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The Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist was developed to improve the reporting quality in clinical practice guidelines (CPGs). CPGs could provide the recommendations for key clinical issues with alternative care options and adherence to them could improve the outcomes. And, high reporting quality CPGs can assist health workers to incorporate the best evidence into the individual practice. There is no evaluation study on the reporting quality of CPGs in bladder cancer (BLCA). This study assessed the reporting quality of CPGs on BLCA and provided new insights for the development of CPGs in this disease.We conducted a systematic search in multiple literature databases, including PubMed, Wanfang, China National Knowledge Infrastructure (CNKI) and China Biology Medicine (CBM) as well as the medical associations and websites of guideline development organizations. Relevant CPGs published between January 2017 and December 2021 were identified. Four trained investigators independently screened the extracted documents to include all eligible CPGs and evaluated whether the items in the RIGHT checklist were reported in each CPG. Subsequently, the reporting rate of each CPG and item, as well as the mean reporting rate of each domain in the RIGHT checklist was calculated.A total of 23 CPGs related to BLCA were finally included, of which, 22 guidelines were written in English and 1 was published in Chinese. The mean reporting rate of the included CPGs was approximately 65%. The reporting rates of the items in each RIGHT domain were 77% for basic information domain, 75% for recommendations domain, 72% for evidence domain, 69% for background domain, 43% for funding and declaration and management of interest domain, 35% for review and quality assurance domain, and 41% for other information domain. The reporting rate was determined as the mean value in Office Excel 2019.The reporting quality of BLCA CPGs related to the domains of funding and declaration and management of interest domain, review and quality assurance domain, and other information domain is poor and warrants improvement in the future.

Cuproptosis is the recently defined regulatory cell death (RCD) that plays essential roles in tumorigenesis and progression. Long noncoding RNAs (lncRNAs) regulate the gene expression through various means. However, the clinical value of cuproptosis-related lncRNAs in bladder cancer (BLCA) remains poorly described.We downloaded the transcriptome sequencing data and clinical information from The Cancer Genome Atlas (TCGA) database. Univariate, multivariate, and lasso Cox regression analyses were performed to construct the prognostic risk signature, the predictive accuracy of which was validated in the subsequent independence and stratification analyses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to explore the underlying molecular mechanisms involved in the signature to explore therapeutic vulnerabilities and potential targets in BLCA. Tumor mutational burden (TMB) and tumor immune dysfunction and exclusion (TIDE) were used to estimate the response to immune checkpoint inhibitors (ICIs). We further explored the potential new drug-target candidates based on the half maximal inhibitory concentration for this patient population.Fifteen cuproptosis-related lncRNAs significantly associated with survival were identified to construct the risk signature based on the normalized expression level and regression coefficient of each gene. The patients with BLCA and high-risk scores defined by the signature were associated with worse survival outcomes. The differentially expressed genes (DEGs) between the 2 risk groups had different biological activity. Furthermore, the patients in the low-risk group exhibited a higher TMB index and a lower TIDE score. The sensitivity of multiple antitumor drugs was negatively related to risk score, including AR-42, AS605240, FK866, TAK-715, and tubastatin A, while the sensitivity of some antitumor drugs, such as AMG-706, BX-795, and RO-3306, were positively correlated with risk score.Our study established and verified a novel clinical risk signature with cuproptosis-related lncRNAs that may predict therapy response and prognosis with robust and stable accuracy in patients with BLCA and enhance the personalized management of this patient population.

