A Novel Dual-Fc Bispecific Antibody with Enhanced Fc Effector Function.

Bispecific antibodies (BsAbs) are undergoing continued development for applications in oncology and autoimmune diseases. While increasing activity by having more than one targeting arm, most BsAb engineering employs single Fc engagement as monoclonal antibodies. Here, we designed a novel immunoglobulin gamma-1 (IgG1)-derived dual-Fc BsAb containing two Fc regions and two distinct asymmetric antigen binding arms comprising a Fab arm and another VHH domain. In conjunction with the knob-into-hole technology, dual-Fc BsAbs could be produced with a high yield and good stability. We explore how Fc engineering effects on dual-Fc constructs could boost the desired therapeutic efficacy. This new format enabled simultaneous bispecific binding to corresponding antigens. Furthermore, compared to the one-Fc control molecules, dual-Fc BsAbs were shown to increase the avidity-based binding to FcγRs to result in higher ADCC and ADCP activities by potent avidity via binding to two antigens and Fc receptors. Overall, this novel BsAb format with enhanced effector functionalities provides a new option for antibody-based immunotherapy.

Vagococcus fluvialis isolation from the urine of a bladder cancer patient: a case report.

Vagococcus fluvialis infection is rare in humans, and there is limited research on the clinical manifestations and antimicrobial susceptibility testing of Vagococcus fluvialis infection. Here, We isolated Vagococcus fluvialis from the urine samples of bladder cancer patients at Hunan Provincial People's Hospital, and it is the first reported case of Vagococcus fluvialis isolated from the urine. The fully automated microbial identification system and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) identified the bacterium as Vagococcus fluvialis with a confidence level of 99.9%. The VITEK-2Compact fully automated microbial susceptibility analysis system indicated that it was most sensitive to tigecycline, vancomycin, quinupristin/dalfopristin, linezolid, and showed moderate sensitivity to erythromycin, levofloxacin, ciprofloxacin, ampicillin/sulbactam, and tetracycline. Additionally, it exhibited synergy when combined with high-level gentamicin and vancomycin, showing sensitivity. However, it displayed poor activity against penicillin and furanth. According to our knowledge, this is the first study to isolate and identify Vagococcus fluvialis from the urine of bladder cancer patients and the systematically reviewed other reported Vagococcus infections on human, which provide an experimental basis for guiding the rational use of drugs in the clinical treatment and diagnose of Vagococcus fluvialis infection and related pathogenic mechanism research. Meanwhile, we have systematically reviewed other reported.

miR-373 promotes invasion and metastasis of colorectal cancer cells via activating ERK/MAPK pathway.

To explore the relationship between miR-373 and the occurrence and development of colorectal cancer. Additionally, it aims to predict the potential cellular signaling pathways and regulatory mechanisms in which miR-373 may be involved and provides a theoretical basis and experimental evidence for the clinical application of miR-373 as a potential biomarker, molecular target, and prognostic indicator in colorectal cancer. Real-time quantitative PCR is used to analyze the expression of miR-373 in human colorectal cancer cell lines and normal human colonic epithelial cells. Further validation of the differential expression of miR-373 in colorectal cancer cell lines is being performed. Biological functions such as cell proliferation, invasion and apoptosis are being detected by MTT, CCK-8, transwell, cell cycle analysis, and flow cytometry experiments to verify the changes in the biological behavior of colon cancer cells after overexpression and interference of miR-373 in SW-480 cells and to explore the effects of miR-373 on cell proliferation, invasion, and apoptosis in colon cancer cells. Proteomic analysis is being conducted on proteins extracted from miR-373 overexpressing SW480 cells, and mass spectrometry is used for protein identification. GO, KEGG, and enrichment analysis are being employed to analyze the significantly differentially expressed proteins. The expression levels of pathway-related proteins are being verified using Western blot. Overexpression of miR-373 increased the invasive and metastatic ability of SW-480 cells; knockdown of miR-373 decreased the invasive and metastatic ability of SW-480 cells. However, there was no statistically significant effect on cell proliferation and apoptosis in SW-480 cells. Proteomic analysis identified 78 differentially expressed proteins based on fold change (FC) > 1.2 and P < 0.05. Annotation of differentially changed proteins revealed that the MAPK signaling pathway, PI3K-Akt signaling pathway, and FAK signaling pathway may play crucial roles in the migration and invasion of colorectal cancer. Western blot analysis showed that overexpression of miR-373 significantly increased the levels of p-ERK1/2 in SW480 cells. miR-373 may activate the ERK/MAPK signaling pathway to promote the invasion and migration of colorectal cancer cells.

