[Analysis of the safety, accuracy, and factors influencing bleeding complications in CT-guided puncture biopsy of brain occupying lesions].

Objective: To investigate the safety and accuracy of CT-guided intracranial puncture biopsy and the possible influencing factors of postoperative bleeding complications. Methods: A case series study. A retrospective analysis was conducted on 101 patients who underwent CT-guided intracranial puncture biopsy at the First Affiliated Hospital of Zhengzhou University from January 2017 to December 2021. The basic data of patients and the safety and accuracy of CT-guided intracranial puncture biopsy were analyzed statistically. Univariate and multivariate logistic regression analysis were used to screen the influencing factors of bleeding complications in CT-guided intracranial puncture biopsy, and the bleeding complications in glioma subgroup were analyzed. Results: Among the 101 patients, 53 were males and 48 were females, aged (53.7±17.2) years. The average diameter of intracranial lesions was (3.5±1.4) cm, while the vertical distance from the lesion to the meninges was (2.4±1.7) cm. The needle's intracranial depth reached (3.2±1.8) cm, with adjustments averaging (3±1) occurrences and an average procedural duration of (40.2±12.9) minutes. Pathological diagnoses included glioma (36 cases), gliosis (3 cases), lymphoma (32 cases), metastatic tumors (7 cases), inflammatory lesions (13 cases), and 10 indeterminate cases. The positive rate of puncture pathology was 90.1% (91/101), and the diagnostic coincidence rate was 94.0% (78/83). The incidence of bleeding complications in CT-guided intracranial puncture biopsy was 26.7% (27/101), of which 23 cases had small intratoma or needle path bleeding, 4 cases had massive bleeding, and 2 cases died. The patients were divided into bleeding group (n=27) and no bleeding group (n=74), according to the presence or absence of bleeding. The results of univariate logistic regression analysis showed that thrombin time≥15 s and the number of needle adjustment were the factors affecting the occurrence of bleeding complications (both P<0.05), and the results of multivariate logistic regression showed that thrombin time≥15 s was the related factor for bleeding. Patients with thrombin time≥15 s had a 3.045 times higher risk of bleeding than those with thrombin time<15 s (OR=3.045,95%CI:1.189-7.799,P=0.020). Among the 101 patients, 36 cases of midbrain glioma were divided into low-grade glioma group (n=11) and high-grade glioma group (n=25) according to the pathological grade. Subgroup analysis showed that the risk of bleeding for high-grade gliomas was 9.231 times higher than that for low-grade gliomas (OR=9.231,95%CI:1.023-83.331,P=0.031). Conclusions: CT-guided intracranial puncture biopsy is safe and feasible with high accuracy. Complication rates are associated with thrombin time≥15 s, especially high-grade glioma, which increases the risk of postoperative bleeding.

Extreme terahertz magnon multiplication induced by resonant magnetic pulse pairs.

Nonlinear interactions of spin-waves and their quanta, magnons, have emerged as prominent candidates for interference-based technology, ranging from quantum transduction to antiferromagnetic spintronics. Yet magnon multiplication in the terahertz (THz) spectral region represents a major challenge. Intense, resonant magnetic fields from THz pulse-pairs with controllable phases and amplitudes enable high order THz magnon multiplication, distinct from non-resonant nonlinearities such as the high harmonic generation by below-band gap electric fields. Here, we demonstrate exceptionally high-order THz nonlinear magnonics. It manifests as 7th-order spin-wave-mixing and 6th harmonic magnon generation in an antiferromagnetic orthoferrite. We use THz two-dimensional coherent spectroscopy to achieve high-sensitivity detection of nonlinear magnon interactions up to six-magnon quanta in strongly-driven many-magnon correlated states. The high-order magnon multiplication, supported by classical and quantum spin simulations, elucidates the significance of four-fold magnetic anisotropy and Dzyaloshinskii-Moriya symmetry breaking. Moreover, our results shed light on the potential quantum fluctuation properties inherent in nonlinear magnons.

