B-cell lymphoma with cytokine storm in serosal effusion: A case report and literature review.

RATIONALE: Cytokine storm is now considered to be a systemic inflammatory response, but local cytokine storm may exist in systemic diseases of the blood system. Monitoring of regional cytokine storm is an important clue for the diagnosis of systemic diseases. PATIENT CONCERNS: A 72-years-old male presented to our hospital with multiple serosal effusion without solid mass or enlarged lymph nodes. We found that the level of cytokines in ascites was tens to hundreds of times higher than that in plasma, mainly IL-6 and IL-8. DIAGNOSES: The patient was diagnosed with multiple serous effusion, hemophagocytic syndrome, B-cell lymphoma, Epstein-Barr virus infection, and hypoproteinemia. INTERVENTIONS: During hospitalization, the patient was treated with 5 courses of R-CVEP therapy and supportive treatment. OUTCOMES: After the first R-CVEP regimen, the patient's condition was evaluated as follows: hemophagocytic syndrome improved: no fever; Serum triglyceride 2.36 mmol/L; Ferritin 70.70 ng/L; no hemophagocyte was found in the bone marrow; the lymphoma was relieved, ascites disappeared, and bone marrow cytology showed: the bone marrow hyperplasia was reduced, and small platelet clusters were easily seen. Bone marrow flow cytometry showed that lymphocytes accounted for 13.7%, T cells increased for 85.7%, CD4/CD8 = 0.63, B cells decreased significantly for 0.27%, and NK cells accounted for 10.2%. Blood routine returned to normal: WBC 5.27 × 109/L, HB 128 g/L, PLT 129 × 109/L; Epstein-Barr virus DNA < 5.2E + 02 copies/mL; correction of hypoproteinemia: albumin 39.7 g/L. LESSONS: Cytokines in ascites are significantly higher than those in plasma by tens to hundreds of times, suggesting that "regional cytokine storms" may cause serosal effusion.

Mining the Metabolic Capacity of Clostridium sporogenes Aided by Machine Learning.

Anaerobes dominate the microbiota of the gastrointestinal (GI) tract, where a significant portion of small molecules can be degraded or modified. However, the enormous metabolic capacity of gut anaerobes remains largely elusive in contrast to aerobic bacteria, mainly due to the requirement of sophisticated laboratory settings. In this study, we employed an in silico machine learning platform, MoleculeX, to predict the metabolic capacity of a gut anaerobe, Clostridium sporogenes, against small molecules. Experiments revealed that among the top seven candidates predicted as unstable, six indeed exhibited instability in C. sporogenes culture. We further identified several metabolites resulting from the supplementation of everolimus in the bacterial culture for the first time. By utilizing bioinformatics and in vitro biochemical assays, we successfully identified an enzyme encoded in the genome of C. sporogenes responsible for everolimus transformation. Our framework thus can potentially facilitate future understanding of small molecules metabolism in the gut, further improve patient care through personalized medicine, and guide the development of new small molecule drugs and therapeutic approaches.

Predicting the Elastic Modulus of Recycled Concrete Considering Material Nonuniformity: Mesoscale Numerical Method.

