Oral arsenic plus imatinib versus imatinib solely for newly diagnosed chronic myeloid leukemia: a randomized phase 3 trial with 5-year outcomes.

PURPOSE: The synergistic effects of combining arsenic compounds with imatinib against chronic myeloid leukemia (CML) have been established using in vitro data. We conducted a clinical trial to compare the efficacy of the arsenic realgar-indigo naturalis formula (RIF) plus imatinib with that of imatinib monotherapy in patients with newly diagnosed chronic phase CML (CP-CML). METHODS: In this multicenter, randomized, double-blind, phase 3 trial, 191 outpatients with newly diagnosed CP-CML were randomly assigned to receive oral RIF plus imatinib (n = 96) or placebo plus imatinib (n = 95). The primary end point was the major molecular response (MMR) at 6 months. Secondary end points include molecular response 4 (MR4), molecular response 4.5 (MR4.5), progression-free survival (PFS), overall survival (OS), and adverse events. RESULTS: The median follow-up duration was 51 months. Due to the COVID-19 pandemic, the recruitment to this study had to be terminated early, on May 28, 2020. The rates of MMR had no significant statistical difference between combination and imatinib arms at 6 months and any other time during the trial. MR4 rates were similar in both arms. However, the 12-month cumulative rates of MR4.5 in the combination and imatinib arms were 20.8% and 10.5%, respectively (p = 0.043). In core treatment since the 2-year analysis, the frequency of MR4.5 was 55.6% in the combination arm and 38.6% in the imatinib arm (p = 0.063). PFS and OS were similar at five years. The safety profiles were similar and serious adverse events were uncommon in both groups. CONCLUSION: The results of imatinib plus RIF as a first-line treatment of CP-CML compared with imatinib might be more effective for achieving a deeper molecular response (Chinadrugtrials number, CTR20170221).

Predicting the risk of interstitial lung disease in patients with primary Sjögren's syndrome: Novel nomogram and elevated Th2 cells.

OBJECTIVE: Interstitial lung disease (ILD) is one of the most common pulmonary complications in patients with primary Sjögren's syndrome (pSS). This study was performed to identify immunological risk factors of pSS-associated ILD (pSS-ILD) and to further establish and evaluate of nomograms predicting the risk of ILD in patients with pSS. METHODS: A total of 622 patients with pSS (117 with ILD and 505 without lung involvement) and 166 healthy control subjects (HCs) were ultimately recruited to this retrospective study. Routine examination indicators, tumour markers and lymphocyte (LYMP) subpopulations were extracted. Simple and multiple logistic regressions analyses were performed to screen for independent predictors. Restricted cubic splines were used to examine associations of independent predictors with ILD, and a risk assessment model was constructed. A nomogram prediction model was developed, and receiver operating characteristic (ROC) curve analysis was performed to assess its performance. RESULTS: Univariate and multivariate logistic regression analyses showed that the older age, white blood cell (WBC) count, haemoglobin (HB) level, albumin (ALB) level, CA242 level, and the C-reactive protein (CRP)/LYMP ratio (CLR) were independent predictors of pSS-ILD in a linear manner, these factors were integrated and used to construct a nomogram prediction model. The model had clinical predictive value. In addition, the elevated Th2 cells proportion in pSS patients was significantly positively correlated with lung involvement, while it was negatively correlated with HB and ALB levels. Remarkably, the numbers of Th2 cells were correlated with the CLR in both pSS patients and those with pSS-ILD. CONCLUSIONS: Our novel ILD nomogram could be used to assess the risk of ILD in pSS patients with good discrimination ability. As well as, elevated peripheral blood Th2 cell levels may be related to ILD in patients with pSS.

Targeting transcription factors through an IMiD independent zinc finger domain.

