Role of microRNAs deregulation in initiation of rheumatoid arthritis: A retrospective observational study.

Rheumatoid arthritis (RA) is a joint disorder and is considered an important public health concern nowadays. So, identifying novel biomarkers and treatment modalities is urgently needed to improve the health standard of RA patients. Factors involved in RA pathogenesis are genetic/epigenetic modification, environment, and lifestyle. In the case of epigenetic modification, the expression deregulation of microRNAs and the role of histone deacetylase (HDAC) in RA is an important aspect that needs to be addressed. The present study is designed to evaluate the expression pattern of microRNAs related to the HDAC family. Five microRNAs, miR-92a-3p, miR-455-3p, miR-222, miR-140, and miR-146a related to the HDAC family were selected for the present study. Real-time polymerase chain reaction was used to estimate the level of expression of the above-mentioned microRNAs in 150 patients of RA versus 150 controls. Oxidative stress level and histone deacetylation status were measured using the enzyme-linked immunosorbent assay. Statistical analysis showed significant downregulation (P < .0001) of selected microRNAs in RA patients versus controls. Significantly raised level of HDAC (P < .0001) and 8-hydroxy-2'-deoxyguanosine (P < .0001) was observed in patients versus controls. A good diagnostic potential of selected microRNAs in RA was shown by the receiver operating curve analysis. The current study showed a significant role of deregulated expression of the above-mentioned microRNAs in RA initiation and can act as an excellent diagnostic marker for this disease.

Genome-wide DNA methylation profiling of CD4+ T lymphocytes identifies differentially methylated loci associated with adult primary refractory immune thrombocytopenia.

BACKGROUND: DNA methylation played a crucial role in the pathogenesis of immune thrombocytopenia (ITP). However, genome-wide DNA methylation analysis has not been applied thus far. The present study aimed to provide the first DNA methylation profiling for ITP. METHODS: Peripheral blood CD4+ T lymphocytes samples were collected from 4 primary refractory ITP cases and 4 age-matched healthy controls, and DNA methylome profiling was performed using Infinium MethylationEPIC BeadChip. Differentially methylated CpG sites were further validated in another independent cohort of 10 ITP patients and 10 healthy controls using qRT-PCR. RESULTS: The DNA methylome profiling identified a total of 260 differentially methylated CpG sites mapping to 72 hypermethylated and 64 hypomethylated genes. These genes were mainly enriched in the actin nucleation of the Arp2/3 complex, vesicle transport, histone H3-K36 demethylation, Th1 and Th2 cell differentiation, and Notch signaling pathway according to the GO and KEGG databases. The mRNA expression of CASP9, C1orf109, and AMD1 were significantly different. CONCLUSIONS: Given the altered DNA methylation profiling of ITP, our study provides new insights into its genetic mechanism and suggests candidate biomarkers for the diagnosis and treatment of ITP.

[Effects of miR-144-3p on Proliferation, Cell Cycle and Apoptosis of K562 Cells].

OBJECTIVE: To investigate the effects of miR-144-3p on cell proliferation, cell cycle and apoptosis of blast phase chronic myelogenous leukemia (CML) K562 cells. METHODS: K562 cells were cultured in vitro and mimics negative control, hsa-miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor were respectively transfected into K562 cells with transfection reagents. The cells were divided into five groups including blank control, mimics negative control, miR-144-3p mimics, inhibitor negative control and miR-144-3p inhibitor. After transfection, the cell proliferation activity was detected by CCK-8 assay. The cell cycle distribution and apoptosis were detected by flow cytometry. RESULTS: Compared with the blank control and mimics negative control groups, the proliferation rate of miR-144-3p mimics group was significantly decreased (P<0.05), the proportion of S phase cells was markedly increased (P<0.05), while the proportion of G1 phase cells was obviously decreased (P<0.05), and the apoptosis rate was significantly increased (P<0.05). Compared with the blank control and inhibitor negative control groups, the proliferation rate of miR-144-3p inhibitor group was obviously increased (P<0.05), the proportion of S phase cells was markedly decreased (P<0.05), while the proportion of G1 phase cells was obviously increased (P<0.05), and the apoptosis rate was significantly decreased (P<0.05). CONCLUSION: miR-144-3p can inhibit the proliferation and promote apoptosis of K562 cells, affect the cell cycle, and block K562 cells in S phase, which indicates that miR-144-3p is involved in the cell cycle activity of CML during blastic phase.