The evaluation of the elastic modulus of recycled concrete is one of the focuses of civil engineering and structural engineering, which is not only related to the stability of building structures but also related to the resource utilization of concrete. Therefore, based on the IRSM method in mesoscale, a novel model for predicting the elastic modulus of recycled concrete is proposed which has the advantages of being low-cost and high-precision, amongst others, compared to theoretical and experimental methods. Then, the influence of coarse aggregate, contact surface, gelling material, and air bubbles on the elastic modulus of recycled concrete is studied. The IRSM model includes four processes: Identification, Reconstruction, Simulation, and Monte Carlo, which can accurately reconstruct the geometric characteristics of coarse aggregate, efficiently reconstruct the coarse aggregate accumulation model, and quickly analyze the elastic modulus of concrete, as well as fully consider the nonuniform characteristics of coarse aggregate distribution and shape. Compared with the experimental results, the error is less than 5%, which verifies the rationality of the IRSM method. The results of the parametric analysis show that the influence of each factor on the elastic modulus of concrete in descending order is elastic modulus of cement, elastic modulus of coarse aggregate, content of coarse aggregate, content of air voids, elastic modulus of contacting surface, and thickness of contacting surface, and the corresponding Pearson's Coefficients are 0.688, 0.427, 0.412, -0.269, 0.188, and -0.061, respectively, in which the content of air voids and thickness of contact surface have a negative effect on the elastic modulus of concrete. These influences mainly affect the deformation resistance (elastic modulus) of concrete through "force chain" adjustment, including the force transfer effect, number of paths, and integrity.

Clinical Features of Paediatric Inflammatory Epidermolysis Bullosa Acquisita: A Case Series Study.

Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal-epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.

Whole-Exome Sequencing Reveals the Genomic Profile and IL6ST Variants as a Prognostic Biomarker of Paraneoplastic Pemphigus-Associated Unicentric Castleman Disease.

Unicentric Castleman disease (UCD) is a rare lymphoproliferative disorder. Paraneoplastic pemphigus (PNP) is a major complication associated with poor UCD prognosis. However, the genomic profiles and prognostic biomarkers of PNP-associated UCD remain unclear. In this study, we performed whole-exome sequencing analysis for 28 matched tumor-normal pairs and 9 tumor-only samples to define the genomic landscape of Chinese patients with PNP-associated UCD. An integrative analysis was performed to identify somatic variants, the mutational signatures, and key pathways in tumors. Besides, we analyzed the relationship among mutated genes, clinical characteristics, and prognosis. Sixty-one somatic mutant genes were identified in >1 patient with PNP-associated UCD. Specifically, IL6ST and PDGFRB were the most frequently mutated genes (32%), followed by DPP6 (18%) and MUC4 (18%). Signaling molecules and interactions, cellular processes, and signal transduction pathways were enriched. Furthermore, we found that poor overall survival was related to IL6ST variants (P = .02). Finally, we classified PNP-associated UCD into 4 genomic subgroups: IL6ST, PDGFRB, IL6ST-PDGFRB, and an unknown subgroup. In summary, we defined the molecular profile of PNP-associated UCD and identified a potential molecular biomarker for predicting prognosis, which may provide therapeutic targets for treating this severe disorder.

Specific residues and conformational plasticity define the substrate specificity of short-chain dehydrogenases/reductases.

Short-chain dehydrogenases/reductases (SDRs) are one of the most prevalent enzyme families distributed among the sequenced microorganisms. Despite the presence of a conserved catalytic tetrad and high structural similarity, these enzymes exhibit different substrate specificities. The insufficient knowledge regarding the amino acids underlying substrate specificity hinders the understanding of the SDRs' roles in diverse and significant biological processes. Here, we performed bioinformatic analysis, molecular modeling, and mutagenesis studies to identify the key residues that regulate the substrate specificities of two homologous microbial SDRs (i.e., DesE and KduD). Further, we investigated the impact of altering the physicochemical properties of these amino acids on enzyme activity. Interestingly, molecular dynamics simulations also suggest a critical role of enzyme conformational flexibility in substrate recognition and catalysis. Overall, our findings improve the understanding of microbial SDR substrate specificity and shed light on future rational design of more efficient and effective biocatalysts.

[Research advances in the etiology and pathogenesis of immunoglobulin A vasculitis]. / å ç–«çƒè›‹ç™½Aè¡€ç®¡ç‚Žç— å› åŠå‘ç— æœºåˆ¶çš„ç ”ç©¶è¿›å±•.