[Analysis of symptoms and influencing factors of low back work-related musculoskeletal disorders among workers in a container manufacturing factory].

Objective: To investigate the occurrence of low back work-related musculoskeletal disorders (WMSDs) among workers in a container manufacturing factory, and to explore the influencing factors. Methods: In June 2022, 952 workers from a container factory were selected as the research objects by cluster random sampling. Through questionnaire survey, the incidence of low back WMSDs symptoms among workers in the past one year was collected, and the influencing factors of low back WMSDs were analyzed by logistic regression. Results: The incidence rate of low back WMSDs was 46.7% (445/952). The factors with higher exposure at work were frequent slight bending (77.0%, 733/952), frequent overtime (74.1%, 705/952), and the need to turn around while working (62.3%, 593/952). Multivariate logistic regression analysis showed that age over 40 years old, smoking, drinking, often bending over slightly, sitting for a long time, maintaining a large bending posture for a long time, often working overtime, limited operating space, and there was always a need to complete conflicting things in the container manufacturing factory workers were the risks of increasing the low back WMSDs (OR=1.68, 1.96, 2.47, 1.49, 1.84, 2.11, 1.90, 1.82, 2.00, P<0.05). Standing at work, always friendly colleagues, and always supportive and helpful leaders were protective factors for low back WMSDs (OR=0.60, 0.32, 0.40, P<0.05) . Conclusion: The incidence of low back WMSDs symptoms in container manufacturing workers is high, and work-related factors such as frequent slight bending, long time holding large bending posture and limited operating space are the focus of ergonomic intervention in container manufacturing enterprises.

[The characteristics and impact on prognosis of cytopenia after anti-BCMA-CAR-T therapy in patients with relapsed and refractory multiple myeloma].

Objective: To investigate the characteristics of cytopenia and its impact on prognosis in patients with relapsed and refractory multiple myeloma (RRMM) after B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR-T) immunotherapy therapy. Methods: Clinical data of 36 RRMM patients received BCMA CAR-T therapy at the First Affiliated Hospital of Nanjing Medical University from April 2017 to March 2023 were retrospectively collected. Among them, there were 17 males and 19 females, with an age [M (Q1, Q3)] of 62 (53, 67) years. The follow-up deadline was August 31, 2023, and the follow-up time [M (Q1, Q3)] was 33 (10, 30) months. The characteristics of cytopenia at different time points before lymphodepleting chemotherapy and after CAR-T cell infusion in all patients were analyzed. Kaplan-Meier method was used to compare the differences in progression-free survival (PFS) and overall survival (OS) in patients with different clinical characteristics. Single-cell sequencing analysis was used to analyze the changes in hematopoietic stem cells in three patients after CAR-T cell therapy. Results: The incidence of cytopenia after BCMA CAR-T cell therapy in 36 RRMM patients reached 100%. The incidence of neutropenia peaked on the 7th and 28th day after cell infusion with a biphasic pattern of change.Patients with all grade neutropenia reached 61.1% (22/36) and grade 3 or higher reached 33.3% (12/36) on the 7th day, while patients with all grade neutropenia reached 67.9% (19/28) and grade 3 or higher reached 28.6% (8/28) on the 28th day (P<0.001),respectively. The occurrence rate of lymphopenia reached a peak on the day of CAR-T cell infusion [97.2% (35/36) patients showed lymphopenia, while 80.6% (29/36) patients showed grade 3 or higher lymphopenia] (P<0.001).The incidence of all grade of thrombocytopenia and severe thrombocytopenia (grade 3 or higher) peaked on the 14th day after cell infusion, with the rates of 69.4% (25/36) and 30.6% (11/36) respectively, which had a prolonged duration(P<0.001). Even after 12 months, 40% (8/20) of patients still experienced thrombocytopenia.The incidence of anemia peaked on the 7th and 14th day after cell infusion, with a rate of 100% (36/36) (P<0.001). 50% (10/20) of patients still had anemia even 12 months after cell infusion. Kaplan-Meier survival analysis showed that patients with thrombocytopenia < grade 3 had undefined OS, while patients with thrombocytopenia ≥grade 3 had shorter OS [17 (95%CI: 2-32) months, χ2=4.154, P=0.042], indicating a poorer prognosis. However, there was no statistically significant difference in the relationship between other cytopenia and survival (all P>0.05). Single-cell sequencing analysis of bone marrow cells revealed decreased proliferation, increased apoptosis, and cell cycle arrest of hematopoietic stem cells after CAR-T cell infusion. Conclusions: All patients experienced varying degrees of cytopenia after receiving BCMA CAR-T cell infusion, and patients with thrombocytopenia ≥grade 3 had shorter OS and poorer prognosis.

