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A retrospective cohort study.To evaluate the clinical efficacy of the self-locking stand-alone (SA) cage and conventional cage-plate construct (CPC) in treating degenerative cervical spondylosis with a five-year follow-up.The SA approach was designed to reduce complications associated with traditional anterior cervical discectomy and fusion. These techniques have been shown to have satisfactory short-term clinical outcomes. Literature describing the mid-term clinical outcomes of SA cage is limited.We retrospectively analyzed patients with cervical spondylosis who had received an SA device or CPC between 2014 and 2016 at the Xijing Hospital. Participants were matched for sex, age, and operative level. Differences in clinical and radiographic outcomes and the occurrence of postoperative complications between the two groups were analyzed.In total, 207 patients were included (101 with SA and 106 with CPC), the median follow-up for both groups were 60.2 and 60.9 months. Both groups exhibited significant improvements in all measured values compared with the preoperative values. The SA group had a shorter operation time, less intraoperative blood loss, and a significantly lower incidence of dysphagia after surgery than the CPC group ( P0.05). At the last visit, cage subsidence was 6.9% and 3.8% in the SA and CPC groups, respectively ( P =0.365). The radiographic adjacent segment degeneration (ASD) was significantly lower in the SA group than in the CPC group (6.9% vs. 27.4%, P0.01). No symptomatic ASD was observed in the SA group, and six (5.7%) cases occurred in the CPC group ( P =0.029).In this study, the SA cage showed similar efficacy to that of the conventional CPC in treating cervical spondylosis using anterior cervical discectomy and fusion, with a significant reduction in the incidence of immediate postoperative dysphagia and mid-term ASD.

Background: Despite substantial research highlighting the importance of exogenous dietary cholesterol intake and endogenous serum cholesterol level in human health, a thorough evaluation of the associations is lacking. Our study objective was to examine overall and cause-specific mortality in relation to dietary and serum cholesterol, as well as egg consumption, and conduct an updated meta-regression analysis of cohort studies. Methods: We conducted a prospective analysis of 27 078 men in the ATBC Study (Alpha-Tocopherol, Beta-Carotene Cancer Prevention). Multivariable-controlled cause-specific Cox proportional hazards regression models were used to calculate hazard ratios and 31-year absolute mortality risk differences. A systematic review and meta-analysis of cohort studies was also performed (PROSPERO [URL: https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021272756]). Results: Based on 482 316 person-years of follow-up, we identified 22 035 deaths, including 9110 deaths from cardiovascular disease (CVD). Greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Hazard ratios for each additional 300 mg cholesterol intake per day were 1.10 and 1.13 for overall and CVD-related mortality, respectively; for each additional 50-g egg consumed daily, hazard ratios were 1.06 and 1.09, respectively, for overall and CVD-related mortality (all P valuesP 2 =80.1%). In the subgroup analysis of geographic regions ( P interaction =0.02), an increase of 50-g egg consumed daily was associated with a higher risk of CVD in US cohorts (pooled relative risk, 1.08 [95% CI, 1.02–1.14]) and appeared related to a higher CVD risk in European cohorts with borderline significance (pooled relative risk, 1.05), but was not associated with CVD risk in Asian cohorts. Conclusions: In this prospective cohort study and updated meta-analysis, greater dietary cholesterol and egg consumption were associated with increased risk of overall and CVD-related mortality. Our findings support restricted consumption of dietary cholesterol as a means to improve long-term health and longevity.

Chocolate is a rich dietary source of various bioactive flavonoid compounds. Despite being one of the most popular foods worldwide, the association between chocolate consumption and long-term mortality remains unclear. The objective of this study is to determine the associations between chocolate consumption and long-term overall and cause-specific mortality, to evaluate dose-response and potential mediators, and to conduct an updated meta-analysis based on prospective cohort studies. We performed a prospective analysis in the Alpha-Tocopherol, Beta-Carotene cancer prevention (ATBC) Study with a total of 27,111 men who were recruited between 1985 and 1988 and followed through 2015. Exposure data of daily chocolate consumption was obtained from validated baseline food frequency questionnaire. Hazard ratios (HRs) and 30-year absolute risk differences (ARDs) including 95% confidence intervals (CI) for overall and cause-specific mortality were estimated using multivariable-adjusted Cox proportional hazards regression models. An updated meta-analysis of cohort studies was also conducted. During 482,807 person-years of follow-up, a total of 22,064 men died. The multivariable analyses showed a statistically significant inverse association between chocolate consumption and risk of overall mortality, with HRs of 0.91, 0.89, 0.89, and 0.88 for the increasing categories 2-5 as compared with those in the lowest category (P

Context Oxidative stress plays an indispensable role in pathogenesis of Graves’ orbitopathy (GO). Ferroptosis is a newly discovered form of cell death resulting from lipid peroxidation. Little is known about the role of ferroptosis in GO. Objective We aimed to identify the divergent role of ferroptosis in the GO and control orbital fibroblasts (OFs). Methods Orbital fat/connective tissues and serum immunoglobulins (Igs) were collected from GO and control subjects. Cell viability and lipid peroxidation were measured to evaluate ferroptosis sensitivity. Pyruvate dehydrogenase kinase 2 (PDK2) level and oxygen consumption rate were quantified to assess glycolysis status. Results Primary OFs were cultured from orbital tissues. Ferroptosis was induced by cystine deprivation and/or erastin treatment. The GO OFs possessed stronger resistance to ferroptosis than the control OFs. Selenium, a potential ferroptosis inhibitor, protected the control OFs from ferroptosis. Both transcriptomic and proteomic analyses indicated glycolytic shift in the GO OFs. Metabolic profiling, PDK2 quantification, and oxygen consumption assay confirmed enhanced glycolysis in the GO OFs. Inhibition of glycolysis by PDK2 knockdown and dichloroacetic acid (DCA) promoted ferroptosis sensitivity in the GO OFs. The ferroptosis-sensitizing effects of DCA were also observed when the GO OFs were treated with GO-Igs. IGF1R overexpression in the GO OFs contributed to glycolysis shift. IGF1R inhibitory antibodies facilitated ferroptosis induction in the GO OFs, but the effects were less remarkable under GO-Igs treatment. Conclusion These study findings establish that glycolysis facilitates ferroptosis resistance in the GO OFs, providing insights into the therapeutic role of glycolysis for GO treatment.

Extensive research is currently being conducted into a variety of bio-inspired biomimetic nanoparticles (NPs) with new cell simulation functions across the fields of materials science, chemistry, biology, physics, and engineering. Cells such as erythrocytes, platelets, and stem cells have been engineered as new drug carriers. The platelet-derived drug delivery system, which is a new targeted drug delivery system (TDDS), can effectively navigate the blood circulatory system and interact with the complex tumor microenvironment; it appears to outperform traditional anticancer drugs; hence, it has attracted considerable research interest. In this review, we describe innovative studies and outline the latest progress regarding the use of platelets as tumor targeting and drug delivery vehicles; we also highlight opportunities and challenges relevant to the manufacture of tumor-related platelet TDDSs.

