Beneficial Effects of Traditional Chinese Medicine Fuzheng Huayu on the Occurrence of Hepatocellular Carcinoma in Patients with Compensated Chronic Hepatitis B Cirrhosis Receiving Entecavir: A Multicenter Retrospective Cohort Study.

Background and Aims: The application of antifibrotic drugs to treat patients with chronic liver diseases who are receiving antiviral therapies for hepatocellular carcinoma (HCC) has not been established. Here, we aimed to assess the impact of the Traditional Chinese Medicine Fuzheng Huayu (FZHY) on the occurrence of HCC in patients with hepatitis B virus-related compensated cirrhosis receiving the antiviral drug entecavir (ETV). Methods: A multicenter retrospective cohort study was performed. Compensated liver cirrhosis patients were divided into the ETV+FZHY group or the ETV group according to treatment. The cumulative incidence of HCC was analyzed using Kaplan-Meier and log-rank tests. Propensity score matching was used for confounding factors. Stratified analysis and Cox regression were used to determine the effects of FZHY on the occurrence of HCC and liver function decompensation. Results: Out of 910 chronic hepatitis B patients, 458 were in the ETV+FZHY group and 452 were in the ETV group. After propensity score matching, the 5-year cumulative incidence of HCC was 9.8% in the ETV+FZHY group and 21.8% in the ETV group (p<0.01). The adjusted hazard ratio for HCC was 0.216 (0.108, 0.432) when FZHY treatment was >36 months. Age, diabetes, alanine aminotransferase, γ-glutamyl transpeptidase, albumin, hepatitis B e-antigen, and fibrosis 4 score were associated with the occurrence of HCC. FZHY decreased the risk of HCC in patients aged >45 years with a hepatitis B virus DNA level of ≥2,000 IU/l. Conclusion: Adjunctive FZHY treatment reduced HCC occurrence in patients with hepatitis B virus cirrhosis who were treated with ETV, possibly due to the antifibrotic properties of FZHY.

An integrative model with HLA-DR, CD64, and PD-1 for the diagnostic and prognostic evaluation of sepsis.

BACKGROUND: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection and progressive immunosuppression with high mortality. HLA-DR, CD64, and PD-1 were assumed to be useful biomarkers for sepsis prediction. However, the ability of a combination of these biomarkers has not been clarified. METHODS: An observational case-control study was conducted that included 30 sepsis patients, 30 critically ill patients without sepsis admitted to the intensive care unit (ICU), and 32 healthy individuals. The levels of HLA-DR, CD64, and PD-1 expression in peripheral blood immune cells and subsets was assayed on Days 1, 3, and 5, and the clinical information of patients was collected. We compared these biomarkers between groups and evaluated the predictive validity of single and combined biomarkers on sepsis mortality. RESULTS: The results indicate that PD-1 expression on CD4- CD8- T (PD-1+ CD4- CD8- T) (19.19% ± 10.78% vs. 9.88% ± 1.79%, p = .004) cells and neutrophil CD64 index (nCD64 index) (9.15 ± 5.46 vs. 5.33 ± 2.34, p = .001) of sepsis patients were significantly increased, and HLA-DR expression on monocytes (mHLA-DR+ ) was significantly reduced (13.26% ± 8.06% vs. 30.17% ± 21.42%, p = 2.54 × 10-4 ) compared with nonsepsis critically ill patients on the first day. Importantly, the expression of PD-1+ CD4- CD8- T (OR = 0.622, 95% CI = 0.423-0.916, p = .016) and mHLA-DR+ (OR = 1.146, 95% CI = 1.014-1.295, p = .029) were significantly associated with sepsis mortality. For sepsis diagnosis, the mHLA-DR+ , PD-1+ CD4- CD8- T, and nCD64 index showed the moderate individual performance, and combinations of the three biomarkers achieved greater diagnostic value (AUC = 0.899, 95% CI = 0.792-0.962). When adding PCT into the combined model, the AUC increased to 0.936 (95% CI = 0.840-0.983). For sepsis mortality, combinations of PD-1+ CD4- CD8- T and mHLA-DR+ , have a good ability to predict the prognosis of sepsis patients, with an AUC = 0.921 (95% CI = 0.762-0.987). CONCLUSION: These findings indicate that the combinations of HLA-DR, CD64, and PD-1 outperformed each of the single indicator in diagnosis and predicting prognosis of sepsis.

