Bispecific antibody targeting both B7-H3 and PD-L1 exhibits superior antitumor activities.

Clinical application of PD-1 and PD-L1 monoclonal antibodies (mAbs) is hindered by their relatively low response rates and the occurrence of drug resistance. Co-expression of B7-H3 with PD-L1 has been found in various solid tumors, and combination therapies that target both PD-1/PD-L1 and B7-H3 pathways may provide  additional therapeutic benefits. Up to today, however, no bispecific antibodies targeting both PD-1 and B7-H3 have reached the clinical development stage. In this study, we generated a stable B7-H3×PD-L1 bispecific antibody (BsAb) in IgG1-VHH format by coupling a humanized IgG1 mAb against PD-L1 with a humanized camelus variable domain of the heavy-chain of heavy-chain antibody (VHH) against human B7-H3. The BsAb exhibited favorable thermostability, efficient T cell activation, IFN-γ production, and antibody-dependent cell-mediated cytotoxicity (ADCC). In a PBMC humanized A375 xenogeneic tumor model, treatment with BsAb (10 mg/kg, i.p., twice a week for 6 weeks) showed enhanced antitumor activities compared to monotherapies and, to some degree, combination therapies. Our results suggest that targeting both PD-1 and B7-H3 with BsAbs increases their specificities to B7-H3 and PD-L1 double-positive tumors and induces a synergetic effect. We conclude that B7-H3×PD-L1 BsAb is favored over mAbs and possibly combination therapies in treating B7-H3 and PD-L1 double-positive tumors.

High expression of BHLHE40 promotes immune infiltration and tumor progression in thyroid cancer.

Thyroid cancer (THCA) is a common malignancy of the endocrine system which threatens people's health and life quality. It is urgent to find the marker gene of THCA. BHLHE40 is a key gene involved in tumor malignant progression. However, the role of BHLHE40 in THCA remains unclear. In this study, 346 upregulated and 302 downregulated genes were found by analyzing the Gene Expression Omnibus database. BHLHE40 was upregulated in THCA. BHLHE40 and its related differentially expressed genes were involved in cell adhesion and differentiation in THCA. Moreover, BHLHE40 was also highly expressed in THCA cells and tissues. Downregulation of BHLHE40 inhibited cell growth and metastasis. Knockdown of BHLHE40 conditioned media retarded cell migration in M2 macrophages. In addition, knockdown of BHLHE40 inhibited CD206 and CD163 expression and decreased the secretion of interleukin-10 in M2 macrophage. Therefore, BHLHE40 has the potential to be used as a biomarker of immune infiltration and tumorigenesis in THCA.

The meaning of therapists' hope for their clients: A phenomenological study.

Hope is often identified as a central process in psychotherapy, with researchers supporting links between clients' hope, symptom distress, and process variables. However, this body of literature is yet to specifically ask what it means for psychotherapists to have hope for their clients. Our purpose, with this descriptive phenomenological study, was to understand the meaning of therapists' hope for their clients. This information has the potential to better inform how therapists think about their own hope for clients and the ways in which this is transmitted to clients who may enter therapy in a state of hopelessness. To accomplish this, we interviewed psychologists (N = 8) using a semistructured interview protocol. Interviews were transcribed then analyzed in accordance with descriptive phenomenology guidelines. Four themes were identified: (a) a sense of holding and possibility; (b) fundamental, dynamic, and reflective practice; (c) client influence (positive and negative) on hope; and (d) connection through hope. The findings are discussed in light of therapist effects in psychotherapy, the internal world of therapists, and training implications. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Microbiological Diagnostic Performance of Metagenomic Next-generation Sequencing When Applied to Clinical Practice.