An effective and chemotherapy-free strategy of all-trans retinoic acid and arsenic trioxide for acute promyelocytic leukemia in all risk groups (APL15 trial).

The combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has been demonstrated to have comparable effectiveness or better to ATRA and chemotherapy (CHT) in non-high-risk acute promyelocytic leukemia (APL). However, the efficacy of ATRA-ATO compared to ATRA-ATO plus CHT in high-risk APL remains unknown. Here we performed a randomized multi-center non-inferiority phase III study to compare the efficacy of ATRA-ATO and ATRA-ATO plus CHT in newly diagnosed all-risk APL to address this question. Patients were assigned to receive ATRA-ATO for induction, consolidation, and maintenance or ATRA-ATO plus CHT for induction followed by three cycles of consolidation therapy, and maintenance therapy with ATRA-ATO. In the non-CHT group, hydroxyurea was used to control leukocytosis. A total of 128 patients were treated. The complete remission rate was 97% in both groups. The 2-year disease-free, event-free survival rates in the non-CHT group and CHT group in all-risk patients were 98% vs 97%, and 95% vs 92%, respectively (P = 0.62 and P = 0.39, respectively). And they were 94% vs 87%, and 85% vs 78% in the high-risk patients (P = 0.52 and P = 0.44, respectively). This study demonstrated that ATRA-ATO had the same efficacy as the ATRA-ATO plus CHT in the treatment of patients with all-risk APL.

Post-flowering Soil Waterlogging Curtails Grain Yield Formation by Restricting Assimilates Supplies to Developing Grains.

Soil waterlogging is among the major factors limiting the grain yield of winter wheat crops in many parts of the world, including the middle and lower reaches of the Yangtze River China. In a field study, we investigated the relationship between leaf physiology and grain development under a varying duration of post-flowering waterlogging. A winter wheat cultivar Ningmai 13 was exposed to soil waterlogging for 0 (W0), 3 (W3), 6 (W6), and 9 d (W9) at anthesis. Increasing waterlogging duration significantly reduced flag leaf SPAD (soil plant analysis development) values and net photosynthetic rate (Pn). There was a linear reduction in flag leaf Pn and SPAD as plant growth progressed under all treatments; however, the speed of damage was greater in the waterlogged leaves. For example, compared with their respective control (W0), flag leaves of W9 treatment have experienced 46% more reduction in Pn at 21 d after anthesis (DAA) than at 7 DAA. Increasing waterlogging duration also induced oxidative damage in flag leaves, measured as malondialdehyde (MDA) contents. The capacity to overcome this oxidative damage was limited by the poor performance of antioxidant enzymes in wheat leaves. Inhibited leaf Pn and capacity to sustain assimilate synthesis under waterlogged environments reduced grain development. Compared with W0, W6 and W9 plants experienced a 20 and 22% reduction in thousand grain weight (TGW) in response to W6 and W9, respectively at 7 DAA and 11 and 19%, respectively at 28 DAA. Sustained waterlogging also significantly reduced grain number per spike and final grain yield. Averaged across two years of study, W9 plants produced 28% lesser final grain yield than W0 plants. Our study suggested that wheat crops are highly sensitive to soil waterlogging during reproductive and grain filling phases due to their poor capacity to recover from oxidative injury to photosynthesis. Management strategies such as planting time, fertilization and genotype selection should be considered for the areas experiencing frequent waterlogging problems.

Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas.

Research has suggested a significant prognostic value of ST-T changes in various cardiovascular diseases and malignant tumors. However, their role in predicting prognosis in patients with peripheral T-cell lymphomas (PTCLs) remains unknown. Here, we investigated the prognostic potential of ST-T changes in all-cause mortality of PTCLs patients. In total, 131 patients with PTCLs between January 2015 and April 2020 were enrolled. Univariable and multivariable COX proportional hazards regression models were used to find the relationship between ST-T changes and all-cause mortality in these patients. A significant difference in all-cause mortality was found between patients with ST-T abnormalities and those without definite abnormalities in the ST-T segments (P = 0.027). Multivariable Cox risk regression analysis indicated that patients with ST-T changes had greater all-cause mortality than patients with normal ST-T segments in the intermediate-high/high-risk groups (P < 0.001). In addition, ST-T changes were markedly distinction in patients with hypoproteinemia than in those with no definite abnormalities in the ST-T segments (P = 0.021). ST-T changes may serve as potential, simple, and effective prognostic factors for all-cause mortality in PTCLs patients, especially in the intermediate-high/high-risk and hypoproteinemia groups. Therefore, regular ECG monitoring is recommended to guide the clinical treatment of patients with PTCLs.