Clinical efficacy and safety of coseasonal initiation of Artemisia annua sublingual immunotherapy on patients with Artemisia-induced rhinoconjunctivitis.

PURPOSE: Patients with seasonal allergic rhinoconjunctivitis (SARC) might seek evaluation and treatment when symptoms appear during the pollen season. It is unclear whether coseasonal-initiated sublingual immunotherapy (SLIT) would be effective and safe for SARC. This study aims to identify the feasibility of initiating Artemisia annua SLIT during the pollen season. MATERIALS AND METHODS: Sixty patients with Artemisia-induced SARC were equally recruited into the SLIT and control groups during the pollen season in 2021. The SLIT group was treated with standardized Artemisia annua SLIT drops using a modified dosing schedule combined with pharmacotherapy, while the control group only received pharmacotherapy. Diary cards for clinical symptoms, rescue medication use, and adverse events (AEs) were recorded during the pollen seasons. Objective measures, including average daily combined scores of medication and rhinoconjunctivitis symptoms (CSMRS), total rhinoconjunctivitis symptom score (TRSS), total medication score (TMS), and the score of visual analog scale (VAS) were calculated to evaluate the efficacy of SLIT. Safety was assessed through the occurrence and severity of AEs. RESULTS: In total, 80.0 % (24/30) patients in the SLIT group and 86.67 % (26/30) patients in the control group completed the study. The severity of SARC, which was assessed by objective measures including CSMRS, TRSS, TMS, and VAS of the SLIT group and the control group, was generally at the same level during the 2021 pollen season, except for the medical consumption, which the score of TMS was slightly higher in the SLIT group. After one year of treatment, the scores of CSMRS, TRSS, and VAS in the SLIT group were significantly improved compared with the control group (all P < 0.001), and the difference in the TMS between the two groups disappeared (P > 0.05). Moreover, clinical improvement of the four objective measures was also observed in the SLIT group compared with the baseline value (P < 0.001). Overall, 9/24 patients in the SLIT group experienced mild local AEs, and two patients experienced mild systemic AEs during the SLIT period. CONCLUSIONS: This controlled preliminary study identified that coseasonal-initiated Artemisia annua SLIT treatment for one year was generally safe and effective in improving the symptoms of SARC patients induced by Artemisia annua pollen.

Electrotaxis of alveolar epithelial cells in direct-current electric fields.

PURPOSE: This study aims to elucidate the electrotaxis response of alveolar epithelial cells (AECs) in direct-current electric fields (EFs), explore the impact of EFs on the cell fate of AECs, and lay the foundation for future exploitation of EFs for the treatment of acute lung injury. METHODS: AECs were extracted from rat lung tissues using magnetic-activated cell sorting. To elucidate the electrotaxis responses of AECs, different voltages of EFs (0, 50, 100, and 200 mV/mm) were applied to two types of AECs, respectively. Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs. Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration. To further demonstrate the impact of EFs on the pulmonary tissue, the human bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B cells) were obtained and experimented under the same conditions as AECs. To determine the influence on cell fate, cells underwent electric stimulation were collected to perform Western blot analysis. RESULTS: The successful separation and culturing of AECs were confirmed through immunofluorescence staining. Compared with the control, AECs in EFs demonstrated a significant directionality in a voltage-dependent way. In general, type Ⅰ alveolar epithelial cells migrated faster than type Ⅱ alveolar epithelial cells, and under EFs, these two types of cells exhibited different response threshold. For type Ⅱ alveolar epithelial cells, only EFs at 200 mV/mm resulted a significant difference to the velocity, whereas for, EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference. Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11. CONCLUSION: EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects, which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.

Influence of medium modifications (optimization) on high nematicidal activity of the fermentation broth of Clostridium beijerinckii.

