Pseudomonas ZY-1 and Bacillus FY-1 protecting the rice seedlings from the harm of Pseudomonas aeruginosa via indirect seawead lysis.

The local ecosystems, fishery and human health are all threatened by water blooms, so effectively controlling water blooms has become an urgent and challenging issue. Biological control of water blooms is given priority due to its low cost, high efficiency and environmental friendliness. In this study, Pseudomonas ZY-1 and Bacillus FY-1, two highly-effective algicidal bacteria strains which are able to indirectly lyse algae by separating and screening from the vigorous water body in the paddy alga of Northeast China were obtained. The two bacterial strains have stronger ability to lyse alga in the bacterial liquid concentration of 106 CFU/ml, and the alga-lysing rate on 7 d reached 84.03% and 83.11% respectively. The active substance secreted by ZY-1 is not sensitive to the changes of temperature and pH value, while as FY-1 cell-free filtrate is not stable in high temperature above 50 ℃ and pH of 5, it requires the sun light to have the algaecidal effect. The cell-free filtrates of strains ZY-1 and FY-1 had the best lysis effect on Microcystis aeruginosa cells, and the chlorophyll a content of algae decreased to 0.13 ± 0.02 mg/L and 0.14 ± 0.03 mg/L respectively and the Fv/Fm of Microcystis aeruginosa decreased by 97.22% after 7 days. The algaecidal process of ZY-1 and FY-1 may be that the cell-free filtrate inhibits the photosynthesis of Microcystis aeruginosa, and meanwhile it avoids the regeneration and repair of photosynthesis of algal cells by affecting the gene expression and damaging the repair system of algal cells, so the membrane lipid peroxidation is exacerbated and then the membrane of algal cells is broken, the algal cells can't do normal life activities, and finally the algal cell would be killed. The rice seedlings in the algal liquid treatment group are short and show root dysplasia, few roots and brown roots. After treated with cell-free filtrate of ZY-1 and FY-1, the oxidative damage of the rice is obviously reduced, and the harm from Microcystis aeruginosa is reduced, which has the repair effect to the roots of rice seedlings and its aboveground growth. The cell-free filtrate of FY-1 works better than ZY-1. The bacteria strains of ZY-1 and FY-1 have the indirect algaecide trait, which makes them the potential environmentally-friendly algaecidal bacteria and they show broad application in the agricultural production and the control of water blooms.

Comparison of SOX and CAPOX in patients with advanced gastric cancer after laparoscopic D2 gastrectomy: A randomized controlled trial.

BACKGROUND: Optimal adjuvant chemotherapy after laparoscopic surgery in gastric cancer (GC) patients is still undefined. We aimed to evaluate the efficacy of S-1 plus oxaliplatin (SOX) and capecitabine plus oxaliplatin (CAPOX) in patients with GC after laparoscopic gastrectomy. METHODS: A non-inferiority randomized controlled clinical trial was performed in China. Patients with advanced GC who underwent laparoscopic D2 gastrectomy were randomly assigned to receive SOX and CAPOX regimens. RESULTS: In total, 191 patients were screened between May 2018 and June 2019, and 140 (73.3%) were included in the modified intent-to-treat analysis (mITT), of whom 69 and 71 were assigned to the SOX and CAPOX groups, respectively. The SOX group had similar 3-year overall survival (OS) and disease-free survival to the CAPOX group. Subgroup analysis revealed significantly better OS in the SOX group for male patients ([HR] = 0.395; 95% [CI], 0.153-1.019; p = 0.045), age >60 (HR = 0.219; 95% [CI], 0.064-0.753; p = 0.016), tumors in the gastric antrum (HR = 0.273; 95% [CI], 0.076-0.981; p = 0.047), and moderately differentiated tumors (HR = 0.338; 95% [CI], 0.110-1.041; p = 0.041). There were no significant differences observed in terms of adverse events and recurrence patterns between the two groups. CONCLUSION: Adjuvant SOX was non-inferior to CAPOX treatments for patients with GC who underwent curative laparoscopic D2 gastrectomy. For male patients, aged >60 years, tumors in the gastric antrum, and moderately differentiated tumors, adjuvant SOX may achieve an improvement compared with CAPOX.

