Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

Patient-Reported Outcomes in Young Adults with Myeloproliferative Neoplasms.

INTRODUCTION: Genetic landscape, disease characteristics, and clinical outcomes of young adults with myeloproliferative neoplasms (MPNs) were reported. However, data on patient-reported outcomes (PROs) in young adults with MPNs were rare. METHODS: We conducted a multicenter, cross-sectional study to compare the PROs in respondents with thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF) by age at survey, including the young group (18-40 years), middle-aged group (41-60 years), and elderly group (>60 years). RESULTS: Of the 1,664 respondents with MPNs, 349 (21.0%) were young including 244 (69.9%) with ET, 34 (9.7%) with PV, and 71 (20.3%) with MF. In multivariate analyses, the young groups with ET and MF were associated with the lowest MPN-10 scores among the 3 age groups; those with MF, highest proportion of reporting negative impact of disease and therapy on their daily life and work. The young groups with MPNs had the highest physical component summary scores but the lowest mental component summary scores in those with ET. The young groups with MPNs were most concerned about fertility; those with ET, treatment-related adverse events and long-term efficacy of treatment. CONCLUSIONS: We concluded that young adults with MPNs have different PROs compared with middle-aged and elderly patients.

Identification of autophagy-associated genes and prognostic implications in adults with acute myeloid leukemia by integrated bioinformatics analysis.

Acute myeloid leukemia (AML) is one of the most common malignant blood neoplasma in adults. The prominent disease heterogeneity makes it challenging to foresee patient survival. Autophagy, a highly conserved degradative process, played indispensable and context-dependent roles in AML. However, it remains elusive whether autophagy-associated stratification could accurately predict prognosis of AML patients. Here, we developed a prognostic model based on autophagy-associated genes, and constructed scoring systems that help to predicte the survival of AML patients in both TCGA data and independent AML cohorts. The Nomogram model also confirmed the autophagy-associated model by showing the high concordance between observed and predicted survivals. Additionally, pathway enrichment analysis and protein-protein interaction network unveiled functional signaling pathways that were associated with autophagy. Altogether, we constructed the autophagy-associated prognostic model that might be likely to predict outcome for AML patients, providing insights into the biological risk stratification strategies and potential therapeutic targets.

[Clinical Significance of Peripheral Blood EBV-DNA Determination and Genotyping in Lymphoma Patients].

OBJECTIVE: To explore the clinical significance of Epstein-Barr virus（EBV） detection and classification in peripheral blood of lymphoma patients. METHODS: 101 lymphoma patients were enrolled, the clinical characteristics of the patients were collected, including ages, sex, types of lymphoma, Ann Arbor stages, extranodal infiltration and lactate dehyhrogenase. Fluorescent quantitative PCR technology was used to detect the EBV-DNA. Polymerase chain reaction and Agarose gel electrophoresis was used for determination of EB genotyping. The difference between curative effect in EBV-DNA+ and EBV-DNA－ patients, the correlation of adverse factors and EBV infection of the patients were analyzed. RESULTS: 68.3% (69/101) of the patients showed EBV-DNA positive. EBV-positive lymphoma patients showed more adverse prognostic factors than the patients with EBV-negative, which may lead to poorer disease outcome. Among the 46 B-cell non-Hodgkin's lymphoma patients, the overall response rate of EBV-positive patients (60.7%) was lower than EBV-negative patients(88.9%) (P<0.05); For 19 patients with Hodgkin's lymphoma, the overall response rate of EBV-positive patients (46.2%) was lower than EBV-negative patients (100%), the differences were statistically significant (P<0.05). Among 69 patients with EBV-infected lymphoma, 98.6% (68/69) showed type-2 EB virus, and 1.4% (1/69) were type-1 and type-2 mixed infections. CONCLUSION: Most of EBV-positive in lymphoma patients were EBV type 2, patients with EBV-DNA+ shows poorer efficacy than EBV-DNA－ patients.

Variables associated with patient-reported outcomes in patients with myeloproliferative neoplasms.

We explored variables associated with patient-reported outcomes (PROs) including symptom burden, impact on daily life and work, obstacles during therapy, satisfaction level with therapy, and health-related quality of life in 1500 respondents with myeloproliferative neoplasms (MPNs) including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) in a multicenter, cross-sectional study across China, a representative of the developing countries. In multivariate analyses, urban household registration and higher education level were significantly-associated with no symptoms at diagnosis in respondents with ET or MF. CALR mutation was significantly-associated with lower MPN-10 scores in respondents with MF. Higher MPN-10 scores were significantly-associated with negative impact on daily life and work as well as lower satisfaction level in respondents with ET, PV and MF. Receiving ruxolitinib was significantly-associated with high satisfaction and satisfaction in respondents with MF. In addition, other demographics and clinical variables were also impacting PROs.

