Comprehensive understanding of intrinsic mobility and sub-10 nm quantum transportation in Ga2SSe monolayer.

Two-dimensional chalcogenides could play an important role in solving the short channel effect and extending Moore's law in the post-Moore era due to their excellent performances in the spintronics and optoelectronics fields. In this paper, based on theoretical calculations combining density functional theory and non-equilibrium Green's function, we have systematically explored the intrinsic mobility in the Ga2SSe monolayer and quantum transport properties of sub-10 nm Ga2SSe field-effect transistors (FET). Interestingly, the Ga2SSe monolayer presents high intrinsic electron mobility up to 104 cm2 (V s)-1. It is highlighted that the intrinsic mobility in the Ga2SSe monolayer is significantly restrained by phonon scattering, where the out-of-plane acoustic mode and high-frequency optic phonon mode are found predominantly coupled with the electrons. As a result, the n-type doping sub-10 nm Ga2SSe FETs represent distinguished transport properties. In particular, even the gate length is shortened to 3 nm, the on-state current, delay time and power consumption of the n-type doping Ga2SSe FET along the armchair direction can reach the International Technology Roadmap for Semiconductor industry standards for high-performance requirements. Our present study paves the way for the application of Ga2SSe monolayers in ultra-small sized FETs in the post-silicon era.

Potential material for fabricating optical mirrors: polished diamond coated silicon carbide.

Polished diamond coated silicon carbide can be a potential candidate material for making optical mirrors, due to the excellent properties. At present, five typical types of diamond films are deposited on RB-SiC substrates by hot filament chemical vapor deposition, and then polished by mechanical polishing. It is found that the boron-doped micro-crystalline and undoped nano-crystalline composite diamond (BDMC-UNCCD) coated specimen performs the best before, during, and after polishing. The film surface composed of nano-sized diamond grains has relatively low surface roughness and hardness, which are beneficial for the efficient polishing, and under the present condition only such a surface can be completely polished to a homogeneous mirror surface. The micro-sized diamond grains and the boron incorporation in the underlying BDMCD layer can enhance the film-substrate adhesion, which plays an important role in the film integrity during the polishing or subsequent applications. In conclusion, the polished BDMC-UNCCD coated RB-SiC specimen indeed shows low surface roughness (Ra=5.41 nm), high hardness (71.47 GPa), high elastic modulus (746 GPa), favorable surface shape accuracy (RMS=0.083λ), and considerable reflectivity in the short-wavelength range.

Employee education, labor protection intensity and auditor risk perception.

Prior literature finds senior executives can influence auditor decision making. However, few studies have discussed the impact of employee's personal characteristics. Our research aims to fill the above research gaps by examining the impact of employee level education on audit costs. Taking A-share listed companies in Shanghai and Shenzhen from 2006 to 2021 as the research object, this paper examines the impact of employee education on audit fees. It is found that highly educated employees can effectively reduce the audit fees borne by the company, but the implementation of the Labor Protection Law weakens this inhibitory effect. In the case of low marketization level and weak Confucian culture intensity, employee education level has a more significant inhibitory effect on audit fees of listed companies. This study provides a basis for empirical research on the impact of employee attributes on auditor decision making, provides a new research perspective on the impact of labor protection law at the corporate micro level, and enriches the theoretical research on corporate governance rooted in traditional Chinese culture. We contribute to the practice that implications for evaluating the effectiveness of adopting labor protection.

Establishment of homotrimer collagen type I signature and its association with clinical manifestation and tertiary lymphoid structures formation in liver cancer.

