Invivo and invitro evaluation of antitumor effects of iron oxide and folate core shell-iron oxide nanoparticles

Nanoparticles are considered viable options in the treatment of cancer. This study was conducted to investigate the effect of magnetite nanoparticles (MNPs) and magnetite folate core shell (MFCS) on leukemic and hepatocarcinoma cell cultures as well as their effect on the animal model of acute myelocytic leukemia (AML). Through current study nanoparticles were synthesized, characterized by various techniques, and their properties were studied to confirm their nanostructure. Invivo study, nanoparticles were evaluated to inspect their cytotoxic activity against SNU-182 (human hepatocellular carcinoma), K562 (human leukemia), and THLE2 (human normal epithelial liver) cells via MTT test. Apoptotic signaling proteins Bcl-2 and Caspase-3 expression were inspected through RT-PCR method. A cytotoxic effect of MNPs and MFCS was detected in previous cell cultures. Moreover, the apoptosis was identified through significant up-regulation of caspase-3, with Bcl-2 down-regulation. Invitro study, AML was induced in rats by N-methyl-N-nitrosourea followed by oral treatment with MNPS and MFCS. Biochemical indices such as aspartate and alanine amino transferases, and lactate dehydrogenase activities, uric acid, complete blood count, and Beta -2-microglubulin were assessed in serum. Immunophenotyping for CD34 and CD38 detection was performed. Liver, kidney, and bone marrow were microscopically examined. Bcl-2 promoter methylation, and mRNA levels were examined. Although, both MNPs and MFCS depict amelioration in biochemical parameters, MFCS alleviated them toward normal control. Anticancer activity of MNPs and MFCS was approved especially for AML. Whenever, administration of MFCS was more effective than MNPs. The present work is one of few studies used MFCS as anticancer agent.

Integrative genomic analysis of a novel small nucleolar RNAs prognostic signature in patients with acute myelocytic leukemia

<abstract> <p>This study mainly used The Cancer Genome Atlas (TCGA) RNA sequencing dataset to screen prognostic snoRNAs of acute myeloid leukemia (AML), and used for the construction of prognostic snoRNAs signature for AML. A total of 130 AML patients with RNA sequencing dataset were used for prognostic snoRNAs screenning. SnoRNAs co-expressed genes and differentially expressed genes (DEGs) were used for functional annotation, as well as gene set enrichment analysis (GSEA). Connectivity Map (CMap) also used for potential targeted drugs screening. Through genome-wide screening, we identified 30 snoRNAs that were significantly associated with the prognosis of AML. Then we used the step function to screen a prognostic signature composed of 14 snoRNAs (SNORD72, SNORD38, U3, SNORA73B, SNORD79, SNORA73, SNORD12B, SNORA74, SNORD116-12, SNORA65, SNORA14, snoU13, SNORA75, SNORA31), which can significantly divide AML patients into high- and low-risk groups. Through GSEA, snoRNAs co-expressed genes and DEGs functional enrichment analysis, we screened a large number of potential functional mechanisms of this prognostic signature in AML, such as phosphatidylinositol 3-kinase-Akt, Wnt, epithelial to mesenchymal transition, T cell receptors, NF-kappa B, mTOR and other classic cancer-related signaling pathways. In the subsequent targeted drug screening using CMap, we also identified six drugs that can be used for AML targeted therapy, they were alimemazine, MG-262, fluoxetine, quipazine, naltrexone and oxybenzone. In conclusion, our current study was constructed an AML prognostic signature based on the 14 prognostic snoRNAs, which may serve as a novel prognostic biomarker for AML.</p> </abstract>

SAMHD1 Mutations and Expression in Mantle Cell Lymphoma Patients

SAMHD1 (sterile alpha motif domain and histidine-aspartate domain-containing protein 1) is a deoxynucleoside triphosphate triphosphohydrolase regulating innate immune and modulating DNA damage signaling. It plays an important role in the development of some tumors. SAMHD1 was also reported as a barrier to cytarabine, a common chemotherapy drug for mantle cell lymphoma (MCL), and as a biomarker of grim prognosis for acute myelocytic leukemia (AML) patients. However, SAMHD1 expression and function in MCL have not been well-defined. In the present study, we evaluated SAMHD1 expression by immunohistochemistry and its gene structure by Sanger sequencing in MCL. Our results showed that SAMHD1 was positive in 36 (62.1%) patients. Importantly, SAMHD1-positive patients were associated with lower chemotherapy response rate (p = 0.023) and shorter overall survival (p = 0.039) than SAMHD1-negative cases. These results suggest that SAMHD1 is an adverse biomarker for MCL patients, which is due to the high expression of SAMHD1 and rapid cell proliferation. These findings were confirmed in an in vitro study using the siRNA technique. Silencing the SAMHD1 gene in the MCL cell line Jeko-1 significantly decreased cell proliferation and increased cell apoptosis. The MCL cell line with SAMHD1 knockdown showed lower Ki-67 proliferation index, higher caspase-3, and higher sensitivity to cytarabine. Furthermore, for the first time, four previously unreported missense mutations (S302Y, Y432C, E449G, and R451H) in exon 8 and exon 12 of the SAMHD1 gene were discovered by sequencing. The mutations had not been found to corelate with SAMHD1 protein expression detected by immunohistochemistry. The biological functions of this mutated SAMHD1 remain to be investigated.