Immunomodulatory imide drugs (IMiDs) degrade specific C2H2 zinc finger degrons in transcription factors, making them effective against certain cancers. SALL4, a cancer driver, contains seven C2H2 zinc fingers in four clusters, including an IMiD degron in zinc finger cluster two (ZFC2). Surprisingly, IMiDs do not inhibit growth of SALL4 expressing cancer cells. To overcome this limit, we focused on a non-IMiD degron, SALL4 zinc finger cluster four (ZFC4). By combining AlphaFold and the ZFC4-DNA crystal structure, we identified a potential ZFC4 drug pocket. Utilizing an in silico docking algorithm and cell viability assays, we screened chemical libraries and discovered SH6, which selectively targets SALL4-expressing cancer cells. Mechanistic studies revealed that SH6 degrades SALL4 protein through the CUL4A/CRBN pathway, while deletion of ZFC4 abolished this activity. Moreover, SH6 led to significant 62% tumor growth inhibition of SALL4+ xenografts in vivo and demonstrated good bioavailability in pharmacokinetic studies. In summary, these studies represent a new approach for IMiD independent drug discovery targeting C2H2 transcription factors in cancer.

MicroRNA-193a Promotes Apoptosis in Retinal Neuronal Cells in Early-Stage Diabetic (DM) Rat via Wilms' Tumor Gene 1.

OBJECTIVE: This study aimed to investigate the role and mechanism of microRNA (miR)-193a in promoting apoptosis of retinal neuronal cells in early diabetic (DM) rats. METHODS: Seventy-two male SD-grade rats were selected to establish a DM model by intraperitoneal injection of streptozotocin (STZ), and randomly divided into a control group (blank control group), a DM group (diabetic model group), a DM+miR-NC inhibitor group (miR-193a inhibition negative control group), a DM+miR-193a inhibitor group (miR-193a inhibitor group), DM+miR-NC mimic group (miR-193a overexpression negative control group), DM+miR-193a mimic group (miR-193a overexpression group), with12 rats in each group. RESULTS: The miR-193a expression, apoptosis rate, and Bax, Caspase3, and Caspase9 protein expression levels were elevated, and Bcl-2 protein expression was decreased in the retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells, while miR-193a inhibitors reversed these processes. These dual luciferase reporter assay showed that WT1CDS, and WT1Mut were lower in the miR-193a group than in the miR-NC group (P<0.05); WT1 protein expression was reduced in the retinal tissues of DM rat and high glucose-induced rat retinal neuronal cells, and miR-193a inhibitors increased WT1 protein expression. Compared with cells co-transfected with miR-193a and WT1vector, miR-193a and WT1 cotransfection inhibited high glucose-induced apoptosis in retinal neuronal cells and regulated apoptotic protein expression. miR-193a was highly expressed and WT1 was lowly expressed in retinal tissues of DM rats and high glucose-induced rat retinal neuronal cells. CONCLUSION: miR-193a could inhibit early retinal neuronal cell apoptosis in DM rats by targeting and negatively regulating WT1 expression.

New sights of low dose IL-2: Restoration of immune homeostasis for viral infection.

Viral infection poses a significant threat to human health. In addition to the damage caused by viral replication, the immune response it triggers often leads to more serious adverse consequences. After the occurrence of viral infection, in addition to the adverse consequences of infection, chronic infections can also lead to virus-related autoimmune diseases and tumours. At the same time, the immune response triggered by viral infection is complex, and dysregulated immune response may lead to the occurrence of immune pathology and macrophage activation syndrome. In addition, it may cause secondary immune suppression, especially in patients with compromised immune system, which could lead to the occurrence of secondary infections by other pathogens. This can often result in more severe clinical outcomes. Therefore, regarding the treatment of viral infections, restoring the balance of the immune system is crucial in addition to specific antiviral medications. In recent years, scientists have made an interesting finding that low dose IL-2 (ld-IL-2) could potentially have a crucial function in regulating the immune system and reducing the chances of infection, especially viral infection. Ld-IL-2 exerts immune regulatory effects in different types of viral infections by modulating CD4+ T subsets, CD8+ T cells, natural killer cells, and so on. Our review summarised the role of IL-2 or IL-2 complexes in viral infections. Ld-IL-2 may be an effective strategy for enhancing host antiviral immunity and preventing infection from becoming chronic; additionally, the appropriate use of it can help prevent excessive inflammatory response after infection. In the long term, it may reduce the occurrence of infection-related autoimmune diseases and tumours by promoting the restoration of early immune homeostasis. Furthermore, we have also summarised the application of ld-IL-2 in the context of autoimmune diseases combined with viral infections; it may be a safe and effective strategy for restoring immune homeostasis without compromising the antiviral immune response. In conclusion, focusing on the role of ld-IL-2 in viral infections may provide a new perspective for regulating immune responses following viral infections and improving prognosis.

