle signaling pathway.

Background and aimsInflammatory bowel disease (IBD) places a heavy medical burden on countries and families due to repeated and prolonged attacks, and the incidence and prevalence of IBD are increasing worldwide. Therefore, finding an effective treatment is a matter of great urgency. Glycerol monolaurate (GML), which has a twelve-carbon chain, is a compound naturally found in human breast milk. Some studies have shown that GML has antibacterial and anti-inflammatory effects. However, the specific mechanism of action remains unclear.MethodsAcute colitis was established in mice using 3% DSS, and glycerol monolaurate (500 mg·kg−1) was administered for two weeks. QPCR and western blotting were performed to examine the inflammatory status. Mice described were subjected to flow cytometry analysis for immune cell activation.ResultsGML treated alleviated macroscopic symptoms such as shortened colons, increased spleen weight, and caused weight loss in mice with DSS-induced colitis. In addition, GML decreased the expression of pro-inflammatory factors (NF-α, IL-1β and IL-1α) and increased the expression of anti-inflammatory factors (IL-10 and TGF-β). GML inhibited the activation of the MAPK and NF-κB signalling pathways, improved tissue damage, and increased the expression of intestinal tight junction proteins. In addition, LPMCs extracted from intestinal tissue via flow cytometry showed that GML treatment led to a decrease of Th17 cells, Neutrophils and Macrophages. 16S rDNA sequencing showed that GML increased the abundance of commensal bacterium such as Akkermansia and Lactobacillus murinus.ConclusionsWe showed that oral administration of GML ameliorated DSS-induced colitis by inhibiting infiltration of Th17 cells, Neutrophils, and Macrophages, protecting the intestinal mucosal barrier and altered the abundance of commensal bacterium. This study provides new insights into the biological function and therapeutic potential of GML in the treatment of IBD.

Abstract Chronic cerebral hypoperfusion‐derived brain damage contributes to the progression of vascular cognitive impairment and dementia (VCID). Cumulative evidence has shown that microRNAs (miRs) are emerging as novel therapeutic targets for CNS disorders. In this study, it is sought to determine the regulatory role of miR‐15a/16‐1 in VCID. It is found that miR‐15a/16‐1 knockout (KO) mice exhibit less cognitive and sensorimotor deficits following VCID. Genetic deficiency of miR‐15a/16‐1 in VCID mice also mitigate myelin degeneration, axonal injury, and neuronal loss. Mechanistically, miR‐15a/16‐1 binds to the 3’‐UTR of AKT3 and IL‐10RA. Genetic deletion of miR‐15a/16‐1 increases AKT3 and IL‐10RA expression in VCID brains, and intranasal delivery of AKT3 and IL‐10RA siRNA‐loaded nanoparticles partially reduce brain protection and cognitive recovery in miR‐15a/16‐1 KO mice after VCID. In conclusion, the miR‐15a/16‐1‐IL/10RA/AKT3 axis plays a critical role in regulating vascular brain damage and cognitive decline after VCID. Targeting miR‐15a/16‐1 is a novel therapeutic approach for the treatment of VCID.

BACKGROUND In order to quickly identify and screen high pressure and high temperature (HPHT) grown synthetic diamonds, a lot of research about their luminescent and spectral characteristics has been done. However, the comparative analysis is lacking, and less attention is paid to electrical and magnetic properties. OBJECTIVES To summarize the spectral characteristics and investigate the electrical and magnetic properties of HPHT synthetic diamonds systematically. METHODS Conventional gemological observation, high precision spectroscopy and electrical conductivity and magnetism testing were used for comparative analysis of 49 colorless and yellow samples. RESULTS The residual metal catalysts, including iron, cobalt, and nickel, caused the ferromagnetism of diamonds. All of the HPHT synthetic diamond samples could be attracted by the magnetic bar with magnetic intensity up to 12000Gs. The colorless samples were type Ⅱa+Ⅱb diamonds. The presence of boron led to its good conductivity, and the conductivity increased with increased boron content. The yellow samples were Ib+IaA type diamonds, and about one-third of the single nitrogen was converted into A aggregate. The synthetic diamond had undergone high temperature annealing treatment after growth. The ubiquitous presence of boron, and the presence of nitrogen mainly as single atoms and A aggregates led to the characteristic infrared spectra of HPHT synthetic diamonds. HPHT synthetic diamonds often contained crystal lattice defects caused by impurity elements such as nitrogen, nickel and silicon, which led to characteristic photoluminescence spectra. Colorless samples showed strong blue-green fluorescence and phosphorescence, whereas yellow samples had green fluorescence, with obvious cube-octahedron patterns. CONCLUSIONS Spectral and luminescent characteristics are still an important basis for screening and identification of HPHT synthetic diamonds. HPHT synthetic diamonds under the current growth technology also have obvious differences from natural diamonds in both conductivity and magnetism, which can be used as an auxiliary basis for rapid identification.

