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Non-invasive brain stimulation (NIBS), especially repetitive transcranial magnetic stimulation (rTMS), is a promising therapeutic tool for managing the psychiatric symptoms of Parkinson's disease (PD). This meta-analysis aims to assess the effect of NIBS on psychiatric symptoms in patients with PD.Several electronic databases were systematically searched for relevant literature from inception to October 18, 2021. The therapeutic effects of NIBS were evaluated using a random-effects meta-analysis based on the standard mean difference (SMD) and multivariable-adjusted effect estimates and subgroup analyses. Publication bias and sensitivity analyses were used to explore the sources of heterogeneity.Finally, 57 and 15 studies with 4,010 participants were obtained from the meta-analysis and systematic review, respectively. Significant differences were found between NIBS and sham-stimulation/placebo participants for depression (SMD = -0.75, 95 % confidence interval [CI]: -0.99 to -0.50, INIBS can be considered an effective non-pharmacological option for treating PD depression; moreover, rTMS combined with antidepressants was demonstrated to be a useful tool against depression and anxiety in PD.

Multifocal esophageal squamous cell carcinomas (ESCCs) can be diagnosed as of multicentric origin (MO) or intramural metastasis (IMM). We aimed here to accurately discriminate MO from IMM and explore the tumor immune microenvironment of multifocal ESCCs. Multifocal ESCCs were identified in 333 ESCC patients, and in 145 patients discrimination between MO and IMM was not possible by histopathological examination. Of the 145 patients, tissues of 14 were analyzed by whole-exome sequencing (WES) of 71 different tumor regions, and MO, IMM, and MO/IMM mixed groups were identified in three, ten, and one cases, respectively, based on the similarity of genomic architecture between or among different tumors from one patient. Further phylogenetic analyses revealed complex clonal evolution patterns in IMM cases, and tumor cells disseminated from the primary tumors to IMM tumors were independent of lymph node metastasis. The NanoString-based assay showed that immune cell infiltrates were significantly enriched, and that the immune and proliferation pathways were more activated, in large tumors than in small ones in MO but not IMM cases. Similarly, PD-L1 expression and the density of paratumoral CD8

The development of triple-negative breast cancer (TNBC) is highly associated with G-quadruplex (G4); thus, targeting G4 is a potential strategy for TNBC therapy. Because concomitant histone deacetylases (HDAC) inhibition could amplify the impact of G4-targeting compounds, we designed and synthesized two novel series of G4/HDAC dual-targeting compounds by connecting the zinc-binding pharmacophore of HDAC inhibitors to the G4-targeting isaindigotone scaffold (

CSL112 (apolipoprotein A-I [apoA-I, human]) is a novel drug in development to reduce the risk of recurrent cardiovascular events following acute myocardial infarction by increasing cholesterol efflux capacity (CEC). This phase I study aimed to compare the pharmacokinetics (PKs), pharmacodynamics (PDs), and safety of CSL112 in Japanese and White subjects. A total of 34 Japanese subjects were randomized to receive a single infusion of CSL112 (2, 4, or 6 g) or placebo and 18 White subjects were randomized to receive a single dose of 6 g CSL112 or placebo, followed by PK/PD assessment and adverse events monitoring. In addition, PK/PD parameters were compared across the CSL112 clinical development program. Plasma exposure of apoA-I increased in a dose-dependent but nonlinear manner in Japanese subjects receiving a single dose of CSL112. Mean baseline-corrected area under the curve from 0 to 72 h (AUC

The most devastating sequela of Kawasaki disease (KD) is coronary artery complications that may lead to myocardial infarction and cardiac mortality. Percutaneous coronary intervention (PCI) and bypass grafting are recommended for KD patients with inducible myocardial ischemia and amendable coronary anatomy. However, there are few reports about coronary revascularization with drug-eluting balloons among KD patients, especially at an early age. We present a case report of multi-modality guidance of PCI with a drug-coated balloon (DCB) for a young patient with acute coronary syndrome and a history of KD. Post-procedural optical coherence tomography, angiography-derived fractional flow reserve, and 12-month coronary artery magnetic resonance showed favorable outcomes. The present case indicated that DCB therapy with intravascular imaging and physiologic assessment guidance may be an alternative strategy to treat severe coronary artery stenosis in selected patients with KD.

Vaccination is an important preventive measure against the coronavirus disease 19 (COVID-19) pandemic. We aimed to examine the willingness to vaccination and influencing factors among college students in China.From March 18 to April 26, 2021, we conducted a cross-sectional online survey among college students from 30 universities in Wuhan, Hubei Province, China. The survey was composed of the sociodemographic information, psychological status, experience during pandemic, the willingness of vaccination and related information. Students' attitudes towards vaccination were classified as 'vaccine acceptance', 'vaccine hesitancy', and 'vaccine resistance'. Multinomial logistic regression analyses were performed to identify the influencing factors associated with vaccine hesitancy and resistance.Among 23,143 students who completed the survey, a total of 22,660 participants were included in the final analysis with an effective rate of 97.9% after excluding invalid questionnaires. A total of 60.6% of participants would be willing to receive COVID-19 vaccine, 33.4% were hesitant to vaccination, and 6.0% were resistant to vaccination. Social media platforms and government agencies were the main sources of information vaccination. Worry about the efficacy and adverse effects of vaccine were the top two common reason of vaccine hesitancy and resistance. Multiple multinomial logistic regression analysis identified that participants who worried about the adverse effects of vaccination were more likely to be vaccine hesitancy (aOR = 2.44, 95% CI = 2.30, 2.58) and resistance (aOR = 2.71, 95% CI = 2.40, 3.05).More than half of college students are willing to receive the COVID-19 vaccine, whereas nearly one-third college students are still hesitant or resistant. It is crucial to provide sufficient and scientific information on the efficacy and safety of vaccine through social media and government agencies platforms to promote vaccine progress against COVID-19 and control the pandemic in China.

PURPOSE: Congenital bilateral absence of the vas deferens (CBAVD) is a major cause of obstructive azoospermia and male factor infertility. CBAVD is mainly caused by mutations in the genes encoding CFTR (cystic fibrosis transmembrane conductance regulator) and ADGRG2 (adhesion G protein-coupled receptor G2). This study aimed to describe CFTR and ADGRG2 variations in 46 Chinese CBAVD patients and evaluated sperm retrieval and assisted reproductive technology outcomes. METHODS: The CFTR and ADGRG2 genes were sequenced and analyzed by whole-exome sequencing (WES), and variations were identified by Sanger sequencing. Bioinformatic analysis was performed. We retrospectively reviewed the outcomes of patients undergoing sperm retrieval surgery and intracytoplasmic sperm injection (ICSI). RESULTS: In total, 35 of 46 (76.09%) patients carried at least one variation in CFTR, but no copy number variants or ADGRG2 variations were found. In addition to the IVS9-5 T allele, there were 27 CFTR variations, of which 4 variations were novel and predicted to be damaging by bioinformatics. Spermatozoa were successfully retrachieved in 46 patients, and 39 of the patients had their own offspring through ICSI. CONCLUSION: There are no obvious hotspot CFTR mutations in Chinese CBAVD patients besides the IVS9-5 T allele. Therefore, WES might be the best detection method, and genetic counseling should be different from that provided to Caucasian populations. After proper counseling, all patients can undergo sperm retrieval from their epididymis or testis, and most of them can have their own children through ICSI.

