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Epstein-Barr virus (EBV) infection is closely linked to several human malignancies including endemic Burkitt's lymphoma, Hodgkin's lymphoma and nasopharyngeal carcinomas (NPC). Latent membrane protein 2 (LMP-2) of EBV plays a pivotal role in pathogenesis of EBV-related tumors and thus, is a potential target for diagnosis and targeted therapy of EBV LMP-2+ malignant cancers. Affibody molecules are developing as imaging probes and tumor-targeted delivery of small molecules. In this study, four EBV LMP-2-binding affibodies (ZEBV LMP-212, ZEBV LMP-2132, ZEBV LMP-2137, and ZEBV LMP-2142) were identified by screening a phage-displayed LMP-2 peptide library for molecular imaging and targeted therapy in EBV xenograft mice model. ZEBV LMP-2 affibody has high binding affinity for EBV LMP-2 and accumulates in mouse tumor derived from EBV LMP-2+ xenografts for 24 h after intravenous (IV) injection. Subsequent fusion of Pseudomonas exotoxin PE38KDEL to the ZEBV LMP-2 142 affibody led to production of Z142X affitoxin. This fused Z142X affitoxin exhibits high cytotoxicity specific for EBV+ cells in vitro and significant antitumor effect in mice bearing EBV+ tumor xenografts by IV injection. The data provide the proof of principle that EBV LMP-2-speicifc affibody molecules are useful for molecular imaging diagnosis and have potentials for targeted therapy of LMP-2-expressing EBV malignancies.

Epidermal growth factor receptor 2 ( ) and programmed cell death ligand 1 (PD-L1) are pivotal therapeutic targets for advanced gastric cancer (GC). Nevertheless, the correlation between them, along with the clinical and genomic characteristics and prognosis differences across distinct molecular subtypes, remains elusive. In this retrospective study, 390 advanced GC patients provided both tumor tissue and paired blood samples for Next-Generation Sequencing (NGS) of 639 tumor-related genes, along with PD-L1 immunohistochemical staining. amplification was further validated using FISH in 254 patients. We analyzed the clinical and molecular characteristics of the subgroups based on amplification and PD-L1 CPS scores. The highest consistency with FISH for amplification was observed when the positive threshold for NGS detection was set to 2.5. mutation rate peaked at 59%, which was significantly higher in cases with amplification (P<0.01). Patients with both amplification and mutations exhibited notably shorter survival rates than cases with only mutations (P<0.05). Furthermore, amplification did not correlate with PD-L1 expression. A stratified analysis of PD-L1 expression revealed distinct clinical and molecular features. When the CPS threshold is set at 5, 10, and 20, PD-L1 positive patients have a significantly higher proportion of high tumor mutational burden (TMB-H) and high microsatellite instability (MSI-H) status compared to PD-L1 negative patients. Additionally, patients with PD-L1 CPS ≥5 demonstrate an enrichment of mutations in key signaling pathways, such as PI3K, TGFβ, and Wnt/β-catenin. Overall, our study highlights the prognostic significance of amplification and TP53 mutations in patients with advanced GC. Stratified analysis of PD-L1 expression may help to identify candidates for targeted immunotherapy in this patient population.