Background: collagen type I is a fundamental composition of extracellular matrix. Typically it exists in the form of a heterotrimer, consisting of two α1 chains encoded by COL1A1 and one α2 chain encoded by COL1A2. However, in cancer a homotrimeric form of collagen type I comprises three α1 chains encoded by COL1A1 was founded. There is still a lack of transcriptional and histologic methods for detecting homotrimeric collagen type I. Furthermore, a comprehensive analysis of the pan-cancer distribution pattern and clinical relevance of homotrimeric collagen type I is conspicuously absent. Method: Using transcriptional and immunoflourance method, we established homocol signature, which is able to transcriptionally and histologically detect homotrimeric collagen type I. We investigated the diagnostic and prognostic potential of homocol as a novel cancer biomarker in a pan-cancer cohort. Furthermore, we assessed its association with clinical manifestations in a liver cancer cohort undergoing treatment at our institute. Result: Homotrimer Collagen Type I is predominantly expressed by cancer cells and is linked to several critical cancer hallmarks, particularly inflammatory response and proliferation. Survival analyses have indicated that a high Homocol expression is correlated with poor outcomes in most types of cancer studied. In terms of cancer detection, Homocol demonstrated strong performance in Receiver Operating Characteristic (ROC) analysis, with an Area Under Curve (AUC) of 0.83 for pan-cancer detection and between 0.72 and 0.99 for individual cancers.In cohorts undergoing PD1 treatment, we noted a higher presence of Homocol in the response group. In a Hepatocellular Carcinoma (HCC) clinical set, high Homocol expression was associated with an increased formation of intra-tumor tertiary lymphoid structures (TLS), larger tumor sizes, more advanced Barcelona Clinic Liver Cancer (BCLC) stages, higher microvascular invasion (MVI) grades, absence of a capsule, and an enriched para-tumor collagen presence. Conclusion: our research has led to the development of a novel gene signature that facilitates the detection of Homotrimer Collagen Type I. This may greatly assist efforts in cancer detection, prognosis, treatment response prediction, and further research into Homotrimer Collagen Type I.

Disruption of MerTK increases the efficacy of checkpoint inhibitor by enhancing ferroptosis and immune response in hepatocellular carcinoma.

Immune checkpoint inhibitors, particularly PD-1/PD-L1 blockades, have been approved for unresectable hepatocellular carcinoma (HCC). However, high resistance rates still limit their efficacy, highlighting the urgent need to understand the underlying mechanisms and develop strategies for overcoming the resistance. In this study, we demonstrate that HCC with high MER proto-oncogene tyrosine kinase (MerTK) expression exhibits anti-PD-1/PD-L1 resistance in two syngeneic mouse models and in patients who received anti-PD-1/PD-L1 therapy. Mechanistically, MerTK renders HCC resistant to anti-PD-1/PD-L1 by limiting ferroptosis with the upregulation of SLC7A11 via the ERK/SP1 pathway and facilitating the development of an immunosuppressive tumor microenvironment (TME) with the recruitment of myeloid-derived suppressor cells (MDSCs). Sitravatinib, an inhibitor of MerTK, sensitizes resistant HCC to anti-PD-L1 therapy by promoting tumor ferroptosis and decreasing MDSC infiltration into the TME. In conclusion, we find that MerTK could serve as a predictive biomarker for patient stratification and as a promising target to overcome anti-PD-1/PD-L1 resistance in HCC.