[Radiological assessment of interstitial lung disease: what can lung ultrasound do?]

The use of lung ultrasound in the screening, diagnosis, and evaluation of interstitial lung disease has been relatively well studied, but has not been widely accepted and applied in clinical practice. There are also some differences in the examination methods applied in these studies. This paper summarized the application, advantages, and disadvantages of lung ultrasound in the diagnosis and follow-up of interstitial lung disease by comprehensively reviewing the examination methods, research results and progress of new technologies of lung ultrasound in interstitial lung disease.

Long-term prognostic value of thyroid hormones in left ventricular noncompaction.

PURPOSE: Thyroid function is closely related to the prognosis of cardiovascular diseases. This study aimed to explore the predictive value of thyroid hormones for adverse cardiovascular outcomes in left ventricular noncompaction (LVNC). METHODS: This longitudinal cohort study enrolled 388 consecutive LVNC patients with complete thyroid function profiles and comprehensive cardiovascular assessment. Potential predictors for adverse outcomes were thoroughly evaluated. RESULTS: Over a median follow-up of 5.22 years, primary outcome (the combination of cardiovascular mortality and heart transplantation) occurred in 98 (25.3%) patients. For secondary outcomes, 75 (19.3%) patients died and 130 (33.5%) patients experienced major adverse cardiovascular events (MACE). Multivariable Cox analysis identified that free triiodothyronine (FT3) was independently associated with both primary (HR 0.455, 95%CI 0.313-0.664) and secondary (HR 0.547, 95%CI 0.349-0.858; HR 0.663, 95%CI 0.475-0.925) outcomes. Restricted cubic spline analysis illustrated that the risk for adverse outcomes increased significantly with the decline of serum FT3. The LVNC cohort was further stratified according to tertiles of FT3 levels. Individuals with lower FT3 levels in the tertile 1 group suffered from severe cardiac dysfunction and remodeling, resulting in higher incidence of mortality and MACE (Log-rank P < 0.001). Subgroup analysis revealed that lower concentration of FT3 was linked to worse prognosis, particularly for patients with left atrial diameter ≥ 40 mm or left ventricular ejection fraction ≤ 35%. Adding FT3 to the pre-existing risk score for MACE in LVNC improved its predictive performance. CONCLUSION: Through the long-term investigation on a large LVNC cohort, we demonstrated that low FT3 level was an independent predictor for adverse cardiovascular outcomes.

[A pan-cancer analysis of TTC9A expression level and its correlation with prognosis and immune microenvironment].