Immunoglobulin A vasculitis (IgAV), also known as Henoch-Schönlein purpura, has complex etiology and pathogenesis which have not been fully clarified. The latest research shows that SARS-CoV-2 and related vaccines, human papilloma vaccine, and certain biological agents can also induce IgAV. Most studies believe that the formation of galactose-deficient IgA1 (Gd-IgA1) and Gd-IgA1-containing immune complex plays a crucial role in the pathogenesis of IgAV. It is hypothesized that the pathogenesis of IgAV is associated with the binding of IgA1 to anti-endothelial cell antibodies. In addition, genetics also constitutes a major focus of IgAV research. This article reviews the new advances in the etiology of IgAV and summarizes the role of Gd-IgA1, Gd-IgA1-containing immune complex, anti-endothelial antibody, IgA1 conjugates, T lymphocyte immunity, and genetic factors in the pathogenesis of IgAV.

Polyethylene Degradation by a Rhodococcous Strain Isolated from Naturally Weathered Plastic Waste Enrichment.

Polyethylene (PE) is the most widely produced synthetic polymer and the most abundant plastic waste worldwide due to its recalcitrance to biodegradation and low recycle rate. Microbial degradation of PE has been reported, but the underlying mechanisms are poorly understood. Here, we isolated a Rhodococcus strain A34 from 609 day enriched cultures derived from naturally weathered plastic waste and identified the potential key PE degradation enzymes. After 30 days incubation with A34, 1% weight loss was achieved. Decreased PE molecular weight, appearance of C-O and C═O on PE, palmitic acid in the culture supernatant, and pits on the PE surface were observed. Proteomics analysis identified multiple key PE oxidation and depolymerization enzymes including one multicopper oxidase, one lipase, six esterase, and a few lipid transporters. Network analysis of proteomics data demonstrated the close relationships between PE degradation and metabolisms of phenylacetate, amino acids, secondary metabolites, and tricarboxylic acid cycles. The metabolic roadmap generated here provides critical insights for optimization of plastic degradation condition and assembly of artificial microbial communities for efficient plastic degradation.

Evaluation of Dupilumab in Patients With Bullous Pemphigoid.

Importance: Dupilumab is a theoretically novel therapy for bullous pemphigoid (BP). However, its effectiveness and safety have yet to be confirmed in a large-scale study. Objective: To assess the efficacy and safety of dupilumab in patients with BP and evaluate factors that potentially affect short-term and long-term outcomes. Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 2021, to July 31, 2022. The median (IQR) follow-up period was 24.6 (11.5-38.4) weeks. This multicenter study was performed in 6 dermatology departments of the National Autoimmune Bullous Diseases Cooperative Group of China. Adult patients with BP that received 300 mg of dupilumab every 2 weeks following an initial dose of 600 mg were included. Patients were eligible if they had a clinical presentation of BP combined with immunological or pathological evidence. Patients with drug-induced BP, with less than 4 weeks of follow-up, and who received dupilumab or any other biologics within 6 months were excluded. Main Outcomes and Measures: The primary outcome was the proportion of patients who achieved disease control within 4 weeks. Disease control was defined as the absence of new lesions and pruritus, combined with the healing of existing lesions. Complete remission rates, relapse rates, changes in Bullous Pemphigoid Disease Area Index (BPDAI) scores, itching numerical rating scale (NRS) scores, laboratory results within 64 weeks, and adverse events (AEs) were also assessed. Results: Among 146 patients (median [IQR] age, 73 [64-85] years; 86 [58.9%] male patients) included in the study, 127 (87.0%) patients achieved disease control within 4 weeks, with a median (IQR) time of 14 (7-14) days. A total of 52 (35.6%) patients achieved complete remission, and 13 (8.9%) patients relapsed during the observation period. The complete remission rate and cumulative relapse rate at week 64 were 62.5% (5 of 8) and 30.9%, respectively. There was rapid and sustained improvement in clinical indicators and laboratory examination results after dupilumab treatment, including BPDAI scores, itching NRS scores, serum anti-BP180 and anti-BP230 antibodies, total IgE levels, and eosinophil count. Of these 146 patients, 107 (73.3%) did not report any AEs. The most common AEs were infections and eosinophilia. Serum anti-BP180 antibody levels of greater than 50 relative units (RU)/mL (OR, 3.63; 95% CI, 0.97-12.61; P = .045) were associated with 4-week disease control, and male patients were more likely to relapse (HR, 10.97; 95% CI, 1.42-84.92; P = .02). Conclusions and Relevance: In this retrospective cohort study, dupilumab treatment was associated with improved clinical symptoms in patients with BP. The safety profile was favorable, although concurrent infection and eosinophilia might pose potential concerns. This study suggests that patients with anti-BP180 antibody levels of at least 50 RU/mL and female sex may respond better.

