[Research Progress of CAR-T Cell Immunotherapy in B-Cell Non-Hodgkin's Lymphoma--Review].

Chimeric antigen receptor T (CAR-T) cell therapy is a rapidly developing new immunotherapy in recent years. Compared with other therapies, CAR-T has significant advantages for high-risk and relapsed/refractory B cell non-Hodgkin's lymphoma (B-NHL) patients. Currently, a variety of anti-CD19 CAR-T cells have been approved by the FDA for the treatment of B-NHL, such as axicabtagene ciloleucel, tisagenlecucel, lisocababtagene maraleucel and brexucabtagene autoleucel. In addition, many studies are actively exploring and developing different targeted CAR-T cells, which show great potential in B-NHL. This review briefly summarized the latest research progress on the application of CAR-T in common B-NHL.

[Research Progress of Targeted Therapy for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma --Review].

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is a relatively inert B lymphocyte proliferative disease. In recent years with the launch of new drugs, chemotherapy has been gradually replaced by targeted therapy, which significantly prolongs the survival of patients and reduces the side effects of treatment. At present, BTK inhibitors, PI3K inhibitors, spleen tyrosine kinase (SYK) inhibitors and BCL-2 inhibitors are the most studied targeted therapeutic drugs for CLL/SLL. This article reviews the research progress of different types of targeted therapeutic drugs in the treatment of CLL/SLL.

A sensitive liquid chromatography-tandem mass spectrometry method for determination biomarkers of monoamine neurotransmitter disorders in cerebrospinal fluid.

BACKGROUND: Cerebrospinal fluid (CSF) monoamine neurotransmitters, their precursors and metabolites are essential biomarkers in the diagnosis and follow-up of monoamine neurotransmitter disorders (MNDs). However, their extra low concentrations and potential instability challenge the detection method. Here, we present a method that enables simultaneous quantification of these biomarkers. METHOD: With propyl chloroformate /n-propanol, 16 biomarkers in 50 µL of CSF were derivatized in situ within seconds under an ambient temperature. The derivatives were extracted by ethyl acetate and separated by a reverse phase column followed by mass spectrometric detection. The method was fully validated. Optimal conditions for standard solution preparation and storage, as well as CSF sample handling, were investigated. CSF samples from 200 controls and 16 patients were analyzed. RESULTS: The derivatization reaction stabilized biomarkers and increased sensitivity. Most biomarkers were quantifiable in concentrations between 0.02 and 0.50 nmol/L that were sufficient to measure their endogenous concentrations. The intra- and inter-day imprecision were < 15% for most analytes, and accuracy ranged from 90.3% to 111.6%. The stability study showed that standard stock solutions were stable at -80 °C for six years when prepared in the protection solutions; Analytes in CSF samples were stable for 24 h on wet ice and at least two years at -80 °C; But repeated freeze-thaw should be avoided. With this method, age-dependent reference intervals for each biomarker in the pediatric population were established. Patients with MNDs were successfully identified. CONCLUSION: The developed method is valuable for MNDs diagnosis and research, benefiting from its advantages of sensitivity, comprehensiveness, and high throughput.

High-Altitude Exposure and Time Interval Perception of Chinese Migrants in Tibet.

High-altitude exposure can negatively impact one's ability to accurately perceive time. This study focuses on Chinese migrants who have traveled to the Tibetan plateau and explores the effects of high-altitude exposure on their time interval judgment abilities based on three separate studies. In Study 1, it was found that exposure to high altitudes negatively impacted the time interval judgment functions of the migrants compared with a low-altitude control group; they exhibited a prolonged response time (540 ms: p = 0.006, 95% CI (−1.70 −0.32)) and reduced accuracy (1080 ms: p = 0.032, 95% CI (0.06 1.26)) in certain behavioral tasks. In Study 2, the results showed that high-altitude exposure and sleepiness had an interactive effect on time interval judgment (1080 ms) (p < 0.05, 95% CI (−0.83 −0.40)). To further verify our interaction hypothesis, in Study 3, we investigated the time interval judgment of interactions between acute high-altitude exposure and sleepiness level. The results revealed that the adaptation effect disappeared and sleepiness significantly exacerbated the negative effects of high-altitude exposure on time interval judgment (p < 0.001, 95% CI (−0.85 −0.34)). This study is the first to examine the effects of high-altitude exposure on time interval judgment processing functions and the effects of sleep-related factors on individual time interval judgment.