Background: Metagenomic next-generation sequencing (mNGS) was suggested to potentially replace traditional microbiological methodology because of its comprehensiveness. However, clinical experience with application of the test is relatively limited. Methods: From April 2017 to December 2017, 511 specimens were collected, and their retrospective diagnoses were classified into infectious disease (347 [67.9%]), noninfectious disease (119 [23.3%]), and unknown cases (45 [8.8%]). The diagnostic performance of pathogens was compared between mNGS and culture. The effect of antibiotic exposure on detection rate was also assessed. Results: The sensitivity and specificity of mNGS for diagnosing infectious disease were 50.7% and 85.7%, respectively, and these values outperformed those of culture, especially for Mycobacterium tuberculosis (odds ratio [OR], 4 [95% confidence interval {CI}, 1.7-10.8]; P < .01), viruses (mNGS only; P < .01), anaerobes (OR, ∞ [95% CI, 1.71-∞]; P < .01) and fungi (OR, 4.0 [95% CI, 1.6-10.3]; P < .01). Importantly, for mNGS-positive cases where the conventional method was inconclusive, 43 (61%) cases led to diagnosis modification, and 41 (58%) cases were not covered by empirical antibiotics. For cases where viruses were identified, broad-spectrum antibiotics were commonly administered (14/27), and 10 of 27 of these cases were suspected to be inappropriate. Interestingly, the sensitivity of mNGS was superior to that of culture (52.5% vs 34.2%; P < .01) in cases with, but not without, antibiotic exposure. Conclusions: mNGS could yield a higher sensitivity for pathogen identification and is less affected by prior antibiotic exposure, thereby emerging as a promising technology for detecting infectious diseases.

Parental occupational exposures to endocrine disruptors and the risk of simple isolated congenital heart defects.

This study aims to explore the associations between parental occupational exposures to endocrine disruptors (EDs) and simple isolated congenital heart defects (CHDs). A case-control study with standardized data collection involving 761 children with isolated CHDs and 609 children without any congenital malformations was conducted in Sichuan Province of China from March in 2012 to August in 2013. An adjusted job exposure matrix was used for occupational EDs exposure assessment. Logistic regression analysis was performed to assess the associations between parental occupational EDs exposures and CHDs. Maternal age at births, maternal education level, gravity, parity, induced abortion, folic acid use, medication use, drinking capacity and area of residence periconceptionally were selected as confounding factors for mothers. For fathers, we selected the following confounding factors: paternal education level, smoking, drinking frequencies and drinking capacity periconceptionally. Maternal occupational exposures to phthalates are associated with perimembranous ventricular septal defect (PmVSD) (P = 0.001, adjusted OR 3.7, 95 % CI 1.7-8.0), patent ductus arteriosus (PDA) (P = 0.002, adjusted OR 3.8, 95 % CI 1.6-8.9), secundum atrial septal defect (s-ASD) (P = 0.008, adjusted OR 3.5, 95 % CI 1.4-8.7) and pulmonary valve stenosis (PS) (P = 0.035, adjusted OR 4.2, 95 % CI 1.1-16.0), to alkylphenolic compounds and PmVSD (P = 0.003, adjusted OR 2.2, 95 % CI 1.3-3.6), PDA (P = 0.005, adjusted OR 2.0, 95 % CI 1.1-3.5) and PS (P = 0.004, adjusted OR 3.8, 95 % CI 1.5-9.4), to heavy metals with PmVSD (P = 0.003, adjusted OR 7.3, 95 % CI 2.0-27.6) and s-ASD (P = 0.034, adjusted OR 6.5, 95 % CI 1.1-36.7). Paternal occupational exposures to phthalates are associated with PmVSD (P = 0.035, adjusted OR 1.6, 95 % CI 1.0-2.4) and PS (P = 0.026, adjusted OR 2.4, 95 % CI 1.1-5.2), to alkylphenolic compounds (P = 0.027, adjusted OR 1.5, 95 % CI 1.0-2.2) with PmVSD. In conclusion, parental occupational exposures to some specific EDs, in particular phthalates and alkylphenolic compounds, are associated with an increased risk of some CHD phenotypes. However, the findings need to be considered more circumspectly regarding a crude measure of exposure probabilities and small numbers.

Enhanced efficiency of cadmium removal by Boehmeria nivea (L.) Gaud. in the presence of exogenous citric and oxalic acids.

Boehmeria nivea (L.) Gaud. is a potential candidate for the remediation of Cd contaminated sites. The present investigation aims to explore Cd tolerance threshold and to quickly identify the role of exogenous organic acids in Cd uptake and abiotic metal stress damage. Elevated Cd levels (0-10mg/L) resulted in an obvious rise in Cd accumulation, ranging from 268.0 to 374.4 in root and 25.2 to 41.2mg/kg dry weight in shoot, respectively. Citric acid at 1.5 mmol/L significantly facilitated Cd uptake by 26.7% in root and by 1-fold in shoot, respectively. Cd translocation efficiency from root to shoot was improved by a maximum of 66.4% under 3 mmol/L of oxalic acid. Citric acid exhibited more prominent mitigating effect than oxalic acid due to its stronger ligand affinity for chelating with metal and avoiding the toxicity injury of free Cd ions more efficiently. The present work provides a potential strategy for efficient Cd remediation with B. nivea.