Association of Oral or Intravenous Vitamin C Supplementation with Mortality: A Systematic Review and Meta-Analysis.

Mortality is the most clinically serious outcome, and its prevention remains a constant struggle. This study was to assess whether intravenous or oral vitamin C (Vit-C) therapy is related to reduced mortality in adults. Data from Medline, Embase, and the Cochrane Central Register databases were acquired from their inception to 26 October 2022. All randomized controlled trials (RCTs) involving intravenous or oral Vit-C against a placebo or no therapy for mortality were selected. The primary outcome was all-cause mortality. Secondary outcomes were sepsis, COVID-19, cardiac surgery, noncardiac surgery, cancer, and other mortalities. Forty-four trials with 26540 participants were selected. Although a substantial statistical difference was observed in all-cause mortality between the control and the Vit-C-supplemented groups (p = 0.009, RR 0.87, 95% CI 0.78 to 0.97, I2 = 36%), the result was not validated by sequential trial analysis. In the subgroup analysis, mortality was markedly reduced in Vit-C trials with the sepsis patients (p = 0.005, RR 0.74, 95% CI 0.59 to 0.91, I2 = 47%), and this result was confirmed by trial sequential analysis. In addition, a substantial statistical difference was revealed in COVID-19 patient mortality between the Vit-C monotherapy and the control groups (p = 0.03, RR 0.84, 95% CI 0.72 to 0.98, I2 = 0%). However, the trial sequential analysis suggested the need for more trials to confirm its efficacy. Overall, Vit-C monotherapy does decrease the risk of death by sepsis by 26%. To confirm Vit-C is associated with reduced COVID-19 mortality, additional clinical random control trials are required.

Role of posttranslational modifications in memory and cognitive impairments caused by neonatal sevoflurane exposure.

With the advancement of technology, increasingly many newborns are receiving general anesthesia at a young age for surgery, other interventions, or clinical assessment. Anesthetics cause neurotoxicity and apoptosis of nerve cells, leading to memory and cognitive impairments. The most frequently used anesthetic in infants is sevoflurane; however, it has the potential to be neurotoxic. A single, short bout of sevoflurane exposure has little impact on cognitive function, but prolonged or recurrent exposure to general anesthetics can impair memory and cognitive function. However, the mechanisms underlying this association remain unknown. Posttranslational modifications (PTMs), which can be described roughly as the regulation of gene expression, protein activity, and protein function, have sparked enormous interest in neuroscience. Posttranslational modifications are a critical mechanism mediating anesthesia-induced long-term modifications in gene transcription and protein functional deficits in memory and cognition in children, according to a growing body of studies in recent years. Based on these recent findings, our paper reviews the effects of sevoflurane on memory loss and cognitive impairment, discusses how posttranslational modifications mechanisms can contribute to sevoflurane-induced neurotoxicity, and provides new insights into the prevention of sevoflurane-induced memory and cognitive impairments.

Altered Brain Activity in Strabismic Amblyopic Children as Determined by Regional Homogeneity: A Resting-State Functional Magnetic Resonance Imaging Study.