Introduction: The nematode species Meloidogyne incognita has been responsible for significant financial losses within the agricultural sector. Nematophagous bacteria, characterised by their extensive distribution and broad spectrum of hosts, exhibit remarkable efficacy as natural antagonists against nematodes. Sneb518 (Clostridium beijerinckii) fermentation broth displayed substantial biocontrol activity against M. incognita in previous research. Optimizing fermentation conditions is a fundamental technique for dramatically enhancing end product performance. There has been no such study conducted yet on enhancing the nematicidal activities of Sneb518 (Clostridium beijerinckii) fermentation using response surface methodology (RSM). Methods: The influence of strain Sneb518 fermentation media and conditions on nematicidal activity was examined using the three-factor technique and a Plackett-Burman design, and the interaction between various fermentation factors was examined using a Box-Behnken design. The present study employed response surface methodology (RSM) to examine and enhance the nematicidal activity of Sneb518 culture filtrates by identifying and optimising the influential components. Results: Glucose, peanut cake flour, and potassium chloride as carbon, nitrogen, and inorganic salts displayed considerably increased nematicidal potential in the present study. Furthermore, the corrected mortality of J2 ranged from 52.24% to 91.15% when utilizing the Box-Behnken design. These findings clearly support the application of RSM for medium optimization. Moreover, the outcomes of the validation experiment corresponded to the model predictions. Discussion: This research has enhanced the biocontrol ability of C. beijerinckii to control M. incognita and this research has led to the advancement of new biocontrol agents.

[Value of peripheral blood monocyte subsets and CD64 expression in the diagnosis and prognosis of sepsis].

OBJECTIVE: To explore the value of monocyte subsets and CD64 expression in the diagnosis and prognosis of sepsis. METHODS: A prospective case-control study was designed. 30 septic patients and 30 non-septic patients who were admitted to the intensive care unit (ICU) of the PLA Army Characteristic Medical Center from March 2021 to March 2022 were enrolled. After 1, 3, and 5 days of ICU admission, peripheral blood samples were taken from patients. Flow cytometry was used to detect the proportion of monocyte subsets and the expression level of CD64 on the surface, and the difference of expression between patients in two group was analyzed. The risk variables for sepsis were analyzed using single-factor and multi-factor Logistic regression. The diagnostic efficacy of each risk factor for sepsis was determined using the receiver operator characteristic curve (ROC curve). RESULTS: One day after ICU admission, the proportions of monocytes and classic monocytes in white blood cells (WBC) of septic patients were significantly lower than those of non-septic patients [proportion of monocytes to WBC: (4.13±2.03)% vs. (6.53±3.90)%, proportion of classic monocytes to WBC: 1.97 (1.43, 2.83)% vs. 3.37 (1.71, 5.98)%, both P < 0.05]. The proportion of non-classical monocytes in monocytes was significantly higher in septic patients than that in non-septic patients [(11.42±9.19)% vs. (6.57±4.23)%, P < 0.05]. The levels of CD64 expression in monocytes, classic monocytes, intermediate monocytes and non-classic monocytes were significantly higher in sepsis patients than those in non-septic patients [mean fluorescence intensity (MFI): 13.10±6.01 vs. 9.84±2.83 for monocytes, 13.58±5.98 vs. 10.03±2.84 for classic monocytes, 13.48±6.35 vs. 10.22±2.99 for intermediate monocytes, 8.21±5.52 vs. 5.79±2.67 for non-classic monocytes, all P < 0.05]. Multivariate Logistic regression research showed that CD64 in typical monocytes [odds ratio (OR) = 1.299, 95% confidence interval (95%CI) was 1.027-1.471, P = 0.025] and the proportion of non-typical monocytes in monocytes (OR = 1.348, 95%CI was 1.034-1.758, P = 0.027) were the independent risk factors for sepsis. ROC curve showed that the area under the ROC curve (AUC) of CD64 expression of classical monocytes, the fraction of non-classical monocytes in monocytes, and procalcitonin (PCT) in the diagnosis of sepsis was 0.871. A correlation analysis revealed a negative relationship between the acute physiology and chronic health status evaluation II (APACHE II) on the first, third, and fifth days following ICU admission and the expression level of CD64 in patients' classic monocytes (r values were -0.264, -0.428 and -0.368, respectively, all P < 0.05). CONCLUSIONS: Combining the proportion of non-classical monocytes in monocytes, the level of plasma PCT, and the CD64 expression of classic monocytes in peripheral blood has good efficacy in identifying sepsis and assessing its severity.

Two-Year Health Outcomes in Hospitalized COVID-19 Survivors in China.