Data-Driven Indirect Iterative Learning Control.

In this work, a data-driven indirect iterative learning control (DD-iILC) is presented for a repetitive nonlinear system by taking a proportional-integral-derivative (PID) feedback control in the inner loop. A linear parametric iterative tuning algorithm for the set-point is developed from an ideal nonlinear learning function that exists in theory by utilizing an iterative dynamic linearization (IDL) technique. Then, an adaptive iterative updating strategy of the parameter in the linear parametric set-point iterative tuning law is presented by optimizing an objective function for the controlled system. Since the system considered is nonlinear and nonaffine with no available model information, the IDL technique is also used along with a strategy similar to the parameter adaptive iterative learning law. Finally, the entire DD-iILC scheme is completed by incorporating the local PID controller. The convergence is proved by applying contraction mapping and mathematical induction. The theoretical results are verified by simulations on a numerical example and a permanent magnet linear motor example.

Effect of Nitrogen on Precipitate Characteristics and Pitting Resistance of Martensitic Stainless Steel.

High-carbon-chromium martensitic stainless steel (MSS) is widely used in many fields due to its excellent mechanical properties, while the coarse eutectic carbide in MSS deteriorates corrosion resistance. In this work, nitrogen was added to the MSS to improve corrosion resistance. The effects of nitrogen on the microstructure and corrosion resistance of MSS were systematically studied. The results showed that the addition of nitrogen promoted the development of Cr2N and reversed austenite, effectively inhibiting the formation of δ-ferrite. Therefore, the durability of the passivation film was improved, the passivation zone was expanded, and the susceptibility to metastable pitting was decreased. As a consequence, nearly two orders of magnitude have been achieved in the pitting potential (Epit) of MSS containing nitrogen, and the polarization resistance value (Rp) has gone up from 4.05 kΩ·cm2 to 1.24 × 102 kΩ·cm2. This means that in a corrosive environment, nitrogen-treated MSS stainless steel is less likely to form pitting pits, which further extends the service life of the material.

Data-Driven Dynamic Internal Model Control.

A data-driven dynamic internal model control (D3IMC) scheme is proposed for unknown nonlinear nonaffine systems bypassing modeling steps. Different from the traditional internal model constructed by either a first-principle or an identified model, a dynamic internal model (DIM) is developed in this work using I/O data where a compact form dynamic linearization approach is introduced for addressing the nonlinearity and nonaffine structure. Then, the D3IMC is proposed with both a nominal control algorithm and an uncertainty compensation control algorithm. The former can quickly respond to the feedback errors and the latter can compensate the model-plant mismatch and external disturbances. Meanwhile, the adaptive parameter updating law in the proposed D3IMC method inherits the robustness against uncertainties. A nominal D3IMC is also designed without including the compensator when there is no exogenous disturbance since the adaptive mechanism can handle system uncertainty. Further, the results are extended and a full-form dynamic linearization-based D3IMC is developed to address control of nonlinear systems with more complex dynamics. All the proposed D3IMC methods are data-driven without need of an explicit model, and thus they are significant extensions from the traditional model-based IMC. Simulation study verifies the results.

Research on the Mechanism and Material Basis of Corn (Zea mays L.) Waste Regulating Dyslipidemia.

Corn (Zea mays L.) is an essential gramineous food crop. Traditionally, corn wastes have primarily been used in feed, harmless processing, and industrial applications. Except for corn silk, these wastes have had limited medicinal uses. However, in recent years, scholars have increasingly studied the medicinal value of corn wastes, including corn silk, bracts, husks, stalks, leaves, and cobs. Hyperlipidemia, characterized by abnormal lipid and/or lipoprotein levels in the blood, is the most common form of dyslipidemia today. It is a significant risk factor for atherosclerosis and can lead to cardiovascular and cerebrovascular diseases if severe. According to the authors' literature survey, corn wastes play a promising role in regulating glucose and lipid metabolism. This article reviews the mechanisms and material basis of six different corn wastes in regulating dyslipidemia, aiming to provide a foundation for the research and development of these substances.