Cancer is one of the diseases with the highest morbidity and mortality rates worldwide, and its therapeutic options are inadequate. The endothelial glycoprotein, also known as CD105, is a type I transmembrane glycoprotein located on the surface of the cell membranes and it is one of the transforming growth factor-β (TGF-β) receptor complexes. It regulates the responses associated with binding to transforming growth factor β1 egg (Activin-A), bone morphogenetic protein 2 (BMP-2), and bone morphogenetic protein 7 (BMP-7). Additionally, it is involved in the regulation of angiogenesis. This glycoprotein is indispensable in the treatment of tumor angiogenesis, and it also plays a leading role in tumor angiogenesis therapy. Therefore, CD105 is considered to be a novel therapeutic target. In this study, we explored the significance of CD105 in the diagnosis, treatment and prognosis of various tumors, and provided evidence for the effect and mechanism of CD105 on tumors.

Background After treatment of intrauterine adhesions, the rate of re-adhesion is high and the pregnancy outcome unpredictable and unsatisfactory. This study established and verified a decision tree predictive model of live birth in patients after surgery for moderate-to-severe intrauterine adhesions (IUAs). Methods A retrospective observational study initially comprised 394 patients with moderate-to-severe IUAs diagnosed via hysteroscopy. The patients underwent hysteroscopic adhesiolysis from January 2013 to January 2017, in a university-affiliated hospital. Follow-ups to determine the rate of live birth were conducted by telephone for at least the first postoperative year. A classification and regression tree algorithm was applied to establish a decision tree model of live birth after surgery. Results Within the final population of 374 patients, the total live birth rate after treatment was 29.7%. The accuracy of the model was 83.8%, and the area under the receiver operating characteristic curve (AUC) was 0.870 (95% CI 7.699–0.989). The root node variable was postoperative menstrual pattern. The predictive accuracy of the multivariate logistic regression model was 70.3%, and the AUC was 0.835 (95% CI 0.667–0.962). Conclusions The decision tree predictive model is useful for predicting live birth after surgery for IUAs; postoperative menstrual pattern is a key factor in the model. This model will help clinicians make appropriate clinical decisions during patient consultations.

The perioperative trauma-related platelet recruitment and activation severely affect tumor recurrence and metastasis. Therefore, efficiently killing residual tumor cells and simultaneously inhibiting platelet activation to block platelet-cancer cell interaction might be a promising strategy to prevent postoperative tumor recurrence and metastasis.

An aptamer is a short oligonucleotide chain that can specifically recognize targeting analytes. Due to its high specificity, low cost, and good biocompatibility, aptamers as the targeting elements of biosensors have been applied widely in non‐invasive tumor imaging and treatment in situ to replace traditional methods. In this review, we will summarize recent advances in using aptamer‐based biosensors in tumor diagnosis. After a brief introduction of the advantage of aptamers compared with enzyme sensors and immune sensors, the different sensing designs and mechanisms based on 3 signal transduction modes will be reviewed to cover different kinds of analytical methods, including: electrochemistry analysis, colorimetry analysis, and fluorescence analysis. Finally, the prospective advantages of aptamer‐based biosensors in tumor theranostics and post‐treatment monitoring are also evaluated in this review., This review introduces the advantages of aptamer sensors in disease diagnosis compared with traditional biosensors. It also shows the design strategies of the 3 most studied aptamer sensors: fluorescent aptasensors, electrochemical aptasensors, and colorimetric aptasensors, and their application in early tumor diagnosis. Moreover, taking the fluorescent aptasensor as an example, the design of aptasensors combined with nanomaterials can not only be used for tumor imaging, but also has important significance in tumor treatment and efficacy evaluation. The design provides a new idea for the integration of tumor theranostics.

Accumulation of very long chain fatty acids (VLCFAs) due to defects in ATP binding cassette protein D1 (ABCD1) is thought to underlie the pathologies observed in adrenoleukodystrophy (ALD). Pursuing a substrate reduction approach based on the inhibition of elongation of very long chain fatty acid 1 enzyme (ELOVL1), we explored a series of thiazole amides that evolved into compound 27─a highly potent, central nervous system (CNS)-penetrant compound with favorable in vivo pharmacokinetics. Compound 27 selectively inhibits ELOVL1, reducing C26:0 VLCFA synthesis in ALD patient fibroblasts, lymphocytes, and microglia. In mouse models of ALD, compound 27 treatment reduced C26:0 VLCFA concentrations to near-wild-type levels in blood and up to 65% in the brain, a disease-relevant tissue. Preclinical safety findings in the skin, eye, and CNS precluded progression; the origin and relevance of these findings require further study. ELOVL1 inhibition is an effective approach for normalizing VLCFAs in models of ALD.

BackgroundFlowering plants (angiosperms) are dominant components of global terrestrial ecosystems, but phylogenetic relationships at the familial level and above remain only partially resolved, greatly impeding our full understanding of their evolution and early diversification. The plastome, typically mapped as a circular genome, has been the most important molecular data source for plant phylogeny reconstruction for decades.ResultsHere, we assembled by far the largest plastid dataset of angiosperms, composed of 80 genes from 4792 plastomes of 4660 species in 2024 genera representing all currently recognized families. Our phylogenetic tree (PPA II) is essentially congruent with those of previous plastid phylogenomic analyses but generally provides greater clade support. In the PPA II tree, 75% of nodes at or above the ordinal level and 78% at or above the familial level were resolved with high bootstrap support (BP ≥ 90). We obtained strong support for many interordinal and interfamilial relationships that were poorly resolved previously within the core eudicots, such as Dilleniales, Saxifragales, and Vitales being resolved as successive sisters to the remaining rosids, and Santalales, Berberidopsidales, and Caryophyllales as successive sisters to the asterids. However, the placement of magnoliids, although resolved as sister to all otherMesangiospermae, is not well supported and disagrees with topologies inferred from nuclear data. Relationships among the five major clades ofMesangiospermaeremain intractable despite increased sampling, probably due to an ancient rapid radiation.ConclusionsWe provide the most comprehensive dataset of plastomes to date and a well-resolved phylogenetic tree, which together provide a strong foundation for future evolutionary studies of flowering plants.