OBJECTIVE: To investigate the expression level of tetratricopeptide repeat protein 9A in tumors and its association with the patients' prognosis and immune infiltration. METHODS: TTC9A expression in different tumor tissues and its association with prognosis, DNA methylation, tumor mutation burden (TMB), and microsatellite instability (MSI) were analyzed based on data from TCGA and GTEx. TIMER and xCell were used to analyze the relationship between TTC9A expression and immune infiltration. Western blotting and RT-qPCR were used to detect the expression of TTC9A in 4 types of cancer cell lines. RESULTS: TTC9A expressions were significantly increased in many tumors and down-regulated in a few cancer types (P < 0.05). Western blotting and RT-qPCR showed that TTC9A expressions were elevated in lung, colon and liver cancer cells but decreased in bladder cancer cells. In head and neck squamous cell carcinoma, renal clear cell carcinoma, renal papillary cell carcinoma, low-grade glioma, malignant mesothelioma, and endometrial carcinoma tumors, a high expression of TTC9A was strongly correlated with better overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) (P < 0.05), but was correlated with worse OS, DSS, and PFI in lung adenocarcinoma, pancreatic adenocarcinoma, adrenal carcinoma, and rectal adenocarcinoma (P < 0.05). TTC9A hypermethylation was associated with a more favorable prognosis of glioblastoma multiforme, low- grade glioma, uveal melanoma, and ovarian plasmacytoid cystadenocarcinoma (P < 0.05) but with poor prognosis of squamous cell carcinoma of the uterine cervix and intracervical adenocarcinoma, squamous cell carcinoma of head and neck, squamous cell carcinoma of the lungs, adrenal carcinoma, and endometrial carcinoma (P < 0.05). In most of the cancer types, TTC9A was significantly correlated with the level of immune cell infiltration (P < 0.05). CONCLUSION: TTC9A can be used as a prognostic marker for a variety of cancers and is strongly associated with TBM, MSI and immune cell infiltration.

[Pathogenic agents causing acute respiratory tract infections in pediatric patients in Spring, 2023, in Beijing].

Objective: To explore the pathogenic agents of acute respiratory infection (ARI) in children in Beijing. Methods: In the cross-sectional study, 3 groups of children from different departments were enrolled from Feb 6th, 2023 (6th week) to May 28th (21th week), 2023, including influenza-like case group from emergency department for nucleic acid testing of influenza virus (Flu) and human metapneumovirus (HMPV), the outpatient ARI group under nucleic acid testing for Flu, respiratory syncytial virus (RSV), adenovirus (ADV), and parainfluenza virus (PIV), and the inpatient ARI group under nucleic acid testing for Flu, RSV, HMPV, ADV, human bocavirus (HBoV), Rhinovirus (Rh), PIV, coronavirus (HCoV), Mycoplasma pneumoniae (Mp) and Chlamydia pneumonia (Cp). Results: There were 320 influenza-like cases enrolled, including 192 males and 128 females, aged 4.7 (3.6, 6.9) years, and 117 cases (36.6%) positive for Flu A, which contained similar proportion of pandemic H1N1 (H1N1) 47.0% (55/117) and H3N2 53.0% (62/117), and 13 cases for HMPV 4.1% (13/320). The rate of Flu reached its peak at the 10th week, with H1N1 as the predominant one from the 6th to 9th week (10.0%-50.0%) and then H3N2 from the 10th to 16th week (15.0%-90.0%). HMPV was detected from the 15th week 5.0% (1/20), and then reached to 30.0% (6/20) at the 20th week. In the outpatient ARI group, 7 573 were enrolled, including 4 131 males and 3 442 females, aged 4.0 (2.1, 5.3) years, and the highest positive rate for RSV 32.9% (2 491/7 573), followed by Flu A 12.1% (915/7 573). The dominant one was Flu A in weeks 6-14 (23.2%-74.7%), then RSV in the 15th week 24.8% (36/145). In the inpatient ARI group, 1 391 patients were enrolled, including 804 males and 587 females, aged 3.3 (0.4, 5.8) years, and the highest positive rate for Rh 18.7% (260/1 391), followed by RSV 12.4% (173/1 391), Flu A 10.2% (142/1 391, of which 116 cases (81.7%) were H1N1, and 26 cases (18.3%) were H3N2) and HMPV 3.1% (43/1 391). H1N1 was detected from the 7th week 10% (6/60), to peak in the 11th week 31.8% (21/66). H3N2 was detected from the 8th week 1.5% (1/68), and then kept in low level. The proportion of H1N1 among Flu was 81.7% (116/142) in the inpatient ARI group. RSV was detected from 12th week 1.3% (1/80), reaching 30.4% (35/115) at 19th week. The positive rate of HMPV reached 12.1% (14/116) at 21th week. Conclusions: In the spring of 2023, the first one in Beijing is the Flu epidemic, with H1N1 being the predominant one in the early stage and H3N2 in the later stage. Then, there is a postponed RSV epidemic and an increased HMPV detection. In addition, nucleic acid testing for outpatient children should be strengthened to provide early warning of epidemics.

