Extramedullary infiltration in pediatric acute myeloid leukemia: Results from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) initiative.

BACKGROUND: The outcome of extramedullary infiltration (EMI) in pediatric acute myeloid leukemia (AML) is controversial, and little is known about the implications of stem cell transplantation (SCT) and gemtuzumab ozogamicin (GO) treatment on patients with EMI. METHODS: We retrieved the clinical data of 713 pediatric patients with AML from the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset, and analyzed the clinical and prognostic characteristics of patients with EMI at diagnosis and relapse. RESULTS: A total of 123 patients were identified to have EMI at diagnosis and 64 presented with EMI at relapse. The presence of EMI was associated with age ≤2 years, M5 morphology, abnormal karyotype, and KMT2A rearrangements. Hyperleukocytosis and complex karyotype were more prevalent in patients with EMI at relapse. Additionally, patients with EMI at diagnosis had a reduced incidence of FLT3 ITD-/NPM1+, whereas those with EMI at relapse displayed a lower frequency of FLT3 ITD+. Patients with EMI at diagnosis exhibited a lower complete remission (CR) rate at the end of Induction Course 1 and higher relapse incidence. Importantly, EMI at diagnosis independently predicted both shorter event-free survival (EFS) and overall survival (OS). Regarding relapse patients, the occurrence of EMI at relapse showed no impact on OS. However, relapse patients with myeloid sarcoma (MS)/no central nervous system (CNS) exhibited poorer OS compared to those with CNS/no MS. Furthermore, regarding patients with EMI at diagnosis, SCT failed to improve the survival, whereas GO treatment potentially enhanced OS. CONCLUSION: EMI at diagnosis is an independent adverse prognostic risk factor for pediatric AML, and GO treatment potentially improves survival for patients with EMI at diagnosis.

CD7-positive leukemic blasts with DNMT3A mutations predict poor prognosis in patients with acute myeloid leukemia.

Background: DNMT3A mutations can be detected in premalignant hematopoietic stem cells and are primarily associated with clonal hematopoiesis of indeterminate potential; however, current evidence does not support assigning them to a distinct European Leukemia Net (ELN) prognostic risk stratification. CD7 is a lymphoid antigen expressed on blasts in approximately 30% of acute myeloid leukemia (AML), and its role in AML remains unclear and depends on subgroup evaluation. This study investigated the prognostic value of DNMT3A mutation combined with CD7 expression in AML. Methods: We retrospectively analyzed the clinical data of 297 newly diagnosed non-M3 AML patients. According to the DNMT3A mutation and CD7 expression in AML cells, patients were divided into the DNMT3A-mutated/CD7-positive (CD7+), DNMT3A-mutated/CD7-negative (CD7-), DNMT3A-wild-type/CD7+, and DNMT3A-wild-type/CD7- groups. Results: The DNMT3A-mutated/CD7+ group had lower complete remission rates and higher relapse rates. Importantly, these patients had significantly shorter overall survival (OS) and relapse-free survival (RFS). Furthermore, multivariate analysis showed that CD7+ with DNMT3A mutation was an independent risk factor for OS and RFS. Conclusion: CD7+ with DNMT3A mutation predicts a poor prognosis in AML patients, and the immunophenotype combined with molecular genetic markers can help to further refine the current risk stratification of AML.

Correlation between red blood cell distribution width/platelet count and prognosis of newly diagnosed diffuse large B-cell lymphoma.

Background: Red blood cell distribution width/platelet count ratio (RPR) is a reliable prognostic assessment indicator for numerous diseases. However, no studies to date have examined the relationship between RPR and the prognosis of diffuse large B-cell lymphoma (DLBCL). Therefore, this study aimed to investigate the correlation between RPR and the clinical characteristics and prognosis of patients with diffuse large B-cell lymphoma. Methods: We retrospectively studied 143 patients with newly diagnosed DLBCL and used the median value as the RPR threshold. We also investigated the correlation of pretreatment RPR level with clinical characteristics and its impact on DLBCL prognosis. Results: Using the median value as the cut-off, patients with DLBCL were divided into a low RPR group (＜0.0549) and a high RPR group (≥0.0549). Patients in the high RPR group were older, had a later Ann Arbor stage, were prone to bone marrow invasion, and had a higher National Comprehensive Cancer Network International Prognostic Index score (P＜0.05). A survival analysis showed that progression-free survival (PFS) (P=0.003) and overall survival (OS) (P＜0.0001) were significantly shorter in the high versus low RPR group. A multifactorial Cox analysis showed that bone marrow invasion and elevated lactate dehydrogenase (LDH) were separate risk factors for PFS (P＜0.05), while an RPR ≥0.0549 and elevated LDH were separate risk factors for OS (P＜0.05). Conclusion: A high RPR (≥0.0549) in patients with newly diagnosed DLBCL is an independent risk factor for a poor prognosis.