Haijun Li,1,* Dongbei Li,2,* Fangman Chen,3 Chao Yang,3 Xiaogai Li,1 Yuan Zhang,1 Chunlan Hua,1 Xiaoxu Ma,1 Xin Zhao,1 Dan Shao,3 Yingshuai Wang,4 Liang Ming1 1Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of China; 2Department of Hematology, Affiliated Tumor Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, 450000, People’s Republic of China; 3Institutes for Life Sciences, School of Biomedical Sciences and Engineering, Guangzhou International Campus, South China University of Technology, Guangzhou, 510630, People’s Republic of China; 4School of Life Science and Technology, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yingshuai WangSchool of Life Science and Technology, Weifang Medical University, Weifang, Shandong, 261053, People’s Republic of ChinaEmail yingshuaiwang1987@163.comLiang MingDepartment of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, People’s Republic of ChinaEmail mingliang3072@163.comPurpose: Antibiotic-resistant bacteria are pathogens that have emerged as a serious public health risk. Thus, there is an urgent need to develop a new generation of anti-bacterial materials to kill antibiotic-resistant bacteria.Methods: Nanosilver-decorated mesoporous organosilica nanoparticles (Ag-MONs) were fabricated for co-delivery of gentamicin (GEN) and nanosilver. After investigating the glutathione (GSH)-responsive matrix degradation and controlled release of both GEN and silver ions, the anti-bacterial activities of Ag-MONs@GEN were systematically determined against several antibiotic-susceptible and antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Furthermore, the cytotoxic profiles of Ag-MONs@GEN were evaluated.Results: The GEN-loaded nanoplatform (Ag-MONs@GEN) showed glutathione-responsive matrix degradation, resulting in the simultaneous controlled release of GEN and silver ions. Ag-MONs@GEN exhibited excellent anti-bacterial activities than Ag-MONs and GEN alone via inducing ROS generation, especially enhancing synergetic effects against four antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Moreover, the IC50 values of Ag-MONs@GEN in L929 and HUVECs cells were 313.6 ± 15.9 and 295.7 ± 12.3 μg/mL, respectively, which were much higher than their corresponding minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values.Conclusion: Our study advanced the development of Ag-MONs@GEN for the synergistic and safe treatment of antibiotic-resistant bacteria.Keywords: mesoporous organosilica nanoparticles, nanosilver, gentamicin, GSH-responsive release, antibiotics-resistant bacteria

Acute myeloid leukemia (AML) is prone to relapse. Targeted therapy with a specific inhibitor of the anti-apoptotic protein Bcl-2 ABT-199 is an effective method for relapsed and refractory patients, but drug resistance is likely, which is primarily related to high Mcl-1 and S100A8 expression. All-trans retinoic acid (ATRA) can inhibit Bcl-2 and Mcl-1 expression. The study purpose was to determine whether ATRA can enhance the antileukemia effect of ABT-199 on AML cells. Our data showed that ATRA combined with ABT-199 exerts a synergistic antileukemic effect by inducing apoptosis and cell cycle arrest in AML. In vivo, combination therapy prolonged the survival of AML xenograft mice. The possible mechanism involves promoting apoptosis through downregulation of S100A8 expression by inhibiting the PI3K/AKT signaling pathway. This study provides a potential treatment strategy and theoretical support for overcoming the clinical ABT-199 resistance problem in AML patients.

Purpose Photodynamic therapy (PDT) with spatiotemporal controlled and noninvasive advantages has obtained growing attention in cancer treatment. Nevertheless, PDT still suffers from self-aggregation-induced photosensitizer quenching and reactive oxygen species (ROS) scavenging in cancer cells with abundant glutathione (GSH) pools, leading to insufficient performance. Methods In this study, we develop a versatile nanocarrier (SSNs) with a disulfide-bond-bridged silica framework for enhanced photo-immunotherapy. Such SSNs spatially confine photosensitizers Ce6 in the matrix to prevent self-aggregation. Under the high GSH level of cancer cells, the disulfide-bond-bridged framework was degradable and triggered the exposure of photosensitizers to oxygen, accelerating the ROS generation during PDT. In addition, GSH depletion via the break of the disulfide-bond increased the ROS level, together resulting in efficient tumor killing outcomes with a considerable immunogenic cell death effect in vitro. Importantly, the SSNs@Ce6 accumulated in the tumor site and exhibited enhanced PDT efficacy with low systemic toxicity in vivo. Results The GEN-loaded nanoplatform (Ag-MONs@GEN) showed glutathione-responsive matrix degradation, resulting in the simultaneous controlled release of GEN and silver ions. Ag-MONs@GEN exhibited excellent anti-bacterial activities than Ag-MONs and GEN alone, especially enhancing synergetic effects against four antibiotic-resistant bacteria including Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis. Moreover, Ag-MONs@GEN showed good biocompatibility on L929 and HUVECS. Conclusion Notably, SSNs@Ce6-mediated PDT completely eradicated 4T1 tumors when combined with the PD-1 checkpoint blockade. Overall, the confinement of photosensitizers in a biodegradable disulfide-bridged-framework provides a promising strategy to unleash the potential of photosensitizers in PDT, especially in combined cancer photo-immunotherapy., Graphical Abstract