Sensitivity of Acute Myelocytic Leukemia Cells to the Dienone Compound VLX1570 Is Associated with Inhibition of the Ubiquitin-Proteasome System

Dienone compounds with a 1,5-diaryl-3-oxo-1,4-pentadienyl pharmacophore have been widely reported to show tumor cell selectivity. These compounds target the ubiquitin-proteasome system (UPS), known to be essential for the viability of tumor cells. The induction of oxidative stress, depletion of glutathione, and induction of high-molecular-weight (HMW) complexes have also been reported. We here examined the response of acute myeloid leukemia (AML) cells to the dienone compound VLX1570. AML cells have relatively high protein turnover rates and have also been reported to be sensitive to depletion of reduced glutathione. We found AML cells of diverse cytogenetic backgrounds to be sensitive to VLX1570, with drug exposure resulting in an accumulation of ubiquitin complexes, induction of ER stress, and the loss of cell viability in a dose-dependent manner. Caspase activation was observed but was not required for the loss of cell viability. Glutathione depletion was also observed but did not correlate to VLX1570 sensitivity. Formation of HMW complexes occurred at higher concentrations of VLX1570 than those required for the loss of cell viability and was not enhanced by glutathione depletion. To study the effect of VLX1570 we developed a zebrafish PDX model of AML and confirmed antigrowth activity in vivo. Our results show that VLX1570 induces UPS inhibition in AML cells and encourage further work in developing compounds useful for cancer therapeutics.

Platelet transcriptome profiles provide potential therapeutic targets for elderly acute myelocytic leukemia patients

Background Acute myeloid leukemia (AML) is the most common acute leukemia in adults, with a median age of 68 in clinical diagnosis. About 60% patients are over 60 years old. There are various treatment options for AML patients. But for elderly patients, the complete remission rates are disappointing due to genetic, molecular, and age-related factors. Development of next-generation sequencing technologies makes it possible to seek individual strategies for patients in different ages. This study analyzed transcriptome profiles in platelets of AML patients in different ages for the first time. Methods Platelet RNA sequencing in AML of ten elderly and seven young patients were performed with Illumina TruSeq Stranded mRNA library Prep Kit and Illumina HiSeq4000 sequencing instrument. With the FASTQ sequencing data obtained, statistical analyses between elderly with young AML patients were analyzed by R program. GO and KEGG enrichment analyses were performed via R package clusterProfiler. TOP 10 down-regulated/up-regulated genes in elderly patients compared to young patients were selected with the threshold of |L2FC| > 2 and padj ≤ 0.0001. The down-regulated gene ATF4 was chosen by GSEA analysis and ROC analysis with AUC > 0.95. Results We found 3059 genes with differential transcript levels (GDTLs) in AML patients of different age. Among them, 2048 genes are down-regulated and 651 genes are up-regulated in elderly patients. We found that gene transcript profiles in elderly patients is obviously different from those in young patients, including a collection of down-regulated genes related to proteins processing in endoplasmic reticulum and immunity. We further identified that genes of pathway in cancer and mitogen activated protein kinase (MAPK) pathway, involved in natural immunity and metabolism, are significantly down-regulated in elderly patients. Among all screened genes with decreased transcript levels, we believe that activating transcription factor 4 (ATF4) is a biomarker indicating different chemotherapy strategies for elderly patients. Conclusions In summary, gene transcript profiles are different in platelets of elderly and young AML patients. And ATF4 can be a useful biomarker indicating different chemotherapy strategies for AML patients with different ages.

Evaluation Of Oral Health-Related Quality Of Life In Children With Hematological Malignances

Objective: Chemotherapy and radiotherapy, used to treat childhood hematological malignancies (HM), can negatively impact oral tissues and organs. This study aimed to evaluate oral health-related quality of life in children with HM. Material and Methods: A total of 99 children, including 49 undergoing HM (41 for acute lymphocytic leukemia, 8 for acute myelocytic leukemia,) and 50 healthy volunteers, were included in this cross-sectional study. The mean age of the entire study group was 78.63 ± 34.41 months. The mean age of the HM and control groups was 87.12 ± 35.04 and 70.95 ± 34.85 months, respectively. The Simplified Oral Hygiene Index (SOHI), Decayed, Missing, and Filled Teeth (DMFT/dmft) index, and Turkish version of the Early Childhood Oral Health Impact Scale (ECOHIS-T) were administered to all children. The data were analyzed using SPSS software (version 22.0). Results: The age and gender distributions of the two groups were similar. The SOHI was significantly higher in the HM group, whereas the DMFT/dmft score was similar between the groups. No significant difference in the total ECOHIS-T score was observed between the two groups, but there was a group difference in the responses to questions on pain and psychological processes. Conclusions: Oral health and self-care were negatively affected by childhood HM and the treatment thereof. Close clinical dental follow-up of such patients is required.