Cirrhotic-extracellular matrix attenuates aPD-1 treatment response by initiating immunosuppressive neutrophil extracellular traps formation in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is closely associatedwith chronic liver diseases, particularly liver cirrhosis, which has an altered extracellular matrix (ECM) composition. The influence and its mechanism of the cirrhotic-ECM on the response of HCC to immune checkpoint inhibitor (ICI) remains less clarified. METHODS: In silico, proteomic and pathological assessment of alteration of cirrhotic-ECM were applied in clinical cohort. Multiple pre-clinical models with ECM manipulation were used to evaluate cirrhotic-ECM's effect on ICI treatment. In silico, flow cytometry and IHC were applied to explore how cirrhotic-ECM affect HCC microenvironment. In vitro and in vivo experiments were carried out to identify the mechanism of how cirrhotic-ECM undermined ICI treatment. RESULTS: We defined "a pro-tumor cirrhotic-ECM" which was featured as the up-regulation of collagen type 1 (Col1). Cirrhotic-ECM/Col1 was closely related to impaired T cell function and limited anti PD-1 (aPD-1) response of HCC patients from the TCGA pan cancer cohort and the authors' institution, as well as in multiple pre-clinical models. Mechanically, cirrhotic-ECM/Col1 orchestrated an immunosuppressive microenvironment (TME) by triggering Col1-DDR1-NFκB-CXCL8 axis, which initiated neutrophil extracellular traps (NETs) formation to shield HCC cells from attacking T cells and impede approaching T cells. Nilotinib, an inhibitor of DDR1, reversed the neutrophils/NETs dominant TME and efficiently enhanced the response of HCC to aPD-1. CONCLUSIONS: Cirrhotic-ECM modulated a NETs enriched TME in HCC, produced an immune suppressive TME and weakened ICI efficiency. Col1 receptor DDR1 could be a potential target synergically used with ICI to overcome ECM mediated ICI resistance. These provide a mechanical insight and novel strategy to overcome the ICI resistance of HCC.

Rapid purification and enrichment of viral particles using self-propelled micromotors.

Virus infections remain one of the principal causes of morbidity and mortality worldwide. The current gold standard approach for diagnosing pathogens requires access to reverse transcription-polymerase chain reaction (RT-PCR) technology. However, separation and enrichment of the targets from complex and diluted samples remains a major challenge. In this work, we proposed a micromotor-based sample preparation concept for the efficient separation and concentration of target viral particles before PCR. The micromotors are functionalized with antibodies with a 3D polymer linker and are capable of self-propulsion by the catalytic generation of oxygen bubbles for selective and positive virus enrichment. This strategy significantly improves the enrichment efficiency and recovery rate of virus (up to 80% at 104 tu mL-1 in a 1 mL volume within just 6 min) without external mixing equipment. The method allows the Ct value in regular PCR tests to appear 6-7 cycles earlier and a detection limit of 1 tu mL-1 for the target virus from swap samples. A point-of-need test kit is designed based on the micromotors which can be readily applied to pretreat a large volume of samples.

Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern.

Background: Neutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed. Methods: We systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups. Results: A gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs. Conclusion: NETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.

A Prognostic Nomogram for Hepatocellular Carcinoma Based on Wound Healing and Immune Checkpoint Genes.

Background and Aims: Wound healing and tumor progression share some common biological features; however, how variations in wound healing patterns affect hepatocellular carcinoma (HCC) prognosis remains unclear. Methods: We analyzed the wound healing patterns of 594 HCC samples from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) and correlated them with immune infiltration and the expression levels of immune checkpoint genes. A risk score, which we named the "heal.immune" score, was established via stepwise Cox estimation. We constructed a nomogram based on age, sex, TNM stage, and heal.immune score and explored its predictive value for HCC prognosis. Seventy-four clinical patients were enrolled in this study, and all were from Huashan Hospital of Fudan University between 2015 and 2017 to serve as an independent validation group. Results: We identified two distinct wound healing patterns in HCC. The biological processes of healing cluster 1 (C1) are related to metabolism, while those of healing cluster 2 (C2) are related to the inflammatory response and immune cell accumulation. A total of 565 wound healing-related genes (based on Gene Ontology) and 25 immune checkpoint genes were considered. By analyzing differentially expressed genes and implementing a stepwise Cox estimation analysis, six genes with p values less than 0.02 in a multivariate Cox estimation were chosen as the "heal.immune" gene set (FCER1G, PLAT, ITGA5, CCNB1, CD86 and CD40). The "heal.immune" gene set, as an OS risk factor, was further validated in Fudan cohort. We constructed a nomogram to predict the 1-, 3- and 5-year overall survival (OS) in the TCGA cohort. The area under curve vales of the receiver characteristic operator curves were 0.82, 0.76 and 0.73 in the training group and 0.84, 0.76 and 0.72 in the test group. Conclusions: We established a prognostic nomogram based on the heal.immune gene signature, which includes six wound healing- and immunity-related genes. This nomogram accurately predicts the OS of HCC patients.