BACKGROUND: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy. Clinical practice guidelines (CPGs) on the management of AML have great value in clinical practice. However, the reporting quality of CPGs for AML has not yet been evaluated. This is the first study aiming to evaluate the reporting quality of the most recent AML CPGs published worldwide using the Reporting Items for Practice Guidelines in Healthcare (RIGHT) checklist. METHODS: We systematically searched PubMed, Chinese National Knowledge Infrastructure (CNKI), Wanfang, and Chinese Biomedical Literature (CBM) to extract CPGs for AML published between January 2016 and December 2020. Websites for guideline development organizations and medical associations were also searched. Two independent researchers assessed compliance of the guidelines to each of the 35 checklist items and summarized reporting rates for the 7 domains of the RIGHT checklist. RESULTS: We identified 16 guidelines, of which 3 (18.8%) were written in Chinese and 13 (81.3%) were written in English. The average overall reporting rate of the 16 guidelines was 52.9%, and only 7 CPGs (43.8%) had a reporting rate >50%. The average reporting rates of the 7 domains (basic information; background; evidence; recommendations; review and quality assurance; funding, declaration, and management of interests; and other information) were 79.2%, 62.5%, 38.8%, 53.6%, 21.9%, 32.8%, and 43.8%, respectively. For the 35 checklist items, the average reporting rate was 52.9%, and only 16 items had a reporting rate >50%, of which 5 items were reported by all the guidelines. There was 1 item which was not reported by any of the guidelines. CONCLUSIONS: The reporting quality of recently published AML guidelines remains poor. While the recommendations of CPGs have great value in clinical practice, the reporting quality of CPGs for AML still needs to be improved.

Background: Acute myeloid leukemia (AML) is a hematological malignancy with a low remission rate and a high recurrence rate. The 5-year overall survival rate is only approximately 25%. The overexpression of the antiapoptotic protein Bcl-2 is associated with a lower overall survival rate in AML patients. Venetoclax (ABT199) is a selective inhibitor of Bcl-2 that has a significant effect in AML, but single-drug resistance often occurs due to the high expression of Mcl-1 protein. Chidamide is a histone deacetylase inhibitor that was independently developed in China. Studies have confirmed that chidamide can downregulate the expression levels of Bcl-2 and Mcl-1 and induce apoptosis. We examined whether the combination of venetoclax and chidamide could synergistically inhibit AML.Methods: This study aimed to use AML cell lines and primary cells to study the effects of venetoclax and chidamide combination therapy on AML cell apoptosis, the cell cycle and changes in related signaling pathways in vitro; establish an AML mouse model to observe the efficacy and survival time of combination therapy in vivo; and analyze the drug effects with multi-omics sequencing technology. The changes in gene and protein expression before and after treatment were examined to clarify the molecular mechanism driving the synergistic effect of the two drugs.Results: (1) Both venetoclax and chidamide promoted apoptosis in AML cell lines and primary cells in a time- and concentration-dependent manner. The effect was further enhanced when the two drugs were combined, and they had a synergistic effect (Combination Index < 1). (2) The cell cycle of the AML cell line was arrested in the G1 phase by chidamide monotherapy. The primary cells were arrested in S phase by monotherapy with chidamide or venetoclax. The cell-cycle-blocking effect was further strengthened by the combination of the two drugs. (3) At both the mRNA and protein levels, the expression of Mcl-1 was upregulated by venetoclax and downregulated by chidamide. The expression of Mcl-1 decreased further after combination treatment. (4) Transcriptome sequencing showed that the differentially expressed genes in the combination group compared with the venetoclax monotherapy group were mainly enriched in the PI3K-AKT pathway and JAK2/STAT3 pathway. Moreover, qRT-PCR and Western blotting confirmed the following results. 1) Chidamide downregulated the expression of the AKT gene and P-AKT protein, upregulated the expression of p21, and downregulated the expression of CDK2 and c-myc. 2) The expression of the SOCS3 gene and protein was upregulated, whereas the expression of the JAK2 gene and p-Jak2 protein was downregulated, by chidamide. 3) The expression of the HDAC1 gene and protein was upregulated in the chidamide monotherapy and combination therapy groups. (5) Compared with the monotherapy groups and control group, the combination therapy group exhibited significantly inhibited disease progression and a prolonged survival time among AML mice.Conclusion: First, venetoclax combined with chidamide synergistically promoted apoptosis in AML cell lines and primary cells. Second, transcriptome sequencing, qRT-PCR and Western blotting showed that chidamide synergistically promoted the apoptosis of AML cells by inhibiting the activation of the PI3K/AKT pathway and Jak2/STAT3 pathway. Third, compared with monotherapy, combination therapy with chidamide and venetoclax significantly inhibited tumor progression and prolonged the survival time of mice.、