A number of studies have demonstrated that N6-methyladenosine (m6A) plays a vital role in the pathological process of various tumours. Recently, it was found that m6A writers or erasers affect the tumourigenesis of melanoma. However, the relationship between m6A readers such as YTH domain family (YTHDF) proteins and melanoma was still elusive.RT-qPCR, Western blot and immunohistochemistry were conducted to measure the expression level of YTH N6-methyladenosine RNA binding protein 3 (YTHDF3) and lysyl oxidase-like 3 (LOXL3) in melanoma tissues and cells. The effects of YTHDF3 and LOXL3 on melanoma were verified in vitro and in vivo. Multi-omics analysis including RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses was performed to identify the target. The interaction between YTHDF3 and LOXL3 was verified by RT-PCR, Western blot, MeRIP-qPCR, RIP-qPCR and CRISPR-Cas13b-based epitranscriptome engineering.In this study, we found that m6A reader YTHDF3 could affect the metastasis of melanoma both in vitro and in vivo. The downstream targets of YTHDF3, such as LOXL3, phosphodiesterase 3A (PDE3A) and chromodomain helicase DNA-binding protein 7 (CHD7) were identified by means of RNA-seq, MeRIP-seq, RIP-seq and mass spectrometry analyses. Besides, RT-qPCR, Western blot, RIP-qPCR and MeRIP-qPCR were performed for subsequent validation. Among various targets of YTHDF3, LOXL3 was found to be the optimal target of YTHDF3. With the application of CRISPR-Cas13b-based epitranscriptome engineering, we further confirmed that the transcript of LOXL3 was captured and regulated by YTHDF3 via m6A binding sites. YTHDF3 augmented the protein expression of LOXL3 without affecting its mRNA level via the enrichment of eukaryotic translation initiation factor 3 subunit A (eIF3A) on the transcript of LOXL3. LOXL3 downregulation inhibited the metastatic ability of melanoma cells, and overexpression of LOXL3 ameliorated the inhibition of melanoma metastasis caused by YTHDF3 downregulation.The YTHDF3-LOXL3 axis could serve as a promising target to be interfered with to inhibit the metastasis of melanoma.

Objectives: The treatment of acute herpangina is inconsistent. We aim to evaluate the effectiveness and safety of interferon α-2b spray versus Ribavirin for this disease. Methods: A randomized, controlled trial was conducted in eight hospitals in China between 2016 and 2018. 668 patients (1–7 years old) were randomized into an experimental group (treated with Interferon α-2b spray) or control group (received Ribavirin Aerosol). Body temperature returning to normal within 72 h and remaining so for 24 h was the primary outcome; release of oral herpes and adverse events were the secondary outcomes. Results: (1) The average age of onset was 2.5 years old. (2) After 72 h treatment, body temperature of 98.5% patients in experimental group and 94.3% in control group returned to normal and remained so for 24 h (P = 0.004). The differences were greater at 48 h treatment (95.2% vs. 85.9%, P < 0.001) and at 24 h (77.5% vs. 66.5%, P = 0.001). (3) The rate of improved oral herpes in the experimental group was higher than that in control group (46.7% vs.37.1%, P = 0.011). No adverse reaction occurred. Conclusions: Local application of recombinant interferon α-2b spray showed better efficacy for acute herpangina in children. It was safe for use.

In this study, the enrichment factor (EF) and pollution load index (PLI) were used to evaluate the pollution of potential toxic elements (PTEs) in the soil near the oil production plants in central China, and the potential ecological risk (PER) and human health risk (HHR) assessment model were used to evaluate the PER and HHR caused by the soil PTEs in the study area. The mean EFs of all PTEs were greater than 1, PTEs have accumulated to varying degrees, especially Cr, Ni and Pb were the most serious. The average value of PLI was 2.62, indicating that the soil PTEs were seriously polluted. The average $${E}_{r}^{i}$$ E r i values of PTEs were Cr > Pb > Cd > Ni > As > Cu > Zn > Mn, of which Cr, Pb, Cd and Ni were at medium and above PER levels. Both adults and children in the study area suffered from varying degrees of non-carcinogenic and carcinogenic risks. The total hazard index (THI) values of children (7.31) and adults (1.03) were all > 1, and the total carcinogenic risk index (TCRI) of children (9.44E−04) and adults (5.75E−04) were also > 10–4. In particular, the hazardous quotient (HQ) of Cr and Pb for children under the oral intake route were 4.91 and 1.17, respectively, caused serious non-carcinogenic risk. And the carcinogenic risk index (CRI) values of the PTEs in adults and children under the three exposure routes were Cr > Ni > > As > Pb > > Cd. Among them, the CRI values of Cr and Ni in children and adults by oral intake were both greater than 10–4, showing a strong carcinogenic risk. The results will provide scientific basis for environmental protection and population health protection in this area.

To compare the clinical efficacy of the minimally invasive technique and the open method in the treatment of irreducible unilateral subaxial cervical facet joint dislocation (SCFD).From March 2015 to September 2018, 62 patients with unilateral SCFD were studied. The cases were divided into 2 groups based on different surgery strategies. Thirty-one patients were enrolled in the minimally invasive surgery (MIS) group, and 31 patients were enrolled in the open surgery group. The duration of prone position operation, blood loss, and total hospitalization costs were recorded. The clinical effects were evaluated using visual analogue scale scores, the Oswestry Disability Index, and Japanese Orthopedic Association scores at each follow-up. In addition, the segmental Cobb angle and intervertebral height were recorded and compared.The amount of intraoperative blood loss, prone position operation duration, and total hospital costs in the MIS group were significantly lower than in the open surgery group. The visual analogue scale, Oswestry Disability Index, and Japanese Orthopedic Association scores of the 2 groups significantly improved after the operation. A satisfactory fusion rate was obtained in both groups, and the segmental Cobb angle and intervertebral height scores in both groups improved significantly.Minimally invasive reduction had equal clinical efficacy to posterior open surgery. However, MIS was less invasive and had lower costs. Therefore, it is a potential option in the treatment of SCFD.

Hyalomma tick species are considered the competent vector tick species that carry and transmit Crimean-Congo hemorrhagic fever virus (CCHFV) to humans and animals. Hyalomma asiaticum is one of the major tick species widespread in the Xinjiang Uygur Autonomous Region (XUAR) of China. To determine the potential prevalence of H. asiaticum in XUAR, species distribution modeling was performed using MaxEnt algorithm assembled with bioclimatic variables and curated tick presence records. The results indicate that potential habitats of H. asiaticum mainly cover the northern and western XUAR. The suitable habitats included the west rim of the Taklimakan Desert, Turpan Basin, and Junggar Basin. The models show a mean area under the curve of 0.865 ± 0.068 for H. asiaticum based on 10-fold cross-validation. Despite limited tick presence records used in the study, this work describes the potential distribution and the association of important bioclimatic variables that are crucial for the survival of H. asiaticum in many arid areas in XUAR. The model could be helpful in tick distribution study and surveillance of CCHFV in the region.