Diagnostic accuracy of circulating miR-126 for malignant pleural mesothelioma: a systematic review and meta-analysis.

BACKGROUND: Circulating microRNAs are novel diagnostic markers for various types of cancer. Several studies have investigated the diagnostic accuracy of circulating miR-126 for malignant pleural mesothelioma (MPM), but the results varied. Therefore, we performed a systematic review and meta-analysis to investigate the diagnostic value of circulating miR-126 for MPM. METHODS: The PubMed database was searched to identify potentially eligible studies published before October 2020. The studies investigating the diagnostic value of circulating miR-126 for MPM were included in a systematic review and meta-analysis. A bivariate model was used to pool eligible studies' sensitivity and specificity. The revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2) was used to assess eligible studies' quality. RESULTS: Four studies with 156 MPM patients and 459 controls were included in this systematic review and meta-analysis. The pooled diagnostic sensitivity and specificity of circulating miR-126 for MPM were 0.71 and 0.69, respectively. A high risk of bias was observed in the domains of patient selection, index test, and flow and timing. CONCLUSIONS: Circulating miR-126 has limited value for diagnosing MPM. Considering that the available studies have a high risk of bias, further rigorous studies are needed to assess the diagnostic value of circulating miR-126 for MPM.

Diagnostic value of microRNAs for malignant pleural mesothelioma: A mini-review.

Malignant pleural mesothelioma (MPM) is a type of cancer originating from the pleura with high aggressiveness and poor prognosis. A timely diagnosis is crucial to improve its prognosis. Laboratory biomarkers have significant advantages of reduced invasiveness, low cost, and are observer-independent, and therefore represent a promising diagnostic tool for MPM. MicroRNA is a family of non-coding RNA that regulates gene expression at the post-transcriptional level. Accumulated studies showed that microRNA, either in tissue, circulating, and body fluid, has potential diagnostic value for various disorders. Here, we reviewed the diagnostic value of microRNA for MPM.

Path analysis of non-enzymatic browning in Dongbei Suancai during storage caused by different fermentation conditions.

A non-enzymatic browning reaction occurs easily in Dongbei Suancai (DS) during storage. Using the method of path analysis, the changes in contents of VC (ascorbic acid), polyphenol, reducing sugar, amino nitrogen, and 5-HMF (5-hydroxymethyl furfural) were investigated to analyze the direct pathways and determinants of browning caused by pre-production blanching at 100 °C (R-100), salt-addition increased from 2% to 6% (Y-6) and fermentation time extended from 30 d to 40 d (T-40), respectively. The results showed that R-100 could delay the browning by inhibiting two direct pathways of oxidative decomposition of VC and oxidation-polymerization of polyphenols, but T-40 could lead to an increase in degree of browning for which primary determinant was the interaction between polyphenol and reducing sugar, while Y-6 had no obvious effect on browning pathway and determinants. R-100 was thus deemed to be a good measure with inhibiting non-enzymatic browning in DS during storage.

[Detection of JAK2V617F and CALR Gene Mutations by Multiplex of Patients with Myeloproliferative Neoplasms PCR-Capillary Electrophoresis].

OBJECTIVE: To evaluate the proformance of multiplex PCR and capillary electrophoresis(MPCE) in the detection of JAK2V617F and CALR mutation in myeloproliferative neoplasms(MPN). METHODS: The specificity primers of JAK2617F gene mutation and the primers of CALR gene were designed at the same time. The JAK2V617F and CALR gene primers were labeled with Cy5 fluorescence, all the primers were mixed in one tube for multiplex PCR and the PCR prodcuts were analysised by capillary electrophoresis. Then detection limit and sensitivity of MPCE were evaluated, and compared with comercial diagnostic kit. RESULTS: JAK2V617F and CALR gene mutations could be detect by MPCE in one PCR test. JAK2V617F mutation could be detected at 0.01 ng genomic DNA, double positive JAK2V617F and CLAR gene mutations could be detected at 0.1 ng genomic DNA, at least 0.1% JAK2V617F positive mutation could be detected. The consistency between MPCE and commercial diagnostic gene mutation kit was 100%. CONCLUSION: It is developed that a new gene mutation detection method of JAK2 V617F and CLAR gene based on MPCE in our experiment and it can be used as a new reagent for molecular diagnosis of MPN patients.

Higher Prevalence of Multi-Antimicrobial Resistant Bacteroides spp. Strains Isolated at a Tertiary Teaching Hospital in China.