Nasopharyngeal carcinoma (NPC) induced by latent infection with Epstein-Barr virus (EBV) remains the most common head and neck cancer in Southeast Asia, especially in the southern part of China. It is well known that persistent expression of two EBV latent membrane proteins (LMP1/LMP2A) plays a key role in nasopharyngeal carcinogenesis. Therefore, the therapeutic approach of targeting the LMP1/LMP2A protein and subsequently blocking the LMP1/LMP2A-mediated signalling pathway has been considered for treating patients with NPC. Recently, affibody molecules, a new class of small (~6.5 kDa) affinity proteins, have been confirmed to be powerful generalisable tools for developing imaging or therapeutic agents by targeting specific molecules. In this study, three EBV LMP2A N-terminal domain-binding affibody molecules (Z LMP2A-N 85, Z LMP2A-N 110 and Z LMP2A-N 252) were identified by screening a phage-displayed peptide library, and their high affinity and specificity for the EBV LMP2A N-terminal domain were confirmed by surface plasmon resonance (SPR), indirect immunofluorescence, co-immunoprecipitation and near-infrared small animal fluorescence imaging in vitro and in vivo. Moreover, affibody molecules targeting the EBV LMP2A N-terminal domain significantly reduced the viability of the EBV-positive cell lines C666-1, CNE-2Z and B95-8. Further investigations showed that affibody Z LMP2A-N 110 could inhibit the phosphorylation of AKT, GSK-3β and β-catenin signalling proteins, leading to suppression of β-catenin nuclear translocation and subsequent inhibition of c-Myc oncogene expression, which may be responsible for the reduced viability of NPC-derived cell lines. In conclusion, our findings provide a strong evidence that three novel EBV LMP2A N-terminal domain-binding affibody molecules have great potential for utilisation and development as agents for both molecular imaging and targeted therapy of EBV-related NPC.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background Viruses are the main infectious agents of acute respiratory infections in children. We aim to describe the epidemiological characteristics of viral pathogens of acute respiratory tract infections in outpatient children. Methods From April 2018 to March 2019, the results of viral detection using oral pharyngeal swabs from 103,210 children with acute respiratory tract infection in the outpatient department of the Children’s Hospital, Zhejiang University School of Medicine, were retrospectively analyzed. Viral antigens, including adenovirus (ADV), influenza A (FLUA), influenza B (FLUB) and respiratory syncytial virus (RSV), were detected by the colloidal gold method. Results At least one virus was detected in 38,355 cases; the positivity rate was 37.2%. A total of 1910 cases of mixed infection with two or more viruses were detected, and the positivity rate of multiple infection was 1.9%. The ADV positivity rate was highest in the 3–6-year-old group (18.7%), the FLUA positivity rate was highest in the > 6-year-old group (21.6%), the FLUB positivity rate was highest in the > 6-year-old group (6.6%), and the RSV positivity rate was highest in the < 1-year-old group (10.6%). There was a significant difference in the positivity rate of viral infection among different age groups (χ 2  = 1280.7, P  < 0.001). The rate of positive viral infection was highest in winter (47.1%). The ADV infection rate was highest in spring (18.2%). The rates of FLUA and FLUB positivity were highest in winter (28.8% and 3.6%, respectively). The rate of RSV positivity was highest in autumn (17.4%). The rate of positive viral infection in different seasons was significantly different (χ 2  = 6459.1, P  < 0.001). Conclusions Viral infection rates in children differ for different ages and seasons. The positivity rate of ADV is highest in the preschool period and that of RSV is highest in infants; that of FLU increases with age. The total positive rate of viral infection in different seasons is highest in winter, as is the rate of FLU positivity.

Activated phosphoinositide 3-kinase δ syndrome (APDS) is an autosomal dominant primary immunodeficiency caused by gain-of-function (GOF) mutations in PIK3CD or PIK3R1 genes. The phenotypes of APDS are highly variable, ranging from asymptomatic adults to profound immunodeficiency causing early death in childhood. Herein, we reported two pediatric patients with APDS presented with recurrent lung infections, sinusitis, hematuria, and positive anti-neutrophil cytoplasmic antibody (ANCA), previously diagnosed as granulomatosis with polyangiitis (GPA). Bronchoscopy showed mucosal nodule lymphoid hyperplasia in the entire airway. Many inflammatory cells infiltrated around the airway and in the lung parenchyma, and numbers of CD3 + T cells and CD20 + B cells were significantly increased, especially CD3+ T cells. Whole exome sequencing showed that they had the E1021K (c.3061 G >A) mutation in the PIK3CD gene. These are the first reported cases of APDS presenting as childhood-onset GPA. Pediatricians should suspect of APDS in the differential diagnosis of children who present with GPA-like symptoms. Additionally, timely and repeated bronchoscopies could contribute to providing an important diagnostic clue for APDS.

Tuning photocatalytic selectivity towards industrially significant yet thermodynamically unfavourable products remains challenging. Here a Ga-N5 atomic site on macroporous inverse-opal-type carbon nitride (CNIO-GaSA) is designed and synthesized for visible-light-driven direct photosynthesis of hydrogen peroxide from molecular oxygen and water. The conversion of oxygen and water into hydrogen peroxide was found to occur via a metastable two-electron water oxidation and two-electron oxygen reduction pathway. The CNIO-GaSA photocatalyst exhibits a high reactivity of 331.7 μmol g−1 h−1 for H2O2 production, with a solar-to-chemical conversion efficiency of 0.4%, which is much higher than that for natural photosynthesis in plants (∼0.1%). Additionally, CNIO-GaSA installed in a photocatalytic flow system device can kill bacteria with 100% efficiency and retain high stability, indicating this system could be suitable for purifying natural water. Combined experimental characterizations and density functional theory simulations reveal that the intermediate states consisting of hybridized Ga 4p and N 2p from the Ga-N5 site can not only enhance the separation/transfer of charge carriers, but also promote the adsorption/activation of water and the formation of a *OH intermediate, which is the rate-determining step for two-electron water oxidation.Hydrogen peroxide is an important industrial feedstock but its synthesis is energy intensive. Now, a highly efficient Ga-N5 atomic site is reported with a high solar-to-chemical conversion efficiency for direct photocatalysis of water into hydrogen peroxide.