The prediction of drug sensitivity by multi-omics fusion reveals the heterogeneity of drug response in pan-cancer.

Cancer drug response prediction based on genomic information plays a crucial role in modern pharmacogenomics, enabling individualized therapy. Given the expensive and complexity of biological experiments, computational methods serve as effective tools in predicting cancer drug sensitivity. In this study, we proposed a novel method called Multi-Omics Integrated Collective Variational Autoencoders (MOICVAE), which leverages integrated omics knowledge, including genomic and transcriptomic data, to fill in missing cancer-drug associations and enhance drug sensitivity prediction. Our method employs an encoder-decoder network to learn latent feature representations from cell lines. These learned feature vectors are then fed into a collective variational autoencoder network to train an association matrix. We evaluated MOICVAE on the GDSC and CCLE benchmark datasets using 10-fold cross-validation and achieved impressive AUCs of 0.856 and 0.808, respectively, outperforming state-of-the-art methods. Furthermore, on the TCGA dataset, consisting of 25 drugs across 7 cancer types, MOICVAE exhibited an average AUC of 0.91 in predicting drug sensitivity. Additionally, significant differences were observed in survival, tumor inflammatory assessment, and tumor microenvironment between the predicted drug-sensitive and drug-resistant groups. These results are consistent with predictions made on the METABRIC dataset. Moreover, we discovered that fusing omics data based on mRNA and CNV (copy number variations) yielded superior results in drug sensitivity prediction. MOICVAE not only achieved higher accuracy in drug sensitivity prediction but also provided additional value for combining immunotherapy with chemotherapy, offering patients with more precise treatment options. The code and dataset for MOICVAE are freely available at https://github.com/wanggnoc/MOICVAE.

High Red Blood Cell Distribution Width to Platelet Ratio is an Independent Poor Prognostic Factor in Patients with Newly Diagnosed Multiple Myeloma.

BACKGROUND: The red blood cell distribution width to platelet ratio (RPR) is an inflammatory marker that is a convenient and reliable prognostic indicator for several solid malignancies. However, the correlation between RPR and myeloma prognosis has not been reported. Therefore, this study aims to explore the correlation between RPR level and the prognosis of multiple myeloma (MM) patients. METHODS: We retrospectively analyzed 145 newly diagnosed patients with MM. The receiver operating characteristic curve (ROC) method was used to determine the RPR cut-off value. In addition, we studied the correlation between pre-treatment RPR levels and clinical characteristics, immunophenotype, cytogenetics, and its impact on the disease prognosis. RESULTS: The optimal cut-off value for RPR was 0.12 and was divided into high RPR and low RPR groups. Patients in the high RPR group are more likely to have anemia, thrombocytopenia, high ß2-macroglobulinemia, a high percentage of bone marrow plasma cells, late-stage status by Dury-Salmon (DS) and international staging system (ISS) (p < 0.05). More notably, between the high RPR and low RPR groups, the incidence rates of CD56-positive, D13S319-positive, RB1-positive, and 1q21 amplification were statistically significant (p < 0.05). Additionally, survival analysis revealed that compared with patients in the low RPR group, the median progression-free survival (PFS) and overall survival (OS) of patients in the high RPR group were substantially shortened (p < 0.05). Multivariate analysis confirmed that RPR ≥0.12, D13S319-positive, and 1q21 amplification were independent risk factors for poor PFS and OS. CONCLUSIONS: RPR is a practical and effective prognostic marker in newly diagnosed patients with MM, and a high RPR is an independent poor prognostic factor.

Differential effects of recombinant human thrombopoietin on clinical outcomes in CD7-positive and CD7-negative acute myeloid leukaemia.