Is platelet-rich plasma better than hyaluronic acid in the treatment of knee osteoarthritis? A meta-analysis of randomized controlled trials.

Introduction: Due to the complicated surgical procedure of knee arthroplasty and low effectivity of hyaluronic acid (HA) in the treatment of knee osteoarthritis, various studies highly recommend the use of platelet-rich plasma (PRP). However, some studies also reported lower efficacy and limited use of PRP. Aim: To analyze systematically the different randomized controlled trials (RCTs) comparing the effectiveness of HA vs. PRP for the treatment of knee osteoarthritis. Material and methods: A systematic literature review was conducted using Medline and Central databases for RCTs about the comparison of HA vs. PRP for the treatment of knee osteoarthritis. Studies were included as per the PICOS criteria and relevant event data were extracted. Risk of bias was analyzed and a random-effects model was used to calculate the pooled odds ratio and risk ratio using RevMan software. Results: A total of 14 studies were included in the meta-analysis from year 2000 to 2021 including 613 patients. The current meta-analysis has a low risk of publication bias and we obtained the pooled odds ratio (OR) of 2.55 (95% CI: 1.35-4.84) with a τ 2 value of 1.01, χ 2 value of 52.79, I2 value of 77%, Z value of 2.87 and p-value < 0.00001. The pooled risk ratio was 1.34 (95% CI: 1.09-1.65) with a τ 2 value of 0.09, χ 2 value of 73.48, I2 value of 84%, Z value of 2.80 and p-value < 0.00001. Conclusions: The current meta-analysis highly recommends the use of PRP for the treatment of knee osteoarthritis.

Comprehensive analysis of clinicalf eatures, treatment options, overall survival, and prognostic factors in lymphoma cell leukemia patients: A retrospective study.

Objective: Lymphoma cell leukemia (LCL) is regarded as patients presenting a high extensive lymphoma cell ratio in bone marrow (BM), which is recognized as lymphoma of stage IV by invading into BM. This study aimed to investigate the clinical characteristics, treatment options, survival profiles, and prognostic factors in patients with LCL. Methods: Clinical data of 42 patients with LCL were retrospectively reviewed, and baseline characteristics and treatment records were extracted. In addition, overall survival (OS) was calculated, and the causes of death were analyzed. Results: Out of the 42 patients with LCL, 9 (21.4%) had primary BMLCL, 20 (47.6%) had Non-Hodgkin lymphoma (NHL) complicated with LCL, and 13 (31.0%) had NHL evolving into LCL. Common clinical characteristics included B syndromes (n = 21, 50.0%), abnormal white blood count (n = 28, 66.5%), decreased hemoglobin (n = 28, 66.7%), and platelet (n = 30, 71.4%). Additionally, elevated Eastern Cooperative Oncology Group (ECOG) with a score greater than one occurred in 26 patients (61.9%), and elevated lactate dehydrogenase (LDH) occurred in 25 patients (59.5%). For treatments, chemotherapy was the most common therapy (n = 35, 83.2%), followed by symptomatic treatment and radiotherapy plus chemotherapy. Additionally, the mean OS of the patients was 16.9 (95% CI: 12.8-20.9) months, among which primary patients with BMLCL showed shorter OS than those with NHL complicated with LCL and NHL evolving into patients with LCL. A total of 9 (21.4%) patients with LCL died during follow-up, among which the central nervous system (CNS) invasion was the most common cause of death. Furthermore, primary BMLCL, higher ECOG, and higher LDH were potential predictive factors for worse OS in patients with LCL. Conclusion: This study gives an overview of the treatment and prognosis of LCL, which provides additional information for the management of LCL.