Preparation of Rechargeable Antibacterial Polypropylene/N-Halamine Materials Based on Melt Blending and Surface Segregation.

Polypropylene (PP) has been widely used in health care and food packaging fields, however, it lacks antibacterial properties. Herein, we prepared the polymeric antibacterial agents (MPP-NDAM) by an in situ amidation reaction between 2,4-diamino-6-dialkylamino-1,3,5-triazine (NDAM) and maleic anhydride grafted polypropylene (MPP) using the melt grafting method. The effects of reaction time and monomer content on the grafting degree of N-halamine were investigated, and a grafting degree of 4.86 wt % was achieved under the optimal reaction conditions. PP/MPP-NDAM composites were further obtained by a melt blending process between PP and MPP-NDAM. With the adoption of surface segregation technology, the content of N-halamine structure on the surface of PP/MPP-NDAM composites was significantly increased. The antibacterial tests showed that the PP/MPP-NDAM composite could achieve 99.9% bactericidal activity against 1.0 × 107 CFU/mL of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) within 10 and 5 min of contact, respectively. The antibacterial effect became more pronounced with the prolongation of chlorinated time, and it could achieve 99.9% bactericidal activity against E. coli within merely 1 min of contact.

Lyoniresinol attenuates cerebral ischemic stroke injury in MCAO rat based on oxidative stress suppression via regulation of Akt/GSK-3ß/Nrf2 signaling.

Stroke is one of the predominant causes of death and disability. Currently, besides thrombolytic therapy, neuroprotection is also generally recognized as a promising way for stroke treatment, which would be very important for the functional recovery of stroke patients. However, it's reported that all the current available neuroprotective drugs have failed in clinical investigations of stroke treatments so far. Lyoniresinol (LNO) is a natural lignan with powerful antioxidant and cytoprotective activities. In this study, OGD/R leaded HT22 cell damage models and Middle Cerebral Artery Occlusion (MCAO) rats were used to investigate the effect of LNO on cerebral ischemic stroke injury and related mechanisms. The cell experiments revealed LNO can suppress the oxygen glucose deprivation-reoxygenation (OGD/R) induced apoptosis of HT22 cells. Subsequently, LNO can improve nerve function deficit and brain injury in MCAO rats with a higher neurological function scores and less infarct size. And the further molecular mechanisms studies suggested LNO activated the PI3K/AKT/GSK-3ß/NRF2 signaling and improved the oxidative stress in cells to inhibit the OGD/R induced apoptosis in HT22 cells. Collectively, our findings would be useflu for the further drug development of LNO as new drug for stroke and its related diseases.

Pterostilbene exerts cytotoxicity on activated hepatic stellate cells by inhibiting excessive proliferation through the crosstalk of Sirt1 and STAT3 pathways.

Pterostilbene (PTE), a natural analogue of resveratrol, abundantly exists in blueberries and grapes and has several beneficial potentials against oxidative stress, inflammation, and cancer. In current study, we investigated the effects of PTE on hepatic fibrosis in vitro and in vivo. Activation of hepatic stellate cells (HSCs) is an initiating event in the initiation of hepatic fibrosis. MTT assay revealed that PTE (3.125-12.5 µM) displayed cytotoxicity on activated HSCs, no cytotoxicity on AML-12 and quiescent HSCs. PTE significantly inhibited the expressions of α-SMA, collagen Ⅰ and TIMP-1/MMP13 ratio; suppressed inflammatory cascade activation to reduce inflammatory cytokines release, such as Caspase-1, IL-1ß and IL-6. PTE activated Sirt1 and decreased STAT3 phosphorylation, functioning as SRT1720 and Niclosamide. Sirt1 deficiency significantly elevated p-STAT3 expression, while STAT3 deficiency resulted in Sirt1 increasing and inhibited fibrosis and inflammatory cytokines expressions. In mice with hepatic fibrosis induced by thioacetamide (TAA), PTE significantly decreased ALT and AST activities, reduced fibrosis markers, STAT3 phosphorylation and activated Sirt1 expression. PTE showed cytotoxicity on activated HSCs to ameliorate hepatic fibrosis via regulating fibrogenesis, energy metabolism and inflammation and targeting the crosstalk of Sirt1 and STAT3. In conclusion, PTE could be potentially beneficial as a natural plant metabolite in preventing and treating hepatic fibrosis.