To investigate the effect of recombinant human thrombopoietin (rhTPO) application on the clinical outcomes of CD7-positive acute myeloid leukaemia (CD7 + AML) patients following chemotherapy, we retrospectively studied 159 newly diagnosed non-M3 AML patients. Patients were divided into the following four groups according to the expression of CD7 in AML blasts and the use of rhTPO after chemotherapy: the CD7 + rhTPO group (n = 41), the CD7 + non-rhTPO group (n = 42), the CD7 negative (CD7-) rhTPO group (n = 37), and the CD7- non-rhTPO group (n = 39). The complete remission rate was higher in the CD7 + rhTPO group than in the CD7 + non-rhTPO group. Importantly, patients in the CD7 + rhTPO group had significantly higher 3-year overall survival (OS) rates and event-free survival (EFS) rates than those in the CD7 + non-rhTPO group, whereas they did not differ statistically between the CD7- rhTPO and CD7- non-rhTPO groups. In addition, multivariate analysis showed that rhTPO was an independent prognostic factor for OS and EFS in CD7 + AML. In conclusion, rhTPO led to better clinical outcomes for patients with CD7 + AML, while it had no significant effect on those with CD7- AML.

Inhibition of chaperone­mediated autophagy reduces tumor growth and metastasis and promotes drug sensitivity in colorectal cancer.

Chaperone­mediated autophagy (CMA) is a selective type of autophagy whereby a specific subset of intracellular proteins is targeted to the lysosome for degradation. The present study investigated the mechanisms underlying the response and resistance to 5­fluorouracil (5­FU) in colorectal cancer (CRC) cell lines. In engineered 5­FU­resistant CRC cell lines, a significant elevation of lysosome­associated membrane protein 2A (LAMP2A), which is the key molecule in the CMA pathway, was identified. High expression of LAMP2A was found to be responsible for 5­FU resistance and to enhance PLD2 expression through the activation of NF­κB pathway. Accordingly, loss or gain of function of LAMP2A in 5­FU­resistant CRC cells rendered them sensitive or resistant to 5­FU, respectively. Taken together, the results of the present study suggested that chemoresistance in patients with CRC may be mediated by enhancing CMA. Thus, CMA is a promising predictor of chemosensitivity to 5­FU treatment and anti­CMA therapy may be a novel therapeutic option for patients with CRC.

NDRG1 was downregulated and worked as favorable biomarker in the development of gastric cancer.

BACKGROUND: This study clarified the relationship between N-myc downstream regulated gene 1 (NDRG1) expression and the clinicopathological features, DNA methylation, prognosis and relevant signal pathways in gastric cancer (GC). METHODS: NDRG1 expression was examined by Western blot, immunohistochemistry and qRT-PCR. The clinical, transcriptome and methylation data of GC was downloaded from The Cancer Genome Atlas (TCGA), and extracted by R software. The overall survival (OS) rate of NDRG1 was analyzed by Kaplan-Meier plotter. The NDRG1-related gene set enrichment analysis (GSEA) was performed by GSEA-3.0. RESULTS: NDRG1 expression was down-regulated at both mRNA and protein levels, and immunohistochemically correlated with tumor diameter, depth of invasion, lymph node metastasis and lymphatic invasion, tissue differentiation at a negative manner. The mRNA expression of NDRG1 was negatively related to its methylation. Kaplan-Meier plotter results indicated that NDRG1 was positively correlated with the prognosis of GC patients. NDRG1 was involved in cancer, Notch, PPAR, ERBB, adherens junction, and tight junction signal pathways. CONCLUSIONS: In GC, NDRG1 expression was down-regulated, possibly due to DNA methylation. NDRG1 could play a role of tumor suppressor in the tumorigenesis by inhibiting multiple oncogenic signal pathways. The hypo-expression of NDRG1 was positively associated with malignant biological behavior and adverse prognosis in gastric cancer.

Nobiletin prevents cadmium-induced neuronal apoptosis by inhibiting reactive oxygen species and modulating JNK/ERK1/2 and Akt/mTOR networks in rats.