Study on the Relationship Between the Expression of B Cell Mature Antigen and the Classification, Stage, and Prognostic Factors of Multiple Myeloma.

The expression level of BCMA in bone marrow of 54 MM patients was detected in this study to explore the relationship between the BCMA expression and the classification, stage, and prognostic factors of MM. The BCMA expression level of the stable group and remission group was lower than that of the newly diagnosed group and relapse group (P=0.001). There was no significant difference in BCMA expression of MM patients in different types and stages (P>0.05), but it was found that for the newly diagnosed MM patients, the BCMA expression level of IgG patients was higher than that of IgA or light-chain patients (rank average 11.20 vs 5.44, P=0.014). There was no significant correlation between the BCMA expression and the age and serum creatinine of MM patients (P>0.05). And there was no significant difference in BCMA expression between patients with different levels of age and serum creatinine (P>0.05). But it was found that the BCMA expression level of the newly diagnosed MM patients was moderately positively correlated with their age (P=0.025, r=0.595). There was no significant correlation between the BCMA expression and serum ß2-microglobulin, serum lactate dehydrogenase, free kap/lam ratio, and urine ß2-microglobulin (P>0.05). But we found that the BCMA expression of patients with high serum ß2-microglobulin was higher than that of patients with low serum ß2-microglobulin (rank average 28.89 vs 17.54, P=0.017). And the BCMA expression of patients with abnormal serum free kap/lam ratio was higher than that of patients with normal ratio (rank average 28.49 vs 13.55, P=0.004). The BCMA expression was strongly positively correlated with 24-h urine protein, was moderately positively correlated with serum M protein and the percentage of plasma cells in bone marrow, was moderately negatively correlated with albumin and hemoglobin count, and was weakly positively correlated with serum corrected calcium (P<0.05). And it was found that the BCMA expression of positive serum immunofixation electrophoresis patients was higher than that of negative patients (rank average 29.94 vs 16.75, P=0.017). And we try to clarify the relationship between the bone marrow BCMA expression and the peripheral blood sBCMA expression. However, we have not found a clear correlation between them so far (P>0.05).

Prognostic Potential of Heart Rate and Hypertension in Multiple Myeloma Patients.

Background: The prognosis of patients with multiple myeloma (MM) is variable and partly depends on their cardiovascular status. The presence of arrhythmias can lead to worse outcomes. Therefore, this study aimed to evaluate the potential of heart rate (HR) and hypertension in predicating the outcomes of MM patients. Methods: This study retrospectively enrolled patients with MM between January 1, 2010, and December 31, 2018, at the First Affiliated Hospital of Xi'an Jiaotong University. The endpoint was all-cause mortality. The Pearson's chi-square test was used to assess the association between hypertension and outcomes. Univariate and multivariate Cox proportional hazards models were developed to evaluate the relationship between HR and all-cause mortality. Results: A total of 386 patients were included. The mean HR was 83.8 ± 23.1 beats per minute (bpm). Patients with HR >100 bpm had a higher all-cause mortality (79.4%, 50/63) than those with 60 ≤ HR ≤ 100 bpm (39.9%, 110/276) and <60 bpm (19.1%, 9/47) (p < 0.001). Subgroup analysis based on the International Staging System and sex revealed similar relationships (p < 0.01). When stratified by age, patients with HR >100 bpm had higher all-cause mortality than those with a lower HR when age was <65 years or 65-75 years (p < 0.001) but not >75 years. The proportion of patients with hypertension was 54.7% (211/386). However, hypertension was not associated with all-cause mortality in MM patients (χ2=1.729, p > 0.05). MM patients with HR >100 bpm had the highest all-cause mortality. Conclusions: The prognostic potential of HR may be useful in aiding risk stratification and promoting the management of these patients.

Neck Circumference is Associated with Incidence of Angina Pectoris in a Large Community-Based Population.