PURPOSE: The study investigates the molecular epidemiology of multi-drug resistant (MDR) Bacteroides spp. isolates and the clinical characteristics of the patients. MATERIALS AND METHODS: Bacteroides spp. clinical strains were identified through MALDI-TOF MS and VITEK-2 anaerobes and corynebacterium (ANC) cards. A broth microdilution method was employed to detect the antimicrobial sensitivities of Bacteroides spp. isolates. PCR was used to detect the resistance genes, including cfxA, cepA, cfiA, ermF, nim, as well as the upstream insertion sequence (IS) element of the cfiA gene. The effects of broad-spectrum efflux pump inhibitors (EPIs) on the minimal inhibitory concentration (MICs) of cefoxitin, moxifloxacin, and imipenem for MDR Bacteroides spp. were investigated. RESULTS: The total resistance rates of 115 Bacteroides spp. isolates to cefoxitin, moxifloxacin, clindamycin, metronidazole, imipenem and meropenem were 4.3%, 16.5%, 80.0%, 5.2%, 13.9% and 13.9%, respectively. The positive rates of carbapenem resistance gene cfiA were 38.9% and 8.6% for B. fragilis and non-B. fragilis isolates, respectively. The isolation rate of MDR isolates reached up to 18.26% (21/115), and the isolation rate among the gastrointestinal cancer patients was significantly higher when compared to the non-gastrointestinal cancer patients (52.38%/26.08%, P = 0.006). Furthermore, MDR isolates were more likely to be isolated from the patients exposed to cephalosporins 3 months before Bacteroides spp. isolation (76.19%/31.52%, P = 0.000). CONCLUSION: The overall resistance rates of Bacteroides spp. isolates against multiple antimicrobials were at a high level, especially for B. fragilis. The CfiA gene carrying rate among B. fragilis isolates was as high as 38.9%, and its mediated carbapenem resistance was the major resistance mechanism for B. fragilis. The findings of this study imply that the real resistance tendency of Bacteroides spp. may be underestimated and need to be given more attention.

Anti-SOX1 antibody-positive paraneoplastic neurological syndrome presenting with Lambert-Eaton myasthenic syndrome and small cell lung cancer: A case report.

Paraneoplastic neurological syndromes (PNS) are rare disorders affecting any part of the central, peripheral or autonomic nervous system that occur in association with cancer. Among cancer patients, less than 1% overall develop PNS. Anti-SOX1 antibodies' positive paraneoplastic neurological disorders are rare and are usually associated with small cell lung cancer (SCLC). Here, we report a case of a 61-year-old male patient who presented with an unusual anti-SOX1 positive PNS. The right tibialis anterior showed noticeable low-amplitude motor unit potentials and high amplitude motor potentials in electrodiagnostic study, suggesting the presence of Lambert-Eaton myasthenic syndrome (LEMS). Typical MRI and PET-CT found a hyperintense lesion with contrast enhancement in the thorax in front of 5-6 centrum of vertebrae, and thoracoscopic biopsy revealed pathological findings for SCLC. The patient underwent several lines of chemotherapy and radiotherapy and survived for 15 months after the diagnosis of SCLC.

[Expression and Clinical Significance of Serum LRG1 in Patients with Diffuse Large B-Cell Lymphoma before Treatment].

OBJECTIVE: To investigate the clinical significance of serum LRG1, LDH and ß2-MG in the recurrence of diffuse large B-cell lymphoma(DLBCL) after chemotherapy. METHODS: The serum levels of LRG1, LDH and ß2-MG of 80 patients with DLBCL were detected before treatment and followed up for these patients was performed. The cut-off value of non-recurrent survival was determined by ROC analysis. The correlation of three serum markers for predicting recurrence with prognostic factors of diffuse large B-cell lymphoma patients after treatment was analyzed by ROC curve. RESULTS: The serum levels of LDH, LRG1 and ß2-MG were higher in the groups with high tumor stageing, extranodal invasion and bone marrow involvement, respectively(P＜0.05). The optimal cut-off values for predicting recurrence risk determined by ROC analysis: LDH 402.37 U/L, LRG1 1.81 mg/L and ß2-MG 168.3 ng/L, respectively.COX multivariate regression analysis showed that serum LRG1 was an independent factor affecting the recurrence of diffuse large B-cell lymphoma(P＜0.05). CONCLUSION: The serum level of LRG1 may become a new biological marker to predict the recurrence risk of diffuse large B-cell lymphoma.

Diagnostic accuracy of cancer ratio for malignant pleural effusion: a systematic review and meta-analysis.