Isostructural and Multivalent Anion Substitution toward Improved Phosphate Cathode Materials for Sodium-Ion Batteries.

Polyanion-type phosphate materials are highly promising cathode candidates for next-generation batteries due to their excellent structural stability during cycling; however, their poor conductivity has impeded their development. Isostructural and multivalent anion substitution combined with carbon coating is proposed to greatly improve the electrochemical properties of phosphate cathode in sodium-ion batteries (SIBs). Specifically, multivalent tetrahedral SiO4 4- substitute for PO4 3- in Na3 V2 (PO4 )3 (NVP) lattice, preparing the optimal Na3.1 V2 (PO4 )2.9 (SiO4 )0.1 with high-rate capability (delivering a high capacity of 82.5 mAh g-1 even at 20 C) and outstanding cyclic stability (≈98% capacity retention after 500 cycles at 1 C). Theoretical calculation and experimental analyses reveal that the anion-substituted Na3.1 V2 (PO4 )2.9 (SiO4 )0.1 reduces the bandgap of NVP lattice and enhanced its structural stability, Na+ -diffusion kinetics and electronic conductivity. This strategy of multivalent and isostructural anion substitution chemistry provides a new insight to develop advanced phosphate cathodes.

Infection with the dengue RNA virus activates TLR9 signaling in human dendritic cells.

Toll-like receptors (TLRs) are important sensors that recognize pathogen-associated molecular patterns. Generally, TLR9 is known to recognize bacterial or viral DNA but not viral RNA and initiate an immune response. Herein, we demonstrate that infection with dengue virus (DENV), an RNA virus, activates TLR9 in human dendritic cells (DCs). DENV infection induces release of mitochondrial DNA (mtDNA) into the cytosol and activates TLR9 signaling pathways, leading to production of interferons (IFNs). The DENV-induced mtDNA release involves reactive oxygen species generation and inflammasome activation. DENV infection disrupts the association between transcription factor A mitochondria (TFAM) and mtDNA and activates the mitochondrial permeability transition pores. The side-by-side comparison of TLR9 and cyclic GMP-AMP synthase (cGAS) knockdown reveals that both cGAS and TLR9 comparably contribute to DENV-induced immune activation. The significance of TLR9 in DENV-induced immune response is also confirmed in examination with the bone marrow-derived DCs prepared from Tlr9-knockout mice. Our study unravels a previously unrecognized phenomenon in which infection with an RNA virus, DENV, activates TLR9 signaling by inducing mtDNA release in human DCs.

Translational Implication of Galectin-9 in the Pathogenesis and Treatment of Viral Infection.

The interaction between galectin-9 and its receptor, Tim-3, triggers a series of signaling events that regulate immune responses. The expression of galectin-9 has been shown to be increased in a variety of target cells of many different viruses, such as hepatitis C virus (HCV), hepatitis B virus (HBV), herpes simplex virus (HSV), influenza virus, dengue virus (DENV), and human immunodeficiency virus (HIV). This enhanced expression of galectin-9 following viral infection promotes significant changes in the behaviors of the virus-infected cells, and the resulting events tightly correlate with the immunopathogenesis of the viral disease. Because the human immune response to different viral infections can vary, and the lack of appropriate treatment can have potentially fatal consequences, understanding the implications of galectin-9 is crucial for developing better methods for monitoring and treating viral infections. This review seeks to address how we can apply the current understanding of galectin-9 function to better understand the pathogenesis of viral infection and better treat viral diseases.