Evaluation of the effect of GSK-3ß on liver cancer based on the PI3K/AKT pathway.

The PI3K/AKT/GSK-3ß signaling pathway plays a pivotal role in numerous physiological and pathological processes, including cell proliferation, apoptosis, differentiation, and metabolic regulation. Aberrant activation of the PI3K/AKT pathway is intricately linked to development of tumor. GSK-3ß, belonging to the serine/threonine protein kinase family, is crucial in the pathogenesis of liver cancer. As a key rate-limiting enzyme in the glucose metabolism pathway, GSK-3ß significantly impacts the growth, proliferation, metastasis, and apoptosis of liver cancer cells. It is also implicated in chemotherapy resistance. Elevated expression of GSK-3ß diminishes the sensitivity of liver cancer cells to chemotherapeutic agents, thereby playing a substantial role in the development of drug resistance. Consequently, targeting of GSK-3ß, particularly within the PI3K/AKT signaling pathway, is regarded as a promising therapeutic strategy for liver cancer. The precise identification and subsequent modulation of this pathway represent a substantial potential for innovative clinical interventions in the management of liver cancer.

Double Dynamic Linearization-Based Higher Order Indirect Adaptive Iterative Learning Control.

In this article, a higher order indirect adaptive iterative learning control (HO-iAILC) scheme is developed for nonlinear nonaffine systems. The inner loop adopts a P -type controller whose set-point is updated iteratively by learning from the iterations. To this end, an ideal nonlinear learning control law is designed in the outer loop. It is then transferred to a linear parametric-learning controller with a corresponding parameter estimation law by introducing an iterative dynamic linearization (IDL) method. This IDL method is also used to gain an iterative linear data model of the nonlinear system. A parameter iterative updating algorithm is utilized for estimating the unknown parameters of the obtained linear data model. Finally, the HO-iAILC is presented that utilizes additional error information to improve the control performance and employs two iterative adaptive mechanisms to deal with uncertainties. The convergence of the proposed HO-iAILC scheme is proved by using two basic mathematical tools, namely: 1) contraction mapping and 2) mathematical induction. Simulation studies are conducted for the verification of the theoretical results.

LncRNA LINC01569 promotes M2 macrophage polarization to accelerate hypopharyngeal carcinoma progression through the miR-193a-5p/FADS1 signaling axis.

Background: Long non-coding RNA (lncRNA) LINC01569 plays an important role in regulating the tumor microenvironment (TME) and macrophage polarization. However, whether it participates in the progression of hypopharyngeal carcinoma by regulating the TME remains unclear. Methods: An online database was used to analyze clinical data. Macrophage polarization was detected using qRT-PCR and flow cytometry. In vivo experiments were performed using tumor-bearing nude mice. A co-culture system of hypopharyngeal carcinoma cells and macrophages was used to explore the interactions between the two cell types. Results: LINC01569 enhancement was observed in hypopharyngeal carcinoma tumor-associated macrophages (TAMs). In IL4-induced M2 macrophages, the expression of LINC01569 increased, while LINC01569 expression declined significantly in LPS-induced M1 macrophages. SiRNA-mediated downregulation of LINC01569 inhibits IL4-induced M2 macrophage polarization. Using online databases and a dual-luciferase reporter, miR-193a-5p was confirmed as a potential downstream sponge of LINC01569. MiR-193a-5p expression decreased in IL4-mediated M2 macrophages, which was restored by LINC01569 downregulation. Additionally, LINC01569 inhibition-mediated blocking of M2 macrophage polarization was moderately abolished by transfection with the miR-193a-5p inhibitor. Fatty acid desaturase 1 (FADS1) was verified as a downstream target of miR-193a-5p, and LINC01569 downregulation-mediated inhibition of FADS1 was blocked by miR-193a-5p mimics. Importantly, LINC01569 downregulation-mediated decline in M2 macrophage polarization was abolished by miR-193a-5p mimics, which was further reversed by FADS1 knockdown. Implantation of a mixture of FaDu cells and IL4-induced macrophages promoted tumor growth and proliferation, which were abrogated by the knockdown of LINC01569 in macrophages. Using an in co-culture system of FaDu cells and macrophages in vitro, M2 macrophage-regulated cell growth and apoptosis of FaDu cells were found to be mediated by the LINC01569/miR-193a-5p signaling axis. Conclusion: LINC01569 is highly expressed in the TAMs of hypopharyngeal carcinoma. LINC01569 downregulation restrains macrophages from polarizing toward M2 through the miR-193a-5p/FADS1 signaling axis, thereby helping tumor cells escape inherent immune surveillance and promoting the occurrence and development of hypopharyngeal carcinoma.