Safety and efficacy of Pimecrolimus in atopic dermatitis among Chinese infants: a sub-group analysis of a five-year open-label study.

INTRODUCTION: Atopic dermatitis (AD) exhibits difference in immune polarization between Caucasians and Asian races due to which an evaluation of the efficacy and safety of Pimecrolimus (PIM) in Asian population is called for. The current study addresses the need via a sub-group analysis of the PETITE study (NCT00120523) to evaluate the safety and efficacy of PIM in Chinese infants. MATERIALS AND METHODS: Patients with AD (≥3 months-<12 months of age) were randomized in a 1:1 ratio to either PIM 1% cream or topical corticosteroids (TCS). The primary endpoint was safety. The secondary endpoint was efficacy. RESULTS: 120 patients were randomized to either PIM 1% or TCS (n = 61 for PIM, n = 59 for TCS). The most often reported adverse events were reported by similar proportions of patients treated with PIM or TCS. There was a progressive increase in overall IGA treatment success in infants treated with PIM (82.9%, p < .05, 95% CI: 70.4, 95.3) after 26 weeks which was comparable to the TCS group (88.5%, p < .05, 95% CI: 79.8, 97.1). CONCLUSION: PIM showed an early and sustained efficacy in the Chinese sub-population with a substantial corticosteroid-sparing effect in patients with AD.

Heterogeneous kinetics of the OH-initiated degradation of fenthion and parathion.

Fenthion and parathion are two representative kinds of organophosphorus pesticides and widely used in agriculture. They are directly or indirectly released into the atmosphere by spraying or volatilization processes. However, their heterogeneous reactivity toward OH radicals has not yet been well understood. Therefore, this work investigated the heterogeneous kinetics of the OH-initiated degradation of surface-bound fenthion and parathion using a flow reactor. The results showed that OH radicals played an important role in the atmospheric degradation of fenthion and parathion. Their average rate constants were (7.20 ± 0.77) × 10-12 and (10.40 ± 0.60) × 10-12 cm3/(mol· sec) at a relative humidity (RH) and temperature of 35% and 20 °C, respectively, suggesting that they have relatively short lifetimes in the atmosphere. In addition, a negative RH dependence and a positive temperature dependence of the rate constants were observed. The Arrhenius expressions of fenthion and parathion were k2 = (1.34 ± 0.48) × 10-9exp[-(1432.59 ± 105.29)/T] and k2 = (1.96 ± 1.38) × 10-9exp[-(1619.98 ± 222.02)/T], respectively, and their overall activation energy was estimated to be (11.88 ± 0.87) and (13.48 ± 1.83) kJ/mol. The experimental results will update the kinetic data of fenthion and parathion in the atmosphere and be helpful to further understand their atmospheric transportation processes.

[Inhibitory Effect of Cinobufotalin on Macrophage Inflammatory Factor Storm and Its Mechanism].