BACKGROUND: Previous studies have found that neck circumference (NC) is associated with cardiovascular disease risk factors. This study investigated the relationship between NC and the incidence of angina pectoris (AP). METHODS: Altogether 4821 participants (2212 males and 2609 females) from the Sleep Heart Health Study (SHHS) with a mean age of 63.4±11.0 years were selected in this study. Anthropometric measurements, including NC, waist circumference (WC), hip circumference (HC), and body mass index (BMI), were collected at baseline. AP was defined as the first occurrence between baseline and 2011. Linear and logistic regression analysis was used to explore the association between NC and incidences of AP. RESULTS: There was a significant difference in NC between AP and controls in both male (41.1±3.1 cm vs 40.3±3.2 cm; p<0.001) and female (35.2±3.1 cm vs 34.9±2.9 cm; p=0.006). Multivariable linear regression analysis showed that NC (every cm increase) was independently associated with the incidence of AP in both male (odds ratio [OR] 1.067; 95% confidence interval [CI] 1.035-1.100; p<0.001) and female (OR 1.067; 95% CI 1.035-1.101; p<0.001). CONCLUSION: NC was significantly associated with the incidence of AP in both male and female. The role of NC in the incidence of AP is worthy of further investigation.

Effective mobilization with etoposide and cyclophosphamide for collection of peripheral blood stem cell in patients with multiple myeloma.

PURPOSE: To evaluate the efficacy and toxicity of etoposide and cyclophosphamide for mobilization peripheral stem cells in multiple myeloma patients. METHODS: We retrospectively analyzed 46 patients with multiple myeloma who underwent peripheral blood stem cell collection for upfront autologous hematopoietic stem cell transplantation in the First Affiliated Hospital of Xi'an Jiaotong University between January 2010 and July 2019. The mobilization protocols included cyclophosphamide 2.0 g/m2 with G-CSF (CTX group) before January 2015, and two-days of 5 mg/kg.d etoposide and 1.0 g/m2.d cyclophosphamide with G-CSF (EC group) after January 2015. RESULTS: The success rate of harvest (≥2×106 cells/kg) during the first mobilization attempt was 82.1% in the EC group and 50.0% in the CTX group, and the rate of adequate harvest (≥4×106 cells/kg) was 57.1% in the EC group and 15.8% in the CTX group. After the second mobilization, a sufficient number of CD34+/kg cells for an auto-HSCT was obtained for all patients in the EC group and the majority (68.4%) of patients in CTX group. There was no significant difference of non-hematological adverse events between two groups. The mean neutrophil engraftment time was 11.22±1.56 days and 9.89±2.81days for the CTX and EC groups, respectively (P>0.05). Platelet engraftments were significantly faster in the EC group than the CTX group (P0.05). CONCLUSION: The etoposide and cyclophosphamide regimen could be an effective and safe method for mobilization in patients with multiple myeloma.

HIF-1α suppresses myeloma progression by targeting Mcl-1.

HIF-1α is involved in the carcinogenesis and progression of multiple types of cancer. However, the precise role of HIF-1α is unclear in multiple myeloma. Through the qRT-PCR and CCK-8 assays, we demonstrated that silencing the expression of HIF-1α and Mcl-1, MM proliferation can be decreased and apoptosis can be induced. Next, using the GEO database, we found that Mcl-1 was increased in MMs. Mcl-1 overexpression counterbalanced the tumor suppressing effect of siHIF-1α on MM apoptosis. Additionally, HIF-1α acting as a transcription factor, could directly target the promoter region of Mcl-1 to promote Mcl-1 expression. Based on the experimental result, our findings strongly suggest that HIF-1α regulated the progression of MMs by directly targeting the Mcl-1.

The Influence of Blood Collection Tubes in Biomarkers' Screening by Mass Spectrometry.

PURPOSE: Mass spectrometry is one of the rapidly developing bio-analytical techniques in recent years, and it shows that the results of biomarkers' screening can be influenced by pre-analytical process. The selection of the blood collection tubes is one of the most significant steps of pre-analytical process which is often neglected by researchers. So, it is urgent to define the influence of blood collection tubes clearly in biomarkers' screening. EXPERIMENTAL DESIGN: Two types of blood collection tubes, non-additive tubes and coagulant activator tubes, are used to collect serum samples from patients and healthy controls. All samples are analyzed using matrix-assisted laser desorption ionization-time of flight mass spectrum in this study. RESULTS: The serum protein profile changes while using coagulant tubes whether for patients or healthy controls. It is found that the effect of coagulant on serum protein of patients is smaller than that of control group. There are 27 significantly different peaks between the control group and the control coagulant group. However, between patient group and patient coagulant group, only one differential peak is obtained. Coagulant changes the expression differences between patients and healthy controls, making the differences expand, shrink or reverse, and most of the polypeptides are small molecule, which will change the results of biomarker's screening. CONCLUSIONS AND CLINICAL RELEVANCE: This research suggested that different types of blood collection tubes would influence the final laboratory results. So it's important for clinicians to choose the proper tubes to detect biomarkers and make correct diagnoses.