Potential functions and causal associations of VPS29 in hepatocellular carcinoma: a bioinformatic and Mendelian randomization study.

OBJECTIVE: Vacuolar protein sorting-associated protein 29 (VPS29) plays a certain role in cancer, but its biological significance in hepatocellular carcinoma (HCC) has not been studied. We utilized bioinformatics and Mendelian randomization (MR) analysis to explore the potential function of the VPS29 gene in HCC, as well as the causal relationship between VPS29 protein and HCC. MATERIALS AND METHODS: We downloaded the raw data from TCGA, GEO, and IEU OpenGWAS databases. We used R software for data processing and analysis to explore the relationship between the VPS29 gene and the expression, prognosis, clinical features, methylation, immune microenvironment, tumor mutation burden, and drug sensitivity in HCC patients. Additionally, a two-sample Mendelian randomization analysis was conducted to investigate the causal relationship between the VPS29 protein and HCC. RESULTS: VPS29 was found to be overexpressed in various types of cancer, including HCC, and its elevated expression often predicts poor prognosis in HCC patients. Univariate and multivariate Cox analysis demonstrated that VPS29 was an independent prognostic factor in HCC patients. The ROC curve indicated that VPS29 has a high diagnostic value in HCC. There were differential expressions of VPS29 in various clinical feature subgroups. The expression of VPS29 was negatively correlated with methylation levels, and multiple methylation sites were identified in the promoter region, including cg20877181, cg03867797, cg10025392, cg21605021, which were associated with poorer overall survival (OS) at low methylation levels. VPS29 was associated with immune cell infiltration disorders, including CD8+ T cells, Eosinophils, Neutrophils, Tcm, NK CD56bright cells, TFH, Th2 cells, Th17 cells, etc. Drug sensitivity analysis showed that VPS29 could be indicative of treatment response to 10 common antineoplastic drugs in different expression subgroups. Inverse variance weighted (IVW) analysis revealed a significant increase in HCC risk associated with VPS29 [odds ratio (OR): 1.440; 95% confidence interval (CI): 1.195-1.736], and sensitivity analysis showed no heterogeneity or pleiotropy. CONCLUSIONS: VPS29 is a risk factor for the occurrence and progression of HCC and may serve as a molecular biomarker for the diagnosis and prognosis of HCC.

[Analysis of suspected occupational diseases cases and subsequent diagnosis follow-up investigation in Hubei Province from 2020 to 2021].

Objective: To understand the epidemiological characteristics of suspected occupational diseases cases, and to track the subsequent diagnosis of suspected cases in Hubei Province from 2020 to 2021, and to provide theoretical basis for the supervision of suspected occupational diseases. Methods: In April 2022, the data of suspected occupational diseases cases and occupational diseases in Hubei Province from 2020 to 2021 were collected by the Occupational Diseases and Health Risk Factors Information Surveillance System. The distribution and diagnosis of suspected occupational diseases cases were analyzed. We investigated undiagnosed suspected occupational diseases by telephone. Results: From 2020 to 2021, a total of 1872 cases of suspected occupational diseases in 6 categories and 18 species were reported in Hubei Province. The top three suspected occupational diseases were suspected occupational noise deafness (36.75%, 688/1872), suspected coal worker's pneumoconiosis (33.07%, 619/1872) and suspected silicosis (20.99%, 393/1872). The diagnosis rate of suspected occupational diseases was 33.60% (629/1872). The rate of confirmed diagnosis was 63.59% (400/629). The diagnosis rate (26.86%, 456/1698) and rate of confirmed diagnosis (55.48%, 253/456) of suspected occupational diseases detected by occupational health examination were the lowest. The diagnosis rate of suspected occupational diseases detected by comprehensive medical institutions and private medical institutions were lower than disease prevention and control institutions and occupational disease prevention center (P<0.05). The main reasons for not entering the diagnostic procedure included that workers were not informed that they were diagnosed as suspected occupational diseases (31.55%, 124/393), workers were unwilling to apply for occupational disease diagnosis (18.56%, 73/393), and some workers planned to apply for diagnosis but had not yet applied (10.69%, 42/393) . Conclusion: Occupational noise deafness, coal worker's pneumoconiosis and silicosis are the main diseases of suspected occupational diseases in Hubei Province. In order to increase the diagnosis rate and confirmed diagnosis rate of suspected occupational diseases, it is suggested to strengthen management and supervision from the aspects of case management, information warning and worker notification.