Neutrophil extracellular traps in hepatocellular carcinoma are enriched in oxidized mitochondrial DNA which is highly pro-inflammatory and pro-metastatic.

Background: Neutrophil extracellular traps (NETs) are net like extracellular structure formed by neutrophils in response to certain stimulation. It works as inflammatory regulator and metastasis promoter in cancer. Mitochondrial-(mt)DNA is a circular, mitochondria derived double strain molecule, which is involved in NETs formation. Its role in NETs induced inflammatory alteration in hepatocellular carcinoma (HCC) remained unexplored. Method: We evaluated the mitochondrial reactive oxygen species (mitoROS) level in peripheral neutrophils from HCC patients and the oxidative level of mtDNA in derived NETs. The association between the NETs and oxidized mtDNA was assessed to reveal their relevance. A function assay was applied to uncover how the oxidation state of mtDNA directed the metastasis promoting inflammation state in HCC cells in a NETs protein dependent manner. Finally, using animal models, we explored the potential of a therapy strategy against NETs-drove metastasis by targeting the oxidized mtDNA with metformin. Results: Neutrophils in HCC patients contained high level of mitoROS level, and formed NETs that were enriched in oxidized mtDNA in a mitoROS dependent manner. NETs and oxidized mtDNA were clinically relevant. Bound with NETs protein, oxidized mtDNA is more capable of triggering the metastasis-promoting inflammatory mediators in HepG2 cells. Targeting the oxidized mtDNA with metformin attenuated the metastasis-promoting inflammatory state and hereby undermine the metastasis capacity of HCC. Conclusion: HCC is capable to stimulate NETs enriched in oxidized mtDNA, which are highly pro-inflammatory and pro-metastatic. Oxidized mtDNA in NETs may serve as a potential anti-metastatic target by metformin therapy.

Inhibition of EGFR Overcomes Acquired Lenvatinib Resistance Driven by STAT3-ABCB1 Signaling in Hepatocellular Carcinoma.

Lenvatinib is an inhibitor of multiple receptor tyrosine kinases that was recently authorized for first-line treatment of hepatocellular carcinoma (HCC). However, the clinical benefits derived from lenvatinib are limited, highlighting the urgent need to understand mechanisms of resistance. We report here that HCC cells develop resistance to lenvatinib by activating EGFR and stimulating the EGFR-STAT3-ABCB1 axis. Lenvatinib resistance was accompanied by aberrant cholesterol metabolism and lipid raft activation. ABCB1 was activated by EGFR in a lipid raft-dependent manner, which significantly enhanced the exocytosis of lenvatinib to mediate resistance. Furthermore, clinical specimens of HCC showed a correlation between the activation of the EGFR-STAT3-ABCB1 pathway and lenvatinib response. Erlotinib, an EGFR inhibitor that has also been shown to inhibit ABCB1, suppressed lenvatinib exocytosis, and combined treatment with lenvatinib and erlotinib demonstrated a significant synergistic effect on HCC both in vitro and in vivo. Taken together, these findings characterize a mechanism of resistance to a first-line treatment for HCC and offer a practical means to circumvent resistance and treat the disease. SIGNIFICANCE: HCC cells acquire resistance to lenvatinib by activating the EGFR-STAT3-ABCB1 pathway, identifying combined treatment with erlotinib as a strategy to overcome acquired resistance and improve the clinical benefit of lenvatinib.

Therapeutic Effect of Aerobic Exercise for Adolescents After Mild Traumatic Brain Injury and Sport-Related Concussion: A Meta-Analysis from Randomized Controlled Trials.