Dengue virus infection induces interferon-lambda1 to facilitate cell migration.

A marked increase in the rate of dengue virus (DENV) infection has resulted in more than 212 deaths in Taiwan since the beginning of 2015, mostly from fatal outcomes such as dengue hemorrhagic fever and dengue shock syndrome. The pathogenic mechanisms of these fatal manifestations are poorly understood. Cytokines induce an overwhelming immune reaction and thus have crucial roles. Interferon-lambda (IFN-λ), a newly identified IFN subtype, has antiviral effects, but its immunologic effects in DENV infection have not been investigated. In the present study, we show that DENV infection preferentially induced production of IFN-λ1 in human dendritic cells (DCs) and human lung epithelial cells. Virus nonstructural 1 (NS1) glycoprotein was responsible for the effect. DENV-induced production of IFN-λ1 was dependent on signaling pathways involving toll-like receptor (TLR)-3, interferon regulation factor (IRF)-3, and nuclear factor-kappaB (NF-κB). Blocking interaction between IFN-λ1 and its receptor IFN-λR1 through siRNA interference reduced DENV-induced DC migration towards the chemoattractants CCL19 and CCL21, by inhibiting CCR7 expression. Furthermore, IFN-λ1 itself induced CCR7 expression and DC migration. Our study presents the first evidence of the mechanisms and effects of IFN-λ1 induction in DENV-infected DCs and highlights the role of this cytokine in the immunopathogenesis of DENV infection.

Up-regulation of galectin-9 induces cell migration in human dendritic cells infected with dengue virus.

Galectin-9 (Gal-9) exerts immunosuppressive effects by inducing apoptosis in T cells that produce interferon-γ and interleukin (IL)-17. However, Gal-9 can be pro-inflammatory in lipopolysaccharide-stimulated monocytes. Using microarray analysis, we observed that Gal-9 was up-regulated in human dendritic cells (DCs) after dengue virus (DV) infection. The investigation into the immunomodulatory effects and mechanisms of Gal-9 in DCs exposed to DV revealed that DV infection specifically increased mRNA and protein levels of Gal-9 but not those of Gal-1 or Gal-3. Blocking p38, but not c-Jun N-terminal kinase or extracellular signal-regulated kinase (ERK), inhibited DV-induced expression of Gal-9. Reduction in Gal-9 by small interference RNA treatment suppressed DV-stimulated migration of DCs towards the chemoattractants CCL19 and CCL21. In addition, DV-induced IL-12p40 production was reduced after knockdown of Gal-9 in DCs. Furthermore, Gal-9 deficiency suppressed DV-induced activation of nuclear factor-κB. Inhibition of DV-induced DC migration under conditions of Gal-9 deficiency was mediated through suppressing ERK activation but not by regulating the expression of CCR7, the receptor for CCL19 and CCL21. Both the reduction in IL-12 production and the suppression of ERK activity might account for the inhibition of DV-induced DC migration after knockdown of Gal-9. In summary, this study reveals the roles of Gal-9 in DV-induced migration of DCs. The findings indicate that Gal-9 might be a therapeutic target for preventing immunopathogenesis induced by DV infection.

Administration of mycobacterial Ag85A and IL-17A fusion protein attenuates airway inflammation in a murine model of asthma.