BACKGROUND AND AIMS Metabolic reprogramming plays an important role in tumorigenesis. However, the metabolic types of different tumors are diverse and lack in-depth study. Here, through analysis of big databases and clinical samples, we identified a carbamoyl phosphate synthetase 1 (CPS1)-deficient hepatocellular carcinoma (HCC) subtype, explored tumorigenesis mechanism of this HCC subtype, and aimed to investigate metabolic reprogramming as a target for HCC prevention. APPROACH AND RESULTS A pan-cancer study involving differentially expressed metabolic genes of 7,764 tumor samples in 16 cancer types provided by The Cancer Genome Atlas (TCGA) demonstrated that urea cycle (UC) was liver-specific and was down-regulated in HCC. A large-scale gene expression data analysis including 2,596 HCC cases in 7 HCC cohorts from Database of HCC Expression Atlas and 17,444 HCC cases from in-house hepatectomy cohort identified a specific CPS1-deficent HCC subtype with poor clinical prognosis. In vitro and in vivo validation confirmed the crucial role of CPS1 in HCC. Liquid chromatography-mass spectrometry assay and Seahorse analysis revealed that UC disorder (UCD) led to the deceleration of the tricarboxylic acid cycle, whereas excess ammonia caused by CPS1 deficiency activated fatty acid oxidation (FAO) through phosphorylated adenosine monophosphate-activated protein kinase. Mechanistically, FAO provided sufficient ATP for cell proliferation and enhanced chemoresistance of HCC cells by activating forkhead box protein M1. Subcutaneous xenograft tumor models and patient-derived organoids were employed to identify that blocking FAO by etomoxir may provide therapeutic benefit to HCC patients with CPS1 deficiency. CONCLUSIONS In conclusion, our results prove a direct link between UCD and cancer stemness in HCC, define a CPS1-deficient HCC subtype through big-data mining, and provide insights for therapeutics for this type of HCC through targeting FAO.

Study objective This study aimed to determine the safety and efficacy of a novel GP Ib receptor inhibitor in patients with non-ST segment elevation myocardial infarction (NSTEMI) undergoing percutaneous coronary intervention (PCI). Design and setting Multicenter, randomized, double-blind, placebo-controlled, dose-escalating, phase Ib-IIa clinical trial. Eligible patients were randomly assigned to the low-dose (n=20, 2 IU/60 kg), moderate-dose (n=20, 3 IU/60 kg), or high-dose anfibatide group (n=20, 5 IU/60 kg), or the placebo group (n=30). Anfibatide was administered for up to 48 hours along with standard aspirin and clopidogrel therapy. Patients Ninety patients with NSTEMI who underwent PCI at six academic hospitals in China. Measurements and main results All three doses of anfibatide showed dose-dependent antiplatelet activity as measured by ex vivo platelet aggregation at 5 minutes, 24 hours, and 48 hours during infusion, and 4 hours post-infusion compared with placebo. Higher inhibition of platelet aggregation occurred in all anfibatide groups compared with the placebo group. The post-procedural TIMI grade flow, myocardial blush grade, and corrected TIMI frame count were not significantly different among the four groups. Thirty-day mortality, non-fatal myocardial infarction, and major bleeding were rare and comparable between patients who received anfibatide and placebo. There was no significant difference in the platelet count among the groups during follow-up. Conclusions This study shows that intravenous administration of the platelet receptor GP Ib antagonist anfibatide is feasible and safe to inhibit platelet aggregation without increasing the risk of bleeding and thrombocytopenia in patients with NSTEMI undergoing PCI.

Infectious diseases, including COVID-19, are crucial public health issues and may lead to considerable fear among the general public and stigmatization of, and discrimination against, specific populations. This meta-analysis aimed to estimate the pooled prevalence of stigma in infectious disease epidemics. We systematically searched PubMed, PsycINFO, Embase, MEDLINE, Web of Science, and Cochrane databases since inception to June 08, 2021, and reported the prevalence of stigma towards people with infectious diseases including SARS, H1N1, MERS, Zika, Ebola, and COVID-19. A total of 50 eligible articles were included that contributed 51 estimates of prevalence in 92722 participants. The overall pooled prevalence of stigma across all populations was 34% [95% CI: 28-40%], including enacted stigma (36% [95% CI: 28-44%]) and perceived stigma (31% [95% CI: 22-40%]). The prevalence of stigma in patients, community population, and health care workers, was 38% [95% CI: 12- 65%], 36% [95% CI: 28-45%], and 30% [95% CI: 20-40%], respectively. The prevalence of stigma in participants from low- and middle-income countries was 37% [95% CI: 29-45%], which is higher than that from high-income countries (27% [95% CI: 18-36%]) though this difference was not statistically significant. A similar trend of prevalence of stigma was also observed in individuals with lower education (47% [95% CI: 23-71%]) compared to higher education level (33% [95% CI: 23-4%]). These findings indicate that stigma is a significant public health concern, and effective and comprehensive interventions are needed to counteract the damaging effects of the infodemics during infectious disease epidemics, including COVID-19, and reduce infectious disease-related stigma.

Aims COVID-19 has long-term impacts on public mental health, while few research studies incorporate multidimensional methods to thoroughly characterise the psychological profile of general population and little detailed guidance exists for mental health management during the pandemic. This research aims to capture long-term psychological profile of general population following COVID-19 by integrating trajectory modelling approaches, latent trajectory pattern identification and network analyses. Methods Longitudinal data were collected from a nationwide sample of 18 804 adults in 12 months after COVID-19 outbreak in China. Patient Health Questionnaire-9, Generalised Anxiety Disorder-7 and Insomnia Severity Index were used to measure depression, anxiety and insomnia, respectively. The unconditional and conditional latent growth curve models were fitted to investigate trajectories and long-term predictors for psychological symptoms. We employed latent growth mixture model to identify the major psychological symptom trajectory patterns, and ran sparse Gaussian graphical models with graphical lasso to explore the evolution of psychopathological network. Results At 12 months after COVID-19 outbreak, psychological symptoms generally alleviated, and five psychological symptom trajectories with different demographics were identified: normal stable (63.4%), mild stable (15.3%), mild-increase to decrease (11.7%), mild-decrease to increase (4.0%) and moderate/severe stable (5.5%). The finding indicated that there were still about 5% individuals showing consistently severe distress and approximately 16% following fluctuating psychological trajectories, who should be continuously monitored. For individuals with persistently severe trajectories and those with fluctuating trajectories, central or bridge symptoms in the network were mainly ‘motor abnormality’ and ‘sad mood’, respectively. Compared with initial peak and late COVID-19 phase, aftermath of initial peak might be a psychologically vulnerable period with highest network connectivity. The central and bridge symptoms for aftermath of initial peak (‘appetite change’ and ‘trouble of relaxing’) were totally different from those at other pandemic phases (‘sad mood’). Conclusions This research identified the overall growing trend, long-term predictors, trajectory classes and evolutionary pattern of psychopathological network of psychological symptoms in 12 months after COVID-19 outbreak. It provides a multidimensional long-term psychological profile of the general population after COVID-19 outbreak, and accentuates the essentiality of continuous psychological monitoring, as well as population- and time-specific psychological management after COVID-19. We believe our findings can offer reference for long-term psychological management after pandemics.

Dementia is one of the greatest global challenges for public health; however, the relationship between anticholinergic drugs and dementia remains unclear. The aim of the present study was to perform a systematic review and meta-analysis of the predictive roles of anticholinergic drugs in dementia risk. After pooling fourteen longitudinal and case-control studies with a total of 1,564,181 subjects, anticholinergic drug use was associated with an increased risk of all-cause dementia and Alzheimer's disease. Both low and high anticholinergic drug burdens were associated with dementia. Moreover, there was a dose-dependent relationship between anticholinergic drugs and risk of dementia. With respect to the categories of anticholinergic drugs, antiparkinson, urological drugs, and antidepressants increased the risk for dementia; however, cardiovascular and gastrointestinal drugs played potentially protective roles. These findings underscore the importance of anticholinergic drugs as a potential modifiable risk factor for dementia and provide treatment priorities to optimize dementia prevention.

