Gilteritinib-based combination therapy in adult relapsed/refractory FLT3-mutated acute myeloid leukaemia.

Gilteritinib, a potent FMS-like tyrosine kinase 3 (FLT3) inhibitor, was approved for relapsed/refractory (R/R) FLT3-mutated acute myeloid leukaemia (AML) patients but still showed limited efficacy. Here, we retrospectively analysed the efficacy and safety of different gilteritinib-based combination therapies (gilteritinib plus hypomethylating agent and venetoclax, G + HMA + VEN; gilteritinib plus HMA, G + HMA; gilteritinib plus venetoclax, G + VEN) in 33 R/R FLT3-mutated AML patients. The composite complete response (CRc) and modified CRc (mCRc) rates were 66.7% (12/18) and 88.9% (16/18) in patients received G + HMA + VEN, which was higher compared with that in G + HMA (CRc: 18.2%, 2/11; mCRc: 45.5%, 5/11) or G + VEN (CRc: 50.0%, 2/4; mCRc: 50.0%, 2/4). The median overall survival (OS) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 160.0 days and 231.0 days. The median duration of remission (DOR) for G + HMA + VEN, G + HMA and G + VEN treatment was not reached, 82.0 days and 77.0 days. Four patients in the G + HMA + VEN group received alloHSCT after remission exhibited prolonged median DOR. The most common grade 3/4 adverse events were cytopenia, febrile neutropenia and pulmonary infection; there were no differences among the three groups. In conclusion, our data demonstrated promising response of G + HMA + VEN combination therapy in R/R FLT3-mutated AML, and it may be considered an effective therapy bridge to transplantation.

New insights into the clinical characteristics of SETD2-mutated acute myeloid leukaemia.

As reported, SETD2 is recurrently mutated in acute myeloid leukaemia (AML), but knowledge about the specifics is limited. We enrolled 530 consecutive newly diagnosed AML patients in our study, and we analysed the distribution pattern and prognostic role of SETD2 mutation in AML. SETD2 mutation was found to affect 6.3% of AML patients, and it frequently co-occurred with IDH2, NRAS and CEBPA mutations. SETD2-mutated patients saw excellent therapeutic responses but failed to gain better survival time than other patients. This could be because of the high recurrence and mortality in SETD2-mutated patients who have additional mutations, such as NRAS mutation.

Trimethoprim-sulfamethoxazole prevents interstitial pneumonitis in B-cell lymphoma patients receiving chemotherapy: a propensity score matching analysis.

B-cell lymphoma is the most prevalent type of non-Hodgkin lymphoma, for which the standard treatment regimen includes rituximab combined with CHOP. However, some patients may develop interstitial pneumonitis (IP), which can be caused by various factors; one of the most important factors is Pneumocystis jirovecii. It is crucial to investigate the pathophysiology of IP and implement preventive measures since IP can be fatal for some people. The data were collected from the First Affiliated Hospital, Zhejiang University School of Medicine, where patients with B-cell lymphoma received the R-CHOP/R-CDOP regimen with or without prophylactic use of trimethoprim-sulfamethoxazole (TMP-SMX). Multivariable logistic regression and propensity score matching (PSM) were used to investigate any potential association. Eight hundred thirty-one patients with B-cell lymphoma were classified into two groups: the non-prophylaxis group without TMP-SMX (n=699) and the prophylaxis group with TMP-SMX (n = 132). IP occurred in 66 patients (9.4%, all in the non-prophylaxis group), with an onset median of three cycles of chemotherapy. Multiple logistic regression analysis demonstrated that IP incidence was associated with pegylated liposome doxorubicin (OR=3.29, 95% CI 1.84-5.90, P<0.001). After utilizing a 1:1 matching algorithm for PSM, 90 patients from each group were obtained. There was a statistical difference between the two cohorts in the IP incidence (non-prophylaxis 12.2% vs prophylaxis 0.0%, P <0.001). The prophylactic use of TMP-SMX could prevent the occurrence of IP whose risk factor was pegylated liposome doxorubicin after chemotherapy for B-cell lymphoma.

Phosphatidylinositol-specific phospholipase C can decrease Müller cell viability and suppress its phagocytic activity by modulating PI3K/AKT signaling pathway.