Norepinephrine-CREB1-miR-373 axis promotes progression of colon cancer.

The adrenergic system contributes to the stress-induced onset and progression of cancer. Adrenergic fibers are the primary source of norepinephrine (NE). The underlying mechanisms involved in NE-induced colon cancer remain to be understood. In this study, we describe the function and regulatory network of NE in the progression of colon cancer. We demonstrate that NE-induced phosphorylation of cAMP response element-binding protein 1 (CREB1) promotes proliferation, migration, and invasion of human colon cancer cells. The downstream effector of NE, CREB1, bound to the promoter of miR-373 and transcriptionally activated its expression. miR-373 expression was shown to be necessary for NE-induced cell proliferation, invasion, and tumor growth. We confirmed that proliferation and invasion of colon cancer cells are regulated in vitro and in vivo by miR-373 through targeting of the tumor suppressors TIMP2 and APC. Our data suggest that NE promotes colon cancer cell proliferation and metastasis by activating the CREB1-miR-373 axis. The study of this novel signaling axis may provide mechanistic insights into the neural regulation of colon cancer and help in the design of future clinical studies on stress biology in colorectal cancer.

Integrating transcriptome-wide association study and copy number variation study identifies candidate genes and pathways for diffuse non-Hodgkin's lymphoma.

BACKGROUND: The genetic basis of diffuse non-Hodgkin's lymphoma (DNHL) is largely unknown now. We conducted a large-scale transcriptome-wide association study (TWAS) of DNHL to identify novel candidates for DNHL. METHODS: The GWAS summary data of DNHL was obtained from the UKBiobank, involving 685 cases and 451,579 controls. TWAS of DNHL was performed using tissue-specific gene expression weights generated from the Genotype-Tissue Expression (GTEx) data. The DNHLTWAS results were further validated by a previous published copy number alterations (CNA) study of DNHL. Gene ontology (GO) and pathway enrichment analysis of identified candidate genes were conducted by the DAVID 6.8. RESULTS: We identified 214 genes with TWAS P value < 0.05 for DNHL, such as MRPL19 (PTWAS = 0.0010), CRCP (PTWAS = 0.0010) and SEMA3C (PTWAS = 0.0010). After further comparing the 214 genes with copy number variations of DNHL patients, we found 1 overlapped gene, BCL10 (PTWAS = 0.0100). We also detected 6 common GO terms shared between gene set enrichment analysis results of TWAS and CNAs, such as cytosol (PTWAS = 0.0003, PCNAs = 4.99 × 10-7) and membrane (PTWAS = 0.0048, PCNAs = 0.0046). The pathway enrichment analysis of TWAS and CNAs detected 3 common pathways, including HIF-1 signaling pathway (PTWAS = 0.0195, PCNAs = 1.96 × 10-5), mTOR signaling pathway (PTWAS = 0.0242, PCNAs = 6.75 × 10-5) and adipocytokine signaling pathway (PTWAS = 0.0392, PCNAs = 0.0103). CONCLUSIONS: Our study identified multiple DNHL associated genes and pathways, providing novel useful information for the pathogenetic studies of DNHL.

Treatment of non-high-risk acute promyelocytic leukemia with realgar-indigo naturalis formula (RIF) and all-trans retinoid acid (ATRA): study protocol for a randomized controlled trial.