We developed a mathematical model for autologous stem cell therapy to cure sickle cell disease (SCD). Experimental therapies using this approach seek to engraft stem cells containing a curative gene. These stem cells are expected to produce a lifelong supply of red blood cells (RBCs) containing an anti‐sickling hemoglobin. This complex, multistep treatment is expensive, and there is limited patient data available from early clinical trials. Our objective was to quantify the impact of treatment parameters, such as initial stem cell dose, efficiency of lentiviral transduction, and degree of bone marrow preconditioning on engraftment efficiency, peripheral RBC numbers, and anti‐sickling hemoglobin levels over time. We used ordinary differential equations to model RBC production from progenitor cells in the bone marrow, and hemoglobin assembly from its constituent globin monomers. The model recapitulates observed RBC and hemoglobin levels in healthy and SCD phenotypes. Treatment simulations predict dynamics of stem cell engraftment and RBC containing the therapeutic gene product. Post‐treatment dynamics show an early phase of reconstitution due to short lived stem cells, followed by a sustained RBC production from stable engraftment of long‐term stem cells. This biphasic behavior was previously reported in the literature. Sensitivity analysis of the model quantified relationships between treatment parameters and efficacy. The initial dose of transduced stem cells, and the intensity of myeloablative bone marrow preconditioning are predicted to most positively impact long‐term outcomes. The quantitative systems pharmacology approach used here demonstrates the value of model‐assisted therapeutic design for gene therapies in SCD.

The angiography and color fundus images are of great assistance for the localization of central serous chorioretinopathy (CSCR) lesions. However, it brings much inconvenience to ophthalmologists because of these two modalities working independently in guiding laser surgery. Hence, a novel fundus image fusion method in non-subsampled contourlet transform (NSCT) domain, aiming to integrate the multi-modal CSCR information, is proposed. Specifically, the source images are initially decomposed into high-frequency and low-frequency components based on NSCT. Then, an improved deep learning-based method is employed for the fusion of low-frequency components, which helps to alleviate the tedious process of manually designing fusion rules and enhance the smoothness of the fused images. The fusion of high-frequency components based on pulse-coupled neural network (PCNN) is closely followed to facilitate the integration of detailed information. Finally, the fused images can be obtained by applying an inverse transform on the above fusion components. Qualitative and quantitative experiments demonstrate the proposed scheme is superior to the baseline methods of multi-scale transform (MST) in most cases, which not only implies its potential in multi-modal fundus image fusion, but also expands the research direction of MST-based fusion methods.

Background: Rheumatoid arthritis is a kind of chronic crippling disease, the condition is complex, the course of the disease is repeated, seriously affecting the quality of life of patients. Adverse reactions and drug resistance associated with conventional treatment can no longer meet the clinical need. Therefore, complementary and alternative therapies need to be explored. The evidence shows that silver needle therapy has advantages in the treatment of rheumatoid arthritis, but there is a lack of standard clinical studies to verify this conclusion. Methods: This is a prospective randomized controlled trial to study the efficacy and safety of silver needles in the treatment of rheumatoid arthritis. Approved by the Clinical Research Ethics Committee of our hospital. The patients are randomly divided into a treatment group (silver needle treatment group) or control group (routine western medicine treatment group). The patients are followed up for 2 months after 4 weeks of treatment. Observation indicators include: TCM symptom score, HAQDI score, DAS-28 score, laboratory indicators, adverse reactions and so on. Data will be analyzed using the statistical software package SPSS version 18.0 (Chicago, IL). Discussion: This study will evaluate the clinical efficacy of a silver needle in the treatment of rheumatoid arthritis. The results of this study will provide a reliable reference for the clinical use of a silver needle in the treatment of rheumatoid arthritis. Trial registration: OSF Registration number: DOI 10.17605/OSF.IO/4X5QB

Novel therapeutics against the global threat of multidrug-resistant

Metabolic inhibition via PFKFB3 inhibition has demonstrated considerable tumor inhibitory effects in various studies; however, PFKFB3 inhibition did not show satisfactory tumor inhibition when used in clinical trials. PFKFB3 is a crucial metabolic enzyme that is highly upregulated in cancer cells and directly affects tumor glycolysis. Here, we showed that PFKFB3 inhibition suppresses tumors in vitro and in vivo in immune-deficient xenografts. However, this inhibition induces the upregulation of PD-L1 levels, which inactivated cocultured T-cells in vitro, compromises anti-tumor immunity in vivo, and reduced anti-tumor efficacy in an immune-competent mouse model. Functionally, PD-1 mAb treatment enhances the efficacy of PFKFB3 inhibition in immunocompetent and hu-PBMC NOG mouse models. Mechanistically, PFKFB3 inhibition increases phosphorylation of PFKFB3 at residue Ser461, which increases interaction with HIF-1α, and their colocalization into the nucleus, where HIF-1α transcriptionally upregulate PD-L1 expression and causes subsequent tumor immune evasion. Higher phos-PFKFB3 correlated with higher PD-L1 expression, lower CD8 and GRZMB levels, and shorter survival time in ESCC patients.

Background Numerous reports on microRNAs have illustrated their role in tumor growth and metastasis. Recently, a new prognostic factor, miR‐125b‐2‐3p, has been identified for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the specific mechanisms and biological functions of miR‐125b‐2‐3p in advanced CRC under chemotherapy have yet to be elucidated. Methods MiR‐125b‐2‐3p expression was detected by real‐time PCR (RT‐PCR) in CRC tissues. The effects of miR‐125b‐2‐3p on the growth, metastasis, and drug sensitivity of CRC cells were tested in vitro and in vivo. Based on multiple databases, the upstream competitive endogenous RNAs (ceRNAs) and the downstream genes for miR‐125b‐2‐3p were predicted by bioinformatic analysis, followed by the experiments including luciferase reporter assays, western blot assays, and so on. Results MiR‐125b‐2‐3p was significantly lowly expressed in the tissues and cell lines of CRC. Higher expression of miR‐125b‐2‐3p was associated with relatively lower proliferation rates and fewer metastases. Moreover, overexpressed miR‐125b‐2‐3p remarkably improved chemotherapeutic sensitivity of CRC in vivo and in vitro. Mechanistically, miR‐125b‐2‐3p was absorbed by long noncoding RNA (lncRNA) XIST regulating WEE1 G2 checkpoint kinase (WEE1) expression. The upregulation of miR‐125b‐2‐3p inhibited the proliferation and epithelial‐mesenchymal transition (EMT) of CRC induced by lncRNA XIST. Conclusions Lower miR‐125b‐2‐3p expression resulted in lower sensitivity of CRC to chemotherapy and was correlated with poorer survival of CRC patients. LncRNA XIST promoted CRC metastasis acting as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. LncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC., Low expression of miR‐125b‐2‐3p in CRC was linked to lower chemotherapeutic sensitivity and poor survival. The lncRNA XIST promoted CRC invasion and migration by functioning as a ceRNA for miR‐125b‐2‐3p to mediate WEE1 expression. Our findings suggest that the lncRNA XIST‐miR‐125b‐2‐3p‐WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance to CRC, which may shed light on their targeted applications.