Neuroendocrine prostate cancer (NEPC) is a highly aggressive variant of castration-resistant prostate cancer. It is characterized by low or no expression of the androgen receptor (AR), activation of AR-independent signaling, and increased neuroendocrine phenotype. Most of NEPC is induced by treatment of androgen deprivation therapy and androgen receptor pathway inhibitors (ARPIs). Currently, the treatment of NEPC follows the treatment strategy for small-cell lung cancer, lacking effective drugs and specific treatment options. This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (zeste homolog 2 inhibitors, lysine-specific demethylase 1 inhibitors), aurora kinase A inhibitors, poly-ADP-ribose polymerase inhibitors, delta-like ligand 3 targeted therapies, a combination of immunotherapies, etc. Other promising targets and future directions are also discussed in this review. These novel targets and therapies may provide new opportunities for the treatment of NEPC. Plain language summary: This review summarizes potential novel targets and therapies for NEPC treatment, including epigenetic regulators (EZH2 inhibitors, LSD-1 inhibitors), AURKA inhibitors, PARP inhibitors, and DLL3 targeted therapies, and combination of immunotherapies, etc. These novel targets and therapies may provide new opportunities in the treatment of NEPC. [ABSTRACT FROM AUTHOR]

Abstract Background Osteonecrosis of the femoral head (ONFH) is a disabling disease, which often involves young patients. Recently, various hip-preserving surgeries were recommended to delay total hip arthroplasty (THA). Questions/purposes This study aimed to compare clinical outcomes and survival rate in the long-term follow-up between core decompression combined with a non-vascularized autologous fibular graft (group A) and an allogeneic fibular graft (group B) for the treatment of ONFH. Patients and methods We retrospectively evaluated 117 patients (153 hips) with ONFH (Association Research Circulation Osseous [ARCO] stages IIa to IIIc) who underwent the abovementioned hip-preserving surgeries between January 2003 and June 2012. The mean (range) follow-up times (years) were 12.9 (7–16) and 9.3 (6–16) in groups A and B, respectively. Clinical outcomes were assessed using the Harris Hip Score (HHS), visual analog scale (VAS) score, and forgotten joint score (FJS). A survival analysis was performed using the Kaplan-Meier method. The end point was THA. Results Groups A and B showed postoperative improvements, respectively, in HHS from 65 ± 7.2 to 80.3 ± 14.5 and from 66 ± 5.9 to 82.4 ± 13.6 (p 0.05) and 15-year survival rate (84.1% and 86%, respectively, p > 0.05) were found between groups A and B. Conclusions Autologous and allogeneic fibular grafts can attain equally good clinical outcomes and high survival rates in long-term follow-up, and thus can greatly delay THA owing to good bone osseointegration and sufficient mechanical support. Notably, the ratio of failure will increase when patients were more than 37 years old. Level of evidence Level III, therapeutic study

Abstract Background Periprosthetic joint infection (PJI) is one of the most devastating complications after total joint replacement (TJA). Up to now, the diagnosis of PJI is still in a dilemma. As a novel biomarker, whether D-dimer is valuable in the diagnosis of PJI remains controversial. This meta-analysis attempts to determine the diagnostic accuracy of D-dimer in PJI. Methods Relevant literature was retrieved from PubMed, Embase, Web of Science, and Cochrane Library (from database establishment to April 2020). Literature quality was evaluated using Revman (version 5.3). The random effect model was used in the Stata version 14.0 software to combine sensitivity, specificity, likelihood ratio (LR), diagnostic odds ratio (DOR), summary receiver operating characteristic (SROC) curve, and area under SROC (AUC) to evaluate the diagnostic value of overall D-dimer for PJI. Meta regression and subgroup analysis were performed according to the threshold, the study design, the sample size, the diagnostic gold standard, the country of study, and the type of sample. Results A total of 9 studies were included in this study, including 1592 patients. The pooled sensitivity and specificity of D-dimer for PJI diagnosis are 0.82 (95% CI, 0.72~0.89) and 0.73 (95% CI, 0.58~0.83), respectively. The pooled positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.99 (95% CI, 1.84~4.88) and 0.25 (95% CI, 0.15~0.41), respectively. The pooled AUC and diagnostic odds ratios were 0.85 (95% CI, 0.82~0.88) and 12.20 (95% CI, 4.98~29.86), respectively. Conclusion D-dimer is a promising biomarker for the diagnosis of PJI, which should be used in conjunction with other biomarkers or as an adjunct to other diagnostic methods to enhance diagnostic performance.