Bacillus cereus endophthalmitis is a devastating eye infection that causes rapid blindness through the release of extracellular tissue-destructive exotoxins. The phagocytic and antibacterial functions of ocular cells are the keys to limiting ocular bacterial infections. In a previous study, we identified a new virulence gene, plcA-2 (different from the original plcA-1 gene), that was strongly associated with the plcA gene of Listeria monocytogenes. This plcA gene had been confirmed to play an important role in phagocytosis. However, how the Bc-phosphatidylinositol-specific phospholipase C (PI-PLC) proteins encoded by the plcA-1/2 genes affect phagocytes remains unclear in B. cereus endophthalmitis. Here, we found that the enzymatic activity of Bc-PI-PLC-A2 was approximately twofold higher than that of Bc-PI-PLC-A1, and both proteins inhibited the viability of Müller cells. In addition, PI-PLC proteins reduced phagocytosis of Müller cells by decreasing the phosphorylation levels of key proteins in the PI3K/AKT signaling pathway. In conclusion, we showed that PI-PLC proteins contribute to inhibit the viability of and suppress the phagocytosis of Müller cells, providing new insights into the pathogenic mechanism of B. cereus endophthalmitis.

Divergent response of hay and grain yield of oat: effects of environmental factors and sowing rate.

BACKGROUND: Oat (Avena sativa L.) is recognized for its impressive productivity in marginal environments, and the sowing rate is an important crop management practice that potentially enhances oat productivity. Previous studies have reported the effect of sowing rate on oat yield; however, the results from such studies are inconsistent. Thus, based on 43 studies across eight countries, this study aimed to assess changes in hay and grain yields in response to sowing rate and, in combination with a boosted regression tree, to evaluate and rank the dominant factors (e.g. climate conditions, soil conditions, and sowing rate) affecting changes in hay and grain yields of oat. RESULTS: The results revealed that increasing the sowing rate significantly increased the response ratio of grain yields and hay yields by averages of 7.3% and 7.9% respectively. However, the response ratios of grain yields and hay yields in response to changes in sowing rate were affected by different factors. Climate condition and mean annual precipitation primarily affected the response ratios of hay yields, whereas the sowing rate dominated changes in the response ratios of grain yields, with the response ratios of grain yields peaking at a sowing rate of 85 kg ha-1 . CONCLUSION: Optimizing the sowing rate with site-specific environmental conditions could be a potential strategy for profitable oat production, given that oat can be produced under marginal environments (e.g. cool-wet climates and soil with low fertility). © 2022 Society of Chemical Industry.

A novel regQTL-SNP and the risk of lung cancer: a multi-dimensional study.

RegQTL, a novel concept, indicates that different genotypes of some SNPs have differential effects on the expression patterns of miRNAs and their target mRNAs. We aimed to identify the association between regQTL-SNPs and lung cancer risk and to explore the underlying mechanisms. The two-stage case-control study included the first stage in a Chinese population (626 lung cancer cases and 667 healthy controls) and the second stage in a European population (18,082 lung cancer cases and 13,780 healthy controls). Functional annotations were conducted based on the GTEx and the TCGA databases. Functional experiments were performed to explore the underlying biological mechanisms in vitro and vivo. After strict screening, five candidate regQTL-SNPs (rs7110737, rs273957, rs6593210, rs3768617, and rs6836432) were selected. Among them, the variant T allele of rs3768617 in LAMC1 was found to significantly increase the risk of lung cancer (first stage: P = 0.044; second stage: P = 0.007). The eQTL analysis showed that LAMC1 expression level was significantly higher in subjects with the variant T allele of rs3768617 (P = 1.10 × 10-14). In TCGA paired database, the regQTL annotation indicated the different expression patterns between LAMC1 and miRNA-548b-3p for the distinct genotypes of rs3768617. Additionally, LAMC1 knockdown significantly inhibited malignant phenotypes in lung cancer cell lines and suppressed tumor growth. A novel regQTL-SNP, rs3768617, might affect lung cancer risk by modulating the expression patterns of miRNA-548b-3p and LAMC1. RegQTL-SNPs could provide a new perspective for evaluating the regulatory function of SNPs in lung cancer development.

miRNA sequencing reveals miRNA-4508 from peripheral blood lymphocytes as potential diagnostic biomarker for silica-related pulmonary fibrosis: A multistage study.