Gender difference in the pharmacokinetics and metabolism of VX-548 in rats.

VX-548 is a sodium channel blocker, which acts as an analgesic. This study aims to investigate the gender differences in the pharmacokinetics and metabolism of VX-548 in rats. After intravenous administration, the area under the curve (AUC0-t) of VX-548 was much higher in female rats (1505.8 ± 47.3 ng·h/mL) than in male rats (253.8 ± 6.3 ng·h/mL), and the clearance in female rats (12.5 ± 0.8 mL/min/kg) was much lower than in male rats (65.1 ± 1.7 mL/min/kg). After oral administration, the AUC0-t in female rats was about 50-fold higher than that in male rats. The oral bioavailability in male rats was 11% while it was 96% in female rats. An in vitro metabolism study revealed that the metabolism of VX-548 in female rat liver microsomes was much slower than in male rats. Further metabolite identification suggested that the significant gender difference in pharmacokinetics was attributed to demethylation. The female rat liver microsomes showed a limited ability to convert VX-548 into desmethyl VX-548. Phenotyping experiments indicated that the formation of desmethyl VX-548 was mainly catalyzed by CYP3A2 and CYP2C11 using rat recombinant CYPs. Overall, we revealed that the pharmacokinetics and metabolism of VX-548 in male and female rats showed significant gender differences.

High-fat diet promotes prostate cancer metastasis via RPS27.

BACKGROUND: Metastasis is the leading cause of death among prostate cancer (PCa) patients. Obesity is associated with both PCa-specific and all-cause mortality. High-fat diet (HFD) is a risk factor contributing to obesity. However, the association of HFD with PCa metastasis and its underlying mechanisms are unclear. METHODS: Tumor xenografts were conducted by intrasplenic injections. The ability of migration or invasion was detected by transwell assay. The expression levels of RPS27 were detected by QRT-PCR and western blot. RESULTS: The present study verified the increase in PCa metastasis caused by HFD in mice. Bioinformatics analysis demonstrated increased RPS27 in the experimentally induced PCa in HFD mice, indicating that it is an unfavorable prognostic factor. Intrasplenic injections were used to demonstrate that RPS27 overexpression promotes, while RPS27 knockdown significantly reduces, PCa liver metastasis. Moreover, RPS27 inhibition suppresses the effects of HFD on PCa metastasis. Further mRNA sequencing analysis revealed that RPS27 promotes PCa metastasis by selectively enhancing the expression of various genes. CONCLUSION: Our findings indicate that HFD increases the risk of PCa metastasis by elevating RPS27 expression and, subsequently, the expression of genes involved in PRAD progression. Therefore, RPS27 may serve as a novel target for the diagnosis and treatment of metastatic PCa.

Association between inflammatory bowel disease and frailty: a two-sample Mendelian randomization study.

BACKGROUND: An association has been identified between inflammatory bowel disease (IBD) and frailty; however, the causal nature of this connection remains uncertain. We consequently conducted a two-sample Mendelian randomization (MR) analysis to explore this particular association. METHODS: We acquired distinct datasets for inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), and frailty from the published genome-wide association studies (GWAS) database, meticulously selecting instrumental variables (IVs). Subsequently, we employed a bidirection MR to examine the causal relationship between IBD (including CD and UC) and frailty. We utilized statistical methods, with a primary emphasis on inverse-variance weighted (IVW), accompanied by a series of sensitivity analyses to confirm heterogeneity and pleiotropy influenced the outcomes of the MR. RESULTS: We found positive causal effects of genetically increased frailty risk on IBD (OR: 1.015, 95% CI 1.005-1.025, P = 0.004). Furthermore, when scrutinizing specific IBD subtypes, both Crohn's disease (CD) and ulcerative colitis (UC) demonstrated an increased predisposition to frailty (OR: 1.018, 95% CI 1.01-1.027, P < 0.05) and (OR = 1.016, 95% CI 1.005-1.027, P < 0.05). Nevertheless, despite the consistent trends observed in the weighted median and MR-Egger regression analyses for both conditions, statistical significance remained elusive. Notably, the results of the inverse MR analysis did not establish an association between frailty and an elevated risk of IBD development. CONCLUSIONS: Our research indicates that IBD, encompassing both CD and UC, may augment the propensity for frailty. Clinical practitioners must prioritize early frailty assessment in individuals afflicted with inflammatory bowel disease, inclusive of Crohn's disease and ulcerative colitis, facilitating proactive measures and timely interventions. However, our findings do not provide evidence supporting a causal effect of frailty on IBD (including CD and UC). Consequently, further studies are essential to explore the intricate mechanisms that clarify the effect of frailty on IBD.