Background: Despite significantly reduced acute myocardial infarction (MI) mortality in recent years, ischemic heart failure continues to escalate. Therapeutic interventions effectively reversing pathological remodeling are an urgent unmet medical need. We recently demonstrated that AdipoR1 (APN [adiponectin] receptor 1) phosphorylation by GRK2 (G-protein–coupled receptor kinase 2) contributes to maladaptive remodeling in the ischemic heart. The current study clarified the underlying mechanisms leading to AdipoR1 phosphorylative desensitization and investigated whether blocking AdipoR1 phosphorylation may restore its protective signaling, reversing post-MI remodeling. Methods: Specific sites and underlying molecular mechanisms responsible for AdipoR1 phosphorylative desensitization were investigated in vitro (neonatal and adult cardiomyocytes). The effects of AdipoR1 phosphorylation inhibition upon APN post-MI remodeling and heart failure progression were investigated in vivo. Results: Among 4 previously identified sites sensitive to GRK2 phosphorylation, alanine substitution of Ser 205 (AdipoR1 S205A ), but not other 3 sites, rescued GRK2-suppressed AdipoR1 functions, restoring APN-induced cell salvage kinase activation and reducing oxidative cell death. The molecular investigation followed by functional determination demonstrated that AdipoR1 phosphorylation promoted clathrin-dependent (not caveolae) endocytosis and lysosomal-mediated (not proteasome) degradation, reducing AdipoR1 protein level and suppressing AdipoR1-mediated cytoprotective action. GRK2-induced AdipoR1 endocytosis and degradation were blocked by AdipoR1 S205A overexpression. Moreover, AdipoR1 S205E (pseudophosphorylation) phenocopied GRK2 effects, promoted AdipoR1 endocytosis and degradation, and inhibited AdipoR1 biological function. Most importantly, AdipoR1 function was preserved during heart failure development in AdipoR1-KO (AdipoR1 knockout) mice reexpressing hAdipoR1 S205A . APN administration in the failing heart reversed post-MI remodeling and improved cardiac function. However, reexpressing hAdipoR1 WT in AdipoR1-KO mice failed to restore APN cardioprotection. Conclusions: Ser 205 is responsible for AdipoR1 phosphorylative desensitization in the failing heart. Blockade of AdipoR1 phosphorylation followed by pharmacological APN administration is a novel therapy effective in reversing post-MI remodeling and mitigating heart failure progression.

Lung cancer remains the leading cause of cancer death worldwide. Late diagnosis, chemoresistance, and metastasis are the main reasons for the high mortality rate of lung cancer. Therefore, the development of other treatments is urgent. Cediranib (CED), a vascular endothelial growth factor receptor (VEGFR) kinase inhibitor, shows promising antitumour activities in various cancers including lung cancer. Here, we explored the effects and the underlying molecular mechanism of CED on non-small-cell lung cancer (NSCLC) cell line A549 cells in vitro. Our results show that CED could inhibit A549 cell proliferation and cloning formation. Meanwhile, G1 phase cell cycle arrest was also found, as featured by the increased proportion of G1 phase cells as well as the reduction of G1 phase relative proteins CDK4/cyclin D1 and CDK2/cyclin E. Moreover, the ratio of LC3-II/LC3-I was elevated significantly in CED-treated groups compared with the controls. Furthermore, the expression of p-Akt, p-P38, p-Erk1/2, and p-mTOR proteins was decreased obviously in the treatment groups. These results suggest that CED could induce apoptosis and G1 phase cell cycle arrest in A549 cells. Meanwhile, CED may induce autophagy through MAPK/Erk1/2 and Akt/mTOR signal pathway in A549 cells.

OBJECTIVES: To evaluate the changes of retinal nerve fibre layer (RNFL) and ganglion cell layer/inner plexiform layer (GCL/IPL) with the severity of thyroid eye disease (TED). METHODS: One hundred and forty-five eyes of 75 patients with TED and 70 eyes of 35 healthy controls were included. The eyes with TED were divided into mild group (35 eyes), moderate-to-severe group (42 eyes) and DON group (68 eyes). The thickness of RNFL and GCL/IPL were measured by optic coherence tomography (OCT). Clinical activity score (CAS), best corrected visual acuity (BCVA), intraocular pressure (IOP), proptosis and mean deviation (MD) by Humphrey perimetry were assessed. RESULTS: The CAS had significant difference between the three groups (p

Rationale: Endoglin, also known as CD105, is a homo-dimeric membrane glycoprotein required for angiogenesis and serves as a marker for cancer vasculature. In this study, we constructed a bispecific T-cell engager (BiTE) antibody that targets human endoglin and CD3 (hEND-CD3/BiTE). We examined BiTE binding to endoglin-expressing cells and its effects on the cytolytic activity of T cells and cancer development. Methods: The in vitro effects of hEND-CD3/BiTE, including binding to target cells, T-cell activation, proliferation, and cytotoxicity, were examined in endoglin-expressing 293T cells, human umbilical vascular endothelial cells, tumor-derived endothelial cells, and CD3+ T cells. An in vivo xenograft tumor model was established using A549 human lung cancer cells. The therapeutic efficacy of hEND-CD3/BiTE was assessed by monitoring tumor growth, angiogenesis, and mouse survival. Results: hEND-CD3/BiTE specifically bound to endoglin-expressing cells and CD3+ T cells in vitro and stimulated T-cell activation, proliferation, and Th1 cytokine secretion, and promoted T-cell-mediated cytolysis of endoglin-expressing cells. The hEND-CD3/BiTE in vivo caused minimal toxicity to major organs, reduced tumor neoangiogenesis, inhibited tumor growth, and significantly improved mouse survival. Conclusions: Our study demonstrated the therapeutic potential of hEND-CD3/BiTE and provided a novel approach to clinical cancer treatment.

Development of efficient therapeutic strategy to incorporate ultrasound (US)-triggered sonodynamic therapy (SDT) and ferroptosis is highly promising in cancer therapy. However, the SDT efficacy is severely limited by the hypoxia and high glutathione (GSH) in the tumor microenvironment, and ferroptosis is highly associated with reactive oxygen species (ROS) and GSH depletion. Methods: A manganese porphyrin-based metal-organic framework (Mn-MOF) was constructed as a nanosensitizer to self-supply oxygen (O2) and decrease GSH for enhanced SDT and ferroptosis. In vitro and in vivo analysis, including characterization, O2 generation, GSH depletion, ROS generation, lipid peroxidation, antitumor efficacy and tumor immune microenvironment were systematically evaluated. Results: Mn-MOF exhibited catalase-like and GSH decreasing activity in vitro. After efficient internalization into cancer cells, Mn-MOF persistently catalyzed tumor-overexpressed H2O2 to in-situ produce O2 to relieve tumor hypoxia and decrease GSH and GPX4, which facilitated the formation of ROS and ferroptosis to kill cancer cells upon US irradiation in hypoxic tumors. Thus, strong anticancer and anti-metastatic activity was found in H22 and 4T1 tumor-bearing mice after a single administration of Mn-MOF upon a single US irradiation. In addition, Mn-MOF showed strong antitumor immunity and improved immunosuppressive microenvironment upon US irradiation by increasing the numbers of activated CD8+ T cells and matured dendritic cells and decreaing the numbers of myeloid-derived suppressor cells in tumor tissues. Conclusions: Mn-MOF holds great potential for hypoxic cancer therapy.