Leukemia With TCF3-ZNF384 Rearrangement as a Distinct Subtype of Disease With Distinct Treatments: Perspectives From A Case Report and Literature Review

BackgroundZNF384 rearrangements are found in 5-10% of B-cell acute lymphoblastic leukemia (B-ALL) and 48% of B cell/myeloid mixed phenotype acute leukemia (B/M MPAL). ZNF384-rearranged B-ALL is prone to lineage conversion after chemotherapy. TCF3 is the second most common rearrangement partner of ZNF384 in B-ALL (27.5%) and the most common partner in B/M MPAL (53.3%). TCF3-ZNF384 fusion is related to a poor steroid response and a high frequency of relapse. It is mostly reported in children and adolescents but rarely seen in adults.Patients and MethodsHere, we report a rare case of adult common B-ALL with TCF3-ZNF384 fusion in which the patient relapsed after one cycle of consolidation chemotherapy. Relapsed leukemia cells from the bone marrow were cultured for 72 hours ex vivo, and a panel of 156 kinds of cytotoxic drugs, targeted therapy drugs, combination chemotherapy drugs, etc., was used for sensitivity screening. The literature on TCF3-ZNF384 fusion was reviewed, and reported cases with TCF3-ZNF384 fusion were summarized. Clinical characteristics were compared between B-ALL and MPAL with TCF3-ZNF384 fusion.ResultsThe relapsed lymphoblasts showed moderate sensitivity to both acute myelocytic leukemia (AML) - and acute lymphoblastic leukemia (ALL)-directed combination chemotherapy schemes, as well as to multiple targeted therapeutic drugs. The hyper-CVAD (B) scheme showed synergistic effects with multiple targeted compounds and had the highest sensitivity. The patient chose the hyper-CVAD (B) scheme combined with sorafenib and achieved complete remission (CR), then consolidated with myeloid-directed homoharringtonine+cytarabine+daunorubicin (HAD) scheme and gained molecular CR. By reviewing the literature, we found that both the genomic landscapes and gene expression profiles of ZNF384-rearranged B-ALL and MPAL are similar and that both diseases have lineage plasticity. The gene expression profile in TCF3-ZNF384-positive patients shows enrichment of hematopoietic stem cell features. No significant differences in clinical characteristics were found between TCF3-ZNF384-positive ALL and MPAL.ConclusionTCF3-ZNF384-positive leukemia may be a distinct subtype of leukemia regardless of immunophenotype. Considering the frequent lineage switches and sensitivity to both ALL- and AML-directed schemes, a uniform strategy directed at both lymphoid and myeloid lineages or at hematopoietic stem cells may be better for TCF3-ZNF384-positive leukemia. Small molecule targeted therapies may be promising treatment options and deserve further investigation.

Comprehensive DNA methylation-transcriptome profiles association analysis During the Treatment of Acute Myelocytic Leukemia

Background: Epigenetic modifications have recently attracted much attention in the study of the biological mechanisms of acute myelocytic leukemia (AML) for therapy and prognosis. However, studies on DNA methylation changes during AML treatment are limited. Objective: The comprehensive DNA methylation-transcriptome profiles association analysis in this study aimed to establish whole-genome DNA methylation profiles and explore DNA methylation-related genes and their potential functions before and after treatment. And more appropriate biomarkers are expected to be identified for therapy strategies in AML. Method: Illumina 450K and RNA-Seq data were obtained from The Cancer Genome Atlas. We performed comprehensive DNA methylation-transcriptome profiles association analysis, pathway analysis, correlation analysis, and survival analyses. The StarBase database was utilized to predict interactions between lncRNAs, miRNAs and target mRNAs. Results: In total, 1592 distinct CpG sites and 2419 different expression transcripts were identified between pre-treatment and post-treatment AML. The significantly enriched functions of methylated genes were stem cell differentiation, cell population maintenance, and cell development. The expression of UGT3A2, MOG, and VSTM1 was correlated with DNA methylation levels (r2>0.5). Lastly, we identified 4 lncRNAs, 9 miRNAs and 142 mRNAs to construct a lncRNA-miRNA-mRNA ceRNA network. Conclusion: Our results revealed that DNA methylation was altered before and after treatment. Alterations in DNA methylation affected target gene expression and participated in the key biological processes of AML. Therefore, ceRNA networks may provide further insight into the study of favorable therapeutic markers in AML.