BACKGROUND: To evaluate whether homoharringtonine (HHT) combined with venetoclax could produce a synergistic anti-acute myeloid leukemia (AML) effect and determine the underlying mechanisms. METHODS: The effect of HHT and venetoclax combination on cell viability, apoptosis, and mitochondrial membrane potential was investigated in vitro using AML cell lines and primary cells. High-throughput mRNA sequencing was used to analyze mRNA level changes after the application of HHT and venetoclax on OCI-AML3 cells. Western blotting was used to verify the changes in protein expression within the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK), phosphatidylinositiol 3-kinase (PI3K)/AKT and p53 pathway. The efficacy of HHT and venetoclax in vivo and their effects on survival time were evaluated in a xenograft model established in severe immunodeficiency (NOD/SCID) mice. RESULTS: Venetoclax and HHT synergistically inhibited the proliferation of AML cells, decreased the mitochondrial membrane potential, and promoted AML cell apoptosis in a time- and concentration-dependent manner. Venetoclax combined with HHT increased the expression of the caspase-3, Poly (ADP-ribose) polymerase (PARP), and γH2AX proteins. HHT enhanced the proapoptotic effect of venetoclax by reducing the expression of myeloid cell leukemia sequence 1 (Mcl-1). HHT arrested AML cells in G1 phase of the cell cycle. HHT enhanced the proapoptotic effect of venetoclax by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway. In vivo experiments confirmed that the combination of HHT and venetoclax could inhibit the growth of tumors in AML xenotransplanted mice and prolong the survival time of tumor-bearing mice. CONCLUSIONS: HHT combined with venetoclax synergistically promoted apoptosis in AML cell lines and primary cells by inhibiting the activation of the MAPK/ERK and PI3K/AKT pathways and activating the p53 pathway.

As a transcription factor, autoimmune regulator (Aire) participates in thymic negative selection and maintains immune tolerance mainly by regulating the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs). Aire is also expressed in dendritic cells (DCs). DCs are professional antigen-presenting cells (APCs) that affect the differentiation of T cells toward distinct subpopulations and participate in the immune response and tolerance, thereby playing an important role in maintaining homeostasis. To determine the role of Aire in maintaining immune tolerance by bone marrow-derived dendritic cells (BMDCs), in the present study we utilized Aire-knockout mice to examine the changes of maturation status and TRAs expression on BMDCs, additionally investigate the differentiation of CD4+ T cells. The results showed that expression of costimulatory molecule and major histocompatibility complex class II (MHC-II) molecule was increased and expression of various TRAs was decreased in BMDCs from Aire-knockout mice. Aire deficiency reduced the differentiation of naïve CD4+ T cells into type 2T helper (Th2) cells and regulatory T cells (Tregs) but enhanced the differentiation of naïve CD4+ T cells into Th1 cells, Th17 cells, and follicular helper T (Tfh) cells. The results demonstrate that Aire expressed by BMDCs plays an important role in the maintenance of homeostasis by regulating TRA expression and the differentiation of T cell subsets.

Steel formwork is used for concrete casting and forming, and plays a key role in the construction of high-rise buildings with asymmetrical large loads. In order to make the inner and outer formwork can be lifted synchronously, the difficult problem of unbalanced inner and outer formwork must also be overcome. According to the synchronization principle of the hydraulic lifting system and the performance parameters of its main components, AMESim model was created and the simulation was done for two hydraulic cylinders bearing the same heavy load and different weight load respectively. Therefore, the synchronization scheme of shunt valve is proposed.