A narrative study of unforgettable dying stories of Chinese patients in the intensive care unit: an eight-year experience.

To describe individual perspectives and reflections on unforgettable stories about dying over an eight-year period, in a mixed surgical and general intensive care unit (ICU) in China. The study was carried out at the Second Affiliated Hospital of Soochow University. The research was based on personal experience and reflection. Narrative and experiential reflection synthesis were performed for the data analysis. This was done to understand the current situation regarding dying, then to identify and analyze, and finally to put forward some suggestions regarding the experience. The discussion and preparation for death in the ICU may still require further discussion. For a better acceptance of hospice care and high quality and dignity of death and even the donation of organs, it is important that health care providers learn to talk about death with their patients, and to encourage the patients to participate in the decision-making process.

Construction of a pharmaceutical care mode for cancer pain patients in primary care based on the Delphi method: an effective analysis.

Objective: Pain is one of the most common symptoms of cancer patients. Patients with advanced stages of cancer are always transferred to primary medical institutions or treated with home medication due to their specific pathophysiological characteristics. Studies have shown that continuous pharmaceutical care can improve the effectiveness and safety of drug therapy for cancer pain patients in primary care, but no relevant research has been conducted in China. Based on the Delphi method, this study aims to construct a pharmaceutical care mode for cancer pain patients and analyze its effect in drug therapy treatment in primary care in China. Methods: A pharmaceutical care mode for cancer pain patients in primary care was developed through two rounds of expert consensus. A total of 200 cancer pain patients from January 2022 to January 2023 in Nanjing Drum Tower Hospital were recruited and divided into an intervention group and control group. The self-developed pharmaceutical care mode in primary care was conducted in the intervention group, while the traditional pharmaceutical care mode was conducted in the control group. Comparisons between the groups were performed in terms of pain assessment rate, reasonable rate of pain assessment, pain score, and incidence of adverse reactions. Results: The initiative of experts in the two rounds of consultation was 100%, with an authority coefficient of 0.83. The coordination coefficient of the second round was higher than that of the first round, indicating that the consistency of expert opinions was enhanced. There were 100 cases in each group, and 12 and 8 were lost to follow-up in the intervention group and control group, respectively. Compared with the control group, the intervention group had a significantly higher pain assessment rate, a reasonable rate of pain assessment, and a significantly lower pain score and incidence of adverse reactions. Conclusion: Under the scientific and reasonable mode of pharmaceutical care for cancer pain patients at the primary level, standardized drug therapy could significantly enhance the efficacy of treatment, thereby improving the quality of life of patients.

A study protocol for investigating the sonographic characteristics of neonates with critical illness: an observational cohort study.

BACKGROUND: Haemodynamic instability and hypoxaemia are common and serious threats to the survival of neonates. A growing body of literature indicates that critical care ultrasound has become the optimal evaluation tool for sick neonates. However, few studies have described sonographic characteristics of haemodynamics systematically in the neonates with critical illness. This protocol describes a prospective observational cohort study aimed at (1) characterising the sonographic characteristics of the neonates with critical diseases; and (2) assessing the mortality, significant morbidity, utility of vasoactive medications, fluid resuscitation, duration of ventilation, etc. METHODS AND ANALYSIS: This is a single-centre, prospective and observational study conducted in Chengdu Women's and Children's Central Hospital from 1 December 2022 to 31 December 2027. Neonates admitted to the neonatal intensive care unit will be recruited. After inclusion, the neonates will undergo the neonatal critical care ultrasound. The data collected via case report forms include clinical variables and sonographic measures. The primary outcome is to identify the sonographic characteristics of sick neonates with different diseases, and the secondary outcome is to describe the mortality, significant morbidity, utility of vasoactive medications, fluid resuscitation and duration of ventilation. DISCUSSION: Our study provided an organised neonatal critical care ultrasound workflow, which can be applied in practice. Accordingly, this study will first set up large data on the sonographic description of the neonates with critical illness, which can help to understand the pathophysiology of the critical illness, potentially titrating the treatment. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR2200065581; https://www.chictr.org.cn/com/25/showproj.aspx?proj=184095).