Altered gray matter volume and functional connectivity in lung cancer patients with bone metastasis pain.

Bone metastasis pain (BMP) is a severe chronic pain condition. Our previous studies on BMP revealed functional brain abnormalities. However, the potential effect of BMP on brain structure and function, especially gray matter volume (GMV) and related functional networks, have not yet been clearly illustrated. Voxel-based morphometry and functional connectivity (FC) analysis methods were used to investigate GMV and intrinsic FC differences in 45 right-handed lung cancer patients with BMP(+), 37 lung cancer patients without BMP(-), and 45 healthy controls (HCs). Correlation analysis was performed thereafter with all clinical variables by Pearson correlation. Compared to HCs, BMP(+) group exhibited decreased GMV in medial frontal gyrus (MFG) and right middle temporal gyrus (MTG). Compared with BMP(-) group, BMP(+) group exhibited reduced GMV in cerebelum_6_L and left lingual gyrus. However, no regions with significant GMV differences were found between BMP(-) and HCs groups. Receiver operating characteristic analysis indicated the potential classification power of these aberrant regions. Correlation analysis revealed that GMV in the right MTG was positively associated with anxiety in BMP(+) group. Further FC analysis demonstrated enhanced interactions between MFG/right MTG and cerebellum in BMP(+) patients compared with HCs. These results showed that BMP was closely associated with cerebral alterations, which may induce the impairment of pain moderation circuit, deficits in cognitive function, dysfunction of emotional control, and sensorimotor processing. These findings may provide a fresh perspective and further neuroimaging evidence for the possible mechanisms of BMP. Furthermore, the role of the cerebellum in pain processing needs to be further investigated.

Genomic alterations related to HPV infection status in a cohort of Chinese prostate cancer patients.

BACKGROUND: Human papillomavirus (HPV) has been proposed as a potential pathogenetic organism involved in prostate cancer (PCa), but the association between HPV infection and relevant genomic changes in PCa is poorly understood. METHODS: To evaluate the relationship between HPV genotypes and genomic alterations in PCa, HPV capture sequencing of DNA isolated from 59 Han Chinese PCa patients was performed using an Illumina HiSeq2500. Additionally, whole-exome sequencing of DNA from these 59 PCa tissue samples and matched normal tissues was carried out using the BGI DNBSEQ platform. HPV infection status and genotyping were determined, and the genetic disparities between HPV-positive and HPV-negative PCa were evaluated. RESULTS: The presence of the high-risk HPV genome was identified in 16.9% of our cohort, and HPV16 was the most frequent genotype detected. The overall mutational burden in HPV-positive and HPV-negative PCa was similar, with an average of 2.68/Mb versus 2.58/Mb, respectively, in the targeted whole-exome region. HPV-negative tumors showed a mutational spectrum concordant with published PCa analyses with enrichment for mutations in SPOP, FOXA1, and MED12. HPV-positive tumors showed more mutations in KMT2C, KMT2D and ERCC2. Copy number alterations per sample were comparable between the two groups. However, the significantly amplified or deleted regions of the two groups only partially overlapped. We identified amplifications in oncogenes, including FCGR2B and CCND1, and deletions of tumor suppressors, such as CCNC and RB1, only in HPV-negative tumors. HPV-positive tumors showed unique deletions of tumor suppressors such as NTRK1 and JAK1. CONCLUSIONS: The genomic mutational landscape of PCa differs based on HPV infection status. This work adds evidence for the direct involvement of HPV in PCa etiology. Different genomic features render HPV-positive PCa a unique subpopulation that might benefit from virus-targeted therapy.