Toll-like receptor 4 (TLR4) is a pattern recognition receptors, a member of the Toll-like receptor family and it serves a role in innate and acquired immunity. It has previously been reported that TLR4 was overexpressed in a variety of tumor tissues and cells, including colorectal cancer, gastric cancer and ovarian cancer. In the tumor microenvironment, the TLR4 signaling pathway may be activated in order to upregulate forkhead box P3 (Foxp3) expression in regulatory T cells (Tregs), and thus enhance the immunosuppressive function of Tregs. Also, inflammatory cytokine release would be increased, which promotes tumor immune system evasion. Additionally, it has previously been reported that TLR4 activation may induce histone methylation changes at multiple sites. However, the effects of the alterations to histone methylation in the process of TLR4-associated tumor immune system evasion are not currently known. Histone methylation serves a critical role in regulating gene expression. Abnormal histone methylation is closely associated with tumor development and progression. In order to investigate the epigenetic mechanisms underlying Foxp3 regulation by TLR4, the human lung adenocarcinoma cell line A549 was used. In the present study, it was revealed that the expression level of H3K9me1/2 histone lysine demethylase 3A (KDM3A) was significantly increased following TLR 4 activation in the lung adenocarcinoma A549 cell line, whereas silencing of KDM3A expression led to significantly reduced Foxp3 expression under TLR4 regulation. This result suggests that KDM3A participates in TLR4 regulation of Foxp3 transcription. Additional analysis revealed that during nuclear transport of Foxp3, KDM3A may directly bind to the Foxp3 promoter and activate its transcription. This results in increased secretion of Foxp3-downstream inhibitory cytokines, including transforming growth factor-β1 (TGF-β1), interleukin 35 (IL-35) and heme oxygenase 1 (HO-1), which have immunosuppressive effects and ultimately facilitate the immune escape of lung cancer cells. From the results, the present study concluded that TLR4 activation promoted the expression of H3K9me1/2 demethylase KDM3A. KDM3A bound directly to the Foxp3 promoter and promoted Foxp3 transcription, thereby inducing the secretion of Foxp3-associated downstream inhibitory cytokines (TGF-β1, IL-35, and HO-1), ultimately facilitating the immune system evasion of lung adenocarcinoma.

The antileukemic activity, mechanisms and serum albumin interactions of an arsenomolybdate, K2Na[AsMo6O21(O2CCH2NH3)3]·6H2O (1), was evaluated in the human leukemia HL-60 and U937 cells. The results indicated that 1 could inhibit the proliferation of both leukemia cell lines in a dose-dependent manner with the 50% lethal concentration (IC50) value of 8.61μM for HL-60 and 14.50μM for U937 at 24h, compare to the positive controls, all-trans retinoic acid (ATRA) with IC50 value of 20.76μM and 14.85μM,and As2O3 with IC50 value of 6.40μM and 8.75μM at 24h, respectively (P

The autoimmune regulator (Aire) protein is a transcriptional activator that is essential in central immune tolerance, as it regulates the ectopic expression of many tissue‑restricted antigens in medullary thymic epithelial cells. Aire expression has also been described in hematopoietic cells, such as monocytes/macrophages and dendritic cells (DCs), in the peripheral immune system. However, the role of Aire expression in peripheral immune system cells, including DCs, remains to be elucidated. In the present study, the effects of secreted cytokines from Aire‑overexpressing DCs on cluster of differentiation (CD)4+ T cell subsets were investigated. The dendritic cell line, DC2.4, which overexpresses Aire, was co‑cultured with CD4+ T cells from splenocytes using Transwell inserts. The results indicate that Aire‑overexpressing cells induce T helper (Th)1 subsets by increasing interleukin (IL)‑12 expression, and induce Th17 subsets by upregulating IL‑6 and transforming growth factor (TGF)‑β production. In addition, it was observed that increased levels of phosphorylated extracellular signal‑regulated kinases and p38 upregulated the expression of cytokines in Aire‑overexpressing cells. These data suggest that Aire may have a role in inducing Th1 and Th17 differentiation by upregulating cytokine expression in DCs.