BACKGROUND Based on coronary angiography and mean aortic pressure, a specially designed computational flow dynamics (CFD) method is proposed to determine contrast fractional flow reserve (cFFR) without using invasive pressure wire. This substudy assessed diagnostic performance of coronary angiography-derived cFFR in catheterization laboratory, based on a previous multicenter trial for online assessment of coronary angiography-derived FFR (caFFR). METHODS Patients with diagnosis of stable angina pectoris or unstable angina pectoris were enrolled in six centers. Wire-based FFR was measured in coronary arteries with 30-90% diameter stenosis. Offline angiography-derived cFFR was computed in blinded fashion against the wire-based FFR and caFFR at an independent core laboratory. RESULTS A total of 330 patients were enrolled to fulfill inclusion/exclusion criteria from June 26 to December 18, 2018. Offline angiography-derived cFFR and wire-based FFR results were compared in 328 interrogated vessels. The statistical analysis showed the highest diagnostic accuracy of 89.0 and 86.6% for angiography-derived cFFR with a cutoff value of 0.94 and 0.93 against the wire-based FFR with a cutoff value of 0.80 and 0.75, respectively. The corresponding sensitivity and specificity were 92.2 and 87.3% for the cutoff value of 0.94 and 80.0 and 88.4% for the cutoff value of 0.93, which are similar to those against the caFFR. The receiver-operating curve has area under the curve of 0.951 and 0.972 for the wire-based FFR with the cutoff value of 0.80 and 0.75, respectively. CONCLUSIONS Coronary angiography-derived cFFR showed higher accuracy, sensitivity, and specificity against wired-based FFR and caFFR. Hence, angiography-derived cFFR could enhance the hemodynamic assessment of coronary lesions.

The therapeutic strategies of stage II/III colorectal cancer (CRC) patients after curative surgery remain controversial. In the clinical decision-making process, oncologists need to answer questions such as whether adjuvant chemotherapy is necessary or which therapeutic regimen should be given to each patient. At present, whether adjuvant chemotherapy should be applied is primarily based on histopathological features and clinical risk factors. However, only a fraction of patients can benefit from it. More rigorous stratifying biomarkers are urgently needed to help further distinguishing these populations of patients. Recent progress in next-generation sequencing and high-throughput technologies has greatly promoted biomarker discovery as well as our understanding of the underlying mechanisms in CRC. Novel genetic and epigenetic biomarkers that are associated with prognosis or therapeutic responses have emerged. In this review, we discuss the strategies of biomarker discovery and summarize the status and assess the utility of previously published biomarkers in CRC.

White blood cells (WBCs) are a key component of the mammalian immune system and play an essential role in surveillance, defense, and adaptation against foreign pathogens. Apart from their roles in the active combat of infection and the development of adaptive immunity, immune cells are also involved in tumor development and metastasis. Antibody-based therapeutics have been developed to regulate (i.e. selectively activate or inhibit immune function) and harness immune cells to fight malignancy. Alternatively, non-invasive tracking of WBC distribution can diagnose inflammation, infection, fevers of unknown origin (FUOs), and cancer. Magnetic Particle Imaging (MPI) is a non-invasive, non-radioactive, and sensitive medical imaging technique that uses safe superparamagnetic iron oxide nanoparticles (SPIOs) as tracers. MPI has previously been shown to track therapeutic stem cells for over 87 days with a ~200 cell detection limit. In the current work, we utilized antibody-conjugated SPIOs specific to neutrophils for in situ labeling, and non-invasive and radiation-free tracking of these inflammatory cells to sites of infection and inflammation in an in vivo murine model of lipopolysaccharide-induced myositis. MPI showed sensitive detection of inflammation with a contrast-to-noise ratio of ~8-13.

Aims To characterize relationships between apolipoprotein A-I (apoA-I) exposure and cholesterol efflux capacity (CEC) and covariate effects following CSL112 (apoA-I [human]) administration, in an integrated population including acute myocardial infarction (AMI) patients. Methods A pharmacometric analysis utilized data from seven clinical trials, including patients with AMI, subjects with renal impairment, and healthy subjects. A population pharmacokinetic (PK) analysis was performed to relate CSL112 doses to changes in apoA-I plasma concentrations. Covariate analysis was conducted to identify sources of variability in apoA-I exposure. Exposure-response modeling was conducted to describe the relationship between apoA-I exposure and total or ATP binding cassette transporter A1-(ABCA1)-dependent CEC and to identify clinical predictors of CEC. Results A two-compartment model described apoA-I PK. ApoA-I clearance was slightly lower in subjects with AMI, whereas baseline apoA-I was marginally higher in female and Japanese subjects. Covariate effects on apoA-I exposure were in the order of 10% and thus not clinically relevant. The relationships between apoA-I exposure and CECs were described by nonlinear models. Simulations showed CEC elevation resulting from apoA-I exposure increment was comparable in AMI and non-AMI subjects; no covariate had clinically meaningful effects on CEC. Simulations also demonstrated that CEC in patients with AMI post 6 g CSL112 dosing was substantially elevated compared to placebo and lower dose levels. Conclusions The model-based exposure-response analysis demonstrated, irrespective of body weight, sex and race, that fixed 6 g CSL112 dosing causes a desired CEC elevation, which may benefit AMI patients by potentially reducing early recurrent cardiovascular event risk.

Combination therapies based on photodynamic therapy (PDT) have received much attention in various cancers due to their strong therapeutic effects. Here, we aimed to explore the safety and effectiveness of a new mitochondria-targeting photodynamic material, TPE-IQ-2O, in combination therapies (combined with surgery or immunotherapy). The safety and effectiveness of TPE-IQ-2O PDT were verified with cytotoxicity evaluation in vitro and a zebrafish xenograft model in vivo, respectively. The effectiveness of TPE-IQ-2O PDT combined with surgery or immune checkpoint inhibitors (ICIs) was verified in tumor-bearing mice. Small animal in vivo imaging, immunohistochemistry, and flow cytometry were used to determine the underlying mechanism. TPE-IQ-2O PDT can not only reduce tumor recurrence in surgical treatment but also effectively improve the response to ICIs in immunotherapy without obvious toxicity. It was also found to ameliorate the immunosuppressive tumor microenvironment and promote the antitumor immunity induced by ICIs by increasing CD8+ tumor-infiltrating lymphocyte accumulation. Thus, TPE-IQ-2O PDT is a safe and effective antitumor therapy that can be combined with surgery or immunotherapy.

Currently, there are insufficient indicators for the reliable assessment of treatment response following neoadjuvant chemoradiotherapy (nCRT) in patients with esophageal squamous cell carcinoma (ESCC). Considering the essential role of protein-coding and non-coding RNAs in gene regulation and cellular processes, we systematically explored the molecular features and clinical significance of mRNA and lncRNA in 249 pretreatment biopsies from four hospitals in three districts with a high incidence of ESCC patients in China.During the discovery phrase, 13 differentially expressed genes were identified and validated between samples with a complete pathological response (pCR) and those with an incomplete pathological response (pCR). Subsequently, we constructed a predictive mRNA and lncRNA signature (SERPINE1, LINC00592, and PRKAG2-AS1) using Fisher's linear discriminant analysis (FLDA) with stepwise variant-selection, followed by validation of its predictive ability in both internal and external cohorts.Our signature showed great value in predicting the response to nCRT among ESCC samples and acted as an independent predictive indicator, in addition to demonstrating great potential in estimating patient prognosis. Interestingly, we found that patients with a high signature score had lower PD-L1 and IDO1 expression levels but higher CD8The present study identified a promising three-gene-based predictive signature that has powerful clinical implications for the identification of pCR and a good prognosis among patients with ESCC. Further immune-related exploration may provide an opportunity for future therapeutic combination.