Extracellular vesicles (EVs), a heterogeneous population of membrane vesicles, are secreted by almost all living cells and contain different proteins, lipids and nucleic acid depending on their sources. Recently, numerous reports indicated EVs could interact with diverse cells in tumor microenvironment and influence both physiological and pathological conditions. Given that EVs regulate tumor immune microenvironment, EVs-based strategies are explored for anti-tumor immunotherapy. In this review, about nine kinds of EVs derived from diverse cells are indicated. The biological functions in tumor immunity, strategies for anti-tumor immunotherapy and further clinical trials of these EVs will be introduced in detail.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, but its regulatory mechanism remains unclear and potential clinical biomarkers are still lacking. Co-regulation of TFs and miRNAs in HCC and FFL module studies may help to identify more precise and critical driver modules in HCC development. Here, we performed a comprehensive gene expression and regulation analysis for HCC in vitro and in vivo. Transcription factor and miRNA co-regulatory networks for differentially expressed genes between tumors and adjacent tissues revealed the critical feed-forward loop (FFL) regulatory module miR-9-5p/FOXO1/CPEB3 in HCC. Gain- and loss-of-function studies demonstrated that miR-9-5p promotes HCC tumor proliferation, while FOXO1 and CPEB3 inhibit hepatocarcinoma growth. Furthermore, by luciferase reporter assay and ChIP-Seq data, CPEB3 was for the first time identified as a direct downstream target of FOXO1, negatively regulated by miR-9-5p. The miR-9-5p/FOXO1/CPEB3 FFL was associated with poor prognosis, and promoted cell growth and tumor progression of HCC in vitro and in vivo. Our study identified for the first time the existence of miR-9-5p/FOXO1/CPEB3 FFL and revealed its regulatory role in HCC progression, which may represent a new potential target for cancer therapy.

Background Necroptosis is a new form of programmed cell death that is associated with cancer initiation, progression, immunity, and chemoresistance. However, the roles of necroptosis-related genes (NRGs) in colorectal cancer (CRC) have not been explored comprehensively. Methods In this study, we obtained NRGs and performed consensus molecular subtyping by “ConsensusClusterPlus” to determine necroptosis-related subtypes in CRC bulk transcriptomic data. The ssGSEA and CIBERSORT algorithms were used to evaluate the relative infiltration levels of different cell types in the tumor microenvironment (TME). Single-cell transcriptomic analysis was performed to confirm classification related to NRGs. NRG_score was developed to predict patients’ survival outcomes with low-throughput validation in a patients’ cohort from Fudan University Shanghai Cancer Center. Results We identified three distinct necroptosis-related classifications (NRCs) with discrepant clinical outcomes and biological functions. Characterization of TME revealed that there were two stable necroptosis-related phenotypes in CRC: a phenotype characterized by few TME cells infiltration but with EMT/TGF-pathways activation, and another phenotype recognized as immune-excluded. NRG_score for predicting survival outcomes was established and its predictive capability was verified. In addition, we found NRCs and NRG_score could be used for patient or drug selection when considering immunotherapy and chemotherapy. Conclusions Based on comprehensive analysis, we revealed the potential roles of NRGs in the TME, and their correlations with clinicopathological parameters and patients’ prognosis in CRC. These findings could enhance our understanding of the biological functions of necroptosis, which thus may aid in prognosis prediction, drug selection, and therapeutics development.

Insufficient tumor accumulation and distribution of photosensitizers as well as low antitumor immunity severely restrict the therapeutic efficacy of photothermal therapy (PTT). Cancer-associated fibroblasts (CAFs) play a key role in tumor extracellular matrix (ECM) remodeling and immune evasion. Reshaping tumor microenvironment via CAF regulation might provide a potential approach for complete tumor elimination in combination with PTT. Here, tumor cell-derived microparticles co-delivering calcipotriol and Indocyanine green (Cal/ICG@MPs) are developed to modulate CAFs for improved PTT efficacy. Cal/ICG@MPs efficiently target tumor tissues and regulate CAFs to reduce tumor ECM, resulting in enhanced tumor accumulation and penetration of ICG to generate strong PTT efficacy and activate CD8+ T cell-mediated antitumor immunity. In addition, Cal/ICG@MPs-triggered CAF regulation enhances tumor infiltration of CD8+ T cells and ameliorates CAF-induced antigen-mediated activation-induced cell death of tumor-specific CD8+ T cells in response to PTT, eliciting long-term antitumor immune memory to inhibit tumor recurrence and metastasis. Our results support Cal/ICG@MPs as a promising drug to improve PTT efficacy in cancer treatment.

Although immunotherapy harnessing activity of the immune system against tumors has made great progress, the treatment efficacy remains limited in most cancers. Current anticancer immunotherapy is primarily based on T-cell-mediated cellular immunity, which highly relies on efficiency of triggering the cancer-immunity cycle, namely, tumor antigen release, antigen presentation by antigen presenting cells, T cell activation, recruitment and infiltration of T cells into tumors, and recognition and killing of tumor cells by T cells. Unfortunately, these immunotherapies are restricted by inefficient drug delivery and acting on only a single step of the cancer-immunity cycle. Due to high biocompatibility, low immunogenicity, intrinsic cell targeting, and easy chemical and genetic manipulation, extracellular vesicle (EV)-based drug delivery systems are widely used to amplify anticancer immune responses by serving as an integrated platform for multiple drugs or therapeutic strategies to synergistically activate several steps of cancer-immunity cycle. This review summarizes various mechanisms related to affecting cancer-immunity cycle disorders. Meanwhile, preparation and application of EV-based drug delivery systems in modulating cancer-immunity cycle are introduced, especially in the improvement of T cell recruitment and infiltration into tumors. Finally, opportunities and challenges of EV-based drug delivery systems in translational clinical applications are briefly discussed.

Immune checkpointty inhibitors (ICIs), particularly those targeting programmed death 1 (PD-1) and anti-programmed death ligand 1 (PD-L1), enhance the antitumor effect by restoring the function of the inhibited effector T cells and produce durable responses in a large variety of metastatic and late patients with non-small-cell lung cancer. Although often well tolerated, the activation of the immune system results in side effects known as immune-related adverse events (irAEs), which can affect multiple organ systems, including the lungs. The occurrence of severe pulmonary irAEs, especially checkpoint inhibitor pneumonitis (CIP), is rare but has extremely high mortality and often overlaps with the respiratory symptoms and imaging of primary tumors. The development of CIP may be accompanied by radiation pneumonia and infectious pneumonia, leading to the simultaneous occurrence of a mixture of several types of inflammation in the lungs. However, there is a lack of authoritative diagnosis, grading criteria and clarified mechanisms of CIP. In this article, we review the incidence and median time to onset of CIP in patients with non-small-cell lung cancer treated with PD-1/PD-L1 blockade in clinical studies. We also summarize the clinical features, potential mechanisms, management and predictive biomarkers of CIP caused by PD-1/PD-L1 blockade in non-small-cell lung cancer treatment.