BACKGROUND AND OBJECTIVE: This study aimed to identify miRNA as potential diagnostic biomarkers for silica-related pulmonary fibrosis (SPF). METHODS: We first performed a comprehensive miRNA-seq screening in PBL of eight subjects exposed to silica dust (four individuals with SPF and four healthy controls). The promising miRNA were then evaluated in the first-stage validation using an independent GEO data set (GSE80555) of 6 subjects (3 individuals with SPF and 3 healthy controls), followed by a second-stage validation using 120 subjects exposed to silica dust (60 individuals with SPF and 60 healthy controls). RESULTS: Thirty-five miRNA showed strong expression differences in miRNA-seq screening, while miRNA-4508 (P = 9.52 × 10-3 ) was retained as a candidate after the first-stage validation (GSE80555), which was further confirmed in the second-stage validation with similar and strong effect (P = 9.93 × 10-17 ). ROC analysis showed that miRNA-4508 could distinguish SPF cases from healthy controls with high AUC (0.886), with sensitivity of 81.7% and specificity of 86.7%. In addition, the miRNA-4508 upstream rs6576457 mutant A allele exhibited a strong association with susceptibility to SPF (OR = 1.64, 95% CI = 1.20-2.23, P = 0.002), while eQTL analysis revealed a potential association between different genotypes of rs6576457 and miRNA-4508 expression (P = 0.068) in 60 healthy subjects with silica dust exposure. CONCLUSION: miRNA-4508 may be a potential diagnostic marker for SPF, and rs6576457, a functional variant of miRNA-4508, may affect SPF susceptibility. The detailed mechanism of action of this miRNA remains to be elucidated.

Clinical Significance of Prognostic Nutritional Index for Patients with Diffuse Large B-cell Lymphoma.

To analyze the clinical characteristics and prognostic value of prognostic nutritional index (PNI) for diffuse large B-cell lymphoma (DLBCL) treated in the rituximab era, baseline clinical and disease characteristics were recorded in our hospital. Concentration of T-helper cell type (Th1/Th2/Th17) cytokine profiles were measured by flow cytometry. DLBCL patients were classified into low and high PNI group based on the cutoff value as previously reported. Clinical features and survivals were compared between high and low group. In all, 114 (37%) out of 309 patients were classified as low PNI group. The low group had lower levels of albumin, hemoglobin and lymphocyte counts, and older age, and high lactate dehydroxygenase (LDH), and high frequencies of advanced stage, poor performance status, B symptoms, extranodal involvement, and higher level of interferon gamma (INF-γ). Low PNI was associated with poor overall survival (OS) in univariate analyses. But these significances did not stand in the paired patients matched by the well-established prognostic factors. In parallel, there was no significance between survival and PNI in the multivariate analyses. PNI was closely correlated with the well-established prognostic factors for DLBCL patients and was not an independent prognostic factor in our study.

Up-regulation of miR-24-1-5p is involved in the chemoprevention of colorectal cancer by black raspberry anthocyanins.

As important epigenetic regulators, microRNA regulate protein expression by triggering the degradation of target mRNA and/or by inhibiting their translation. Dysregulation of microRNA expression has been reported in several cancers, including colorectal cancer. In this study, microRNA-array differential analysis revealed strongly enhanced expression of miR-24-1-5p in the colon tissue of azoxymethane/dextran sulphate sodium-induced mice that were fed with black raspberry anthocyanins for 9 weeks. Overexpression of miR-24-1-5p in human colorectal cancer cells significantly repressed ß-catenin expression, and simultaneously decreased cell proliferation, migration and survival. Furthermore, miR-24-1-5p could target ß-catenin and trigger a negative regulatory loop for ß-catenin and its downstream target genes. ß-Catenin signalling is vital to the formation and progression of human colorectal cancer. The current findings therefore identified miR-24-1-5p as a potent regulator of ß-catenin, and this may provide a novel chemopreventive and therapeutic strategy for ß-catenin signalling-driven colorectal cancer.

Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy.

Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.

Combing oncolytic adenovirus expressing Beclin-1 with chemotherapy agent doxorubicin synergistically enhances cytotoxicity in human CML cells in vitro.

Cancer virotherapy provides a new strategy to treat cancer that can directly kill cancer cells by oncolysis. Insertion of therapeutic genes into the genome of a modified adenovirus, thereby creating a so-called gene-virotherapy that shares the advantages of gene therapy and virotherapy. In this study we investigated whether a strategy that combines the oncolytic effects of an adenoviral vector with the simultaneous expression of the autophagy gene Beclin-1 offered a therapeutic advantage for chronic myeloid leukemia (CML) cells with resistance to chemotherapy and evaluated the synergistic effects of SG511-BECN and doxorubicin (Dox) in human CML cells in vitro. Oncolytic virus SG511-BECN was constructed through introducing the Beclin-1 gene into the oncolytic adenoviral backbone. SG511-BECN displayed significantly improved antileukemia activity on multidrug-resistant CML cell line K562/A02, which was mediated via induction of autophagic cell death. Furthermore, Dox could synergize with SG511-BECN to kill the CML cells by improving the infectious efficiency of the oncolytic adenovirus without causing significant damage to normal human mononuclear cells. The results demonstrate that targeting the autophagic cell death pathway and combination of a chemotherapy agent with oncolytic adenovirus may be a novel strategy for the treatment of leukemia with chemotherapy resistance.