BACKGROUND: We searched PubMed, Embase, and the Cochrane Library for randomized controlled trials from January 1980 to April 2018 for adolescents with mild traumatic brain injury (mTBI) to explore the value of aerobic exercise in sport-related concussion (SRC) and mTBI treatment. METHODS: A meta-analysis for the postconcussion symptom scale (PCSS) score and time to recovery was performed with STATA software. RESULTS: We found that aerobic exercise versus usual treatment significantly decreased the PCSS score (weighted mean difference = 6.51, 95% confidence interval: 0.29, 12.72; P = 0.040), as well as the time to recovery (weighted mean difference = -3.87; 95% confidence interval: -6.50, -1.23; P = 0.004). However, aerobic exercise showed no significant improvement in immediate postconcussion assessment and cognitive testing (P = 0.471/0.129/0.648/0.800, respectively, in verbal memory, visual memory, visual motor speed, and reaction time). CONCLUSIONS: Compared with usual treatment, aerobic exercise promoted mTBI adolescents' recovery, assessed by PCSS and time to recovery. However, aerobic exercise may not help with neurocognitive function recovery.

Lipid metabolism in cancer progression and therapeutic strategies.

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune-associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

A portable nucleic acid extraction system based on gigahertz acoustic tweezers.

In this study, a portable and compatible system for extraction of DNA based on gigahertz acoustic was proposed and verified. The system is based on tunable multiple acoustic tweezers which can switch between the mixing and separation mode to enable the efficient DNA extraction with a relatively small and portable setup. Using this system, we extracted DNA from the rat's whole blood and achieved about 80% recovery. By combining with real-time qPCR, this proposed detection method was able to detect adenovirus (ADV) DNA as low as 102 IU/mL.Clinical Relevance-The whole system is only in centimeter scale and can be applied for portable DNA extraction. There is great potential application in molecular diagnostics and point of care test (POCT).

Levetiracetam versus Phenytoin for the Pharmacotherapy of Benzodiazepine-Refractory Status Epilepticus: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Recent studies have shown conflicting results regarding the effectiveness of levetiracetam for treating benzodiazepine-refractory status epilepticus (SE) compared with phenytoin. Therefore, a meta-analysis was carried out to assess the value of levetiracetam versus phenytoin in the pharmacotherapy of benzodiazepine-refractory SE. OBJECTIVE: The aim of this systematic review and meta-analysis was to compare the efficacy and safety of levetiracetam and phenytoin in the treatment of benzodiazepine-refractory SE. METHODS: The MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs) that had been conducted to evaluate levetiracetam versus phenytoin for benzodiazepine-refractory SE, to April 2020. The data were assessed using Review Manager 5.3 software. The risk ratio (RR) was analyzed using dichotomous outcomes, and calculated using a random-effect model. RESULTS: We pooled 1850 patients from 12 RCTs. Patients in the levetiracetam group had a significantly higher rate of clinical seizure cessation than in the phenytoin group (75.2% vs. 67.8%; RR 1.14, 95% confidence interval [CI] 1.05-1.25, p = 0.003). Moreover, less adverse events were observed in the levetiracetam group than in the phenytoin group (17.8% vs. 21.4%; RR 0.82, 95% CI 0.70-0.97, p = 0.02). In subgroup analysis, clinical seizure cessation was achieved more frequently with a higher dose of levetiracetam (> 30 mg/kg) [RR 1.15, 95% CI 1.00-1.32, p = 0.05]. Furthermore, in the subgroup of children, levetiracetam showed a higher rate of clinical seizure cessation than phenytoin (RR 1.13, 95% CI 1.02-1.25, p = 0.02). CONCLUSION: Pharmacotherapy for BZD-refractory SE by LEV is superior to PHT in efficacy and safety outcomes.

The m6A methylation landscape stratifies hepatocellular carcinoma into 3 subtypes with distinct metabolic characteristics.