Importance: Relatively little is known about the persistence of symptoms in patients with COVID-19 for more than 1 year after their acute illness. Objective: To assess the health outcomes among hospitalized COVID-19 survivors over 2 years and to identify factors associated with increased risk of persistent symptoms. Design, Setting, and Participants: This was a longitudinal cohort study of patients who survived COVID-19 at 2 COVID-19-designated hospitals in Wuhan, China, from February 12 to April 10, 2020. All patients were interviewed via telephone at 1 year and 2 years after discharge. The 2-year follow-up study was conducted from March 1 to April 6, 2022. Statistical analysis was conducted from April 20 to May 5, 2022. The severity of disease was defined by World Health Organization guideline for COVID-19. Exposures: COVID-19. Main Outcomes and Measures: The main outcome was symptom changes over 2 years after hospital discharge. All patients completed a symptom questionnaire for evaluation of symptoms, along with a chronic obstructive pulmonary disease assessment test (CAT) at 1-year and 2-year follow-up visits. Results: Of 3988 COVID-19 survivors, a total of 1864 patients (median [IQR] age, 58.5 [49.0-68.0] years; 926 male patients [49.7%]) were available for both 1-year and 2-year follow-up visits. The median (IQR) time from discharge to follow-up at 2 years was 730 (719-743) days. At 2 years after hospital discharge, 370 patients (19.8%) still had symptoms, including 224 (12.0%) with persisting symptoms and 146 (7.8%) with new-onset or worsening of symptoms. The most common symptoms were fatigue, chest tightness, anxiety, dyspnea, and myalgia. Most symptoms resolved over time, but the incidence of dyspnea showed no significant change (1-year vs 2-year, 2.6% [49 patients] vs 2.0% [37 patients]). A total of 116 patients (6.2%) had CAT total scores of at least 10 at 2 years after discharge. Patients who had been admitted to the intensive care unit had higher risks of persistent symptoms (odds ratio, 2.69; 95% CI, 1.02-7.06; P = .04) and CAT scores of 10 or higher (odds ratio, 2.83; 95% CI, 1.21-6.66; P = .02). Conclusions and Relevance: In this cohort study, 2 years after hospital discharge, COVID-19 survivors had a progressive decrease in their symptom burden, but those with severe disease during hospitalization, especially those who required intensive care unit admission, had higher risks of persistent symptoms. These results are related to the original strain of the virus, and their relevance to infections with the Omicron variant is not known.

Efficacy and safety of Fuzheng Huayu tablet on persistent advanced liver fibrosis following 2 years entecavir treatment: A single arm clinical objective performance criteria trial.

ETHNOPHARMACOLOGICAL RELEVANCE: Antiviral therapy can alleviate liver fibrosis in chronic hepatitis B, but it has a limited effect on advanced liver fibrosis/cirrhosis. Traditional Chinese medicine (TCM), particularly FuZheng HuaYu (FZHY) tablet, appears to have an antifibrotic effect, but its improving resolution of hepatitis b virus (HBV) -associated advanced fibrosis and experienced anti-viral treatment has not been investigated. AIM OF THE STUDY: To observe the safety and efficacy of adjunctive FZHY on the HBV-associated cirrhosis patients who received 2 years of entecavir but still with advanced fibrosis. METHODS: An open-label, multicentre, single arm trial. 251 patients were included and treated with TCM consisted of FZHY tablets 1.6 g and granules, three times a day in addition to entecavir 0.5 mg daily for an additional 48 weeks. Primary outcome was regression of fibrosis (the proportion of patients with a 1-point decrease in the Ishak liver fibrosis score from baseline to week 48). RESULTS: Fibrosis regression occurred in 94 of 184 patients with paired liver biopsy (51.09%, 95% CI: 43.9～58.0). In 132 compensated cirrhosis patients (Ishak score ≥5), 56.06% (74/132, 95% CI: 47.5～64.2) showed fibrosis regression and reached the goal of 54% (15% more than entecavir mono-therapy). 10 patients occurred adverse reaction, most of them were mild, and all recovered or achieved remission. CONCLUSIONS: The combination therapy of FZHY, TCM granules and ETV could regress the liver fibrosis in the patients with HBV cirrhosis, who experienced 2 years of ETV treatment, and it is safe and well tolerated.