Prostate cancer cells synergistically defend against CD8+ T cells by secreting exosomal PD-L1.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) remains fatal and incurable, despite a variety of treatments that can delay disease progression and prolong life. Immune checkpoint therapy is a promising treatment. However, emerging evidence suggests that exosomal programmed necrosis ligand 1 (PD-L1) directly binds to PD-1 on the surface of T cells in the drain lineage lymph nodes or neutralizes administered PD-L1 antibodies, resulting in poor response to anti-PD-L1 therapy in mCRPC. MATERIALS AND METHODS: Western blotting and immunofluorescence were performed to compare PD-L1 levels in exosomes derived from different prostate cancer cells. PC3 cells were subcutaneously injected into nude mice, and then ELISA assay was used to detect human specific PD-L1 in exosomes purified from mouse serum. The function of CD8+ T cells was detected by T cell mediated tumor cell killing assay and FACS analysis. A subcutaneous xenograft model was established using mouse prostate cancer cell RM1, exosomes with or without PD-L1 were injected every 3 days, and then tumor size and weight were analyzed to evaluate the effect of exosomal PD-L1. RESULTS: Herein, we found that exosomal-PD-L1 was taken up by tumor cells expressing low levels of PD-L1, thereby protecting them from T-cell killing. Higher levels of PD-L1 were detected in exosomes derived from the highly malignant prostate cancer PC3 and DU145 cell lines. Moreover, exosomal PD-L1 was taken up by the PD-L1-low-expressing LNCaP cell line and inhibited the killing function of CD8-T cells on tumor cells. The growth rate of RM1-derived subcutaneous tumors was decreased after knockdown of PD-L1 in tumor cells, whereas the growth rate recovered following exosomal PD-L1 tail vein injection. Furthermore, in the serum of mice with PCa subcutaneous tumors, PD-L1 was mainly present on exosomes. CONCLUSION: In summary, tumor cells share PD-L1 synergistically against T cells through exosomes. Inhibition of exosome secretion or prevention of PD-L1 sorting into exosomes may improve the therapeutic response of prostate tumors to anti-PD-L1 therapy.

Self-training adversarial learning for cross-domain retinal OCT fluid segmentation.

Accurate measurements of the size, shape and volume of macular edema can provide important biomarkers to jointly assess disease progression and treatment outcome. Although many deep learning-based segmentation algorithms have achieved remarkable success in semantic segmentation, these methods have difficulty obtaining satisfactory segmentation results in retinal optical coherence tomography (OCT) fluid segmentation tasks due to low contrast, blurred boundaries, and varied distribution. Moreover, directly applying a well-trained model on one device to test the images from other devices may cause the performance degradation in the joint analysis of multi-domain OCT images. In this paper, we propose a self-training adversarial learning framework for unsupervised domain adaptation in retinal OCT fluid segmentation tasks. Specifically, we develop an image style transfer module and a fine-grained feature transfer module to reduce discrepancies in the appearance and high-level features of images from different devices. Importantly, we transfer the target images to the appearance of source images to ensure that no image information of the source domain for supervised training is lost. To capture specific features of the target domain, we design a self-training module based on a discrepancy and similarity strategy to select the images with better segmentation results from the target domain and then introduce them into the source domain for the iterative training segmentation model. Extensive experiments on two challenging datasets demonstrate the effectiveness of our proposed method. In Particular, our proposed method achieves comparable results on cross-domain retinal OCT fluid segmentation compared with the state-of-the-art methods.

Iron-doped cross-linked lipoic acid nano-aggregates for ferroptosis-mediated cancer treatment.