Prospero-related homeobox 1 (PROX1) is a homeobox transcription factor known to promote malignant transformation and stemness in human colorectal cancer (CRC). However, the biological function of PROX1 in metabolic rearrangement in CRC remains unclear. Here, we aimed to uncover the relationship between the expression profile and role of PROX1 and CRC cell glucose metabolism and to elucidate the underlying molecular mechanism. PROX1 expression was significantly upregulated in human CRC tissues and positively associated with the maximum standardized uptake value (SUVmax), a measure of tissue 18-fluoro-2-deoxy-D-glucose uptake and an indicator of glycolysis and tumor cell activity, in patients with CRC. Knockdown of PROX1 suppressed CRC cell proliferation and glucose metabolism

Prostate cancer (PCa) is a malignancy with the highest morbidity rate in 105 countries worldwide and was a major cause of cancer‑associated death in men in 2018. Accumulating evidence suggests that microRNAs (miRNAs/miRs) have important functions in the carcinogenesis of PCa, and may provide novel treatment targets. Previous studies have indicated that miR‑16‑5p is associated with PCa. However, the relevance and importance of miR‑16‑5p in PCa carcinogenesis are still not completely understood. In the current study, we aimed to investigate the role and mechanism of miR‑16‑5p in PCa carcinogenesis. The results showed that miR‑16‑5p was markedly downregulated in PCa cells, and MTS assay, colony formation, flow cytometric analyses demonstrated that miR‑16‑5p inhibited PCa cell survival, regulated cell cycle distribution and induced apoptosis. Moreover, luciferase reporter assay and western blot analysis showed that miR‑16‑5p directly targets AKT3 (AKT serine/threonine kinase 3), which is associated with PCa carcinogenesis, and the effects of the downregulation of AKT3 were similar to the effects of upregulation of miR‑16‑5p in PC‑3 cells. In conclusion, our data clarify that miR‑16‑5p has anticancer functions in PCa cells, and our findings provide experimental evidence to highlight the potential value of miR‑targeting treatment strategies for PCa.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target mRNAs at the post-transcriptional level. Increasing evidence shows the involvement of miRNAs in diverse biological processes. miR-302/367 cluster is highly conserved among vertebrates and made up of five members, including miR-367, miR-302a, miR-302b, miR-302c and miR-302d. miR-302/367 cluster plays an important role in cell proliferation, differentiation and reprogramming, affecting the development of tumor, cardiovascular system, nervous system and immune system. In this review, we will summarize the role of miR-302/367 cluster in embryonic stem cells and induced pluripotent stem cells and try to point out its relationship with tumors, cardiovascular system, nervous system and immune system.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with no current effective therapeutics. One of the main reasons for the low efficacy of PDAC immunotherapy is the limited CD8+ T cell infiltration, without neo antigen present in PDAC. Aptamers represent single-stranded oligonucleotides which bind to specific targets with high specificity. We developed DNA conjugates and prepared diacyl phospholipid-aptamer XQ-2d which has potential for the targeted therapy and diagnosis of PDAC. In this study, flow cytometry and fluorescence microscopy were employed to assess whether the Lipo-XQ-2d probe could anchor on activated T cells to constitute ligands specifically recognizing PDAC PL45 cells. Flow cytometry was employed to determine cytotoxicity in activated T cells. Results showed that the Lipo-XQ-2d probe could be inserted into T cells, and was specifically bound to both T cells and PL45 cells. In addition, the Lipo-XQ-2d probe redirected T cells to kill PL45 cells in vitro and was not toxic to cells. In conclusion, lipid-DNA-aptamer-modified T-lymphocytes might effectively kill PDAC in vitro, supporting the clinical application of T cell adoptive immunotherapy.

Purpose: To explore the performance of ultrasound biomicroscopy (UBM) and color Doppler flow imaging (CDFI) in the diagnosis of primary lacrimal canaliculitis.Methods: Subjects with relevant sympto...

Tropifexor (LJN452) is a potent, orally available, non–bile acid farnesoid X receptor agonist under clinical development for chronic liver diseases. Here, we present results from a first‐in‐human study of tropifexor following single‐ and multiple‐ascending doses (SAD/MAD) and food effect substudy in healthy volunteers. The SAD study included 6 fasted cohorts receiving 10‐ to 3000‐µg tropifexor or placebo and 1 cohort receiving 300‐µg tropifexor with a high‐fat meal. The MAD study included 4 lean cohorts receiving 10 to 100 µg and 1 obese cohort receiving 30‐µg once‐daily doses or placebo for 14 days. Pharmacodynamic assessment of fibroblast growth factor 19 and fasting plasma lipids was performed after dosing. Overall, 95 volunteers received at least 1 tropifexor or placebo dose. Tropifexor was well tolerated up to 3000 µg and 100 µg in the SAD and MAD studies, respectively; however, 2 subjects discontinued the MAD study due to asymptomatic elevation of liver transaminases. At single doses, tropifexor showed a moderate rate of absorption (median time to maximum concentration, 4 hours), dose‐proportional increases in exposure, and elimination half‐life of 13.5 to 21.9 hours. When taken with food, tropifexor exposure increased by ∼60%. With multiple dosing, steady state was reached on day 4 with

Background: Diabetes mellitus exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury. Methods: Adult male mice were fed a normal or a high-fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid-challenged nondiabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection. Results: Intramyocardial injection of diabetic serum sEV in the nondiabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or high glucose/high lipid-challenged nondiabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in nondiabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. A mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and high glucose/high lipid-challenged nondiabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and nondiabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in nondiabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced proapoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from patients with type 2 diabetes mellitus. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor. Conclusions: We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple antiapoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.

High-throughput messenger RNA (mRNA) analysis has become a powerful tool for exploring tumor recurrence or metastasis mechanisms. Here, we constructed a signature to predict the recurrence risk of Stages II and III gastric cancer (GC) patients. A least absolute shrinkage and selection operator method Cox regression model was utilized to construct the signature. Using this method, a 16-mRNA signature was identified to be associated with the relapse-free survival of Stages II and III GCs in training dataset GSE62254 (n = 194). Then this signature was validated in an independent Gene Expression Omnibus cohort GSE26253 (n = 297) and a dataset of The Cancer Genome Atlas (TCGA; n = 235). This classifier could successfully screen out the high-risk Stages II and III GCs in the training cohort (hazard ratio [HR] = 40.91; 95% confidence interval [CI] = 5.58-299.7; p < .0001). Analysis in two independent validation cohorts yielded consistent results (GSE26253: HR = 1.69, 95% CI = 1.17-2.43,; p = .0045; TCGA: HR = 2.01, 95% CI = 1.13-3.56, p = .0146). Cox regression analyses revealed that the risk score derived from this signature was an independent risk factor in Stages II and III GCs. Besides, a nomogram was constructed to serve clinical practice. Through gene set variation analysis, we found several gene sets associated with chemotherapeutic drug resistance and tumor metastasis significantly enriched in high-risk patients. In summary, this 16-mRNA signature can be used as a powerful tool for prognostic evaluation and help clinicians identify high-risk patients.

Umbilical cord mesenchymal stem cells (UCMSCs) have been proposed as an ideal source for cell-based therapy to promote endometrial repair and regeneration. Furthermore, increasing evidence has indicated that UCMSC-derived exosomes (UCMSC-exos) act as important paracrine mediators to recapitulate the features of MSCs and may play a vital role in this process. UCMSCs and human endometrial stromal cells (ESCs) were isolated and characterized. ESCs were cocultured with UCMSCs and further assessed by flow cytometry and EdU incorporation assays. UCMSC-exos were extracted by differential ultracentrifugation and identified by western blots, transmission electron microscopy, and nanoparticle tracking analysis. The internalization of UCMSC-exos by ESCs was observed under a confocal microscope. ESCs were treated with UCMSC-exos at different concentrations and for different durations, with cell viability evaluated by CCK-8 assays. The cell cycle analysis showed that the percentage of ESCs in S phase significantly increased after coculture with UCMSCs, whereas it significantly decreased after inhibition of UCMSC-exo secretions. EdU incorporation assays also showed a similar trend. The isolated UCMSC-exos had a typical cup-shaped morphology with a monolayer membrane, expressed the specific exosomal markers Alix, CD63, and TSG101 and were approximately 60 to 200 nm in diameter. The PKH26-labeled UCMSC-exos were incorporated into ESCs. Moreover, UCMSC-exos enhanced the cell growth and viability of ESCs in a dose-dependent manner, and the effects occurred in a short period of time. UCMSC-exos promote the proliferation of ESCs in a dose-dependent manner; thus, they could be used as a potential treatment to promote endometrial repair.