[Update points for the 2022 edition of the European Association for the Study of Liver Diseases Clinical Practice Guidelines for the Management of Hepatic Encephalopathy and comparison with China's 2018 edition guidelines].

The European Association for the Study of Liver Diseases issued the "Clinical Practice Guidelines for the Management of Hepatic Encephalopathy" in 2022, which included recommendations for clinical diagnosis, assessment, treatment, management, and prevention. The Society's "Hepatic Encephalopathy Clinical Practice Guidelines in Chronic Liver Disease," which was last published in 2014, and the "Guidelines for the Diagnosis and Treatment of Hepatic Encephalopathy in Cirrhosis," which the Chinese Society of Hepatology, Chinese Medical Association, released in 2018, have certain differences and updates in terms of comparison to terminology, grading and classification, diagnosis, clinical evaluation and treatment, management, and prevention. Herein, the updated points of this guideline and the differences between it and our nation's guidelines are summarized in order to refine and understand the guiding role of the new version of the guideline for the clinical treatment of hepatic encephalopathy and provide aid for standardizing clinical diagnosis and treatment.

[Novel strategy of sepsis immunomodulation targeting dendritic cells].

Dendritic cells (DCs) are the major antigen-presenting cells that play critical roles in regulating both innate and acquire immune responses. In the state of sepsis, the number of DCs is obviously decreased with inhibited antigen presenting ability as well as abnormal cytokine secretion, thereby resulting in an impairment of T lymphocyte activation. Previous studies have demonstrated that the depletion and dysfunction of DCs appear to be the main causes associated with the development of sepsis-induced immunosuppression. Based on the characteristic changes of DCs in sepsis and analysis of recent research progress, the authors propose a novel strategy of immunomodulation targeting the apoptosis, differentiation, and dysfunction of DCs, in order to provide new ideas for the prevention and treatment of severe burns and trauma complicated with sepsis.

[Influence of family with sequence similarity 134, member B-mediated reticulophagy on lipopolysaccharide-induced apoptosis of mouse dendritic cells].