Recently, Fenton reaction-mediated ferroptosis has attracted great attention in cancer treatment while the metabolism loss of iron and the limited endogenous H2O2 level imped its clinical application. Here, a new ferroptosis inducer (Fe@cLANAs) constructed only by Fe(II) and (R)-(+)-lipoic acid (LA) was developed for tumor ablation. After entering the tumor cells, the Fe@cLANAs dissociated into disdihydrolipoic acid (DHLA) and released iron, which would regenerate each other to continuously provide iron and H2O2 to enhance ferroptosis. The Fe@cLANAs demonstrated the IC50Fe below 10 µM against various tumor cells, an anti-tumor effect comparable to many chemotherapy drugs. In vivo antitumor evaluation based on the tumor cell-derived xenograft model showed a tumor inhibitory rate (TIR) of 97.4% at the iron usage of 1.53 mg/kg, the lowest iron usage reported so far in ferrotherapy using iron as the main agent to treat tumors. Notably, the good anti-tumor effect of Fe@cLANAs was further achieved in the glioma patient-derived xenograft (PDX) model. This strategy utilizing the reciprocal circulation of metal iron and LA to delay the metabolism loss of iron and increase the H2O2 level in the tumor cells holds a great potential for ferroptosis-mediated cancer treatment. STATEMENT OF SIGNIFICANCE: The metabolism loss of iron and the limited endogenous H2O2 level are key factors to impede the clinical application of ferroptosis-mediated cancer treatment. Herein, a new ferroptosis inducer constructed only by lipoic acid and iron is developed to delay the metabolism loss of iron and increase the level of endogenous H2O2 by causing a cyclic regeneration of Fe(II)/Fe(III) and LA/DHLA in the tumor cells. According to the previous reports, at least 75 mg/kg of iron dosage was needed to achieve effective antitumor efficacy, here, the use of only 1.53 mg/kg iron in Fe@cLANAs achieved the TIR of 97.4% and 62.8% in the U251 CDX and glioma PDX models, showing the good prospect of Fe@cLANAs in clinic.

Dietary Antioxidant-Constructed Nanodrugs Can High-Efficiently Kill Cancer Cells while Protecting Noncancer Cells.

Despite great advances, the development of cancer drugs that can efficiently kill cancer cells while protecting noncancer cells has not been achieved. By using only dietary antioxidants vitamin C (VC) and (R)-(+)-lipoic acid (LA), we herein develop a nanodrug VC@cLAV featuring the above function. After entering cells, cLAV dissociates into LA and DHLA (dihydrolipoic acid, reduced form of LA) and releases VC and DHA (dehydroascorbate, oxidized form of VC). In cancer cells, the two redox pairs recycle each other and dramatically promote the intracellular reactive oxygen species production to kill cancer cells at low doses comparable to cytotoxic drugs. Oppositely in noncancer cells, the LA/DHLA and VC/DHA pairs exert anti-oxidant action to actively protect the organism by preventing the normal cells from oxidative stress and repairing cells suffering from oxidative stress. When compared with the first-line cytotoxic drug, VC@cLAV displayed superior therapeutic outcomes yet without side effects in diverse tumor models including patient-derived xenograft (PDX). This drug with efficient cancer cell killing and noncancer cell protection represents a new cancer therapy.

Early Assessment of Atherosclerotic Lesions and Vulnerable Plaques in vivo by Targeting Apoptotic Macrophages with AV Nanobubbles.

Background: The early detection of atherosclerotic lesions is particularly important for risk prediction of acute cardiovascular events. Macrophages apoptosis was significantly associated with the degree of AS lesions and especially contributed to plaque vulnerability. In this research, we mainly sought to explore the feasibility of a home-made AV-nanobubbles (NBAV) for visualization of apoptotic macrophages and assessment of atherosclerosis (AS) lesions by contrast-enhanced ultrasound (CEUS) imaging. Methods: NBAV were prepared by "Optimized Thin-Film Hydration" and "Biotin-Avidin-Biotin" methods. Then, the characterization and echogenicity of NBAV were measured and analyzed in vitro. The targeting ability of NBAV to ox-LDL-induced apoptotic macrophages was observed by laser scanning confocal microscope. The ApoE-/- mice mode fed with high fat diet were observed by high-frequency ultrasound, microanatomy and oil red O staining. CEUS imaging in vivo was performed on AS plaques with NBAV and NBCtrl injection through the tail vein in turn in ApoE-/- mice. After CEUS imaging, the plaques were confirmed and analyzed by histopathological and immunological assessment. Results: The prepared NBAV had a nano-scale size distribution with a low PDI and a negative zeta potential. Moreover, NBAV showed an excellent stability and exhibited a significantly echogenic signal than saline in vitro. In addition, we found that NBAV could target apoptotic macrophages induced by ox-LDL. Compared with NBCtrl, CEUS imaging of NBAV showed strong and sustained echo enhancement in plaque area of aortic arch in vivo. Further research showed that NBAV sensitive plaques presented more significant pathological changes with several vulnerable plaque features and abundant TUNEL-positive area. Conclusion: NBAV displayed a sensitive indicator to evaluate apoptotic macrophages, indicating a promising CEUS molecular probe for AS lesions and vulnerable plaques identification.