SALL4B, not targeted by IMiD, is important for SALL4-mediated tumorigenesis.

Oncofetal transcription factor SALL4 is essential for cancer cell survival. 1-5 Recently, several groups reported that immunomodulatory imide drugs (IMiDs) could degrade SALL4 in a proteasome-dependent manner. 6,7 Intriguingly, we observed that IMiDs had no effect on SALL4-positive cancer cells. Further studies demonstrated that IMiDs could only degrade SALL4A, one of the SALL4 isoforms. This finding raises the possibility that SALL4B, the isoform not affected by IMiDs, may be essential for SALL4-mediated cancer cell survival. SALL4B knockdown led to an increase in apoptosis and inhibition of cancer cell growth. SALL4B gain-of-function alone led to liver tumor formation in mice. Our observation that protein degraders can possess isoform-specific effects exemplifies the importance of delineating drug action and oncogenesis at the isoform level to develop more effective cancer therapeutics.

The decreased of peripheral blood natural killer cell is associated with serum IL-2 level in the renal tubular acidosis in patients with primary sjogren's syndrome.

BACKGROUND: Primary Sjogren's Syndrome (pSS) is a lymphoproliferative disease with autoimmune characteristics, which is characterized by lymphocyte infiltration of exocrine glands and involvement and dysfunction of extraglandular organs. Renal tubular acidosis (RTA) is a common renal involvement in pSS. This study investigated the phenotypic characteristics of peripheral blood lymphocyte subsets and cytokines in pSS patients complicated with RTA (pSS-RTA). METHOD: This retrospective study included 25 pSS patients complicated with RTA and 54 pSS patients without RTA (pSS-no-RTA). To examine the level of peripheral lymphocytes subsets, flow cytometry analysis was used. The level of serum cytokines were detected by flow cytometry bead array(CBA). The influencing factors related to the occurrence of pSS-RTA were identified through logistic regression analyze. RESULTS: The absolute number of CD4 + T cells and Th2 cells in peripheral blood were decreased in pSS-RTA patients than pSS-no-RTA patients. Moreover, the absolute number of NK cells and Treg cells were also decreased in pSS-RTA patients than pSS-no-RTA. The level of serum IL-2 was higher in pSS-RTA patients than pSS-no-RTA patients, and is negatively correlated with the number of NK cells, the number and percentage of Th17 cells, and Th17/Treg. Serum IL-2 level is also correlated with various cytokines. Multivariate logistic analysis proved that elevated ESR and ALP were risk factors for pSS complicated with RTA, while Treg was a protective factor. CONCLUSION: The increase of serum IL-2 level and the decrease of peripheral blood NK cells and Treg cells may be the immune mechanism of the development of pSS-RTA disease.

Serine/threonine kinase TBK1 promotes cholangiocarcinoma progression via direct regulation of ß-catenin.