OBJECTIVE: To investigate the inflammatory effects of Cinobufotalin on monocytes in resting state and macrophages in activated state and its molecular mechanism. METHODS: THP-1 cells were stimulated with Phorbol 12-myristate 13-acetate to induce differentiation into macrophages. Lipopolysaccharides was added to activate macrophages in order to establish macrophage activation model. Cinobufotalin was added to the inflammatory cell model for 24 h as a treatment. CCK-8 was used to detect cell proliferation, Annexin V /PI double staining flow cytometry was used to detect cell apoptosis, flow cytometry was used to detect macrophage activation, and cytometric bead array was used to detect cytokines. Transcriptome sequencing was used to explore the gene expression profile regulated by Cinobufotalin. Changes in the significantly regulated molecules were verified by real-time quantitative polymerase chain reaction and Western blot. RESULTS: 1∶25 concentration of Cinobufotalin significantly inhibited the proliferation of resting monocytes(P<0.01), and induced apoptosis(P<0.01), especially the activated macrophages(P<0.001, P<0.001). Cinobufotalin significantly inhibited the activation of macrophages, and significantly down-regulated the inflammatory cytokines(IL-6, TNF-α, IL-1ß, IL-8) released by activated macrophages(P＜0.001). Its mechanism was achieved by inhibiting TLR4/MYD88/P-IκBa signaling pathway. CONCLUSION: Cinobufotalin can inhibit the inflammatory factors produced by the over-activation of macrophages through TLR4/MYD88/P-IκBa pathway, which is expected to be applied to the treatment and research of diseases related to the over-release of inflammatory factors.

Evaluation of clinical factors and outcome of systemic glucocorticoid therapy discontinuation in patients with pemphigus achieving complete remission.

Therapy discontinuation of systemic glucocorticoid treatment for pemphigus remains uncertain at the clinical end point of complete remission. The objective of this study was to identify the factors associated with achieving complete remission off therapy (CROT) and analyze the occurrence of relapse after therapy discontinuation. A retrospective cohort study was conducted at the Department of Dermatology of Peking University First Hospital. A total of 447 patients with pemphigus treated from 2005 to 2020 were identified. Univariate and multivariate analyses were conducted to analyze the associated factors of CROT and to evaluate the outcomes. The mean age was 48 years (±13.4 years), and 54.6% of the patients were women. During a median follow-up of 59 months (43-87.5 months), 160 of 447 (35.8%) patients achieved CROT after a median treatment duration of 51 months (38-66.2 months). Patients with a shorter therapy duration to complete remission on minimal therapy and negative desmoglein antibodies tested in remission were more likely to achieve early CROT. Thirty-five of 160 (21.9%) patients experienced relapse after CROT. Patients who discontinued therapy without guidance experienced significantly faster and higher occurrences of relapse than those withdrawing under guidance (log-rank p = 0.01). Minimal therapy maintenance ≤8 months from complete remission on minimal therapy and positive desmoglein antibodies tested at withdrawal increased the risk of early relapse after CROT.

[Establishment of a Patient-Derived T-Cell Acute Lymphoblastic Leukemia Xenograft Model in Novel Immunodeficient NCG Mice].

OBJECTIVE: The leukemia cells from patients with T-cell acute lymphoblastic leukemia (T-ALL) were inoculated into NCG mice to establish a stable human T-ALL leukemia animal model. METHODS: Leukemia cells from bone marrow of newly diagnosed T-ALL patients were isolated, and the leukemia cells were inoculated into NCG mice via tail vein. The proportion of hCD45 positive cells in peripheral blood of the mice was detected regularly by flow cytometry, and the infiltration of leukemia cells in bone marrow, liver, spleen and other organs of the mice was detected by pathology and immunohistochemistry. After the first generation mice model was successfully established, the spleen cells from the first generation mice were inoculated into the second generation mice, and after the second generation mice model was successfully established, the spleen cells from the second generation mice were further inoculated into the third generation mice, and the growth of leukemia cells in peripheral blood of the mice in each group was monitored by regular flow cytometry to evaluate the stability of this T-ALL leukemia animal model. RESULTS: On the 10th day after inoculation, hCD45+ leukemia cells could be successfully detected in the peripheral blood of the first generation mice, and the proportion of these cells was gradually increased. On average, the mice appeared listless 6 or 7 weeks after inoculation, and a large number of T lymphocyte leukemia cells were found in the peripheral blood and bone marrow smear of the mice. The spleen of the mice was obviously enlarged, and immunohistochemical examination showed that hCD3+ leukemia cells infiltrated into bone marrow, liver and spleen extensively. The second and third generation mice could stably develop leukemia, and the average survival time was 4-5 weeks. CONCLUSION: Inoculating leukemia cells from bone marrow of patients with T-ALL into NCG mice via tail vein can successfully construct a patient-derived tumor xenografts (PDTX) model.