Common materials, extraordinary behavior: An ultrasensitive and enantioselective strategy for D-Tryptophan recognition based on electrochemical Au@p-L-cysteine chiral interface.

The poly-L-cysteine modified Au nanoparticles (Au@p-L-Cys) were constructed on electrode surface as a highly efficient chiral interface for tryptophan (Trp) enantiomers recognition via one step electropolymerization. With the aid of Cu2+, L-Cys residues and D-Trp target formed a sandwich complex D-Trp-Cu2+-L-Cys, while L-Trp was unable to form such complex due to the steric hindrance provided by the chiral interface, which was confirmed by the electrochemical and SEM results. With the introduction of ferricyanide probe, D-Trp produced significant current decrease while L-Trp produced a slight current increase, which implied the successful enantioselective recognition of Trp enantiomers (specifically D-Trp) in the true sense. This novel sensor showed a surprisingly wide linear range toward D-Trp of 6 × 10-7 M to 1 × 10-2 M, with a detection limit as low as 75 nM (S/N = 3). Moreover, the exclusive enantioselectivity toward D-Trp was discovered since other amino acids showed negligible interference to detection of D-Trp. The recovery of D-Trp in human serum was between 91.30 and 109.3%, which further verified the satisfying specificity and practicality of the proposed strategy. The coordination thermodynamics by UV-Vis spectroscopy and DFT simulation were also used to investigate the enantioselective mechanism. These results highlight the great potential of using Au@p-L-Cys to construct chiral interface for enantiomers recognition and hold the promise of practical application of electrochemical chiral sensors in fields like pharmaceutics and bioanalysis.

The value of urinary gonadotropins in the diagnosis of central precocious puberty: a meta-analysis.

BACKGROUND: The gonadotropin-releasing hormone (GnRH) stimulation test is time-consuming, invasive, and costly. However, it is the diagnostic gold standard for central precocious puberty (CPP), which in girls is defined as the onset of secondary sexual characteristics before the age of 8 years accompanied by breast buds, accelerated growth, and advanced bone age. This meta-analysis was performed to compare the diagnostic value of urinary gonadotropins and the GnRH stimulation test for CPP. METHODS: We searched six databases for relevant literature. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we estimated the sensitivity, specificity, area under the summary receiver operating characteristic curve (AUC), and publication bias. RESULTS: Six eligible trials fulfilled the inclusion criteria. In the meta-analysis of urinary luteinizing hormone (ULH), after excluding the data of one study, we obtained an AUC of 0.90 (sensitivity = 0.81, specificity = 0.85). The meta-analysis of the ULH to urinary follicle-stimulating hormone (UFSH) ratio revealed an AUC of 0.8116 (sensitivity = 0.79, specificity = 0.84). CONCLUSION: Both the ULH level and ULH:UFSH ratio are effective and available approaches for CPP diagnosis. TRIAL REGISTRATION: INPLASY 2021120076 .

TNF-α inhibitor tanfanercept (HBM9036) improves signs and symptoms of dry eye in a phase 2 trial in the controlled adverse environment in China.