Cholangiocarcinoma (CCA) is a highly heterogeneous and metastatic malignancy with a poor prognosis even after curative hepatectomy. Studies exploring its pathogenesis and identifying effective therapeutic targets are urgently needed. In this study, we found that TANK-binding kinase 1 (TBK1), a serine/threonine-protein kinase, showed a dynamic increase during the different stages of murine spontaneous CCA carcinogenesis (hyperplasia, dysplasia, and CCA). TBK1 was upregulated in human tissues, including intrahepatic (n = 182) and extrahepatic (n = 40) CCA tissues, compared with nontumor tissues, and the elevated expression of TBK1 was positively correlated with larger tumour diameter, lymph node metastasis, and advanced TNM stage. Functional studies indicated that TBK1 promoted CCA growth and metastasis both in vitro and in vivo. TBK1 directly interacts with ß-catenin, promoting its phosphorylation at the S552 site and its nuclear translocation, which further activates EMT-related transcriptional reprogramming. GSK-8612, a TBK1 inhibitor or a kinase-inactivating mutation, effectively suppresses the above processes. In addition, we found that low-density lipoprotein receptor (LDLR), which mediates the endocytosis of cholesterol, was upregulated in CCA. Therefore, we designed a cholesterol-conjugated DNA/RNA heteroduplex oligonucleotide targeting TBK1 (Cho-TBK1-HDO), which could accumulate in CCA cells via LDLR, reduce the TBK1 mRNA level and inhibit intrahepatic metastasis of CCA. Besides, in the experimental group of 182 ICC patients, high TBK1 expression combined with high nuclear ß-catenin expression predicted a worse prognosis. In summary, TBK1 might serve as a potential prognostic biomarker and therapeutic target for patients with CCA.

Recognizing the Differentiation Degree of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cells Using Machine Learning and Deep Learning-Based Approaches.

Induced pluripotent stem cells (iPSCs) can be differentiated into mesenchymal stem cells (iPSC-MSCs), retinal ganglion cells (iPSC-RGCs), and retinal pigmental epithelium cells (iPSC-RPEs) to meet the demand of regeneration medicine. Since the production of iPSCs and iPSC-derived cell lineages generally requires massive and time-consuming laboratory work, artificial intelligence (AI)-assisted approach that can facilitate the cell classification and recognize the cell differentiation degree is of critical demand. In this study, we propose the multi-slice tensor model, a modified convolutional neural network (CNN) designed to classify iPSC-derived cells and evaluate the differentiation efficiency of iPSC-RPEs. We removed the fully connected layers and projected the features using principle component analysis (PCA), and subsequently classified iPSC-RPEs according to various differentiation degree. With the assistance of the support vector machine (SVM), this model further showed capabilities to classify iPSCs, iPSC-MSCs, iPSC-RPEs, and iPSC-RGCs with an accuracy of 97.8%. In addition, the proposed model accurately recognized the differentiation of iPSC-RPEs and showed the potential to identify the candidate cells with ideal features and simultaneously exclude cells with immature/abnormal phenotypes. This rapid screening/classification system may facilitate the translation of iPSC-based technologies into clinical uses, such as cell transplantation therapy.

Decreased absolute number of peripheral regulatory T cells in patients with idiopathic retroperitoneal fibrosis.

Objective: In order to determine whether the immune balance of T helper 17(Th17)/regulatory T(Treg) is related to the pathogenesis of idiopathic retroperitoneal fibrosis (IRPF), we analyzed the differences in peripheral blood lymphocytes, CD4+T cell subsets and cytokines between patients with IRPF and healthy people to clarify the CD4+T cell subsets, especially Treg cell subsets, and the role of cytokines in the pathogenesis of IRPF. Methods: This study included 22 patients with IRPF, 36 patients with IgG4-related diseases (IgG4-RD) without retroperitoneal fibrosis (RPF), and 28 healthy controls. The absolute numbers and percentage of peripheral blood lymphocyte subsets and CD4+T cell subsets in each group were detected by flow cytometry, and the serum cytokine level was detected by flow cytometric bead array (CBA). Results: Compared with the healthy group, the absolute value of B cells in peripheral blood of IRPF patients was significantly decreased, and T, natural killer (NK), CD4+ and CD8+ were not significantly abnormal. The absolute numbers of Th2 cells were lower than healthy group(p=0.043). In particular, the absolute numbers of Treg cells were significantly lower than healthy group(p<0.001), while the absolute numbers of Th17 cells increased(p=0.682). Th17/Treg was significantly higher than healthy group (p< 0.001). Cytokine analysis showed that the level of interleukin (IL)-4 in IRPF patients was higher than healthy group(p=0.011), IL-6, IL-10, IL-17, TNF-α and IFN-γ were significantly higher than healthy group (all p<0.001). Receiver operating characteristic (ROC) curves showed that IL-10 and TNF-α could distinguish bilateral ureteral dilatation in IRPF patients, with areas under the ROC curve (AUCs) of 0.813 (95% CI:0.607-1.000, p=0.026) and 0.950 (95% CI:0.856-1.000, p=0.001), respectively. IL-6 could distinguish bilateral ureteral obstruction, with an AUC of 0.861 (95% CI: 0.682-1.000, p=0.015). Conclusions: Our study showed that IRPF patients had reduced Treg cells and indeed had Th17/Treg imbalance, which may be related to the pathogenesis of the disease. The levels of IL-6, IL-10 and TNF-α appear to be associated with the progression of IRPF.