The diagnostic model for early detection of gestational diabetes mellitus and gestational diabetic nephropathy.

BACKGROUND: Gestational diabetes mellitus (GDM) and gestational diabetic nephropathy (GDN) have become an increasingly serious problem worldwide, which can cause a large number of adverse pregnancy consequences for mothers and infants. However, the diagnosis of GDM and GDN remains a challenge due to the lack of optimal biomarkers, and the examination has high requirements for patient compliance. We aimed to establish a simple early diagnostic model for GDM and GDN. METHODS: We recruited 50 healthy pregnant (HP), 99 GDM patients, 99 GDN patients at Daping Hospital. Renal function indicators and blood cell indicators were collected for all patients. RESULTS: Compared with HP, GDM, and GDN patients exhibited significantly higher urea/creatinine ratio and NEU. The diagnostic model1 based on the combination of urea/creatinine ratio and NEU was built using logistic regression. Based on receiver operating characteristic curve analysis, the area under the curve (AUC) of the diagnostic model was 0.77 (0.7, 0.84) in distinguishing GDM from HP, and the AUC of the diagnostic model was 0.94 (0.9, 0.97) in distinguishing GDN from HP. Meanwhile, the diagnostic model2 based on the combination of ß2-mG, PLT, and NEU in GDM and GDN patients was built using logistic regression, and the area under the ROC curve (AUC ROC) was 0.79 (0.73, 0.85), which was larger than the individual biomarker AUC. CONCLUSION: Our study demonstrated that the diagnostic model established by the combination of renal function indicators and blood cell indicators could facilitate the differential diagnosis of GDM and GDN patients.

Genotyping of cerebrospinal fluid in lung cancer patients with leptomeningeal metastasis.

BACKGROUND: The prognosis of non-small-cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is poor. Detection of cell-free DNA (cfDNA) by next generation sequencing (NGS) in cerebrospinal fluid (CSF) may facilitate diagnosis of LM and identification of drug resistance mechanisms, yet its clinical use needs to be further verified. METHODS: We performed a retrospective cohort study to assess the genetic profiles of paired CSF and plasma samples in lung cancer patients with LM. Of 17 patients screened, a total of 14 patients with LM and paired NGS tests were enrolled. RESULTS: All patients harbor driver gene mutations, including 12 epidermal growth factor receptor (EGFR) activating mutations, 1 anaplastic lymphoma kinase (ALK) rearrangement, and 1 ROS-1 fusion. Genetic mutations were detected in CSF cfDNA from 92.9% patients (13/14), which was significantly higher than that from the plasma (9/14, 64.2%). The mutations were highly divergent between CSF and plasma cfDNA, with a concordance rate of 24.38% and 10 mutations shared by the two media. CSF cfDNA could also benefit the analysis of resistance mechanisms to targeted therapies. In five patients who experienced progression on 1st or 2nd generation EGFR-tyrosine kinase inhibitors (TKIs), RB1 mutation, and amplification of MET and EGFR were detected in CSF cfDNA only. In eight patients with LM progression on osimertinib resistance, EGFR amplification was detected in CSF cfDNA from four patients, whereas no CNVs were detected in the matched plasma samples. CONCLUSIONS: In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments.

Medical Image Authentication Method Based on the Wavelet Packet and Energy Entropy.

The transmission of digital medical information is affected by data compression, noise, scaling, labeling, and other factors. At the same time, medical data may be illegally copied and maliciously tampered with without authorization. Therefore, the copyright protection and integrity authentication of medical information are worthy of attention. In this paper, based on the wavelet packet and energy entropy, a new method of medical image authentication is designed. The proposed method uses the sliding window to measure the energy of the detail information. In the time-frequency data distribution, the local details of the data are mined. The complexity of energy is quantitatively described to highlight the valuable information. Based on the energy weight, the local energy entropy is constructed and normalized. The adjusted entropy value is used as the feature vector of the authentication information. A series of experiments show that the authentication method has good robustness against shearing attacks, median filtering, contrast enhancement, brightness enhancement, salt-and-pepper noise, Gaussian noise, multiplicative noise, image rotation, scaling attacks, sharpening, JPEG compression, and other attacks.