BACKGROUND: Several studies have investigated the diagnostic accuracy of serum lactate dehydrogenase (LDH) to pleural fluid adenosine deaminase ratio (cancer ratio, CR) for malignant pleural effusion (MPE), but the results were various. Therefore, we performed this systematic review and meta-analysis to ascertain the diagnostic accuracy of CR for MPE. METHODS: The PubMed and EMBASE databases were searched up to 7 June, 2019 to identify publications concerning diagnostic accuracy of CR for MPE. The sensitivities and specificities of CR in included studies were pooled with a bivariate model. A summary receiver operating characteristic (sROC) curve was used to estimate the global diagnostic accuracy of CR. Quality of the included studies was assessed with the revised tool for the quality assessment of diagnostic accuracy studies (QUADAS-2). RESULTS: Finally, five studies with 596 MPE patients and 863 benign pleural effusion (BPE) patients were included in this systematic review and meta-analysis. The pooled sensitivity and specificity of CR were 0.97 (95% CI: 0.92-0.99) and 0.89 (0.69-0.97), respectively. The area under sROC curve was 0.98 (95% CI: 0.97-0.99). The major design weaknesses of the included studies were patients selection and partial verification bias. CONCLUSIONS: CR has high diagnostic accuracy for MPE. Considering the design weaknesses of available studies, further studies with rigorous design are needed to further validate the findings of this meta-analysis.

[Efficacy of Quercetin-sensitized Adriamycin for Treatment of Refractory Acute Leukemia].

OBJECTIVE: To investigate the chemotherapeutic efficency of quercetin sensitized adriamycin. METHOD: CCK-8 was used to detect the inhibitory effect of different doses of adriamycin, quercetin and quercetin combined with adriamycin on the proliferation of primary leukemia cells from patients with clinically refractory acute leukemia. Quercetin, adriamycin and their combination were used to treat non-irradiated T-ALL leukemia mice to observe the changes of survival curve and myocardial injury. RESULT: There was no significant difference in the inhibition rate of primary leukemia cell proliferation between the adriamycin concentration group (6, 0.6 and 0.06 µg/ml) and the adriamycin half-dose (3, 0.3 and 0.03 µg/ml) plus quercetin (0.25 mmol/L) group at three different time points (24, 48 and 72 hours). There was a significant difference in the inhibition rate of primary leukemia cell proliferation among the drug concentration groups, and the inhibition rate of primary leukemia cell proliferation was time-and concentration-dependent (r24h，a\c\e=0.995、r48h，a\c\e=1.000、r72h，a\c\e=0.984、r24h，b\d\f=0.993、r48h，b\d\f=0.999、r72h，b\d\f=0.960). In vivo experiments showed that the survival time of non-irradiated T-ALL leukemia mice treated with low-dose adriamycin combined with quercetin was not significantly prolonged compared with the high-dose adriamycin treatment group. The survival time of non-irradiated T-ALL leukemia mice treated with high dose of adriamycin and quercetin was significantly prolonged (P＜0.05). Compared with adriamycin group, the SOD activity in adriamycin combined with quercetin group increased significantly and the MDA content decreased. The results of transcriptome sequencing analysis showed that the expression of Ighv1-84 and Igkv6-14 in adriamycin combined quercetin group and quercetin group was lower than that in adriamycin group. The Ms4a1, Podx1, Mecom, Sh3bgr12, Bex4 and Tdrp expression in adriamycin combined quercetin group and adriamycin group were higher than that in quercetin group, while Crabp1 expression was lower. CONCLUSION: Quercetin can inhibit the proliferation of primary leukemia cells in a time-dependent manner. Quercetin combined with adriamycin inhibit the proliferation of primary leukemia cells significantly, and had synergistic and additive effects on the proliferation of primary leukemia cells, and the inhibiting effect of quercetin combined with adriamycin is concentration-and time-dependent. Quercetin combined with high-dose adriamycin can significantly prolong the survival time of non-irradiated T-ALL leukemia mice and reduce the myocardial damage caused by adriamycin.

A Study Investigating Markers in PLeural Effusion (SIMPLE): a prospective and double-blind diagnostic study.