Low-dose IL-2 therapy restores imbalance between Th17 and regulatory T cells in patients with the dermatomyositis combined with EBV/CMV viremia.

OBJECTIVE: Dermatomyositis (DM) is closely associated with infection, the levels of peripheral lymphocyte subpopulations are rarely studied in patients with DM combined with Epstein-Barr virus (EBV)/cytomegalovirus (CMV) infection. Here, we aimed to observe the level of lymphocyte subsets, especially Th17, regulatory T (Treg) cells in DM combined with EBV/CMV viremia, and explore the effects of short-term low-dose IL-2. METHODS: 34 DM patients combined with EBV/CMV viremia (DM infection group), 31 DM patients without infection (DM non-infection group) and 20 healthy controls were entrolled in our study. In DM infection group, 13 patients received low-dose IL-2 at 0.50 Million IU/day for a five-day course on the basis of conventional treatment. All subjects had completed the decetion of the absolute numbers of lymphocytes subsets in peripheral blood by flow cytometry. RESULTS: The infection group had significant decreases levels of total T, total B, NK, CD4 + T cells and CD4 + T subsets (Th1, Th2, Th17, Treg cells). Compare to the healthy controls, Th17 cells was significantly reduced in the infection group, but not in the non-infection group (P < 0.001 vs. P = 0.171). After low-dose IL-2 therapy, the levels of Treg (P = 0.001) cells and Th17 cells were significantly elevated, re-balancing the Th17 and Treg proportions. CONCLUSIONS: The absolute numbers of Th17 and Treg cells in DM patients with EBV/CMV viremia is further reduced. In addition to Treg cells, a decrease in Th17 cells may be also a crucial feature. Low-dose IL-2 treatment may be beneficial and safe prospect immunomodulatory therapy to restores imbalance between Th17 and Treg cells for these patients. Low-dose IL-2 therapy may be a new prospect field with some challenges such as long-term immunoregulatory utility in various virus infection.

Delivery of antigen to porcine dendritic cells by fusing antigen with porcine dendritic cells targeting peptide.

Dendritic cells (DCs) are professional antigen-presenting cells that can recognize, capture, and process antigens. Fusing molecules targeting DCs with antigens can effectively improve the efficiency with which antigens are recognized and captured by DCs. This targeting strategy can be used for vaccine development to effectively improve the efficiency of antigen recognition and capture by DCs. The targeting sequence of porcine cytotoxic T-lymphocyte associated protein 4 (CTLA4), which binds porcine DCs, was identified in this study. Recombinant Lactobacillus reuteri (L. reuteri) expressing CTLA4-6aa (LYPPPY) and CTLA4-87aa fused to the porcine epidemic diarrhea virus (PEDV) protective antigen core neutralizing epitope (COE) were used to evaluate the ability of the two targeting motifs to bind the B7 molecule on DCs. Our results demonstrate that CTLA4-6aa could bind porcine DCs, and recombinant Lactobacillus expressing the CTLA4-6aa captured by porcine DCs was more efficient than those expressing CTLA4-87aa. In addition, the expression of DC markers, toll-like receptors, and cytokines was significantly higher in the 6aa-COE/L. reuteri-stimulated porcine DCs compared to DCs treated with 87aa-COE/L. reuteri (p<0.01) and recombinant Lactobacillus expressing CTLA4-6aa enhanced the ability of porcine DCs to activate T-cell proliferation. Our analysis of the protein structure revealed that CTLA4-87aa contains intramolecular hydrogen bonds, which may have weakened the intermolecular force between the residues on porcine CTLA4 and that on B7. In conclusion, recombinant Lactobacillus expressing CTLA4-6aa were more efficiently captured by porcine DCs and had a stronger ability to promote DC maturation and enhance T-cell proliferation. The LYPPPY motif is the optimal sequence for binding to porcine DCs. Piglets immunized with recombinant Lactobacillus showed that recombinant Lactobacillus expressing CTLA4-6aa induced significant levels of anti-PEDV-specific IgG and IgA antibody responses. Our study may promote research on DC-targeting strategies to enhance the effectiveness of porcine vaccines.