BACKGROUND Spectroscopic characteristics for brown colored Type Ⅱa diamonds treated by high pressure high temperature (HPHT) processes have been investigated extensively. However, almost no reports are available on the variation of the spectroscopic features for the type Ⅰa Cape series brown colored diamonds treated by HPHT processes. OBJECTIVES To help the laboratory to resolve the origin of yellow diamonds. METHODS The ultraviolet-visible (UV-Vis) absorption spectroscopy, Fourier transform infrared spectroscopy (FTIR), and photoluminescence spectroscopy were used to analyze the spectral features for the samples before and after each treatment. RESULTS The color of the diamonds changed from grayish brown to brownish yellow after the HPHT process. Meanwhile, the FTIR/UV-Vis absorption, as well as the photoluminescence was also greatly changed. Besides the 415nm and the 477nm absorption peaks, the treated diamonds also display H3 defect (503.2nm) and the gradually increasing absorption from 550nm to shortwave, resulted in the color changing from grayish brown to brownish yellow. In the mid-infrared region, the three peaks of 1498, 1520 and 1547cm-1 become a broad band centered at 1498cm-1 after treatment, and the photoluminescence spectrum displayed two distinct defects-H3 (503.2nm) and H2 (986.2nm). CONCLUSIONS The spectroscopic features provide a basis for accurate identification of HPHT-treated type Ⅰa Cape series brown diamonds in gem laboratories, and increase understanding of the variation mechanism of the nitrogen and hydrogen related lattice defects in the diamonds during the HPHT processes.

Background: The role of adenosine A2A receptor (A2AR) in the ischemic white matter damage induced by chronic cerebral hypoperfusion remains obscure. Here we investigated the role of A2AR in the process of macrophage polarizations in the white matter damage induced by chronic cerebral hypoperfusion and explored the involved signaling pathways.Methods: We combined mouse model and macrophage cell line for our study. White matter lesions were induced in A2AR knockout mice, wild-type mice, and chimeric mice generated by bone marrow cells transplantation through bilateral common carotid artery stenosis. Microglial/macrophage polarization in the corpus callosum was detected by immunofluorescence. For the cell line experiments, RAW264.7 macrophages were treated with the A2AR agonist CHS21680 or A2AR antagonist SCH58261 for 30 min and cultured under low-glucose and hypoxic conditions. Macrophage polarization was examined by immunofluorescence. The expression of peroxisome proliferator activated receptor gamma (PPARγ) and transcription factor P65 was examined by western blotting and real-time polymerase chain reaction (RT-PCR). Inflammatory cytokine factors were assessed by enzyme-linked immunosorbent assay (ELISA) and RT-PCR.Results: Both global A2AR knockout and inactivation of A2AR in bone marrow-derived cells enhanced M1 marker expression in chronic ischemic white matter lesions. Under low-glucose and hypoxic conditions, CGS21680 treatment promoted macrophage M2 polarization, increased the expression of PPARγ, P65, and interleukin-10 (IL-10) and suppressed the expression of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). The CGS21680-induced upregulation of P65 and IL-10 was abolished in macrophages upon PPARγ knockdown. The downregulation of TNF-α and IL-1β by CGS21680 was less affected by PPARγ knockdown.Conclusions: In the cerebral hypoperfusion induced white matter damage, A2AR signaling in bone marrow-derived cells induces macrophage M2 polarization and increases the expression of the anti-inflammatory factor IL-10 via the PPARγ-P65 pathway, both of which might explain its neuroprotective effect.

Abstract Background A retrospective study was conducted to evaluate and compare the clinical and radiological outcomes of one-stage fibular impaction allografting and vascularized greater trochanter flap autografting for the treatment of bilateral osteonecrosis of the femoral head (ONFH). Methods Patients who underwent one-stage aforementioned hip-preserving surgeries due to bilateral ONFH were retrospectively reviewed from January 2008 to December 2013. Sixty-nine patients (138 hips) with a mean age of 31.5 years and mean follow-up of 7.0 years were included. Hips that underwent fibular impaction allografting and vascularized greater trochanter flap autografting were assigned as group A and group B, respectively. Harris Hip Score (HHS) and Visual Analogue Scale (VAS) were used for clinical evaluation, and a series of X-ray images were used for radiological assessment. For inter-group analysis, the paired t test was used for continuous data, and the Wilcoxon rank sum test was used for non-parametric data, while the Mann-Whitney U test was used for intra-group analysis. Results The HHS and VAS in both groups A and B had a substantial advancement when compared with the preoperative level (p