BACKGROUND: Acute promyelocytic leukemia (APL) is a highly curable disease when treated with all-trans retinoid acid (ATRA) and arsenic trioxide (ATO). The combination of ATO and ATRA has become the standard therapeutic protocol for induction therapy in non-high-risk APL. An oral arsenic realgar-indigo naturalis formula (RIF) has also showed high efficacy and it has a more convenient route of administration than the standard intravenous regimen. Unlike in previous trials, the arsenical agent was used simultaneously with ATRA during post-remission therapy in this trial. METHODS: This study was designed as a multicenter, randomized controlled trial. The trial has a non-inferiority design with superiority being explored if non-inferiority is identified. All patients receive ATRA-ATO during the induction therapy. After achieving hematologic complete remission (HCR), patients were randomly assigned (1:1) to receive treatment with ATRA-RIF (experimental group) or ATRA-ATO (control group) as the consolidation therapy. During the consolidation therapy, the two groups receive ATRA plus RIF or intravenous ATO 2 weeks on and 2 to ~ 4 weeks off until molecular complete remission (MCR), then ATRA and oral RIF 2 weeks on and 2 to ~ 4 weeks off giving a total of six courses. DISCUSSION: This trial aims to compare the efficacy of ATRA-ATO versus ATRA-RIF in non-high-risk patients with APL, to demonstrate that oral RIF application reduces the total hospitalization days and medical costs. The simple schedule was studied in this trial. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02899169. Registered on 14 September 2016.

Causal effects of serum metabolites on amyotrophic lateral sclerosis: A Mendelian randomization study.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that is affected by both genetic and environmental factors. Nowadays, OMIC technologies, such as genomics and metabolomics, are providing a systematic readout of genetic structures and physiological states for understanding human diseases. However, the comprehensive analysis of cross-omics is often lacking. Here, we conducted a Mendelian randomization analysis to provide a comprehensive analysis of metabolomics and genomics to estimate the causal relationships between non-targeted human serum metabolites and the development of ALS. Using genetic variants as predictors, our study detected 18 metabolites that might have causal effects on the development of ALS, including a group of gamma-glutamyl amino acids. Our findings suggested that glutathione metabolism dysfunction might be involved in the pathogenesis of ALS. Furthermore, our study provides a novel method to understand the pathogenesis of human diseases and develop therapeutic strategies for diseases by combining metabolomics with genomics.

As4S4 Exhibits Good Killing Effect on Multiple Myeloma Cells Via Repressing SOCS1 Methylation-Mediated JAK2/STAT3 Signaling Pathway.

OBJECTIVE: This study aimed to investigate the effect of tetra-arsenic tetra-sulfide on treating multiple myeloma and its potential regulation on suppressor of cytokine signaling 1 methylation-mediated Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway. METHODS: Tetra-arsenic tetra-sulfide with different concentrations were used to treat U266 cells, and cell viability was measured at 12, 24, and 48 hours with 0 µM tetra-arsenic tetra-sulfide treatment as control by Cell Counting Kit-8 assay. Suppressor of cytokine signaling 1 methylation and expression were determined by methylation-specific polymerase chain reaction, quantitative polymerase chain reaction, and Western blot, respectively, in U266 cells and normal plasma cells and in U266 cells treated by tetra-arsenic tetra-sulfide. Then, rescue experiments were performed by transfecting suppressor of cytokine signaling 1 small interfering RNA into tetra-arsenic tetra-sulfide-treated U266 cells. Besides, phosphor-Janus kinase 2, Janus kinase 2, phospho-signal transducer and activator of transcription 3, and signal transducer and activator of transcription 3 expressions were determined by Western blot. RESULTS: Tetra-arsenic tetra-sulfide inhibited U266 cell viability efficiently in a dose- and time-dependent manner. Suppressor of cytokine signaling 1 methylation was higher while suppressor of cytokine signaling 1 expression was lower in U266 cells compared to normal plasma cells; when treated by tetra-arsenic tetra-sulfide, suppressor of cytokine signaling 1 methylation was decreased while suppressor of cytokine signaling 1 expression was increased in U266 cells, along with the reduced phospho-Janus kinase 2 and phospho-signal transducer and activator of transcription 3 expressions. Then, suppressor of cytokine signaling 1 small interfering RNA enhanced the cell viability and phospho-Janus kinase 2 as well as phospho-signal transducer and activator of transcription 3 expressions in both tetra-arsenic tetra-sulfide treatment-free and tetra-arsenic tetra-sulfide-treated U266 cells. CONCLUSION: Tetra-arsenic tetra-sulfide exhibits good killing effect on multiple myeloma cells via repressing suppressor of cytokine signaling 1 methylation and downstream Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway, which might serve as a potential treatment option for multiple myeloma.