Objective: Acute myeloid leukemia (AML) is a malignant disease of the hematopoietic system in which arrested maturation, excessive proliferation and inhibition of apoptosis have been observed in the process of hematopoietic stem cell differentiation. Some patients, especially elderly patients, do not tolerate cytotoxic chemotherapy, and some patients are resistant to chemotherapeutic drugs, consequently molecular targeting therapy has brought new hope for AML treatment. Venetoclax (ABT-199) is a selective inhibitor of the antiapoptotic protein Bcl-2. Increased expression of Bcl-2 is an important factor in the inhibition of apoptosis in leukemia cells. The use of a single drug is often limited because of resistance, and a better curative effect can be obtained in combination with other drugs. All-trans retinoic acid (all-trans-retinoic acid, ATRA) was first used by Chinese doctor to treat acute promyelocytic leukemia (APL). Many studies have shown that ATRA can inhibit the expression of Bcl-2 in AML cells and promote apoptosis. We aimed to test for the first time whether the combination of ATRA and venetoclax would produce a stronger anti-AML effect. Methods: The effects of ATRA and ABT-199 on the ABT-199-resistant AML cell lines OCI-AML3 and THP-1 and the sensitive cell lines MV-4-11 and MOLM-13 were observed in vitro. The following methods were used in this study. 1. CCK8 assay was used to detect cell proliferation. 2. Annexin V/FITC and PI double staining were used to detect apoptosis rate by flow cytometry. 3. Flow cytometry was used to detect the expression of CD11b. 4. PI single staining and flow cytometry were used to study the cell cycle. 5. Western blotting was used to detect the expression of Bcl-2, Bax, Mcl-1, PARP, caspase3, GSK-3β and Cyclin-D1 proteins in OCI-AML3 cells. Results:1. Compared with the control group and the ATRA or ABT-199 single drug group, cell proliferation was significantly inhibited in the combined drug group, the apoptosis rate was significantly increased, and the cell cycle was blocked in G1 phase. 2. The expression of CD11b in the ATRA or ABT-199 group and combination group was significantly higher than that in the control group. 3. In OCI-AML3 cells, compared with the ABT-199 drug group, the expression of Bcl-2, Mcl-1 and Cyclin-D1 decreased, and the expression of Bax, cleaved-PARP, cleaved caspase3 and p-GSK-3β expression increased in the combined treatment group. Conclusion: All-trans retinoic acid (ATRA) can enhance the anti-leukemia effect of ABT-199 on AML cell lines by inhibiting cell proliferation as seen by the cell cycle arrest of AML cells in G1 phase, promoting apoptosis and inducing differentiation. ATRA can reverse the drug resistance of AML cells to ABT-199 by inhibiting the expression of Bcl-2 and Mcl-1. Our observations may provide new strategies and theoretical support for the clinical treatment of AML. Key Wor ds :AML, Venetoclax, ATRA, Apoptosis Disclosures No relevant conflicts of interest to declare.

Autoimmune regulator (Aire) plays an indispensable role in maintaining central immune tolerance by promoting the ectopic expression of tissue-restricted antigens (TRAs) in medullary thymic epithelial cells (mTECs) and dendritic cells (DCs), which lead to the deletion of autoreactive T cells or the induction of Tregs and consequently prevent autoimmune disease development. Curing autoimmune diseases has always been a challenge. DC-based immunotherapy represents a new and effective method to establish tolerance. We attempted to transplant Aire-overexpressing bone marrow-derived DCs (Aire-BMDCs) to treat type 1 diabetes (T1D) and to explore a new strategy for autoimmune disease treatment. We observed that the onset of T1D in recipient mice was delayed; insulin autoantibody (IAA) production was significantly decreased; the structure of islets was protected; and the degree of inflammatory infiltration was lower. Furthermore, we found that Aire-BMDCs can promote apoptosis and induce autoreactive CD4+ T cell clonal anergy, inhibit Th1 and Th17 production, and induce Treg production. These results suggest that transplantation of Aire-BMDCs will be a manipulation and effective method for preventing or treating T1D.