The interior of eukaryotic cells is mysterious. How do the large communities of macromolecular machines interact with each other? How do the structures and positions of these nanoscopic entities respond to new stimuli? Questions like these can now be answered with the help of a method called electron cryotomography (cryo-ET). Cryo-ET will ultimately reveal the inner workings of a cell at the protein, secondary structure, and perhaps even side-chain levels. Combined with genetic or pharmacological perturbation, cryo-ET will allow us to answer previously unimaginable questions, such as how structure, biochemistry, and forces are related in situ. Because it bridges structural biology and cell biology, cryo-ET is indispensable for structural cell biology-the study of the 3-D macromolecular structure of cells. Here we discuss some of the key ideas, strategies, auxiliary techniques, and innovations that an aspiring structural cell biologist will consider when planning to ask bold questions.

Over the past few decades, people with epilepsy were advised not to engage in sports based on the fear that sporting activity may cause injuries, potentially induce seizures, and have a negative effect on disease course. However, in recent years, numerous studies have indicated a positive role of physical exercise in reducing the frequency of seizures and improving health condition of patients with epilepsy. The purpose of this study was to compare the effects of different physical exercise programs on the symptomatology and health condition of individuals with epilepsy and provide guidance for selecting the optimal modality of physical exercise for patients with epilepsy via a meta-analysis of available literature.A literature search was carried out in MEDLINE via PubMed, Cochrane Library, EBSCO, Embase, China National Knowledge (CNKI), and Wan fang databases to gather relevant data about different physical exercise modalities and epilepsy. We will use Endnote X9 software for studies selection and Stata16.0 software for the data analysis.This present study aimed to provide the most up to date evidence and recommendations for clinicians and epilepsy patients to choose an optimal type of exercise.Aerobic exercise and resistance exercises both had a positive effect on epilepsy patients. Persons with epilepsy should be encouraged to participate in sports activities.INPLASY registration number: INPLASY202220070.

Extracellular vesicles (EVs), including microparticles and exosomes, have emerged as potential tools for tumor targeting delivery during the past years. Recently, mass of strategies are applied to assist EVs to accumulate and penetrate into deep tumor sites. In this review, EVs from different cells with unique innate characters and engineered approaches (e.g. chemical engineering, genetical engineering and biomimetic engineering) as drug delivery systems to enhance tumor accumulation and penetration are summarized. Meanwhile, efficient biological function modulation (e.g. extracellular matrix degradation, mechanical property regulation and transcytosis) is introduced to facilitate tumor accumulation and penetration of EVs. Finally, the prospects and challenges on further clinical applications of EVs are discussed.

Hypertensive renal injury (HRI) is a main cause of end-stage renal diseases, and CD4

An analytical method for the detection of glucose in human exhaled breath by non-invasive condensation collection coupled with ion chromatography was developed. A self-designed exhaled breath condensation device was constructed, through which human exhaled breath was condensed and collected. And the glucose in collected human exhaled breath condensate (EBC) was analyzed by ion chromatography with a pulsed amperometric instrument. The standard EBC collection method was established, and the key factors such as cooling temperature and sampling flow rate during condensation collection were investigated deeply, and a good linear correlation between blood glucose levels and exhaled breath glucose levels was obtained. The intra-day precision was 3.37%, and the inter-day precision was 3.83%. Furthermore, EBC from healthy people and diabetic patients was collected in fasting state and after meal. We found the breath glucose level in healthy volunteers was 0.11-2.34 ng/L and that in diabetic patients was 0.23-135.92 ng/L. In after meal samples, the breath glucose level is 10-100 times higher than that of healthy subjects, which offering the prospect of a non-invasive approach to the monitoring of diabetes.

Objective. Cultures have essential influences on emotions. However, most studies on cultural influences on emotions are in the areas of psychology and neuroscience, while the existing affective models are mostly built with data from the same culture. In this paper, we identify the similarities and differences among Chinese, German, and French individuals in emotion recognition with electroencephalogram (EEG) and eye movements from an affective computing perspective. Approach. Three experimental settings were designed: intraculture subject dependent, intraculture subject independent, and cross-culture subject independent. EEG and eye movements are acquired simultaneously from Chinese, German, and French subjects while watching positive, neutral, and negative movie clips. The affective models for Chinese, German, and French subjects are constructed by using machine learning algorithms. A systematic analysis is performed from four aspects: affective model performance, neural patterns, complementary information from different modalities, and cross-cultural emotion recognition. Main results. From emotion recognition accuracies, we find that EEG and eye movements can adapt to Chinese, German, and French cultural diversities and that a cultural in-group advantage phenomenon does exist in emotion recognition with EEG. From the topomaps of EEG, we find that the γ and β bands exhibit decreasing activities for Chinese, while for German and French, θ and α bands exhibit increasing activities. From confusion matrices and attentional weights, we find that EEG and eye movements have complementary characteristics. From a cross-cultural emotion recognition perspective, we observe that German and French people share more similarities in topographical patterns and attentional weight distributions than Chinese people while the data from Chinese are a good fit for test data but not suitable for training data for the other two cultures. Significance. Our experimental results provide concrete evidence of the in-group advantage phenomenon, cultural influences on emotion recognition, and different neural patterns among Chinese, German, and French individuals.

Gastric cancer (GC) is the second cause of cancer-related death and metastasis is an important cause of death. Considering difficulties in searching for metastatic driver mutations, we tried a novel strategy here. We conducted an integrative genomic analysis on GC and identified early drivers lead to metastasis. Whole-exome sequencing (WES), transcriptomes sequencing and targeted-exome sequencing (TES) were performed on tumors and matched normal tissues from 432 Chinese GC patients, especially the comparative analysis between higher metastatic-potential (HMP) group with T1 stage and lymph-node metastasis, and lower metastatic-potential (LMP) group without lymph-nodes or distant metastasis. HMP group presented higher mutation load and heterogeneity, enrichment in immunosuppressive signaling, more immune cell infiltration than LMP group. An integrated mRNA-lncRNA signature based on differentially expressed genes was constructed and its prognostic value was better than traditional TNM stage. We identified 176 candidate prometastatic mutations by WES and selected 8 genes for following TES. Mutated TP53 and MADCAM1 were significantly associated with poor metastasis-free survival. We further demonstrated that mutated MADCAM1 could not only directly promote cancer cells migration, but also could trigger tumor metastasis by establishing immunosuppressive microenvironment, including promoting PD-L1-mediated immune escape and reprogramming tumor-associated macrophages by regulating CCL2 through Akt/mTOR axis. In conclusion, GCs with different metastatic-potential are distinguishable at the genetic level and we revealed a number of potential metastatic driver mutations. Driver mutations in early-onset metastatic GC could promote metastasis by establishing an immunosuppressive microenvironment. This study provided possibility for future target therapy of GC.