INTRODUCTION: Serum and fluid laboratory markers are valuable for exploring the aetiologies of pleural effusion (PE) because of their relative non-invasiveness, low cost, objective result and short turnaround time. The diagnostic accuracy of these potential markers needs to be rigorously evaluated before their widespread application in clinical practice. Here, we plan to perform a Study Investigating Markers in PLeural Effusion (SIMPLE). METHODS AND ANALYSIS: This is a prospective and double-blind clinical trial which is being performed at the Affiliated Hospital of Inner Mongolia Medical University, China. Adult patients admitted for the evaluation of aetiology of PE from September 2018 to July 2021 will be enrolled after informed consent. Pleural fluid and serum specimens will be collected and stored at -80°C for the laboratory analysis. The final diagnosis will be concurred with further imaging, microbiology, cytology and biopsy if needed. The results of investigated laboratory markers will be unknown to the clinicians who will make diagnosis and the clinical diagnoses will be unknown to the laboratory technicians who will determine markers. The diagnostic accuracy of investigated markers will be assessed using receiver operating characteristics (ROC) curve analysis, multivariable logistic regression model, decision curve analysis (DCA), net reclassification index (NRI) and integrated discriminatory index (IDI). ETHICS AND DISSEMINATION: The study is approved by the Ethic Committee of the Affiliated Hospital of Inner Mongolia Medical University (NO: 2018011). The results of SIMPLE will be submitted to international scientific peer-reviewed journals or conferences in laboratory medicine or respiratory medicine, thoracic diseases. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1800017449); Pre-results.

Combination of quercetin and Adriamycin effectively suppresses the growth of refractory acute leukemia.

The present study aimed to investigate the effect of combined treatment with quercetin and Adriamycin (doxorubicin) on the development of refractory acute leukemia. Primary leukemic cells were isolated from patients with refractory drug-resistant acute leukemia. The Cell Counting Kit-8 assay was used to detect the proliferation of cells treated with a range of doses of Adriamycin, quercetin and a combination of the two drugs. Non-irradiated mice were used to establish a T cell acute lymphoblastic leukemia (T-ALL) model, which was subsequently treated with Adriamycin, quercetin and a combination of the two drugs. The survival time was recorded, and white and red blood cells and platelets in mouse peripheral blood were counted. Superoxide dismutase (SOD) activity and malondialdehyde (MDA) content of cardiac tissues were measured as indicators of oxidative stress and damage. Proliferation of primary leukemic cells was reduced by Adriamycin depending on the dose (0.06, 0.6 or 6 µg/ml) and treatment duration (24, 48 or 72 h) compared with the vehicle treated group. Co-treatment with quercetin achieved a similar suppression of leukemic cell proliferation when a lower dose of Adriamycin (0.03, 0.3 or 3 µg/ml) was administered for the same duration. The survival of non-irradiated mice with T-ALL was improved by co-treatment with a high dose of Adriamycin and quercetin compared with either treatment alone. Compared with treatment with Adriamycin alone, the combined treatment with Adriamycin and quercetin significantly enhanced the SOD activity and reduced the MDA content in the heart. Therefore, quercetin may enhance the effects of Adriamycin on refractory acute leukemia.

Inonotus obliquus polysaccharides protect against Alzheimer's disease by regulating Nrf2 signaling and exerting antioxidative and antiapoptotic effects.

Inonotus obliquus polysaccharide (IOPS) was initially separated and purified via precipitation from an aqueous extract with 80% alcohol, a DEAE-52 cellulose anion exchange column, and a Sephadex G-100 gel permeation chromatography system. IOPS was found to have a molecular weight of 111.9 kDa. In L-glutamic acid (L-Glu)-damaged HT22 cells, a 3-h pre-incubation with IOPS enhanced cell viability, inhibited apoptosis and caspase-3 activity, reduced the release of lactate dehydrogenase, restored the dissipated mitochondrial membrane potential, and suppressed the excess accumulation of intracellular reactive oxygen species. Compared with L-Glu-exposed cells, IOPS pre-treated cells exhibited reduced levels of Bcl-2 associated X protein (Bax) and Kelch-like ECH-associated protein 1 (Keap1) and enhanced levels of B-cell lymphoma-2 (Bcl-2), NF-E2p45-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), superoxide dismutase-1 (SOD-1), and cysteine ligase catalytic subunit. In amyloid precursor protein/presenilin 1 (APP/PS1) transgenic mice, an 8-week course of IOPS improved the pathological behaviors related to memory and cognition, reduced the deposition of ß-amyloid peptides and neuronal fiber tangles induced by enhanced phosphor-Tau in the brain, and modulated the levels of anti- and pro-oxidative stress enzymes. Additionally, IOPS enhanced the expression levels of Nrf2 and its downstream proteins, including HO-1 and SOD-1, in the brains of APP/PS1 mice. The present study successfully demonstrated the protective effect of IOPS against AD and revealed the possible mechanism underlying the ability of IOPS to modulate oxidative stress, especially Nrf2 signaling, and mediate mitochondrial apoptosis.