PURPOSE: This study evaluated the clinical safety and efficacy of tanfanercept (HBM9036) ophthalmic solution as a novel treatment for dry eye disease (DED) in a controlled adverse environment (CAE) study conducted in China. METHODS: In a single-center, double-masked, randomized, placebo-controlled study, 100 patients received 0.25% tanfanercept, or placebo, twice daily for eight weeks. A mobile international CAE® DE Model was used for patient selection with a standardized challenge endpoint. Primary efficacy endpoint was fluorescein inferior corneal staining score (ICSS) pre- to post-CAE challenge from baseline. Secondary endpoints included Schirmer's Tear Test, Tear-Film Break-Up Time, Ocular Discomfort Score, Ora Calibra® Ocular Discomfort and 4-Symptom Questionnaire, total corneal staining score (TCSS), and drop comfort. Signs and symptoms were assessed both pre- and post-CAE to evaluate the efficacy of tanfanercept on both environmental and CAE endpoints. RESULTS: The tanfanercept treatment group showed improvement in ICSS pre- to post-CAE change from baseline scores when compared to placebo (- 0.61 ± 0.11 and - 0.54 ± 0.11, respectively; mean difference = 0.07, p = 0.65). TCSS pre-post-CAE change from baseline scores was also in favor of active when compared to placebo (- 1.03 ± 0.21 and - 0.67 ± 0.21, respectively; mean difference = 0.37, p = 0.23). Schirmer's score improvement was demonstrated in favor of active (1.87 ± 0.62 mm) as compared to placebo (1.28 ± 0.62 mm; mean difference = 0.59 mm, p = 0.50). Change from baseline in mean Tear-Film Break-up Time favored active treatment over placebo (mean difference = 1.21 s, p = 0.45). Notably, the tanfanercept showed more obvious benefits for each DED sign in a subgroup of subjects ≥ 35 years of age. Tanfanercept was well tolerated with no serious adverse events occurring during the study. CONCLUSION: Tanfanercept demonstrated improvements in favor of active as compared to placebo in the signs of DED, being safe and well tolerated. These data support further evaluation of tanfanercept for the treatment of DED in China. TRIAL REGISTRATION: This study was retrospectively registered at ClinicalTrials.gov (NCT04092907) on September 17, 2019.

Quaternary Ammonium Salts Anchored on Cross-Linked (R)-(+)-Lipoic Acid Nanoparticles for Drug-Resistant Tumor Therapy.

A membrane-lytic mechanism-based nanodrug is developed for drug-resistant tumor therapy by anchoring the small-molecule quaternary ammonium salt (QAS) on cross-linked (R)-(+)-lipoic acid nanoparticles (cLANs). The anchoring of QAS on the nanoparticle avoids the direct attack of long alkyl chains to the cell membrane under physiological conditions, while after entering tumor cells, the QAS is released from the dissociated cLANs, migrates to the phospholipid bilayer via electrostatic interaction, and destroys the cell membrane by the puncture of long alkyl chains. Since the QAS is designed to finally be hydrolyzed to amino acid betaine and food additive cetanol and the cLANs degrade to dihydrolipoic acid (DHLA, reduced form of dietary antioxidant lipoic acid in cells), the QAS@cLANs hold superior biosafety. In addition to the drug-resistant tumors, the QAS@cLANs demonstrate significant inhibition of metastatic tumors. This work provides not only a general and clinic-promising treatment for the refractory tumors but also opens a door for the medicinal use of QAS.

Epidemiological and Clinical Characteristics of Sporadic Creutzfeldt-Jakob Disease: A Retrospective Study in Eastern China.

Objective: We aimed to characterize the epidemiological and clinical characteristics of sporadic Creutzfeldt-Jakob disease (sCJD) in eastern China in this retrospective study. Methods: This study enrolled 67 patients with sCJD hospitalized in a grade-A tertiary hospital in eastern China from January 2010 to January 2020. Demographic data, clinical symptoms, brain magnetic resonance imaging (MRI), electroencephalogram (EEG), cerebrospinal fluid (CSF) 14-3-3 protein test, polymerase chain reaction (PCR), and DNA sequence determination of genes were collected and analyzed. Results: There were 62 patients with probable sCJD and 5 patients with possible sCJD. Male (28 cases) to female (39 cases) ratio was 1:1.39. Mean age at disease onset was 64.42 ± 9.00 years (range: 29-88 years), and mean survival time was 9.39 ± 12.58 months (range: 1-60 months for patients who received the follow-ups). The most common onset symptoms were dementia (49.25%), movement disorder (44.78%), and visual disturbance (22.39%), while the most frequent clinical manifestations were language disorders (74.63%), ataxia (70.15%), and myoclonus (70.15%). The positive rates of brain MRI abnormalities, 14-3-3 protein in CSF, and periodic sharp wave complexes (PSWCs) on EEG were 84.90, 68.00, and 46.03%, respectively. The 14-3-3 protein positive (p = 0.033) and PSWCs on EEG (p = 0.020) acted as the favorable and unfavorable factor for over 1 year of survival time, respectively. Conclusions: There were some differences in epidemiological and clinical characteristics among patients in China and those of other countries. The prognosis and its influencing factors were relatively unexplored in China. The mean survival time of Chinese patients was longer than that of Caucasian patients but shorter than that of Japanese patients. The 14-3-3 protein in CSF and PSWCs on EEG were both closely related to the survival time. It is necessary to promote autopsy or biopsy to better understand sCJD in China.