Objective: Earlier research has determined that amblyopia or strabismus may cause remarkable brain anatomical and functional variations. Nonetheless, thus far, the spontaneous changes in brain activity in children with strabismus amblyopia (SA) remain unclear. The purpose of this study was to determine the association between abnormal brain activity in children with SA and its behavioral manifestations. Patients and Methods: ?A total of 24 children with SA (10 male and 14 female children) as well as 24 healthy controls (HCs), including 10 male and 14 female children were closely matched in sex and age, and examined using resting-state functional magnetic resonance imaging (fMRI). The regional homogeneity (ReHo) technique was applied to evaluate spontaneous cerebral activity variations in children with SA and HCs. Moreover, associations between altered ReHo values in distinct cerebral areas and the degree of strabismus were assessed using Pearson correlation analysis. Results: Remarkably increased ReHo values were observed in the right lingual, right superior frontal medial, bilateral superior parietal, and right inferior parietal gyri of children with SA compared with HCs. In contrast, mean ReHo values in children with SA were lower in the right cerebellum, left superior frontal gyrus, and left putamen nucleus. Furthermore, esotropia showed a positive correlation with ReHo values of the left putamen. Conclusion: The anomalous spontaneous activity changes in several brain areas that are caused by SA may indicate neuropathologic mechanisms of visual deficits and oculomotor disorders in children with SA.

Interhemispheric Functional Connectivity Alterations in Diabetic Optic Neuropathy: A Resting-State Functional Magnetic Resonance Imaging Study.

PURPOSE: Previous research suggests that diabetic optic neuropathy (DON) can cause marked anatomical and functional variations in the brain, but to date altered functional synchronization between two functional hemispheres remains uncharacterized in DON patients. Voxel mirrored homotopic connectivity (VMHC) is a voxel-based method to evaluate the synchronism between two mirrored hemispheric by determining the functional connectivity between each voxel in one hemisphere and its counterpart. In this study, we aim to assess abnormal changes in interhemispheric functional connectivity in DON patients via the VMHC method. METHODS: The study included 28 adult DON patients (12 male, 16 female) and 28 healthy controls (12 male, 16 female) who were closely matched for sex and age. Participants were examined using resting-state functional magnetic resonance imaging. The VMHC method was applied to investigate the abnormal state in bilateral hemispheres in DON patients and the same regions in healthy controls, as well as the receiver operating characteristic (ROC) curves were used to evaluate characteristics. Associations between altered VMHC values in distinct cerebral regions and clinical features were assessed via correlational analysis. RESULTS: Markedly lower VMHC values were evident in the right temporal inferior, the left temporal inferior, the right mid-cingulum, the left mid-cingulum, the right supplementary motor region, and the left supplementary motor region in DON patients compared with healthy controls. ROC curve analysis suggested that the application of VMHC is reliable for the diagnosis of DON. CONCLUSION: Anomalous interhemispheric functional connectivity in specific brain areas caused by DON may indicate neuropathologic mechanisms of vision loss and blurry vision in patients with DON.

Fractional amplitude of low-frequency fluctuation in patients with neovascular glaucoma: a resting-state functional magnetic resonance imaging study.

BACKGROUND: Neovascular glaucoma (NVG) is a secondary refractory disease with a poor prognosis, and there are few advanced studies on its pathogenesis and treatment. In this research, the fractional amplitude of low-frequency fluctuation (fALFF) technology was used in resting-state functional magnetic resonance imaging (rsfMRI) to investigate intrinsic neuron activity in the patient's brain with NVG. METHODS: Sixteen patients with NVG (eight males and eight females) and 16 healthy controls (HCs) of similar age and sex were included. All patients and controls received rsfMRI scans, and the differences between the two groups in fALFF values were compared by independent sample t-test. Receiver operating characteristic (ROC) curves were used to compare fALFF values in the brain regions of NVG patients and HCs and assess accuracy. Finally, Pearson linear correlation analysis assessed the correlation between fALFF signals in brain regions and the clinical evaluation indicators of patients with NVG. RESULTS: In patients with NVG, fALFF signal values in the right Rolandic operculum, left anterior cingulate and paracingulate gyri, and right caudate were significantly decreased. In contrast, fALFF signal values in the left precuneus were significantly higher than those recorded in the HCs. Analysis of the ROC curve for each brain region showed that the area under the ROC curve of NVG patients was large (close to 1), and the accuracy was good. In the NVG group, the hospital anxiety and depression scale (r=-0.952, P<0.001) and left best-corrected visual acuity (r=-0.802, P<0.001) had a negative linear correlation with the fALFF signal value of the right Rolandic operculum. The hospital anxiety and depression scale had a negative linear correlation with the fALFF signal value of the right caudate (r=-0.948, P<0.001). CONCLUSIONS: NVG patients showed dysfunction in several brain regions. These findings may assist in revealing the underlying neural mechanism of brain activity associated with NVG.