Background Resistance to oxaliplatin is a major obstacle for the management of locally advanced and metastatic colon cancer (CC). Although long noncoding RNAs (lncRNAs) play key roles in CC, the relationships between lncRNAs and resistance to oxaliplatin have been poorly understood yet. Methods Chemo-sensitive and chemo-resistant organoids were established from colon cancer tissues of the oxaliplatin-sensitive or -resistant patients. Analysis of the patient cohort indicated that lnc-RP11-536 K7.3 had a potential oncogenic role in CC. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of lnc-RP11-536 K7.3 on CC proliferation, glycolysis, and angiogenesis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between lnc-RP11-536 K7.3, SOX2 and their downstream target HIF-1α. Results In this study, we identified a novel lncRNA, lnc-RP11-536 K7.3, was associated with resistance to oxaliplatin and predicted a poor survival. Knockout of lnc-RP11-536 K7.3 inhibited the proliferation, glycolysis, and angiogenesis, whereas enhanced chemosensitivity in chemo-resistant organoids and CC cells both in vitro and in vivo. Furthermore, we found that lnc-RP11-536 K7.3 recruited SOX2 to transcriptionally activate USP7 mRNA expression. The accumulative USP7 resulted in deubiquitylation and stabilization of HIF-1α, thereby facilitating resistance to oxaliplatin. Conclusion In conclusion, our findings indicated that lnc-RP11-536 K7.3 could promote proliferation, glycolysis, angiogenesis, and chemo-resistance in CC by SOX2/USP7/HIF-1α signaling axis. This revealed a new insight into how lncRNA could regulate chemosensitivity and provide a potential therapeutic target for reversing resistance to oxaliplatin in the management of CC.

The conventional procedure of anterior orbital exenteration is unfavorable for eye socket reconstruction, whereas a modified procedure enables socket reconstruction and prosthesis fitting. Our study aims to compare the cosmetic outcomes between these 2 surgical techniques. We retrospectively recruited patients treated with modified or conventional exenteration during January 2015 to May 2021 in our hospital. The conventional approach was performed along with dermis-fat graft transplantation. The modified approach was conducted followed by eye socket reconstruction and eyelid blepharoplasty. The clinical data were collected and analyzed, including demographics, tumor characteristics, postoperative complications, tumor-related events, and cosmetic outcomes. Forty-nine patients were consecutively recruited in this study, including 22 cases of modified exenteration and 27 cases of conventional exenteration. Forty-four subjects (89.8%) were diagnosed with ocular surface malignancies (conjunctival melanoma and squamous cell carcinoma) and 5 subjects (10.2%) were diagnosed with extraocular stage of uveal melanoma. After follow-up for 31.8 ± 17.1 months, the 1-, 2-, 5-year overall survival rate was calculated as 100%, 79.2%, and 59.2% in the Modified group, and 94.2%, 73.8%, and 51.5% in the Conventional group. Comparison of the survival curves showed no significant differences. In the Modified group, all patients received orbital implant placement and eye socket reconstruction. The implant motility was satisfactory in 12 cases (54.5%) with movements in 3 to 4 directions. The eyelid function was acceptable in 17 cases (77.3%) with no entropion, ectropion or lower lid laxity. Ocular prosthesis was delivered in 17 cases (77.3%) with successful fitting in 11 cases (64.7%). The self-rated cosmetic score was statistically (t test, P

The rational disposal of waste preserved wood is of great significance since its embedded metals (Cu, As, and Cr) pose potential threat to environment and human health. In this study, a biochar catalyst derived from waste preserved wood (PWB) was prepared for the degradation of bisphenol A (BPA) via peroxymonosulfate (PMS) activation. The PWB exhibited prominent catalytic degradation capability towards BPA compared with common wood derived biochar (CWB). Further tests and analysis elucidated that both radical species (OH) and non-radical species (

The monotherapy of mTOR inhibitors (mTORi) in cancer clinical practice has achieved limited success due to the concomitant activation of compensatory pathways, such as Akt signaling and cytoprotective autophagy. Thus, the combination of mTORi and the inhibitors of these pro-survival pathways has been considered a promising therapeutic strategy. Herein, we report the synergistic effects of a natural anti-cancer agent Jolkinolide B (JB) and mTORi (temsirolimus, rapamycin, and everolimus) for the effective treatment of bladder cancer. A mechanistic study revealed that JB induced a dual inhibition of Akt feedback activation and cytoprotective autophagy, potentiating the anti-proliferative efficacy of mTORi in both PTEN-deficient and cisplatin-resistant bladder cancer cells. Meanwhile, mTORi augmented the pro-apoptotic and pro-paraptotic effects of JB by reinforcing JB-activated endoplasmic reticulum stress and MAPK pathways. These synergistic mechanisms are related to cellular reactive oxygen species accumulation. Our study suggests that dual inhibition of Akt feedback activation and cytoprotective autophagy is an effective strategy in mTORi-based therapy, and JB + mTORi combination associated with multiple anti-cancer mechanisms and good tolerance in mouse models may serve as a promising treatment for bladder cancer.

Background The surveillance of vector mosquitoes is essential for prevention and control of mosquito-borne diseases. In this study, we developed an internet-based vector mosquito monitor, MS-300, and evaluated its efficiency for the capture of the important vector mosquitoes, Aedes albopictus and Culex quinquefasciatus, in laboratory and field trials. Methodology/Principal findings The linear sizes of adult Ae. albopictus and Cx. quinquefasciatus were measured and an infrared window was designed based on these data. A device to specifically attract these two species and automatically transmit the number of captured mosquitoes to the internet was developed. The efficiency of the device in capturing the two species was tested in laboratory, semi-field and open field trials. The efficiency results for MS-300 for catching and identifying Ae. albopictus in laboratory mosquito-net cages were 98.5% and 99.3%, and 95.8% and 98.6%, respectively, for Cx. quinquefasciatus. In a wire-gauze screened house in semi-field trials, the efficiencies of MS-300 baited with a lure in catching Ae. albopictus and Cx. quinquefasciatus were 54.2% and 51.3%, respectively, which were significantly higher than 4% and 4.2% without the lure. The real-time monitoring data revealed two daily activity peaks for Ae. albopictus (8:00–10:00 and 17:00–19:00), and one peak for Cx. quinquefasciatus (20:00–24:00). During a 98-day surveillance trial in the field, totals of 1,118 Ae. albopictus and 2,302 Cx. quinquefasciatus were captured by MS-300. There is a close correlation between the number of captured mosquitoes and the temperature in the field, and a positive correlation in the species composition of the captured samples among the mosquitoes using MS-300, BioGents Sentinel traps and human landing catches. Conclusions/Significance The data support the conclusion that MS-300 can specifically and efficiently capture Ae. albopictus and Cx. quinquefasciatus, and monitor their density automatically in real-time. Therefore, MS-300 has potential for use as a surveillance tool for prevention and control of vector mosquitoes.