Objective: Epigenetic aberration plays an important role in the development and progression of hepatocellular carcinoma (HCC). However, the alteration of RNA N6-methyladenosine (m6A) modifications and its role in HCC progression remain unclear. We therefore aimed to provide evidence using bioinformatics analysis. Methods: We comprehensively analyzed the m6A regulator modification patterns of 605 HCC samples and correlated them with metabolic alteration characteristics. We elucidated 390 gene-based m6A-related signatures and defined an m6Ascore to quantify m6A modifications. We then assessed their values for predicting prognoses and therapeutic responses in HCC patients. Results: We identified 3 distinct m6A modification patterns in HCC, and each pattern had distinct metabolic characteristics. The evaluation of m6A modification patterns using m6Ascores could predict the prognoses, tumor stages, and responses to sorafenib treatments of HCC patients. A nomogram based on m6Ascores showed high accuracy in predicting the overall survival of patients. The area under the receiver operating characteristic curve of predictions of 1, 3, and 5-year overall survivals were 0.71, 0.69, and 0.70 in the training cohort, and in the test cohort it was 0.74, 0.75, and 0.71, respectively. M6Acluster C1, which corresponded to hypoactive mRNA methylation, lower expression of m6A regulators, and a lower m6Ascore, was characterized by metabolic hyperactivity, lower tumor stage, better prognosis, and lower response to sorafenib treatment. In contrast, m6Acluster C3 was distinct in its hyperactive mRNA methylations, higher expression of m6A regulators, and higher m6Ascores, and was characterized by hypoactive metabolism, advanced tumor stage, poorer prognosis, and a better response to sorafenib. The m6Acluster, C2, was intermediate between C1 and C3. Conclusions: HCCs harbored distinct m6A regulator modification patterns that contributed to the metabolic heterogeneity and diversity of HCC. Development of m6A gene signatures and the m6Ascore provides a more comprehensive understanding of m6A modifications in HCC, and helps predict the prognosis and treatment response.

PKM2 Drives Hepatocellular Carcinoma Progression by Inducing Immunosuppressive Microenvironment.

Background and Aims: Pyruvate kinase M2 (PKM2) is an essential regulator of the Warburg effect, but its biological function promoting immune escape of hepatocellular carcinoma (HCC) is unclear. Methods: GEPIA web tool and immunohistochemistry (IHC) analysis were employed to evaluate the clinical relevance of PKM2 in HCC patients. Both in vitro CCK-8, colony formation, and transwell assays, and in vivo xenografts were performed to evaluate the malignancy of HCC cells. PKM2 and PD-L1 levels were examined by Western blot, qRT-PCR, and IHC. The role of PKM2 on in vivo immune response was also investigated. Results: PKM2 was significantly upregulated in HCC and associated with a poor prognosis of HCC patients. Knockdown of PKM2 inhibited in vitro proliferation, migration, and invasion of HCC cells, as well as in vivo tumor growth. Strikingly, PKM2 showed a strong correlation with the expression of immune inhibitory cytokines and lymphocyte infiltration in HCC. The overexpression of PKM2 sensitized HCC to immune checkpoint blockade, which enhanced IFN-γ positive CD8 T cells in HCC mice models. Conclusion: PKM2 might be a predictor and a potential therapeutic target for immune checkpoint inhibitors in HCC.

Isolation and characterization of exosomes for cancer research.

Exosomes are a subset of extracellular vesicles that carry specific combinations of proteins, nucleic acids, metabolites, and lipids. Mounting evidence suggests that exosomes participate in intercellular communication and act as important molecular vehicles in the regulation of numerous physiological and pathological processes, including cancer development. Exosomes are released by various cell types under both normal and pathological conditions, and they can be found in multiple bodily fluids. Moreover, exosomes carrying a wide variety of important macromolecules provide a window into altered cellular or tissue states. Their presence in biological fluids renders them an attractive, minimally invasive approach for liquid biopsies with potential biomarkers for cancer diagnosis, prediction, and surveillance. Due to their biocompatibility and low immunogenicity and cytotoxicity, exosomes have potential clinical applications in the development of innovative therapeutic approaches. Here, we summarize recent advances in various technologies for exosome isolation for cancer research. We outline the functions of exosomes in regulating tumor metastasis, drug resistance, and immune modulation in the context of cancer development. Finally, we discuss prospects and challenges for the clinical development of exosome-based liquid biopsies and therapeutics.