Immunological risk factors for nonalcoholic fatty liver disease in patients with psoriatic arthritis: New predictive nomograms and natural killer cells.

Objective: To search for the immunological risk factors of Psoriatic arthritis (PsA) combined with nonalcoholic fatty liver disease (NAFLD), development and assessment of predictive nomograms for NAFLD risk in patients with PsA, and to further explore the correlation between risk factors and dyslipidemia. Methds: A total of 127 patients with PsA (46 with NAFLD and 81 without NAFLD) were included in this retrospective study. The clinical and serological parameters of the patients were collected. The percentage and the absolute number of lymphocytes and CD4+T cells were determined by Flow cytometry. Univariate and multivariate binary logistic regression analysis was used to screen independent risk factors of PsA complicated with NAFLD in the model population, and a nomogram prediction model was developed and assessed. Results: (1) Univariate and multivariate logistic regression analysis of the modeling population showed that the percentage of peripheral blood T helper 1 cells (Th1%) (OR=1.12, P=0.001), body mass index (BMI) (OR=1.22, P=0.005) and triglycerides (TG) (OR=4.78, P=0.003) were independent risk factors for NAFLD in patients with PsA, which were incorporated and established a nomogram prediction model. The model has good discrimination and calibration, and also has certain clinical application value. (2) The number of peripheral blood NK cells in PsA patients was significantly positively correlated with serum triglyceride (TG) (r=0.489, P<0.001), cholesterol (CHOL) (r=0.314, P=0.003) and low-density lipoprotein (LDL) (r=0.362, P=0.001) levels. Conclusions: Our study shows that the novel NAFLD nomogram could assess the risk of NAFLD in PsA patients with good efficiency. In addition, peripheral blood NK cell levels may be associated with dyslipidemia in patients with PsA.

Application value of blood metagenomic next-generation sequencing in patients with connective tissue diseases.

Objective: This study aimed to analyze the application value of blood metagenomic next-generation sequencing (mNGS) in patients with connective tissue diseases (CTDs) to provide a reference for infection diagnosis and guidance for treatment. Methods: A total of 126 CTD patients with suspected infections who were hospitalized in the Department of Rheumatology, the Second Hospital of Shanxi Medical University from January 2020 to December 2021 were enrolled in this study. We retrospectively reviewed the results of mNGS and conventional diagnostic tests (CDTs). Results: Systemic lupus erythematosus (SLE) and polymyositis/dermatomyositis (DM/PM) had the highest incidence of infections. The positive pathogen detection rates of mNGS were higher than those of CDT. The virus infections are the most common type in CTD patients with single or mixed infection, especially Human gammaherpesvirus 4 (EBV), Human betaherpesvirus 5 (CMV), and Human alphaherpesvirus 1. The incidence of prokaryote and eukaryote infections is secondary to viruses. Bloodstream infections of rare pathogens such as Pneumocystis jirovecii should be of concern. Meanwhile, the most common mixed infection was bacterial-virus coinfection. Conclusion: mNGS has incremental application value in patients with CTD suspected of co-infection. It has a high sensitivity, and a wide detection range for microorganisms in CTD patients. Furthermore, the high incidence of opportunistic virus infections in CTD patients should be of sufficient concern.

Mesenchymal stem cells and their microenvironment.