Human Papillomavirus Prevalence and Integration Status in Tissue Samples of Bladder Cancer in the Chinese Population.

BACKGROUND: Human papillomavirus (HPV) infection is associated with multiple types of cancer, but the evidence has not yet been fully elucidated in bladder cancer. METHODS: Frozen tissue samples collected from 146 patients aged 32 to 89 years with bladder cancer pathological diagnosis between 2015 and 2019 were analyzed. HPV genotyping and integration status determination were performed by capture-based next generation sequencing. Statistical analysis of HPV type distributions was performed according to stage, grade, sex, and age group of patients. RESULTS: Mean (SD) age of the 146 patients was 66.64 ±â€…10.06 years and 83.56% were men. Overall HPV infection rate was 28.77% (37.50% in women and 27.05% in men), with 11.90% HPV integration events. Among them, 17.12% single and 11.65% coinfections were observed. HPV18 (24.66%) was the most prevalent genotype, followed by HPV33, 16, and 39. All HPV were European lineage (A). HPV16 was more prevalent in women (P = .04). CONCLUSIONS: HPV infection may contribute to the etiology both in men and women with bladder cancer. HPV18, followed by HPV33, 16, and 39 genotypes, potentially represent the predominant oncogenic risk types for bladder carcinogenesis.

miR­183­5p attenuates cerebral ischemia injury by negatively regulating PTEN.

Cerebral ischemia is a common cerebrovascular disease caused by the occlusion of a cerebral blood vessel. MicroRNAs (miRNAs/miRs) are emerging regulators of various human diseases, including cerebral ischemia. Upregulation of miR­183­5p has been reported to alleviate liver injury induced by ischemia­reperfusion (I/R). However, the effect of miR­183­5p on cerebral ischemia injury remains unknown. The present study evaluated the effects of miR­183­5p on ischemia injury using ischemic models of mouse brains exposed to transient middle cerebral artery occlusion and Neuro­2A (N2A) neuroblastoma cells exposed to oxygen­glucose­deprivation (OGD) and subsequently reoxygenated. Ischemia was evaluated in mice using neurological function scores, cerebral edema, 2,3,5­triphenyltetrazoliumchloride, Nissl and Fluoro­Jade B staining assays. In addition, miR­183­5p expression, N2A cell viability and the expression levels of apoptosis­associated proteins were detected by quantitative PCR, Cell Counting Kit­8 assay, flow cytometry and western blotting. The association between miR­183­5p and phosphatase and tensin homolog (PTEN) was also confirmed by a luciferase reporter assay. The results revealed that miR­183­5p expression was decreased and brain damage was increased in ischemic mice compared with the sham group. Additionally, miR­183­5p levels were reduced, and apoptosis was increased in N2A cells exposed to ischemia compared with the control group. Following transfection with agomiR­183­5p, cerebral ischemic injury and apoptosis levels were reduced in the in vivo I/R stroke model and OGD­induced N2A cells. In addition, PTEN was determined to be a target of miR­183­5p following elucidation of a direct binding site. Overexpression of PTEN reversed the miR­183­5p­induced N2A cell apoptosis inhibition and survival after OGD. The results of the present study suggested that miR­183­5p reduced ischemic injury by negatively regulating PTEN, which may aid the development of a novel therapeutic strategy for cerebral ischemia.