The L1 Global Harmonization Team provides recommendations specifically for run acceptance of ligand binding methods used in bioanalysis of macromolecules in support of pharmacokinetics. The team focused on standard curve calibrators and quality controls for use in both pre-study validation and in-study sample analysis, including their preparation and acceptance criteria. The team also considered standard curve editing and the concept of total error.

Background: Congenital heart disease (CHD) represents one of the most prevalent congenital malformations. However, few studies use whole-population screening by colour Doppler ultrasonic diagnostic system to identify CHD among live infants. We estimate the prevalence of CHD and its major risk indicators among infants aged less than 6 months in urban Tianjin, China. Methods: A colour Doppler ultrasonic diagnostic system was used as the screening tool for the diagnosis of CHD. A total of 90796 infants aged less than 6 months, living in the nine urban districts of Tianjin, China, participated in the CHD screening programme between July 2009 and June 2011. Results: A total of 1817 children were identified as having CHD. The overall prevalence of congenital heart disease was 16.4 per 1000 live births among 47697 boys, 24.1 per 1000 live births among 43099 girls, and 20.0 per 1,000 live births among 90796 boys and girls combined. Atrial septal defect was the most common heart lesion of CHD, with the prevalence of 10.6 per 1000 live births. Several maternal antenatal factors, such as older age, pregnant infections, pregnancy-induced hypertension, gestational diabetes, family history of CHD, and lower education level, and several child factors, such as early screening age, lower birthweight and short gestational age, were associated with an increased risk of CHD. Conclusions: The prevalence of CHD of live infants in Tianjin was found to be relatively high by using a colour Doppler ultrasonic diagnostic system to screen CHD. Several maternal factors were associated with CHD risk.

Adverse reactions to medications account for a substantial number of hospitalizations and in some cases fatalities. The nature of the many drug-drug interactions caused by the inhibition of drug-metabolizing enzymes can now be predicted and examined with a greater deal of accuracy due to research developments in the understanding of the drug-metabolizing enzymes. However, the more troubling aspects of drug-drug interactions are the idiosyncratic reactions that are unpredictable and quite often life-threatening. These reactions are often caused by a prior sensitization of a person's immune system to a given drug or class of drugs. The following work offers a technique to examine in a medium-throughput system the cross-reactivity of drugs to antibodies in order to predict if structures share the same antigenic potential toward a sensitized individual. Two commercially important sulfonamide drugs, sulfamethazine and furosemide, were taken and their binding to their respective antibodies were tested in the presence of other structurally related sulfonamide drugs. The BIACORE 3000 biosensor was used for the study and the solution-phase equilibrium assay principle was employed. The data obtained help us determine which drugs can react, and to what extent, with sulfamethazine and furosemide, giving rise to possible allergic or hypersensitivity reactions. Though sulfamethazine and furosemide were used in this study; this principle and methodology can be applied to study any drug molecule-antibody pair.

Objective: To determine whether the group B streptococcal (GBS) polysaccharide exotoxin CM101, which induces a complement-activated cytokine-driven inflammatory response, is present in body fluids of infants with GBS disease. Study design: With a sandwich enzyme-linked immunosorbent assay, CM101 was measured in plasma, urine, and cerebrospinal fluid from newborn infants who were evaluated for possible infection and from older infants with culture-confirmed GBS disease. Results: Urine from 11 newborn infants with culture-confirmed early-onset disease contained large amounts of CM101 (1.0 to 5.5 mg/48 h). Plasma concentrations were 62.6 ± 10.5 μg/mL in these infants and were 69.0 ± 21.2 μg/mL in 4 older infants with late-onset disease. Plasma CM101 concentrations did not correlate with indexes of illness severity, leukocyte counts, or interleukin-6 or interleukin-8 plasma concentrations. CM101 was present in cerebrospinal fluid of 5 infants with meningitis (8.4 ± 1.6 μg/mL). CM101 was not found in control samples. CM101 isolated from urine had molecular weight and sugar composition similar to those obtained from GBS culture media, and they both elicited a comparable pathophysiologic response when infused intravenously in lambs. Conclusions: CM101 is present in infants with GBS disease, and it appears to be the same as CM101 obtained from GBS culture media. (J Pediatr 2000;137:338-44)