Cloning and characterization of the grass carp (Ctenopharyngodon idella) Toll-like receptor 22 gene, a fish-specific gene.

Toll-like receptor 22 (TLR22) is a fish-specific TLR which recognizes double-strand (ds) RNA and participates in the innate immune response through the Toll-IL-1R homology domain-containing adaptor protein 1 (TICAM-1). To further investigate how the innate immune system of teleosts responds to viral infections, we cloned the full-length cDNA sequence of grass carp (Ctenopharyngodon idella) TLR22 (CiTLR22). The complete cDNA sequence of CiTLR22 was 3647 bp and encodes a polypeptide of 954 amino acids. Analysis of the deduced amino acid sequence indicated that CiTLR22 has typical structural features of proteins belonging to the TLR family. These included 17 LRR domains (residues 88-634) and one C-terminal LRR domain (LRR-CT, residues 694-745) in the extracellular region, and a TIR domain (residues 801-944) in the cytoplasmic region. Comparison with homologous proteins showed that the deduced CiTLR22 has the highest sequence identity to common carp TLR22 (82.9%). Genomic DNA of CiTLR22 was obtained by long-distance (Ld) PCR and structure analysis revealed that the CiTLR22 gene is encoded by uninterrupted exons. Reverse transcriptase-PCR (RT-PCR) revealed that CiTLR22 is a non-maternal gene. It is prominently expressed in immune relevant tissues such as spleen and head kidney. Quantitative RT-PCR analysis showed that CiTLR22 transcripts were upregulated significantly in immune relevant tissues and blood following grass carp reovirus (GCRV) infection. In the whole genomic sequence, nine single nucleotide polymorphisms (SNPs) were detected. Seven of them were sited in the coding region, and the other two located in the 5' and 3' untranslated region (UTR) respectively. None of the SNPs was associated with the resistance of grass carp to GCRV. These results suggested a role for CiTLR22 in mediating immune protection against viral infection in grass carp.

Detection of H-type bronchoesophageal fistula in a newborn: A case report and literature review.

RATIONALE: Congenital tracheoesophageal fistula (TEF) is a rare developmental malformation. The H subtype accounts for approximately 4% of TEFs. Unlike other TEFs, the H-type is not accompanied by esophageal atresia and has nonspecific clinical symptoms, and its specific anatomical abnormalities are not always readily apparent. Furthermore, none of the currently available diagnostic methods for H-type TEF have absolute sensitivity, resulting in misdiagnoses, and accurate diagnoses are often delayed even until adulthood; in our case, we detected a congenital bronchoesophageal fistula, which is even more rare than regular H-type TEF, through a technique that was not previously reported for newborns, involving bronchoscopy, with methylene blue injected through an esophagoscope. We believe that we have provided this kind of case first in newborns.Furthermore, because there is not one literature summarizing the clinical symptoms and the effective methods up to now, we still are not clear which detective method is more efficient or accurate, especially in newborns, so it is very necessary to summarize and compare for improving the early diagnosis of TEFs; our study makes a significant contribution to the literature because we collated previously reported cases, including the clinical features and the usefulness and success rates of major tests, which will be very helpful for the early diagnosis of TEFs. PATIENT CONCERNS: A newborn male presented with an array of nonspecific clinical symptoms from birth, leading to pneumonia and mechanical ventilation. Oral feeding led to an improvement in most but not all symptoms, which returned when oral feeding was resumed. A second round of confirmatory tests was still unable to detect the cause. DIAGNOSIS: The diagnosis of H-type bronchoesophageal fistula was established through a technique that was not previously reported for newborns, involving bronchoscopy, with methylene blue injected through an esophagoscope. INTERVENTIONS: The surgery was performed after diagnosis, and the bronchoesophageal fistula was successfully repaired. OUTCOMES: The patient was discharged on postoperative day 7, and his status was reported to be normal at a follow-up visit 8 months after surgery. LESSONS: H-type TEF is a rare congenital abnormality, and its early diagnosis is highly difficult, especially bronchoesophageal fistula. Increased oral saliva and air-filled stomachs are characteristic manifestations. Bronchoscopy combined with esophagoscopy can improve the rate of early diagnosis. A combination of tests can improve the detection rate.