Primary pulmonary lymphoepithelioma-like carcinoma (PLELC) is an Epstein–Barr virus (EBV)-related, rare subtype of non-small-cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) show durable responses in advanced NSCLC. However, their effects and predictive biomarkers in PLELC remain poorly understood. We retrospectively analyzed the data of 48 metastatic PLELC patients treated with ICI. Pretreated paraffin-embedded specimens (n = 19) were stained for PD-1, PD-L1, LAG3, TIM3, CD3, CD4, CD8, CD68, FOXP3, and cytokeratin (CK) by multiple immunohistochemistry (mIHC). Next-generation sequencing was performed for 33 PLELC samples. Among patients treated with ICI monotherapy (n = 30), the objective response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), and overall survival (mOS) were 13.3%, 80.0%, 7.7 months, and 24.9 months, respectively. Patients with PD-L1 ≥1% showed a longer PFS (8.4 vs. 2.1 months, p = 0.015) relative to those with PD-L1 p = 0.001). Among the 19 mIHC patients, those with high PD-1/PD-L1 and LAG3 expression showed a longer PFS (19.0 vs. 3.9 months, p = 0.003). ICI also showed promising efficacy for treating metastatic PLELC. PD-L1 may be both predictive of ICI treatment efficacy and prognostic for survival in PLELC. PD-1/PD-L1 combined with LAG3 may serve as a predictor of ICI treatment effectiveness in PLELC. Larger and prospective trials are warranted to validate both ICI activity and predictive biomarkers in PLELC.This study was partly presented as a poster at the IASLC 20th World Conference on Lung Cancer 2019, 7–10 September 2019, Barcelona, Spain.

To explore the application and effect of the "one disease, one product" project to the nursing care of patients who have undergone pituitary tumour surgery using the nasal sphenoid approach.This is a prospective research study. In a standard treatment control study, 132 patients undergoing transnasal pituitary tumour surgery were divided into the control group (n = 71) and the observation group (n = 61). The control group was given routine pituitary tumor care, and the "one disease, one product" nursing model was used on the experimental group. The anxiety level of patients, the incidence of postoperative complications, postoperative hospitalization, and levels of satisfaction and capability of group members were measured between the control and experimental groups.There was no difference in the level of anxiety between the 2 groups before admission (P = 0.634). The anxiety level of the patients in the observation group decreased after the "one disease, one product" nursing intervention (P = 0.012), but in the control group, it did not decrease significantly (P = 0.149), and the anxiety level in the control group was significantly higher than in the observation group on day 1 preoperatively (P0.001)."One disease, one product" nursing can reduce the preoperative anxiety and postoperative satisfaction of pituitary adenoma surgery patients through the sphenoid sinus approach. It is worthy of popularization and application in pituitary adenoma resection through the sphenoid sinus approach.

Background PolyC-RNA-binding protein 1 (PCBP1) functions as a tumour suppressor and RNA regulator that is downregulated in human cancers. Here, we aimed to reveal the biological function of PCBP1 in lung adenocarcinoma (LUAD). Methods First, PCBP1 was identified as an important biomarker that maintains LUAD through The Cancer Genome Atlas (TCGA) project screening and confirmed by immunohistochemistry and qPCR. Via colony formation, CCK8, IncuCyte cell proliferation, wound healing and Transwell assays, we confirmed that PCBP1 was closely related to the proliferation and migration of LUAD cells. The downstream gene DKK1 was discovered by RNA sequencing of PCBP1 knockdown cells. The underlying mechanisms were further investigated using western blot, qPCR, RIP, RNA pulldown and mRNA stability assays. Results We demonstrate that PCBP1 is downregulated in LUAD tumour tissues. The reduction in PCBP1 promotes the proliferation, migration and invasion of LUAD in vitro and in vivo. Mechanistically, the RNA-binding protein PCBP1 represses LUAD by stabilizing DKK1 mRNA. Subsequently, decreased expression of the DKK1 protein relieves the inhibitory effect on the Wnt/β-catenin signalling pathway. Taken together, these results show that PCBP1 acts as a tumour suppressor gene, inhibiting the tumorigenesis of LUAD. Conclusions We found that PCBP1 inhibits LUAD development by upregulating DKK1 to inactivate the Wnt/β-catenin pathway. Our findings highlight the potential of PCBP1 as a promising therapeutic target.

Pulmonary sarcomatoid carcinoma (PSC) is a unique form of poorly differentiated nonsmall cell lung cancer (NSCLC) and is notorious for its highly malignant nature and dismal prognosis. To introduce effective treatment for PSC patients, precise subtyping of PSC is demanding. In our study, TTF-1 and P40 immunohistochemistry (IHC) staining were applied to 56 PSC patients with multiomics data. According to IHC results, we categorized these patients into three subgroups and profiled their molecular contexture using bioinformatic skills. IHC results classified these patients into three subgroups: TTF-1 positive subgroup (n = 27), P40 positive subgroup (n = 15) and double-negative subgroup (n = 14). Spindle cell samples accounted for 35.71% (5/14) of double-negative patients, higher than others (P = .034). The three subgroups were heterogeneous in the genomic alteration spectrum, showing significant differences in the RTK/RAS pathway (P = .004) and the cell cycle pathway (P = .030). The methylation profile of the double-negative subgroup was between the other two subgroups. In similarity analysis, the TTF-1 and p40 subgroups were closely related to LUAD and LUSC, respectively. The TTF-1 positive subgroup had the highest leukocyte fraction (LF) among several cancer types, and the tumor mutation burden (TMB) of the p40 positive subgroup ranked third in the TMB list, suggesting the applicability of immunotherapy for PSC. The study established a new subtyping method of PSC based on IHC results and reveals three subgroups with distinct molecular features, providing evidence for refined stratification in the treatment of PSC.

Long non-coding (lnc) RNAs are critical regulators in carcinogenesis. The novel lncRNA DEPDC1 antisense RNA 1 (

Adenosarcoma is a rare type of tumor with a mixture of epithelial and stromal components and often occurs in the female reproductive system. Primary hepatic adenosarcoma (PHAS) is extremely rare, with only two cases reported so far. Both patients had poor outcomes. Here, we report the case of a 36-year-old man with pain under the xiphoid process who was diagnosed with a bile duct tumor. He was treated with adjuvant radiotherapy when surgery was performed on him. Pathologically, the tumor contained benign epithelial tissue, and the submucosa of the bile duct in the liver showed infiltrating growth of spindle cell components. The cells were dense, mildly heterotypic, and occasionally mitotic, and the patient was diagnosed with PHAS. Whole-exome sequencing results showed that a total of 12 mutations were shared by the two tissues. The patient received adjuvant radiotherapy and he was tumor-free until 31 months postoperatively. This case will provide some references of the disease to other researchers.

BackgroundExcept for B7-CD28 family members, more novel immune checkpoints are being discovered. They are closely associated with tumor immune microenvironment and regulate the function of many immune cells. Various cancer therapeutic studies targeting these novel immune checkpoints are currently in full swing. However, studies concerning novel immune checkpoints phenotypes and clinical significance in lung adenocarcinoma (LUAD) are still limited.MethodsWe enrolled 1883 LUAD cases from nine different cohorts. The samples from The Cancer Genome Atlas (TCGA) were used as a training set, whereas seven microarray data cohorts and an independent cohort with 102 qPCR data were used for validation. The immune profiles and potential mechanism of the system were also explored.ResultsAfter univariate Cox proportional hazards regression and stepwise multivariable Cox analysis, a novel immune checkpoints-based system (LTA, CD160, and CD40LG) were identified from the training set, which significantly stratified patients into high- and low-risk groups with different survivals. Furthermore, this system has been well validated in different clinical subgroups and multiple validation cohorts. It also acted as an independent prognostic factor for patients with LAUD in different cohorts. Further exploration suggested that high-risk patients exhibited distinctive immune cells infiltration and suffered an immunosuppressive state. Additionally, this system is closely linked to various classical immunotherapy biomarkers.Conclusionwe constructed a novel immune checkpoints-based system for LUAD, which predicts prognosis and immunotherapeutic implications. We believe that these findings will not only aid in clinical management but will also shed some light on screening appropriate patients for immunotherapy.

Patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are frequently discharged from the emergency department (ED) and treated with antibiotics. The role of antibiotics in the outpatient management of AECOPD is controversial and has never been studied in the ED setting.We conducted a secondary analysis of prospectively collected data from the validation study of the Ottawa COPD Risk Scale. We included adult patients with AECOPD who were discharged from six tertiary care EDs in Canada over a two-year period and assessed rates of rehospitalization within 14 days of ED discharge. To examine the association between antibiotic treatment and rehospitalization, we performed multivariable logistic regression and propensity score-matched analyses.A total of 774 patients were included in the analysis. The mean age was 69.4 years, 388 patients (50.1%) were female, and 451 patients (58.3%) were discharged with antibiotics. Twenty-nine (6.4%) and 36 (11.1%) patients returned to hospital with admission in the antibiotic and no antibiotic groups, respectively (unadjusted OR 0.55; 95% CI 0.33-0.92); adjustment for prespecified baseline characteristics using logistic regression yielded OR 0.65; 95% CI 0.38-1.08. In the propensity score-matched analysis comprising of 197 matched pairs, 15 (7.6%) and 19 patients (9.6%) in the antibiotic and no antibiotic groups returned with admission, respectively (OR 0.69; 95% CI 0.29-1.62).For patients with AECOPD discharged from the ED, we did not find an association between outpatient treatment with antibiotics and lower rates of rehospitalization after accounting for differences in baseline patient characteristics. However, the small sample size and low observed rate of the primary outcome created substantial risk of Type II error. Until further evidence is available, clinicians should continue prescribing antibiotics for patients with AECOPD based on clinical judgement and current practice guidelines.RéSUMé: CONTEXTE: Les patients présentant des exacerbations aiguës de maladie pulmonaire obstructive chronique (EAMPOC) sont fréquemment renvoyés du service des urgences (SU) et traités avec des antibiotiques. Le rôle des antibiotiques dans la prise en charge ambulatoire de l’EAMPOC est controversé et n'a jamais été étudié dans le cadre des urgences. MéTHODES: Nous avons effectué une analyse secondaire des données recueillies prospectivement dans le cadre de l'étude de validation de l'échelle de risque de MPOC d'Ottawa. Nous avons inclus des patients adultes atteints d'EAMPOC qui sont sortis de six urgences de soins tertiaires au Canada sur une période de deux ans et avons évalué les taux de réhospitalisation dans les 14 jours suivant la sortie des urgences. Pour examiner l'association entre le traitement antibiotique et la réhospitalisation, nous avons effectué une régression logistique multivariable et des analyses par appariement de score de propension. RéSULTATS: Un total de 774 patients a été inclus dans l'analyse. L'âge moyen était de 69,4 ans, 388 patients (50,1 %) étaient des femmes et 451 patients (58,3 %) sont sortis avec des antibiotiques. Vingt-neuf (6,4 %) et 36 (11,1 %) patients sont retournés à l'hôpital avec admission dans les groupes avec et sans antibiotique, respectivement (OR non ajusté 0,55 ; IC à 95 % 0,33 à 0,92) ; l'ajustement pour les caractéristiques de base préspécifiées à l'aide de la régression logistique a donné un OR de 0,65 ; IC à 95 % 0,38 à 1,08. Dans l'analyse appariée par score de propension comprenant 197 paires appariées, 15 (7,6 %) et 19 (9,6 %) patients des groupes avec et sans antibiotique sont revenus avec une admission, respectivement (OR 0,69 ; IC 95 % 0,29 à 1,62). CONCLUSION: Pour les patients atteints d'AECOPD sortis des urgences, nous n'avons pas trouvé d'association entre le traitement ambulatoire par antibiotiques et des taux plus faibles de réhospitalisation après avoir pris en compte les différences dans les caractéristiques de base des patients. Toutefois, la petite taille de l’échantillon et le faible taux observé du résultat principal ont créé un risque important d’erreur de type II. Jusqu'à ce que d'autres preuves soient disponibles, les cliniciens doivent continuer à prescrire des antibiotiques aux patients atteints d'AECOPD en se basant sur le jugement clinique et les directives de pratique actuelles.

Sepsis is the major culprit of death among critically ill patients who are hospitalized in intensive care units (ICUs). Although sepsis-related mortality is steadily declining year-by-year due to the continuous understanding of the pathophysiological mechanism on sepsis and improvement of the bundle treatment, sepsis-associated hospitalization is rising worldwide. Surviving Sepsis Campaign (SSC) guidelines are continuously updating, while their content is extremely complex and comprehensive for a precisely implementation in clinical practice. As a consequence, a standardized step-by-step approach for the diagnosis and treatment of sepsis is particularly important. In the present study, we proposed a standardized step-by-step approach for the diagnosis and treatment of sepsis using our daily clinical experience and the latest researches, which is close to clinical practice and is easy to implement. The proposed approach may assist clinicians to more effectively diagnose and treat septic patients and avoid the emergence of adverse clinical outcomes.

Virtual home visits may improve chronic disease management. However, whether they are suitable for peritoneal dialysis (PD) patients has not yet been fully investigated. This study aimed to compare the agreement and acceptance of virtual home visits and in-person home visits in PD patients.This was a paired, single center, noninferiority trial. Participants received a virtual home visit and an in-person home visit simultaneously. A home visit checklist was built for standardization visits. The content was divided into three parts: domestic habits (57 items), bag exchange procedures (56 items), and exit site care (53 items). Satisfaction questionnaires for both patients and nurses were designed to assess attitudes toward home visits and socioeconomic effects.A total of 30 PD patients were enrolled in a single center. The information collected from virtual home visits and in-person home visits was found to be highly consistent. The perfect agreement was found in 52/57, 49/56, and 44/53 items (Cohen's kappa 0.81-1.00), substantial agreement in 4/57, 7/56, and 8/53 items (Cohen's kappa 0.61-0.80). Patients reported almost identical satisfaction for virtual home visits and in-person home visits (Virtual home visits information collection was similar to in-person home visits in PD. There were no differences in participant satisfaction and feasibility between the two visit types.

A two-category model and a segmentation model of pterygium were proposed to assist ophthalmologists in establishing the diagnosis of ophthalmic diseases. A total of 367 normal anterior segment images and 367 pterygium anterior segment images were collected at the Affiliated Eye Hospital of Nanjing Medical University. AlexNet, VGG16, ResNet18, and ResNet50 models were used to train the two-category pterygium models. A total of 150 normal and 150 pterygium anterior segment images were used to test the models, and the results were compared. The main evaluation indicators, including sensitivity, specificity, area under the curve, kappa value, and receiver operator characteristic curves of the four models, were compared. Simultaneously, 367 pterygium anterior segment images were used to train two improved pterygium segmentation models based on PSPNet. A total of 150 pterygium images were used to test the models, and the results were compared with those of the other four segmentation models. The main evaluation indicators included mean intersection over union (MIOU), IOU, mean average precision (MPA), and PA. Among the two-category models of pterygium, the best diagnostic result was obtained using the VGG16 model. The diagnostic accuracy, kappa value, diagnostic sensitivity of pterygium, diagnostic specificity of pterygium, and F1-score were 99%, 98%, 98.67%, 99.33%, and 99%, respectively. Among the pterygium segmentation models, the double phase-fusion PSPNet model had the best results, with MIOU, IOU, MPA, and PA of 86.57%, 78.1%, 92.3%, and 86.96%, respectively. This study designed a pterygium two-category model and a pterygium segmentation model for the images of the normal anterior and pterygium anterior segments, which could help patients self-screen easily and assist ophthalmologists in establishing the diagnosis of ophthalmic diseases and marking the actual scope of surgery.