Background Epstein-Barr virus (EBV) infects more than 90% of the population worldwide. However, chronic active EBV infection (CAEBV) is one of the EBV-positive T- or NK-lymphoproliferative diseases with high morbidity and mortality. Here, we report a case of a 9-year girl with CAEBV, successively presenting with polymyositis and coronary artery dilation (CAD). Case presentation The girl complained of fatigue for more than 1 month. Muscle strength examinations had no abnormal findings. Blood chemistries showed elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatine kinase (CK). Magnetic resonance imaging (MRI) showed spotty high-intensity signals in thigh muscles, and electromyogram suggested myogenic damage. The significant findings were positive EBV antibodies (EBVEA-IgG, EBVCA-IgG, and EBVNA-IgG), increased EBV DNA copies in B, T, and NK cells, and positive EBV-encoded small RNA in biopsy muscle specimen. The girl received ganciclovir, intravenous immunoglobulin, and methylprednisolone, and her symptoms improved. On the 45th day of hospitalization, echocardiograph revealed CAD. She received additional anticoagulants and Tocilizumab. Her condition improved and continued to be followed up at the clinic preparing for hematopoietic stem cell transplantation. Conclusions This is the first reported case of CAEBV successively with polymyositis and CAD. This case makes the diagnoses of autoimmune diseases in children more complicated. Careful investigation of hidden CAEBV should be recommended in children with atypical polymyositis or CAD.

Background Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm affecting infants or young children. KHE includes a spectrum of lesions, ranging from small and superficial tumors to large and invasive lesions with Kasabach-Merritt phenomenon (KMP). Currently, no published studies have reported a KHE presenting as thrombocytopenia and Raynaud phenomenon. Case presentation A 2-year-old boy with right hand swelling and thrombocytopenia was admitted to our hospital. His right hand turned swelling and red, even occasionally cyanotic. This condition became worse in response to cool environments and improved with warming, and platelet counts were between 50 ~ 80 × 10^9/L. Physical examination on admission revealed the swelling and frostbite-like rash of the right-hand fingers, and the skin temperature of the right hand was lower than the left. On day 3 of admission, chest CT results showed an irregular mass on the right side of the spine. The puncture biopsy demonstrated positive CD31, D2-40, and FLI1 immunohistochemical staining, but negative GLUT1 staining, confirming the diagnosis of KHE. Furthermore, endothelin-1 (ET1) expression levels significantly increased, and eNOS and A20 expression levels significantly decreased comparing with control patients. The patient received methylprednisolone and sirolimus treatments, and his condition gradually improved during the follow-up. Conclusions We reported the first case of KHE presenting with thrombocytopenia and Raynaud phenomenon. The development of Raynaud phenomenon could be associated with increased ET-1 and reduced eNOS and A20 expressions. Careful differential diagnosis of hidden KHE should be considered in children with thrombocytopenia and Raynaud phenomenon.

Accurately predicting neurosyphilis prior to a lumbar puncture (LP) is critical for the prompt management of neurosyphilis. However, a valid and reliable model for this purpose is still lacking. This study aimed to develop a nomogram for the accurate identification of neurosyphilis in patients with syphilis. The training cohort included 9,504 syphilis patients who underwent initial neurosyphilis evaluation between 2009 and 2020, while the validation cohort comprised 526 patients whose data were prospectively collected from January 2021 to September 2021. Neurosyphilis was observed in 35.8% (3,400/9,504) of the training cohort and 37.6% (198/526) of the validation cohort. The nomogram incorporated factors such as age, male gender, neurological and psychiatric symptoms, serum RPR, a mucous plaque of the larynx and nose, a history of other STD infections, and co-diabetes. The model exhibited good performance with concordance indexes of 0.84 (95% CI, 0.83–0.85) and 0.82 (95% CI, 0.78–0.86) in the training and validation cohorts, respectively, along with well-fitted calibration curves. This study developed a precise nomogram to predict neurosyphilis risk in syphilis patients, with potential implications for early detection prior to an LP.