Objective: To investigate the influence of family with sequence similarity 134, member B (FAM134B)-mediated reticulophagy on lipopolysaccharide (LPS)-induced apoptosis of mouse dendritic cells (DCs), so as to provide a basis for improving the immune suppression of sepsis caused by wound infection and other factors. Methods: The experimental research methods were used. The DC line DC2.4 of the 3rd to 10th passage in the logarithmic growth stage was collected for experiments. DCs were divided into LPS stimulation 0 h (no stimulation) group, LPS stimulation 6 h group, LPS stimulation 12 h group, LPS stimulation 24 h group, and LPS stimulation 72 h group, which were cultured with 1 µg/mL LPS (the same concentration below) for the corresponding time. The protein expressions of FAM134B, microtubule-associated protein 1 light chain 3B (LC3B), and transporter protein SEC61B were determined by Western blotting, and the ratio of LC3B-Ⅱ/LC3B-Ⅰ was calculated (n=3). DCs were divided into phosphate buffer solution (PBS) group and LPS group for corresponding treatment. After 24 hours of culture, the expression of FAM134B and its co-localization with lysosomal probes and LC3B were detected using immunofluorescence method, while the number of autolysosomes in cells were observed through transmission electron microscope. DCs were divided into the FAM134B-knockdown group that were transfected with lentivirus containing small interfering RNA (siRNA) sequence of FAM134B gene and the empty vector group with empty lentivirus transfected. At post transfection hour 72, the fluorescence expression of cells was observed under the inverted fluorescence phase contrast microscope, meanwhile, the normally cultured DCs were set as blank control group, and the same observation was performed at the corresponding time point. DCs were divided into PBS alone group and LPS alone group, DCs successfully transfected with lentivirus containing siRNA sequence of FAM134B gene were divided into FAM134B-knockdown+PBS group and FAM134B-knockdown+LPS group, and DCs successfully transfected with empty lentivirus were divided into empty vector+PBS group and empty vector+LPS group. These cells were stimulated correspondingly and cultured for 24 hours. The protein expression of FAM134B was detected using Western blotting (n=3); the apoptotic rate of cells was determined by flow cytometry (n=3); the situation of apoptosis was observed by Hoechst staining, and the apoptotic rate was calculated (n=5); the protein expressions of cleaved cysteine aspartic acid specific protease-3 (caspase-3), B cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax) were detected using Western blotting, and the ratio of Bax/Bcl-2 was calculated (n=5). Data were statistically analyzed with one-way analysis of variance (ANOVA), least significant difference test, and ANOVA for factorial design. Results: Compared with those in LPS stimulation 0 h group, the protein expressions of FAM134B of cells in LPS stimulation 12 h group and LPS stimulation 24 h group were significantly increased (P<0.05), the protein expressions of SEC61B of cells in LPS stimulation 6 h group, LPS stimulation 12 h group, LPS stimulation 24 h group, and LPS stimulation 72 h group were significantly decreased (P<0.05), and the ratios of LC3B-Ⅱ/LC3B-Ⅰ of cells in LPS stimulation 24 h group and LPS stimulation 72 h group were obviously increased (P<0.05). As the most significant changes of three proteins were seen in the cells of LPS stimulation 24 h group, 24 h was used as the duration of subsequent LPS stimulation. After 24 hours of culture, the expression of FAM134B and its co-localization with LC3B and lysosomal probes in the cells of LPS group were all significantly enhanced, with a significant increase in the number of autolysosomes in comparison with those in PBS group. Both the empty vector group and the FAM134B-knockdown group showed high intensity fluorescence in the cells at post transfection hour 72, but the blank control group showed no fluorescence in the cells at the corresponding time point. After 24 hours of culture, the protein expression of FAM134B of cells in FAM134B-knockdown+PBS group was significantly lower than the expressions in PBS alone group and empty vector+PBS group (with P values all <0.05), the protein expression of FAM134B of cells in FAM134B-knockdown+LPS group was significantly lower than the expressions in LPS alone group and empty vector+LPS group (with P values all <0.05), the protein expression of FAM134B of cells in LPS alone group was significantly higher than that in PBS alone group (P<0.05), while the protein expression of FAM134B of cells in empty vector+LPS group was significantly higher than that in empty vector+PBS group (P<0.05). After 24 hours of culture, flow cytometry assay revealed that the apoptotic rate of cells in PBS alone group, LPS alone group, empty vector+PBS group, empty vector+LPS group, FAM134B-knockdown+PBS group, and FAM134B-knockdown+LPS group were (13.3±0.8)%, (32.6±4.3)%, (17.0±1.5)%, (51.7±3.3)%, (52.4±3.1)%, and (62.3±2.6)%, respectively. After 24 hours of culture, compared with those in LPS alone group and empty vector+LPS group, the protein expression of cleaved caspase-3, the ratio of Bax/Bcl-2, and the apoptotic rates of cells detected by flow cytometry and Hoechst staining were significantly increased in FAM134B-knockdown+LPS group (P<0.05); compared with those in the corresponding PBS treatment group, namely, PBS alone group, empty vector+PBS group, and FAM134B-knockdown+PBS group, the protein expression of cleaved caspase-3, the ratio of Bax/Bcl-2, and the apoptotic rates of cells detected by flow cytometry and Hoechst staining were significantly increased in LPS alone group, empty vector+LPS group, and FAM134B-knockdown+LPS group (P<0.05). Conclusions: The activation of reticulophagy mediated by FAM134B in mouse DCs is enhanced and peaked in 24 hours under LPS stimulation, and the activated reticulophagy has a significant inhibitory effect on cell apoptosis.