Inflammatory factor tumor necrosis factor-α (TNF-α) activates P-glycoprotein (P-gp) by phosphorylating c-Jun and thus promotes transportation in placental cells.

Background: P-glycoprotein (P-gp), encoded by the ABCB1 gene, actively pumps drugs and other xenobiotics from trophoblast cells back into the maternal circulation and thus acts as one of the most critical protectors of the fetus. The effect of tumor necrosis factor-α (TNF-α) on P-gp and molecule-transporting activity remains unknown. The goal of this study was to investigate the role of TNF-α in placental molecule-transporting activity and the underlies mechanisms. Methods: Cultured human placental choriocarcinoma cell lines, Bewo, JEG-3 and JAR, were used in this study. Cultured cells were incubated with 5, 10 and 20 ng/mL of recombinant TNF-α (rTNF-α) for 24 h, respectively, for follow-up experiments. The dimer form and expression of activator protein-1 (AP-1) family members were detected using Western blot (WB) and chromatin immunoprecipitation (ChIP). mRNA and protein expression of ABCB1 were detected using reverse transcriptional quantitative polymerase chain reaction (RT-qPCR) and WB, respectively. Double luciferase labeling was used to verify the concentration of digoxin. Electromobility shift assay (EMSA) and ChIP were used to identify the binding ability of c-Jun to ABCB1 gene promoter. Proliferation and apoptosis of Bewo cells were determined using flow cytometry. Digoxin concentration were determined using dual luciferase labeling method. Results: Administration of rTNF-α upregulated the expression of c-Jun but not JunB or JunD in a dose-dependent manner and promoted the binding of c-Jun to the ABCB1 promoter region in Bewo cells. rTNF-α also increased the uptake of two P-gp-specific substrates, Rh123 and DiOC2(3), a function reversed by the addition of SP600125 and SR11302. We also found that rTNF-α increased the efflux ratio of digoxin, an outcome that was reversed, as expected, by inhibiting c-Jun and P-gp binding activities. Furthermore, we identified that rTNF-α tightly regulates the molecule-transporting activity of P-gp by promoting the phosphorylation of c-Jun. Conclusions: TNF-α activates P-gp to promote placental molecule-transporting activity by directly upregulating c-Jun expression and phosphorylation. These findings demonstrate the clinical significance of TNF-α in modulating the placental barrier, which plays an important role in protecting fetus against harmful drugs.

C1R, CCL2, and TNFRSF1A Genes in Coronavirus Disease-COVID-19 Pathway Serve as Novel Molecular Biomarkers of GBM Prognosis and Immune Infiltration.

Glioblastoma multiforme (GBM) is a prevalent intracranial brain tumor associated with a high rate of recurrence and treatment difficulty. The prediction of novel molecular biomarkers through bioinformatics analysis may provide new clues into early detection and eventual treatment of GBM. Here, we used data from the GTEx and TCGA databases to identify 1923 differentially expressed genes (DEGs). GO and KEGG analyses indicated that DEGs were significantly enriched in immune response and coronavirus disease-COVID-19 pathways. Survival analyses revealed a significant correlation between high expression of C1R, CCL2, and TNFRSF1A in the coronavirus disease-COVID-19 pathway and the poor survival in GBM patients. Cell experiments indicated that the mRNA expression levels of C1R, CCL2, and TNFRSF1A in GBM cells were very high. Immune infiltration analysis revealed a significant difference in the proportion of immune cells in tumor and normal tissue, and the expression levels of C1R, CCL2, and TNFRSF1A were associated with immune cell infiltration of GBM. Additionally, the protein-protein interaction networks of C1R, CCL2, and TNFRSF1A involved a total of 65 nodes and 615 edges. These results suggest that C1R, CCL2, and TNFRSF1A may be used as molecular biomarkers of prognosis and immune infiltration in GBM patients in the future.