ERG11 Gene Mutations and MDR1 Upregulation Confer Pan-Azole Resistance in Candida tropicalis Causing Disseminated Candidiasis in an Acute Lymphoblastic Leukemia Patient on Posaconazole Prophylaxis.

In this study, we present a rare case of fatal breakthrough Candida tropicalis infection in a patient with acute lymphoblastic leukemia (ALL) while on posaconazole prophylaxis. Then, we explore the mechanisms underlying azole resistance by focusing on enhanced efflux pumps and changes in the azole target enzyme Erg11p, which was encoded by the ERG11 gene. Our study demonstrates that Y132C substitution of Erg11p combined with MDR1 overexpression may be the pan-azole resistance mechanisms in Candida tropicalis.

The Prevalence of Antenatal Depression and its Related Factors in Chinese Pregnant Women who Present with Obstetrical Complications.

OBJECTIVES: The psychological status of Chinese pregnant women who present with obstetrical complications is concerning to Chinese health professionals. This study aimed to investigate the prevalence of antenatal depression and analyzed related risk factors in a population of high-risk Chinese women. DESIGN: A large sample size, cross-sectional study. METHODS: A total of 842 pregnant women with complications completed the Chinese version of the Postpartum Depression Screen Scale (PDSS) in this cross-sectional study. t-Test, ANOVA and Binary logistic regression tests were used in data analysis of antenatal depression and risk factors. RESULTS: The prevalence of major or minor depression in high-risk Chinese pregnant women during antenatal period was 8.3% and 28.9%, respectively. Independent-sample t-test and two-way analysis of variance (ANOVA) indicated significant differences in age, education, occupation and the number of complications (P<0.05). Binary logistic regression analysis indicated a significant negative association between depression and education (P<0.01) with lower educational level (OR: 0.590; 95% CI: 0.424-0.820) associated with a higher risk for depression. A significant positive association was observed between depression and age (P<0.05) with higher age (OR: 1.338; 95% CI: 1.008-1.774) correlated with a higher risk for depression. CONCLUSIONS: Women who experienced obstetric complications presented with higher PDSS depression scores. Screening for antenatal depression in high-risk pregnant women to promote early detection of depression and reduce health risks for universal health promotion is recommended.

[Bortezomib-induced peripheral neuropathy in multiple myeloma patients].

OBJECTIVE: To describe the side effects of bortezomib in treatment of multiple myeloma (MM), especially the incidence of peripheral neuropathy (PN). METHODS: Information of 107 patients with MM who were treated with bortezomib in the First Affiliated Hospital of Zhejiang University from 2009 to 2014, were collected and analyzed retrospectively, to analyze the occurrence of adverse events during the treatment, especially the incidences of PN in each cycle and in different patients. RESULTS: A total of 40 (37%) patients suffered from PN, among which 13 patients were grade 3 PN and no patients reported grade 4 PN. Other common treatment-related side effects were thrombocytopenia, gastrointestinal reactions, fatigue, lung infection, herpes zoster in turn. In 44 MM patients treated strictly with bortezomib 1.3 mg/m(2) (days 1, 4, 8, 11) of each 3-week cycle, 20(45%) patients suffered from PN, of which 6 (14%) patients got grade 3 PN. In other 63 patients who received bortezomib less than 1.3 mg/m(2), 20 (32%) patients got PN and 7(11%) patients were grade 3 PN. There was no significant difference in the incidence of PN between the two groups of MM patients mentioned above (P=0.149), as well as the incidence of grade 3 PN (P=0.694). Univariate and multivariate analyse revealed that gender, age, a history of hypertensive disease, diabetes or hepatitis B virus infection, baseline PN symptoms and a history of neurotoxicity drug therapy were all not risk factors for PN (all P>0.05). CONCLUSIONS: The reduction of bortezomib do not decrease the incidence of PN in bortezomib treatment of MM. Age, a history of diabetes and baseline PN symptoms are not risk factors for PN in bortezomib treatment of MM.

[Apoptosis of acute myeloid leukemia HL-60 cells induced by CDK inhibitor SNS-032 and its molecular mechanisms].