Socio-economic disparities in exposure to and endorsement of COVID-19 vaccine misinformation and the associations with vaccine hesitancy and vaccination.

OBJECTIVES: We examined disparities in vaccine misinformation exposure and endorsement and the associations with vaccine hesitancy and vaccination uptake. STUDY DESIGN: Population-based survey. METHODS: A population-based survey was conducted on 5,002 Hong Kong adults oversampling low socio-economic status (SES, n = 2,200). Information on exposure (13 misinformation statements, total 0-13, median = 2), endorsement (13 statements, score 0-10, high scores indicate higher levels of endorsement, median = 5.75) of misinformation, vaccine hesitancy (14 items, score 1-5), and vaccination (two doses) were collected. Multivariable regression (adjusted ß [aß]) and Poisson regression (adjusted risk ratio [aRR]) adjusting for demographic characteristics were used to examine the associations of exposure to and endorsement of misinformation with vaccine hesitancy and vaccination. RESULTS: A total of 71.8% of respondents had at least exposure to one vaccine misinformation, and 35.7% had a high level of endorsement (median or above). Respondents with lower SES had a lower exposure (≤2 statements, 57.1% vs 50.1%, P < 0.001) but a higher level of endorsement (36.6% vs 34.9%, P = 0.01) of misinformation. Overall, 72.9% had been vaccinated for two or more doses, with a lower proportion in respondents with lower SES (83.6% vs 61.1%; P < 0.001). Compared with no exposure to misinformation, high levels of exposure and endorsement were associated with vaccine hesitancy (aß = 0.44, 95% confidence interval 0.40-0.48; aß = 0.50, 0.47-0.54, respectively) and lower vaccination rates (aRR = 0.98, 0.97-0.99; aRR = 0.92, 0.88-0.96, respectively). Vaccine hesitancy mediated the associations of exposure (fully, 100%) and endorsement (partially, 73%) with vaccination uptake. CONCLUSION: Endorsement of vaccine misinformation in respondents with lower SES was associated with low vaccination uptake.

A novel bivalent anti-c-MET/PD-1 bispecific antibody exhibits potent cytotoxicity against c-MET/PD-L1-positive colorectal cancer.

Previously, we generated a novel bispecific antibody (BsAb) simultaneously targeting both c-MET and PD-1 (PDCD1), which can bridge T cells and c-MET positive tumor cells. However, the specific mechanisms and antitumor activities of the BsAb against c-MET/PD-L1 (CD274) positive colorectal cancer (CRC) is not completely understood. In this study, in addition to the tumor intrinsic mechanism investigation with molecular biology assay in vitro, a humanized mouse model was used to evaluate antitumor activity of the BsAb in vivo. The BsAb could inhibit c-MET/PD-L1+ CRC cell migration and show strong antitumor activity against HCT116 tumors in mice, potentially by inducing the degradation of c-MET protein in a dose and time-dependent manner. The BsAb could suppress the phosphorylation of c-MET downstream proteins GRB2-associated-binding protein 1 (Gab1) and focal adhesion kinase (FAK). Considering the tumor extrinsic mechanism, the BsAb may promote phagocytosis of macrophage. Furthermore, the level of plasma exosomal-c-MET/PD-L1 is able to distinguish CRC patients from healthy controls. In summary, the BsAb exhibited potent anti-tumor activities by two distinguished mechanisms: inhibition of c-MET signal transduction and promotion of macrophage-mediated phagocytosis. Our BsAb may provide a novel therapeutic agent for patients with c-MET/PD-L1+ CRC, and the status of exosomal-c-MET/PD-L1 can serve as a biomarker to predict responsiveness to treatment of our BsAb.