Mesenchymal stem cells (MSCs), coming from a wide range of sources, have multi-directional differentiation ability. MSCs play vital roles in immunomodulation, hematopoiesis and tissue repair. The microenvironment of cells often refers to the intercellular matrix, other cells, cytokines and humoral components. It is also the place for cells' interaction. The stability of the microenvironment is pivotal for maintaining cell proliferation, differentiation, metabolism and functional activities. Abnormal changes in microenvironment components can interfere cell functions. In some diseases, MSCs can interact with the microenvironment and accelerate disease progression. This review will discuss the characteristics of MSCs and their microenvironment, as well as the interaction between MSCs and microenvironment in disease.

Dynamic Immune Function Changes Before and After the First Radioactive Iodine Therapy After Total Resection of Differentiated Thyroid Carcinoma.

The effects of total thyroidectomy or radioactive iodine therapy on immune activation and suppression of the tumor microenvironment remain unknown. We aimed to investigate the effects of these treatments on the immune function in patients with differentiated thyroid carcinoma (DTC). Our cohort included 45 patients with DTC treated with total thyroidectomy and radioactive iodine therapy (RAIT). Immune function tests were performed by flow cytometry at 0, 30, and 90 days post-RAIT. Both the percentage and absolute number of circulating regulatory T cells were significantly lower in the postoperative DTC compared to the healthy controls. Notably, the absolute number of multiple lymphocyte subgroups significantly decreased at 30 days post-RAIT compared to those pre-RAIT. The absolute counts of these lymphocytes were recovered at 90 days post-RAIT, but not at pre-RAIT levels. Additionally, the Th17 cell percentage before RAIT was positively correlated with thyroglobulin (Tg) levels after RAIT. The tumor burden might contribute to increased levels of circulating Tregs. In conclusion, RAIT caused transient radiation damage in patients with DTC and the percentage of Th17 cells before RAIT could be a significant predictor of poor prognosis in patients with DTC.

Identification of biomarkers by machine learning classifiers to assist diagnose rheumatoid arthritis-associated interstitial lung disease.

BACKGROUND: This study aimed to search for blood biomarkers among the profiles of patients with RA-ILD by using machine learning classifiers and probe correlations between the markers and the characteristics of RA-ILD. METHODS: A total of 153 RA patients were enrolled, including 75 RA-ILD and 78 RA-non-ILD. Routine laboratory data, the levels of tumor markers and autoantibodies, and clinical manifestations were recorded. Univariate analysis, least absolute shrinkage and selection operator (LASSO), random forest (RF), and partial least square (PLS) were performed, and the receiver operating characteristic (ROC) curves were plotted. RESULTS: Univariate analysis showed that, compared to RA-non-ILD, patients with RA-ILD were older (p < 0.001), had higher white blood cell (p = 0.003) and neutrophil counts (p = 0.017), had higher erythrocyte sedimentation rate (p = 0.003) and C-reactive protein (p = 0.003), had higher levels of KL-6 (p < 0.001), D-dimer (p < 0.001), fibrinogen (p < 0.001), fibrinogen degradation products (p < 0.001), lactate dehydrogenase (p < 0.001), hydroxybutyrate dehydrogenase (p < 0.001), carbohydrate antigen (CA) 19-9 (p < 0.001), carcinoembryonic antigen (p = 0.001), and CA242 (p < 0.001), but a significantly lower albumin level (p = 0.003). The areas under the curves (AUCs) of the LASSO, RF, and PLS models attained 0.95 in terms of differentiating patients with RA-ILD from those without. When data from the univariate analysis and the top 10 indicators of the three machine learning models were combined, the most discriminatory markers were age and the KL-6, D-dimer, and CA19-9, with AUCs of 0.814 [95% confidence interval (CI) 0.731-0.880], 0.749 (95% CI 0.660-0.824), 0.749 (95% CI 0.660-0.824), and 0.727 (95% CI 0.637-0.805), respectively. When all four markers were combined, the AUC reached 0.928 (95% CI 0.865-0.968). Notably, neither the KL-6 nor the CA19-9 level correlated with disease activity in RA-ILD group. CONCLUSIONS: The levels of KL-6, D-dimer, and tumor markers greatly aided RA-ILD identification. Machine learning algorithms combined with traditional biostatistical analysis can diagnose patients with RA-ILD and identify biomarkers potentially associated with the disease.