CYFRA21-1/TG ratio as an accurate risk factor to predict eye metastasis in nasopharyngeal carcinoma: A STROBE-compliant article.

Nasopharyngeal carcinoma (NPC) has a distinctive geographical distribution in China, especially southern China. There are several risk factors for NPC, such as Epstein-Barr virus, genetics, and environmental exposures. Although the incidence of eye metastasis (EM) is lower than metastasis in other body parts, it often indicates poor prognosis.We assessed several serum biomarkers for their ability to predict EM in NPC. Patients with NPC were selected (n = 963), and were separated into two groups, EM and no eye metastasis. Ten factors were analyzed in both groups including triglyceride (TG), high-density lipoprotein, low-density lipoprotein, alkaline phosphatase, alpha fetoprotein, carbohydrate antigen-199, cancer antigen-153, apolipoproteins AI, apolipoprotein B, and cytokeratin fragment 19 (CYFRA21-1). Independent t tests, binary logistic regression, and receiver operating characteristic curves were used to assess the data.The EM group had significantly higher CYFRA21-1 and lower TG compared with the no eye metastasis group. Areas under the curve for CYFRA21-1, TG and CYFRA21-1/TG were 0.966, 0.771, and 0.976, respectively. The corresponding cut-off values were 12.12 ng/ml, 0.41 mmol/L, and 13.5. The sensitivity and specificity of CYFRA21-1/TG were 100% and 92.2%, respectively.The increased ratio of CYFRA21-1 to TG can be an accurate method to detect EM in patients with NPC.

Prognostic Value and Clinicopathological Features of MicroRNA-206 in Various Cancers: A Meta-Analysis.

It has been reported that microRNA-206(miR-206) plays an important role in cancers and could be used as a prognostic biomarker. However, the results are controversial. Therefore, we summarize all available evidence and present a meta-analysis to estimate the prognostic value of miR-206 in various cancers. The relevant studies were collected by searching PubMed, EMBASE, and Web of Science databases until August 21, 2020. Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were applied to explore the association between miR-206 and survival results and clinicopathologic features. Sources of heterogeneity were investigated by subgroup analysis and sensitivity analysis. Publication bias was evaluated using Egger's test. Twenty articles involving 2095 patients were included in the meta-analysis. The pooled HR showed that low miR-206 expression was significantly associated with unfavourable overall survival (OS) (HR = 2.03, 95 CI%: 1.53-2.70, P < 0.01). In addition, we found that low miR-206 expression predicted significantly negative association with tumor stage (III-IV VS. I-II) (OR = 4.20, 95% CI: 2.17-8.13, P < 0.01), lymph node status (yes VS. no) (OR = 3.58, 95%: 1.51-8.44, P = 0.004), distant metastasis (yes VS. no) (OR = 3.19, 95%: 1.07-9.50, P = 0.038), and invasion depth (T3 + T4 vs. T2 + T1) (OR = 2.43, 95%: 1.70-3.49, P < 0.01). miR-206 can be used as an effective prognostic indicator in various cancers. Further investigations are warranted to validate the present results.