Objectives Cadmium (Cd), an extremely noxious environmental pollutant is known to induce oxidative stress leading to neurodegenerative diseases. Nobiletin, a citrus flavonoid is reported to possess various pharmacological properties. This study investigates the effects of nobiletin over Cd-induced neuronal apoptosis in rodent experimental model. Methods To separate group of male Sprague Dawley rats, Cd (2 mL/kg/day) was subcutaneously injected for one month which results in a dose level of 1 mg/kg Cd. Couple of days prior to Cd injection, the treatment group rats regularly received nobiletin (50, 100, or 200 mg/kg b.wt) orally through the study period. Results Cd-induced ROS levels and malondialdehyde (MDA) content were inhibited by nobiletin and improved glutathione levels. Nobiletin reduced neuronal apoptosis induced by Cd and raised cleaved caspase-3 levels. Intriguingly, nobiletin blocked JNK and Erk1/2 phosphorylation and down-regulated the pathways. Raised expression of kinases - MKK and ASK1 were reduced by nobiletin. Discussion The suppressed expression of phosphatases - PP2A and PP5 were up-regulated on nobiletin treatment. Nobiletin significantly blocked the activation of Akt/mTOR signaling. Enhanced phosphorylation of S6K1, Akt, and 4E-BP1 induced by Cd was significantly inhibited by nobiletin. The raised levels of raptor and rictor proteins were remarkably down-regulated on nobiletin treatment. Collectively, the observations of this study indicate protective effects of nobiletin against Cd-induced neurotoxicity.

The identification of age-associated cancer markers by an integrative analysis of dynamic DNA methylation changes.

As one of the most widely studied epigenetic modifications, DNA methylation has an important influence on human traits and cancers. Dynamic variations in DNA methylation have been reported in malignant neoplasm and aging; however, the mechanisms remain poorly understood. By constructing an age-associated and cancer-related weighted network (ACWN) based on the correlation of the methylation level and the protein-protein interaction, we found that DNA methylation changes associated with age were closely related to the occurrence of cancer. Additional analysis of 102 module genes mined from the ACWN revealed discrimination based on two main patterns. One pattern involved methylation levels that increased with aging and were higher in cancer patients compared with normal controls (HH pattern). The other pattern involved methylation levels that decreased with aging and were lower in cancer compared with normal (LL pattern). Upon incorporation with gene expression levels, 25 genes were filtered based on negative regulation by DNA methylation. These genes were regarded as potential cancer risk markers that were influenced by age in the process of carcinogenesis. Our results will facilitate further studies regarding the impact of the epigenetic effects of aging on diseases and will aid in the development of tailored cancer preventive strategies.

The protective effect of epoxyeicosatrienoic acids on cerebral ischemia/reperfusion injury is associated with PI3K/Akt pathway and ATP-sensitive potassium channels.

Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolite of arachidonic acid, have been demonstrated to have neuroprotective effect. Phosphatidylinositol 3-kinase (PI3K)/Akt and ATP-sensitive potassium (KATP) channels are thought to be important factors that mediate neuroprotection. However, little is known about the role of PI3K/Akt and KATP channels in brain after EETs administration. In vitro experiment, oxygen-glucose deprivation (OGD) was performed in cultured rat cerebral microvascular smooth muscle cells (SMCs) for 4 h. The effect of 14,15-EET on OGD induced cell apoptosis was examined after reoxygenation. Western blot and real-time PCR were used to analyze the expression of Kir6.1, SUR2B (two subunits of KATP channels) and p-Akt on cerebral microvascular SMCs. In vivo experiments, we use 12-(3-adamantan-1-yl-ureido)-dodecanoic acid [AUDA, a specific soluble epoxide hydrolase (sEH) inhibitor] to confirm the effect of EETs indirectly. Rats were injected intraperitoneally with AUDA before being subjected to middle cerebral artery occlusion (MCAO). We detected the apoptosis and the expression of p-Akt, Kir6.1 and SUR2B in ischemic penumbra. The results showed that EETs protect against cerebral ischemia/reperfusion (I/R) injury and upregulated the expression of p-Akt and Kir6.1 in both of ischemic penumbra and OGD induced cerebral microvascular SMCs. The protective effect was inhibited by Wortmannin (a specific PI3K inhibitor) and Glib (a specific KATP inhibitor) respectively in vitro experiment. In conclusion, these results suggested that the protective effect of EETs on cerebral I/R injury is associated with PI3K/Akt pathway and KATP channels. Furthermore, the PI3K pathway may contribute to mediating KATP channels on cerebral microvascular SMCs.