Missed abortion (MA) is a special form of spontaneous abortion that is increasing in incidence. However, the precise molecular mechanisms underlying MA, especially regarding the decidua, are poorly understood. Herein, we identified molecular signaling pathways related to MA by comparing the decidua of women experiencing normal pregnancy and MA using a quantitative proteomics approach based on HPLC-MS/MS and iTRAQ labeling. Integrated bioinformatics analysis of villi and decidua was performed to reveal potential crosstalk signals in closely related tissues. We identified 2277 proteins with high confidence in decidua, of which 232 were differentially expressed in MA samples. Specifically, we reported that integrated quantitative proteomic and bioinformatic analysis revealed altered proteins in MA and the mechanisms underpinning MA involved numerous pathways, especially ribosome and cellular metabolism signaling. Moreover, Importin 9, Cullin 1 and COX6C are critical for MA, and their altered expression might contribute to the pathophysiology of MA. In particular, COX6C was dramatically down-regulated in both decidua and villi of MA. COX6C was also found to be highly expressed in syncytiotrophoblastic and cytotrophoblastic cells in villi and widely expressed in decidua of the control group, but dramatically decreased in the MA group. Functional analysis showed that knockdown of COX6C inhibited apoptosis process in both HTR-8 and SiHa cells, suggesting that COX6C may play protective effects in MA. Thus, this study could help to map the regulatory protein network related to MA and contribute to the pathophysiological mechanisms of MA.

Background Despite guideline recommendations, dual antiplatelet therapy (DAPT) is frequently used for longer than 1 year after an acute coronary syndrome (ACS) event. In Asia, information on antithrombotic management patterns (AMPs), including DAPT post discharge, is sparse. This analysis evaluated real‐world AMPs up to 2 years post discharge for ACS. Hypothesis There is wide variability in AMP use for ACS management in Asia. Methods EPICOR Asia (NCT01361386) is a prospective observational study of patients discharged after hospitalization for an ACS in eight countries/regions in Asia, followed up for 2 years. Here, we describe AMPs used and present an exploratory analysis of characteristics and outcomes in patients who received DAPT for ≤12 months post discharge compared with >12 months. Results Data were available for 12 922 patients; of 11 639 patients discharged on DAPT, 2364 (20.3%) received DAPT for ≤12 months and 9275 (79.7%) for >12 months, with approximately 60% still on DAPT at 2 years. Patients who received DAPT for >12 months were more likely to be younger, obese, lower Killip class, resident in India (vs China), and to have received invasive reperfusion. Clinical event rates during year 2 of follow‐up were lower in patients with DAPT >12 vs ≤12 months, but no causal association can be implied in this non‐randomized study. Conclusions Most ACS patients remained on DAPT up to 1 year, in accordance with current guidelines, and over half remained on DAPT at 2 years post discharge. Patients not on DAPT at 12 months are a higher risk group requiring careful monitoring.

Microtubule‐depolymerizing agents can selectively disrupt tumor vessels via inducing endothelial membrane blebbing. However, the mechanism regulating blebbing is largely unknown. IMB5046 is a newly discovered microtubule‐depolymerizing agent. Here, the functions of focal adhesion kinase (FAK) during IMB5046‐induced blebbing and the relevant mechanism are studied. We found that IMB5046 induced membrane blebbing and reassembly of focal adhesions in human vascular endothelial cells. Both FAK inhibitor and knock‐down expression of FAK inhibited IMB5046‐induced blebbing. Mechanism study revealed that IMB5046 induced the activation of FAK via GEF‐H1/ Rho/ ROCK/ MLC2 pathway. cRGD peptide, a ligand of integrin, also blocked IMB5046‐induced blebbing. After activation, FAK further promoted the phosphorylation of MLC2. This positive feedback loop caused more intensive actomyosin contraction and continuous membrane blebbing. FAK inhibitor blocked membrane blebbing via inhibiting actomyosin contraction, and stimulated stress fibre formation via promoting the phosphorylation of HSP27. Conclusively, these results demonstrate that FAK is a molecular switch controlling endothelial blebbing and stress fibre formation. Our study provides a new molecular mechanism for microtubule‐depolymerizing agents to be used as vascular disrupting agents.

Angiopoietin-2 (Ang-2) is a proangiogenic factor that mediates inflammation and atherosclerosis. We evaluated the predictive value of circulating Ang-2 levels for periprocedural myocardial injury (PMI) in 145 patients undergoing elective percutaneous coronary intervention (PCI), and investigated whether post-PCI Ang-2 levels are influenced by PMI. PMI was defined as a post-procedural troponin elevation above the 5×99th percentile upper reference limit. Blood samples for Ang-2 analysis were collected at admission and on postoperative days 1 and 3. PMI occurred in 40 patients (28%). At baseline, there was no difference in Ang-2 levels between PMI and non-PMI patients (P=0.554). However, a significant interaction effect between PMI occurrence and time on Ang-2 levels was observed (interaction P=0.036). Although serum Ang-2 levels in non-PMI patients gradually decreased, Ang-2 levels in PMI patients did not change between different time-points. Multiple logistic regression analysis revealed that age, total stent length, and serum levels of N-terminal pro-brain natriuretic peptide were independent PMI predictors. These findings indicate that pre-procedural Ang-2 levels do not impact PMI occurrence after elective PCI. However, changes in Ang-2 levels after the procedure are closely related to PMI.

Introduction: Cancer is associated with significant health-care expenditure, but few studies have examined the cost of patients with cancer in the intensive care unit (ICU). We aimed to describe the costs and outcomes of patients admitted to the ICU with cancer. Methods: We conducted a retrospective cohort study of patients admitted between 2011 and 2016 to 2 tertiary-care ICUs. We included patients with a cancer-related most responsible diagnosis using International Classification of Disease, 10th Revision, Canada codes. We compared costs and outcomes of patients having cancer with noncancer controls matched for age, sex, and Elixhauser comorbidity score. We used logistic regression to determine predictors of mortality among patients with cancer. Results: There were 1022 patients with cancer during the study period. Mean age was 63.2 years and 577 (56.5%) were male. Inhospital mortality for all patients with cancer was 24.0%. Total cost per patient was higher for patients with cancer compared to noncancer patients (CAD$57 084 vs CAD$40 730; P < .001) but there were no differences in the cost per day (CAD$2868 vs CAD$2887; P = .76) or ICU cost (CAD$30 495 vs CAD$29 382; P = .42). Among patients with cancer, the cost per day was higher for nonsurvivors (CAD$3477 vs CAD$2677; P < .001). Liver disease (odds ratio [OR]: 2.96; 95% confidence interval [CI]: 1.22-7.81), mechanical ventilation (OR: 1.73; 95% CI: 1.25-2.39), hematologic malignancy (OR: 3.88; 95% CI: 2.31-6.54), and unknown primary site (OR: 2.13; 95% CI: 1.36-3.35) were independently associated with mortality in patients with cancer. Conclusion: Patients admitted to the ICU with cancer did not differ in cost per day, ICU cost, or mortality compared to matched noncancer controls. Among patients with cancer, nonsurvivors had significantly higher cost per day compared to survivors. Hematologic and unknown primaries, liver disease, and mechanical ventilation were independently associated with mortality in patients with cancer.