Variants in KLK11, affecting signal peptide cleavage of kallikrein-related peptidase 11, cause an autosomal-dominant cornification disorder.

BACKGROUND: Mendelian disorders of cornification (MeDOC) are a group of heterogeneous genodermatoses with different genetic bases. The pathogenesis of a substantial group of MeDOC remains to be elucidated. OBJECTIVES: To identify a new causative gene and the pathogenesis of a previously undescribed autosomal-dominant cornification disorder. METHODS: Whole-exome sequencing was performed in three families with the novel cornification disorder to identify the disease-causing variants. As the variants were located around the signal peptide (SP) cleavage site of a kallikrein-related peptidase, SP cleavage, subcellular localization and extracellular secretion of the variants were evaluated in eukaryotic overexpression systems by Western blotting or immunocytochemistry. Then the trypsin-like and chymotrypsin-like proteolytic activity of the peptidase and degradation of its catalytic substrate were assayed using the patients' stratum corneum (SC) samples. The morphology of the lamellar bodies and corneodesmosomes (CDs) in the patients' SC was ultrastructurally examined. A mouse model harbouring the equivalent variant was constructed and evaluated histologically. RESULTS: We identified two heterozygous variants affecting Gly50 in kallikrein-related peptidase (KLK)11 in a familial case and two sporadic cases with the new disorder, which is characterized by early-onset ichthyosiform erythroderma or erythrokeratoderma. KLK11 belongs to the family of kallikrein-related peptidases participating in skin desquamation by decomposing CDs, a process essential for shedding of the SC. In vitro experiments demonstrated that the variants perturbed the SP cleavage of KLK11, leading to subcellular mislocalization and impaired extracellular secretion of the KLK11 Gly50Glu variant. Both trypsin-like and chymotrypsin-like proteolytic activities were significantly decreased in the patients' SC samples. Reduced proteolysis of desmoglein 1 and delayed degeneration of CDs were detected in patients' SC, indicating delayed skin desquamation. Consistently, the patients showed a thickened, dense SC, indicating abnormal skin desquamation. Mice harbouring the homozygous c.131G>A (p.Gly44Glu) Klk11 variant, which is equivalent to KLK11 c.149G>A (p.Gly50Glu) in humans, exhibited hyperkeratosis and abnormal desquamation, partially recapitulating the phenotype. CONCLUSIONS: We provide evidence that variants at Gly50 affecting the SP cleavage of KLK11 cause a new autosomal-dominant cornification disorder with abnormal desquamation. Our findings highlight the essential role of KLKs in maintaining homeostasis of skin keratinization and desquamation.