Interleukin (IL)-17A contributes to the development of asthma, especially in severe asthma which has characteristic neutrophil infiltration in airways. However, IL-17A-blocking antibody could escalate T helper (Th) 2 cytokines, such as IL-13, IL-4 in murine models. We aimed at determining the effect of mycobacterial Ag85A and IL-17A fusion protein­Ag85A-IL-17A on airway inflammation in a murine model of asthma. IL-17A recombinant protein fused mycobacterial immunodominant antigen Ag85A was constructed, expressed and purified. The fusion protein was then administrated into BALB/c mice and its anti-inflammatory effects in the infiltration of inflammatory cells, Th2/Th17 cytokines in BALF, histopathological changes of lung tissues as well as chemokines in lung tissues were evaluated in the murine model of asthma. We found that administration of mycobacterial Ag85A and IL-17A fusion protein induced IL-17A specific immunoglobulin (Ig)G in sera and significantly decreased IL-17A and IL-6 levels in bronchoalveolar lavage fluid (BALF). Ag85A-IL-17A vaccinated mice also showed marked reduction in the infiltration of inflammatory cells in peribronchiolar region and significant decrease in total cells, eosinophil cells and neutrophil cells in BALF. The increased levels of IL-13 and IL-4 in BALF of ovalbumin-sensitized mice were significantly reduced by the administration of Ag85A-IL-17A. Furthermore, CD3+CD4+IL-13+ splenocytes stimulated with OVA and CXCL1 mRNA, CCL2 mRNA and GATA-3 mRNA expressed in lung tissues were decreased markedly in Ag85A-IL-17A vaccinated group. Our results demonstrate remarkable antiallergic effects of Ag85A-IL-17A in a murine model of asthma and it may have protective effects on allergic asthma.

(E)-(2,4-Dichloro-benzyl-idene)amino cyclo-propane-carboxyl-ate.

In the title compound C(11)H(9)Cl(2)NO(2), the dihedral angle between the benzene and cyclo-propane ring planes is 89.95 (13)°. The carbon-yl-oxime grouping is almost coplanar with the benzene ring [dihedral angle = 4.08 (6)°]. In the crystal, mol-ecules are linked by C-H⋯O inter-actions into [100] chains.

[Effects of andrographolide on the expression of eosinophil granulocytes and possible mechanisms].

OBJECTIVE: Andrographolide, the active component in andrographis paniculata, has potent anti-inflammatory actions. This study aimed to evaluate the effects of andrographolide on eosinophil granulocytes (EOS) and the expression of eotaxin and IL-5 in mice with asthma. METHODS: BALB/c mice were randomly assigned into normal control, asthma, budesonide treatment and andrographolide treatment groups (n=8 each). Mice in the latter three groups were sensitized and challenged with ovalbumin (OVA) to induce asthma. ELISA was used to detect the concentrations of eotaxin and IL-5 in bronchoalveolar lavage fluid (BALF) and peripheral blood. The expression of eotaxin mRNA and IL-5 mRNA in lung tissues was detected by real-time quantitative PCR. RESULTS: Andrographolide treatment significantly decreased EOS count in BALF (P<0.05) and the effect of andrographolide was better than the effect of budesonide. Andrographolide treatment significantly down-regulated the expression of eotaxin and IL-5 in BALF, lung eotaxin mRNA expression and blood IL-5 expression (P<0.05), but the effects of andrographolide were poorer than the effects of budesonide. Andrographolide treatment resulted in a decrease in blood eotaxin expression and lung IL-5 mRNA expression and the effects of andrographolide were similar to budesonide. CONCLUSIONS: Andrographolide can down-regulate the expression of IL-5 and eotaxin and thus suppress the inflitration of EOS in a mouse model of asthma.

2-Diethyl-amino-6-methyl-pyrimidin-4(3H)-one.

The title compound, C(9)H(15)N(3)O, contains four mol-ecules (A, B, C and D) in the asymmetric unit. In the crystal, the A+A and D+D pairs form inversion dimers linked by pairs of N-H⋯O hydrogen bonds. The B+C pairing is linked by the same bonds. The dimers are further linked by weak C-H⋯O inter-actions.

Methyl 4-(4-methyl-benzamido)-2-sulfamoylbenzoate.

The title compound, C(16)H(16)N(2)O(5)S, is a potent new fungicide. There are two mol-ecules in the asymmetric unit which are linked by C-H⋯π inter-actions, forming a dimer. The two phenyl rings in each mol-ecules are almost coplanar, with C-N-C-C torsion angles of 177.6 (2) and -172.5 (2)°. There are inter-molecular and intra-molecular N-H⋯O hydrogen bonds in the crystal structure.