DFT calculations of energetic stability and geometry of O-terminated B- and N-doped diamond (1 1 1)-1 × 1 surfaces.

The non- and O-terminated diamond (1 1 1)-1 × 1 surfaces, with the substitutional B (or N) dopants in different atomic layers, have been modelled in the present study. The influences of the O adsorbates, dopant and dopant position on the adsorption energy, have been studied by performing the density functional theory (DFT) calculations. Various parameters were additionally calculated in order to analyze the obtained results: bond lengths, total electron densities, bond populations, atomic charges, Fukui functions (FFs) and density-of-states. Dangling bonds on non-terminated surfaces, O adsorbates, as well as dopants within various atomic layers were all found to induce local effects. In fact, the degree of influences of the dopant on the adsorption energy of the O adsorbates, as well as on parameters like the near-surface bond lengths, total electron density, bond populations and atomic charges, were all found to be dependent on the dopant position. More generally, the deeper the dopant position, the less influence it had on the surface structures and properties. The influences by the dopant in the 1st or 2nd C atomic layer were observed to be significant, but those in the 3rd to 5th C layers were almost negligible. It was also found that the B dopant would decrease the adsorption energy of the adjacent O adsorbates, while the N dopant in the 2nd layer would increase it. Furthermore, the combination of the O adsorbates, together with the dopants within the 1st or 2nd C layer, could induce significant elongation of the bonds between neighboring atoms within the 1st and 2nd layers (i.e. C-C, C-B or C-N bonds). Moreover, all the terminating O atoms could react strongly with either the electrophilic or the nucleophilic species.

Comparative assessment of early versus delayed surgery to treat proximal femoral fractures in elderly patients: A systematic review and meta-analysis.

BACKGROUND: Recently, many studies have suggested that timely surgery to treat proximal femoral fractures can benefit patients in many respects. However, both the short- and long-term outcomes, and the perioperative complications, of early surgery remain controversial. In addition, the optimal cut-off time for early surgery remains unclear. Thus, we performed a meta-analysis to compare and evaluate the benefits of early versus delayed surgery in terms of the clinical outcomes of patients with proximal femoral fractures. METHODS: We searched the Cochrane Library, PubMed, EMBASE, and Web of Science databases to February 1, 2018 and retrieved original studies comparing the efficacy of early versus delayed surgery for proximal femoral fractures. We calculated risk ratios (RRs) and odds ratios (ORs) with 95% confidence intervals (CIs) and compared the outcomes of early and delayed surgery. We performed subgroup analyses to explore mortality and perioperative complications associated with different cut-off times for surgery, for various periods. Two reviewers assessed the quality of the included studies and independently extracted the data. We followed the suggestions of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. All statistical analyses were performed using the standard statistical procedures of Review Manager 5.2. RESULTS: A total of 27 studies (N = 33,727 participants) were included in the present analysis. Compared to delayed surgery, early surgery significantly reduced mortality and complications. The mortality rates of patients who underwent surgery within 48 and 24 h of fracture were 28 and 23% less than those of patients operated upon after 48 h (RR = 0.72; 95% CI: 0.71-0.73) and 24 h (RR = 0.77; 95% CI: 0.65-0.93). In addition, early surgery was associated with fewer perioperative complications than delayed surgery (OR = 0.52; 95% CI: 0.35-0.76), especially in terms of postoperative pressure ulcers (OR = 0.55; 95% CI: 0.45-0.68), urinary tract infections (OR = 0.57; 95% CI: 0.49-0.67), and thromboembolic events (OR = 0.61; 95% CI: 0.39-0.96). CONCLUSIONS: Early surgery reduces mortality associated with proximal femoral fractures and the frequency of serious perioperative complications when comparing with delayed surgery.