Establishment and observation of a mouse model of IL-12-CAR-T cell-induced cytokine release syndrome / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：通过构建表达IL-12的小鼠CAR-T细胞，探讨经尾静脉将其输注于小鼠体内建立细胞因子释放综合征（CRS）模型的方法。方法：构建基于靶向鼠源CD19的CAR分子，包装逆转录病毒载体并感染小鼠T细胞构建mCD19-CAR-T、mCD19/IL-12-CAR-T细胞。通过构建小鼠体内胰腺癌Panc02-CD19细胞移植瘤模型，检测mCD19/IL-12-CAR-T细胞的抗肿瘤活性，ELISA法检测两种CAR-T细胞IL-12和IFN-γ分泌水平；经小鼠尾静脉输注mCD19/IL-12-CAR-T 细胞构建CAR-T细胞CRS小鼠模型，流式细胞术检测小鼠血清中IL-6、MCP-1、IL-1、IL-10、TNF-α、IFN-γ等细胞因子的含量，H-E染色法观察荷瘤小鼠肝、脾、肺和肾的病理组织学变化。结果：经过培养扩增的mCD19/IL-12-CAR-T细胞能有效分泌IL-12，CAR阳性率达（56.9±5.4）%；与非靶细胞Panc02或靶细胞Panc02-CD19共培养时，均能高分泌IFN-γ。成功构建小鼠胰腺癌Panc02-CD19细胞移植瘤模型，经小鼠尾静脉注射1×106个mCD19/IL-12-CAR-T细胞能显著抑制移植瘤的生长，但未能诱发严重CRS；输注2×106个mCD19/IL-12-CAR-T细胞后，小鼠出现体质量减轻、血清炎性因子水平升高、组织损伤，最终导致死亡等一系列典型CRS表现。结论：成功构建IL-12-CAR-T细胞诱发的小鼠CRS模型，其稳定性好、重复性高，具有广泛的应用前景。

Discovery of a novel water-soluble, rapid-release triptolide prodrug with improved drug-like properties and high efficacy in human acute myeloid leukemia.

In this work, a series of water-soluble triptolide prodrugs were synthesized, and their triptolide release rate, pharmacokinetic characteristics and anti-tumor effect were measured. We found that inserting glycolic acid as a linker between triptolide and the cyclic amino acid accelerated the release of triptolide from prodrugs into the plasma while preserving its safety. Among them, prodrug TP-P1 was significantly better than Minnelide (the only water-soluble triptolide prodrug in clinical trials) in terms of release rate in plasma and synthetic yield. In mouse models of human acute myeloid leukemia (AML), TP-P1 was effective in reducing xenograft tumors at dose levels as low as 25 µg/kg, and eliminating tumors at dose 100 µg/kg. Furthermore, TP-P1 could significantly enhance the efficacy of FLT3 inhibitors in the treatment of AML. These experimental results showed the potential of TP-P1 as water-soluble prodrugs of triptolide.

Paraneoplastic Pemphigus Autoantibodies Against C-terminus of Desmoplakin Induced Acantholysis In Vitro and In Vivo.

Paraneoplastic pemphigus (PNP) is an autoimmune bullous disease associated with underlying neoplasms and characterized by antibodies against desmoglein 3 (Dsg 3) and plakins. Autoantibodies against desmoglein 3 in sera of patients with PNP have been proven to cause acantholysis in vivo in neonatal mice. As a member of the plakin family, autoantibodies against desmoplakin were detected frequently by immunoprecipitation in the sera of PNP. The recombinant C-terminus of desmoplakin was expressed and purified to adsorb the specific autoantibodies against the C-terminus of desmoplakin. In vitro dispase-dependent keratinocyte dissociation assay and in vivo IgG passive transfer into neonatal mice assay were performed, followed by the electronic microscopy examination and TUNEL assay. We found that anti-C terminus of desmoplakin autoantibodies caused blisters and acantholysis in mice skin at a dose-dependent manner. Moreover, dissociated fragments were observed after incubation with the purified IgG against desmoplakin, compared with normal human IgG (P-value =0.0207). The electronic microscopy examination showed the disconnection of keratin intermediate filaments from desmosomes. Lastly, apoptosis of keratinocytes in the TUNEL assay was all detected in the skins of neonatal mice after injection of the anti-C terminus of desmoplakin autoantibodies. Taken together, the study suggests that autoantibodies against the C-terminus of desmoplakin might be pathogenic in PNP.