Gemcitabine (Gem) is currently used as the first-line therapy for liver and pancreatic cancer but has limited efficacy in most cases. Dexamethasone (Dex) have been applied as a chemoprotectant and chemosensitizer in cancer chemotherapy. This study further explored the potential of combination of Gem and Dex and tested the hypothesis that glucocorticoid receptor signaling is essential for the synergistic antitumor activity. In the HepG2 and AsPC-1 xenograft models, the combination treatment showed a significantly synergistic antitumor activity. Immunohistochemistry of post-treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. Dex alone and the combination with Gem inhibited the expression of glucocorticoid receptor. The combination of Dex and Gem showed synergistic cytotoxicity in cell lines in vitro. The antiproliferative synergism is prevented by used glucocorticoid receptor (GR) small interfering RNA, demonstrating that the glucocorticoid receptor is required for the antiproliferative synergism of Gem and Dex. The inhibition of glucocorticoid receptor signaling pathway and induction of apoptosis via activation of caspases 3, 8 and 9, PARP, contributed to the synergistic effect of this combination therapy. These results demonstrate that Dex could potentiate the antitumor efficacy of Gem. The synergistic antitumor activity of the combination of Dex and Gem was through glucocorticoid receptor signaling. Taken together, a combination of Dex and Gem shows a significant synergistic antitumor activity and lesser toxicity both in vitro and in vivo and could be a combination chemotherapy for the treatment of highly expression of glucocorticoid receptor patients.

Patient survival remains poor even after diagnosis in lung cancer cases, and the molecular events resulting from lung cancer progression remain unclear. Raman spectroscopy could be used to noninvasively and accurately reveal the biochemical properties of biological tissues on the basis of their pathological status. This study aimed at probing biomolecular changes in lung cancer, using Raman spectroscopy as a potential diagnostic tool. Herein, biochemical alterations were evident in the Raman spectra (region of 600–1800 cm−1) in normal and cancerous lung tissues. The levels of saturated and unsaturated lipids and the protein-to-lipid, nucleic acid-to-lipid, and protein-to-nucleic acid ratios were significantly altered among malignant tissues compared to normal lung tissues. These biochemical alterations in tissues during neoplastic transformation have profound implications in not only the biochemical landscape of lung cancer progression but also cytopathological classification. Based on this spectroscopic approach, classification methods including k-nearest neighbour (kNN) and support vector machine (SVM) were successfully applied to cytopathologically diagnose lung cancer with an accuracy approaching 99%. The present results indicate that Raman spectroscopy is an excellent tool to biochemically interrogate and diagnose lung cancer.

Digital mental health services (DMHSs) have great potential for mitigating the mental health burden related to COVID-19, but public accessibility (ease of acquiring services when needed) to DMHSs during the pandemic is largely unknown. Accessibility to DMHSs was tracked longitudinally among a nationwide sample of 18,804 adults in China from before to one year after COVID-19 outbreak. Unconditional and conditional latent growth curve models and latent growth mixture models were fitted to explore the overall growth trend, influencing factors, and latent trajectory classes of accessibility to DMHSs throughout COVID-19. Generalized estimating equation models and generalized linear mixed models were employed to explore the association between accessibility to DMHSs and long-term mental health symptoms. We found that people generally reported increased difficulty in accessing DMHSs from before to one year after COVID-19 outbreak. Males, youngsters, individuals with low socioeconomic status, and individuals greatly affected by COVID-19 reported greater difficulty in accessing DMHSs. Four DMHS accessibility trajectory classes were identified: “lowest–great increase” (6.3%), “moderate low–slight increase” (44.4%), “moderate high–slight decrease” (18.1%) and “highest–great decrease” (31.2%). Trajectory classes reporting greater difficulty in accessing DMHSs were at higher risk for long-term mental symptoms. In conclusion, an overall increase in difficulty in accessing DMHSs is observed throughout COVID-19, and heterogeneity exists in DMHS accessibility trajectories. Our results suggest that easy access to DMHSs should be consistently facilitated. Moreover, access gaps should be reduced across demographic groups, and target populations for service allocation should alter as the pandemic evolves.

MicroRNA (miRNA)-124 inhibitor may enhance cerebral blood vessel formation in lacunar cerebral infarction (LCI) and mesoporous silica nanoparticles are highlighted as a drug carrier which improves patients' outcome. This study explored the impact of miR-124 and its promising targeted gene P2Y

Atmospheric methane growth reached an exceptionally high rate of 15.1 ± 0.4 parts per billion per year in 2020 despite a probable decrease in anthropogenic methane emissions during COVID-19 lockdowns

Background The pandemic of coronavirus disease 2019 (COVID-19) has changed human behavior in areas such as contact patterns and mask-wearing frequency. Exploring human–human contact patterns and mask-wearing habits in high-risk groups is an essential step in fully understanding the transmission of respiratory infection-based diseases. This study had aims to quantify local human–human (H–H) contacts in high-risk groups in representative provinces of China and to explore the occupation-specific assortativity and heterogeneity of social contacts. Methods Delivery workers, medical workers, preschoolers, and students from Qinghai, Shanghai, and Zhejiang were recruited to complete an online questionnaire that queried general information, logged contacts, and assessed the willingness to wear a mask in different settings. The “group contact” was defined as contact with a group at least 20 individuals. The numbers of contacts across different characteristics were assessed and age-specific contact matrices were established. A generalized additive mixed model was used to analyze the associations between the number of individual contacts and several characteristics. The factors influencing the frequency of mask wearing were evaluated with a logistic regression model. Results A total of 611,287 contacts were reported by 15,635 participants. The frequency of daily individual contacts averaged 3.14 (95% confidence interval: 3.13–3.15) people per day, while that of group contacts was 37.90 (95% CI: 37.20–38.70). Skin-to-skin contact and long-duration contact were more likely to occur at home or among family members. Contact matrices of students were the most assortative (all contacts q-index = 0.899, 95% CI: 0.894–0.904). Participants with larger household sizes reported having more contacts. Higher household income per capita was significantly associated with a greater number of contacts among preschoolers (P50,000–99,999 = 0.033) and students (P10,000–29,999 = 0.017). In each of the public places, the frequency of mask wearing was highest for delivery workers. For preschoolers and students with more contacts, the proportion of those who reported always wearing masks was lower (P Conclusions Contact screening efforts should be concentrated in the home, school, and workplace after an outbreak of an epidemic, as more than 75% of all contacts, on average, will be found in such places. Efforts should be made to improve the mask-wearing rate and age-specific health promotion measures aimed at reducing transmission for the younger demographic. Age-stratified and occupation-specific social contact research in high-risk groups could help inform policy-making decisions during the post-relaxation period of the COVID-19 pandemic. Graphical Abstract

Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related to the cell cycle, immune, and hypoxic properties. Our data also revealed the intratumor heterogeneity (ITH) of key transcription factors (TFs) in SCLC and related gene expression patterns and functions. The non-neuroendocrine (non-NE) tumors were correlated with increased inflammatory gene signatures and immune cell infiltrates in SCLC, which contributed to better responses to immune checkpoint inhibitors. These findings indicate a significant heterogeneity of human SCLC, and intensive crosstalk between cancer cells and the TME at single-cell resolution, and thus, set the stage for a better understanding of the biology of SCLC as well as for developing new therapeutics for SCLC.

Background. Kangai injection is a traditional Chinese medicine (TCM) mixed by extracts from astragalus, ginseng, and kurorinone with modern technology. It is a commonly used antitumor injection in China, but the mechanism of Kangai injection in the treatment of colorectal cancer (CRC) is still unclear. The purpose of this study is to explore the mechanism of Kangai injection against CRC using network pharmacology and molecular docking technology. Methods. Targets of Kangai injection in CRC were predicted by SwissTargetPrediction and DisGeNET databases. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed by using the DAVID database. A component-disease-target gene-pathway network was constructed by Cytoscape 3.8.0 software. Results. 114 overlapping targets of Kangai injection and CRC were used to construct a PPI network, and the top 10 hub targets of Kangai injection were rated from high to low as TP53, VEGFA, EGFR, TNF, ESR1, STAT3, HSP90AA1, HDAC1, AR, and MMP9. The ingredient-target-disease interactive network was constructed, which included 22 compounds and 114 overlapping targets with 161 nodes and 707 edges. Entries of enrichment analysis were obtained based on P value (