Metformin Combining PD-1 Inhibitor Enhanced Anti-Tumor Efficacy in STK11 Mutant Lung Cancer Through AXIN-1-Dependent Inhibition of STING Ubiquitination.

Background: Non-small-cell lung cancer (NSCLC) with STK11 mutation showed primary resistance to immune checkpoint inhibitors (ICIs). The glucose-lowering drug metformin exerted anti-cancer effect and enhanced efficacy of chemotherapy in NSCLC with KRAS/STK11 co-mutation, yet it is unknown whether metformin may enhance ICI efficacy in STK11 mutant NSCLC. Methods: We studied the impact of metformin on ICI efficacy in STK11 mutant NSCLC in vitro and in vivo using colony formation assay, cell viability assay, Ki67 staining, ELISA, CRISPR/Cas9-mediated knockout, and animal experiments. Results: Through colony formation assay, Ki67 incorporation assay, and CCK-8 assay, we found that metformin significantly enhanced the killing of H460 cells and A549 cells by T cells. In NOD-SCID xenografts, metformin in combination with PD-1 inhibitor pembrolizumab effectively decreased tumor growth and increased infiltration of CD8+ T cells. Metformin enhanced stabilization of STING and activation of its downstream signaling pathway. siRNA-mediated knockdown of STING abolished the effect of metformin on T cell-mediated killing of tumor cells. Next, we found that CRISPR/Cas9-mediated knockout of the scaffold protein AXIN-1 abolished the effect of metformin on T cell-mediated killing and STING stabilization. Immunoprecipitation and confocal macroscopy revealed that metformin enhanced the interaction and colocalization between AXIN-1 and STING. Protein-protein interaction modeling indicated that AXIN-1 may directly bind to STING at its K150 site. Next, we found that metformin decreased K48-linked ubiquitination of STING and inhibited the interaction of E3-ligand RNF5 and STING. Moreover, in AXIN-1 -/- H460 cells, metformin failed to alter the interaction of RNF5 and STING. Conclusion: Metformin combining PD-1 inhibitor enhanced anti-tumor efficacy in STK11 mutant lung cancer through inhibition of RNF5-mediated K48-linked ubiquitination of STING, which was dependent on AXIN-1.

Retracted: Targeting Transforming Growth Factor-Beta1 (TGF-ß1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFκB-PUMA Signaling.

The in vitro experiments of TGF-ß1 and the results of RT-PCR could not be repeated. In order not to affect others, the authors have asked for a retraction. Reference: Qiang Yin, Shan Liu, Anbing Dong, Xiufang Mi, Fengyun Hao, Kejun Zhang. Targeting Transforming Growth Factor-Beta1 (TGF-ß1) Inhibits Tumorigenesis of Anaplastic Thyroid Carcinoma Cells Through ERK1/2-NFkappakB-PUMA Signaling. Med Sci Monit 2016; 22: 2267-2277. DOI: 10.12659/MSM.898702.

Retracted: The MEK1/2 Inhibitor AZD6244 Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib.

This publication has been retracted by the Editor due to the identification of falsified figure images and manuscript content that raise concerns regarding the credibility of the study and the manuscript. Reference: Vemurafenib Hao Song, Jinna Zhang, Liang Ning, Honglai Zhang, Dong Chen, Xuelong Jiao, Kejun Zhang. The MEK1/2 Inhibitor AZD6244 Sensitizes BRAF-Mutant Thyroid Cancer to Vemurafenib. Med Sci Monit, 2018; 24: 3002-3010. DOI: 10.12659/MSM.910084.

Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin α5/FAK signaling.

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.

LncRNA LINC00460 takes a stimulating role on hepatocellular carcinoma stemness property.