OBJECTIVE: To investigate the effects of cycle-dependent kinase (CDK) inhibitor SNS-032 on apoptosis in human acute myeloid leukemia (AML) HL-60 cells and its molecular mechanisms. METHODS: Cultured AML HL-60 cells were treated with various concentrations of SNS-032. Cell apoptosis was determined with flow cytometry;cell viability was measured by MTT assay; the profiles of microRNA expression of HL-60 cells were analyzed by microRNA microarray;the protein expressions of JAK2/STAT3 pathway were detected by Western blotting. RESULTS: Apoptosis of AML HL-60 cells was induced by SNS-032; the rate of apoptosis was (5.9±1.7)%, (12.1±3.1)% and (59.4±3.6)% when HL-60 cells were treated with 0,100 and 200 nmol/L SNS-032. MicroRNA microarray analysis revealed that the levels of miR-30a, miR-183, miR-20b, miR-26b, miR-20a, miR-589, miR-107, miR-181a, miR-106a, miR-17 and miR-378c were down-regulated by SNS-032,whereas the levels of miR-320a and miR-H7* were up-regulated. Western blotting showed that SNS-032 strongly inhibited phosphorylation of STAT3 and protein expression of JAK2,C-MYC and MCL-1. CONCLUSION: CDK inhibitor SNS-032 can induce apoptosis of AML HL-60 cells, which is associated with the inhibition of MCL-1,C-MYC and JAK2/STAT3, and down-regulation of miR-17-92 family.

Phosphoproteomic Characterization and Kinase Signature Predict Response to Venetoclax Plus 3+7 Chemotherapy in Acute Myeloid Leukemia.

Resistance to chemotherapy remains a formidable obstacle in acute myeloid leukemia (AML) therapeutic management, necessitating the exploration of optimal strategies to maximize therapeutic benefits. Venetoclax with 3+7 daunorubicin and cytarabine (DAV regimen) in young adult de novo AML patients is evaluated. 90% of treated patients achieved complete remission, underscoring the potential of this regimen as a compelling therapeutic intervention. To elucidate underlying mechanisms governing response to DAV in AML, quantitative phosphoproteomics to discern distinct molecular signatures characterizing a subset of DAV-sensitive patients is used. Cluster analysis reveals an enrichment of phosphoproteins implicated in chromatin organization and RNA processing within DAV-susceptible and DA-resistant AML patients. Furthermore, kinase activity profiling identifies AURKB as a candidate indicator of DAV regimen efficacy in DA-resistant AML due to AURKB activation. Intriguingly, AML cells overexpressing AURKB exhibit attenuated MCL-1 expression, rendering them receptive to DAV treatment and maintaining them resistant to DA treatment. Moreover, the dataset delineates a shared kinase, AKT1, associated with DAV response. Notably, AKT1 inhibition augments the antileukemic efficacy of DAV treatment in AML. Overall, this phosphoproteomic study identifies the role of AURKB as a predictive biomarker for DA, but not DAV, resistance and proposes a promising strategy to counteract therapy resistance in AML.

Identification of the consistently differential expressed hub mRNAs and proteins in lung adenocarcinoma and construction of the prognostic signature: a multidimensional analysis.

BACKGROUND: This study aimed to elucidate the consistency of differentially expressed hub mRNAs and proteins in lung adenocarcinoma (LUAD) across populations and to construct a comprehensive LUAD prognostic signature. METHODS: The transcriptomic and proteomics data from different populations were standardized and analyzed using the same criteria to identify the consistently differential expressed mRNAs and proteins across genders and races. We then integrated prognosis-related mRNAs with clinical, pathological, and EGFR (epidermal growth factor receptor) mutation data to construct a survival model, subsequently validating it across populations. Through plasma proteomics, plasma proteins that consistently differential expressed with LUAD tissues were screened and validated, with their associations discerned by measuring expressions in tumor tissues and tumor vascular normalization. RESULTS: The consistency rate of differentially expressed mRNAs and proteins was ~20-40%, with ethnic factors leading to about 40-60% consistency of differentially expressed mRNA or protein across populations. The survival model based on the identified eight hub mRNAs as well as stage, smoking status, and EGFR mutations, demonstrated good prognostic prediction capabilities in both Western and East Asian populations, with a higher number of unfavorable variables indicating poorer LUAD prognosis. Notably, GPI expression in tumor tissues was inversely correlated with vascular normalization and positively correlated with plasma GPI expression. CONCLUSION: Our study underscores the significance of integrating transcriptomics and proteomics data, emphasizing the need to account for genetic diversity among ethnic groups. The developed survival model may offer a holistic perspective on LUAD progression, enhancing prognosis and therapeutic strategies.