Abundant researches have stated that long noncoding RNAs (lncRNAs) are crucial molecules in intricate progression of various cancers in terms of their influence on cell stemness. However, no research has discussed the role of LINC00460 in the stemness of hepatocellular carcinoma (HCC). RT-qPCR and western blot were utilized to respectively examine the RNA and protein levels. Aldehyde dehydrogenase 1 (ALDH1) assays and sphere formation assay were performed to detect cell stemness property in vitro and in vivo subcutaneous xenograft tumor assay was performed to detect tumor growth. Interaction between RNAs was explored by luciferase reporter assays and RNA pull-down assays. Our results showed that LINC00460 was markedly over-expressed in HCC and silencing LINC00460 impaired cell stemness. Additionally, LINC00460 knockdown curbed proliferation, migration, invasion and epithelial-to-mesenchymal transition (EMT) and drove apoptosis of HCC cells. Further, LINC00460 bound to miR-503-5p and miR-654-3p to protect t-complex 1 (TCP1) from being inhibited by miR-503-5p/miR-654-3p. Rescue experiments confirmed the effect of LINC00460/miR-503-5p/miR-654-3p/TCP1 on HCC cell stemness. In conclusion, LINC00460 aggravated cell stemness in HCC via targeting miR-503-5p/miR-654-3p and TCP1, suggesting that LINC00460 may work as a potential signature for cell stemness in HCC.[Figure: see text].

The impact of health education videos on general public's mental health and behavior during COVID-19.

BACKGROUND: COVID-19 has seriously affected people's mental health and changed their behaviors. Previous studies for mental state and behavior promotion only targeted limited people or were not suitable for daily activity restrictions. Therefore, we decided to explore the effect of health education videos on people's mental state and health-related behaviors. METHODS: Based on WeChat, QQ, and other social media, we conducted an online survey by snowball sampling. Spearman's non-parametric method was used to analyze the correlation related to mental health problems and health-related behaviors. Besides, we used binary logistic regression analyses to examine mental health problems and health-related behaviors' predictors. We performed SPSS macro PROCESS (model 4 and model 6) to analyze mediation relationships between exposure to health education videos and depression/anxiety/health-related behaviors. These models were regarded as exploratory. RESULTS: Binary logistic regression analyses indicated that people who watched the health education videos were more likely to wear masks (OR 1.15, p < 0.001), disinfect (OR 1.26, p < 0.001), and take temperature (OR 1.37, p < 0.001). With higher level of posttraumatic growth (PTG) or perceived social support (PSS), people had lower percentage of depression (For PSS, OR 0.98, p < 0.001; For PTG, OR 0.98, p < 0.01) and anxiety (For PSS, OR 0.98, p < 0.001; For PTG, OR 0.98, p = 0.01) and better health behaviors. The serial multiple-mediation model supported the positive indirect effects of exposure to health education videos on the depression and three health-related behaviors through PSS and PTG (Depression: B[SE] = - 0.0046 [0.0021], 95% CI - 0.0098, - 0.0012; Mask-wearing: B[SE] = 0.0051 [0.0023], 95% CI 0.0015, 0.0010; Disinfection: B[SE] = 0.0059 [0.0024], 95% CI 0.0024, 0.0012; Temperature-taking: B[SE] = 0.0067 [0.0026], 95% CI 0.0023, 0.0013). CONCLUSION: Exposure to health education videos can improve people's self-perceived social support and inner growth and help them cope with the adverse impact of public health emergencies with better mental health and health-related behaviors.

[Dynamic changes of cellular immune function in trauma patients and its relationship with prognosis].

OBJECTIVE: To study the dynamic changes of cellular immune function in peripheral blood of trauma patients and its role in the evaluation of traumatic complications. METHODS: A prospective cohort study design was conducted. Patients with blunt trauma admitted to Chongqing Emergency Medical Center from November 2019 to January 2020 were consecutively enrolled. The peripheral blood samples were collected at 1, 3, 5, 7, and 14 days after injury. The expressions of CD64, CD274, and CD279 on the surface of neutrophils, lymphocytes, and monocytes as well as CD3+, CD4+ and CD8+ T lymphocyte subsets were measured by flow cytometry. The trauma patients were divided into different groups according to the injury severity score (ISS) and sepsis within 28 days after injury, respectively. The dynamic changes of cellular immune function in different time points after injury and differences between different groups were compared. Furthermore, the correlation with acute physiology and chronic health evaluation II (APACHE II), sequential organ failure assessment (SOFA), and ISS were evaluated by Pearson correlation analysis. RESULTS: A total of 42 patients with trauma were finally enrolled, containing 8 severe trauma patients with ISS greater than 25 scores, 17 patients with ISS between 16 and 25 scores, and 17 patients with ISS less than 16 scores. The sepsis morbidity rates were 14.3% (n = 6) within 28 days after injury. CD64 index and CD4+ T lymphocyte subsets were significantly increased at different time points after trauma (H = 15.464, P = 0.004; F = 2.491, P = 0.035). The CD64 index and positive rates of CD279 in neutrophils, lymphocytes, and monocytes were increased with the severity of injury at day 1 and day 3 after injury, respectively. At the first day after injury, CD64 index were 2.81±1.79, 1.77±0.92, 3.49±1.09; positive rate of CD279 in neutrophils were 1.40% (0.32%, 2.04%), 0.95% (0.44%, 2.70%), 12.73% (3.00%, 25.20%); positive rate of CD279 in lymphocytes were 3.77% (3.04%, 5.15%), 4.71% (4.08%, 6.32%), 8.01% (4.59%, 11.59%); positive rate of CD279 in monocytes were 0.57% (0.24%, 1.09%), 0.85% (0.22%, 1.25%), 6.74% (2.61%, 18.94%) from mild to severe injury groups, respectively. The CD64 index in severe injury group was significantly higher than that in moderate group, and the positive rates of CD279 in neutrophils, lymphocytes and monocytes of severe injury patients were higher than those in other two groups (all P < 0.05). At 3rd day after injury, compared to moderate group, severe injury patients had significantly higher CD64 index and positive rate of CD279 in lymphocytes [4.58±2.41 vs. 2.43±1.68, 7.35% (5.90%, 12.28%) vs. 4.63% (3.26%, 6.06%), both P < 0.05]. Compared with the non-sepsis patients, the sepsis patients had significantly higher CD64 index and positive rate of CD279 in monocytes at day 1 after injury [4.06±1.72 vs. 2.36±1.31, 3.29% (1.14%, 12.84%) vs. 0.67% (0.25%, 1.48%), both P < 0.05], and positive rate of CD279 in lymphocytes significantly higher at 3rd day after injury [8.73% (7.52%, 15.82%) vs. 4.67% (3.82%, 6.21%), P < 0.05]. In addition, correlation analysis showed that positive rate of CD279 in lymphocytes was positively correlated with SOFA and ISS, respectively (r values were 0.533 and 0.394, both P < 0.05), positive rate of CD279 in monocytes was positively correlated with APACHE II, SOFA and ISS scores, respectively (r values were 0.579, 0.452 and 0.490, all P < 0.01), positive rate of CD279 in neutrophils was positively correlated with APACHE II and ISS, respectively (r values were 0.358 and 0.388, both P < 0.05). CONCLUSIONS: CD64 index and CD279 expression in neutrophils, lymphocytes, and monocytes are significantly related to the severity and prognosis of trauma. Dynamic monitoring the cellular immune function may be helpful for assessing the prognosis of trauma patients.

Measuring Public Reaction to Violence Against Doctors in China: Interrupted Time Series Analysis of Media Reports.

BACKGROUND: Violence against doctors in China is a serious problem that has attracted attention from both domestic and international media. OBJECTIVE: This study investigates readers' responses to media reports on violence against doctors to identify attitudes toward perpetrators and physicians and examine if such trends are influenced by national policies. METHODS: We searched 17 Chinese violence against doctors reports in international media sources from 2011 to 2020. We then tracked back the original reports and web crawled the 19,220 comments in China. To ascertain the possible turning point of public opinion, we searched violence against doctors-related policies from Tsinghua University ipolicy database from 2011 to 2020, and found 19 policies enacted by the Chinese central government aimed at alleviating the intense patient-physician relationship. We then conducted a series of interrupted time series analyses to examine the influence of these policies on public sentiment toward violence against doctors over time. RESULTS: The interrupted time series analysis (ITSA) showed that the change in public sentiment toward violence against doctors reports was temporally associated with government interventions. The declarations of 10 of the public policies were followed by increases in the proportion of online public opinion in support of doctors (average slope changes of 0.010, P<.05). A decline in the proportion of online public opinion that blamed doctors (average level change of -0.784, P<.05) followed the declaration of 3 policies. CONCLUSIONS: The government's administrative interventions effectively shaped public opinion but only temporarily. Continued public policy interventions are needed to sustain the reduction of hostility toward medical doctors.