Metabolic Reprogramming and Potential Therapeutic Targets in Lymphoma.

Lymphoma is a heterogeneous group of diseases that often require their metabolism program to fulfill the demand of cell proliferation. Features of metabolism in lymphoma cells include high glucose uptake, deregulated expression of enzymes related to glycolysis, dual capacity for glycolytic and oxidative metabolism, elevated glutamine metabolism, and fatty acid synthesis. These aberrant metabolic changes lead to tumorigenesis, disease progression, and resistance to lymphoma chemotherapy. This metabolic reprogramming, including glucose, nucleic acid, fatty acid, and amino acid metabolism, is a dynamic process caused not only by genetic and epigenetic changes, but also by changes in the microenvironment affected by viral infections. Notably, some critical metabolic enzymes and metabolites may play vital roles in lymphomagenesis and progression. Recent studies have uncovered that metabolic pathways might have clinical impacts on the diagnosis, characterization, and treatment of lymphoma subtypes. However, determining the clinical relevance of biomarkers and therapeutic targets related to lymphoma metabolism is still challenging. In this review, we systematically summarize current studies on metabolism reprogramming in lymphoma, and we mainly focus on disorders of glucose, amino acids, and lipid metabolisms, as well as dysregulation of molecules in metabolic pathways, oncometabolites, and potential metabolic biomarkers. We then discuss strategies directly or indirectly for those potential therapeutic targets. Finally, we prospect the future directions of lymphoma treatment on metabolic reprogramming.

Effects of Groove and Steel Fiber on Shear Properties of Concrete with Recycled Coarse Aggregate.

In this paper, a series of shear specimens with or without groove were manufactured to mainly analyze the effects of grooves (or shear section height) and steel fibers on the shear properties of concrete with recycled coarse aggregate through double-side direct shear test. In addition, the relationship between the shear strength and the compressive strength and splitting tensile strength of steel fiber reinforced concrete with recycled coarse aggregate (SFRCAC) was also discussed. The experimental results showed that the peak load, deformation corresponding to the peak load and calculated shear strength of the specimens with grooves were lower than those of the specimens without grooves. The steel fiber and recycled coarse aggregate (RCA) had a significant effect on the shear properties of SFRCAC. As the volume content of steel fibers increased, the shear strength of SFRCAC and the corresponding deformation increased gradually. With the replacement ratio of RCA increasing, the shear strength of SFRCAC decreased but the corresponding deformation increased gradually. Finally, the formula for calculating the shear strength of SFRCAC was proposed by analyzing and fitting the test results and the data of related literature.

MicroRNA-155 controls vincristine sensitivity and predicts superior clinical outcome in diffuse large B-cell lymphoma.

A major clinical challenge of diffuse large B-cell lymphoma (DLBCL) is that up to 40% of patients have refractory disease or relapse after initial response to therapy as a result of drug-specific molecular resistance. The purpose of the present study was to investigate microRNA (miRNA) involvement in vincristine resistance in DLBCL, which was pursued by functional in vitro analysis in DLBCL cell lines and by outcome analysis of patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Differential miRNA expression analysis identified miR-155 as highly expressed in vincristine-sensitive DLBCL cell lines compared with resistant ones. Ectopic upregulation of miR-155 sensitized germinal-center B-cell-like (GCB)-DLBCL cell lines to vincristine, and consistently, reduction and knockout of miR-155 induced vincristine resistance, documenting that miR-155 functionally induces vincristine sensitivity. Target gene analysis identified miR-155 as inversely correlated with Wee1, supporting Wee1 as a target of miR-155 in DLBCL. Chemical inhibition of Wee1 sensitized GCB cells to vincristine, suggesting that miR-155 controls vincristine response through Wee1. Outcome analysis in clinical cohorts of DLBCL revealed that high miR-155 expression level was significantly associated with superior survival for R-CHOP-treated patients of the GCB subclass, independent of international prognostic index, challenging the commonly accepted perception of miR-155 as an oncomiR. However, miR-155 did not provide prognostic information when analyzing the entire DLBCL cohort or activated B-cell-like classified patients. In conclusion, we experimentally confirmed a direct link between high miR-155 expression and vincristine sensitivity in DLBCL and documented an improved clinical outcome of GCB-classified patients with high miR-155 expression level.

Theoretical and Numerical Study on Stress Intensity Factors for FRP-Strengthened Steel Plates with Double-Edged Cracks.

This paper presents a theoretical and numerical study on the stress intensity factors for double-edged cracked steel plates strengthened with fiber reinforced polymer (FRP) plates. Based on the stress intensity factor solution for infinite center-cracked steel plates strengthened with FRP plates, expressions of the stress intensity factors were proposed for double-edged cracked steel plates strengthened with FRP plates by introducing two correction factors: ß and f. A finite element (FE) simulation was carried out to calculate the stress intensity factors of the steel plate specimens. Numerous combinations of the specimen width, crack length, FRP thickness and Young's modulus, adhesive thickness, and shear modulus were considered to conduct the parametric investigation. The FE results were used to investigate the main influencing factors of the stress intensity factors and the correction factor, ß. The expression of the correction factor, ß, was formulated and calibrated based on the FE results. The proposed expressions of the stress intensity factors were a function of the applied stress, the crack length, the ratio between the crack length and the width of the steel plate, the stiffness ratio between the FRP plate and steel plate, the adhesive thickness, and the shear modulus. Finally, the theoretical results and numerical results were compared to validate the proposed expressions.

Clinical Significance of PTEN Deletion, Mutation, and Loss of PTEN Expression in De Novo Diffuse Large B-Cell Lymphoma.

PTEN loss has been associated with poorer prognosis in many solid tumors. However, such investigation in lymphomas is limited. In this study, PTEN cytoplasmic and nuclear expression, PTEN gene deletion, and PTEN mutations were evaluated in two independent cohorts of diffuse large B-cell lymphoma (DLBCL). Cytoplasmic PTEN expression was found in approximately 67% of total 747 DLBCL cases, more frequently in the activated B-cell-like subtype. Nuclear PTEN expression was less frequent and at lower levels, which significantly correlated with higher PTEN mRNA expression. Remarkably, loss of PTEN protein expression was associated with poorer survival only in DLBCL with AKT hyperactivation. In contrast, high PTEN expression was associated with Myc expression and poorer survival in cases without abnormal AKT activation. Genetic and epigenetic mechanisms for loss of PTEN expression were investigated. PTEN deletions (mostly heterozygous) were detected in 11.3% of DLBCL, and showed opposite prognostic effects in patients with AKT hyperactivation and in MYC rearranged DLBCL patients. PTEN mutations, detected in 10.6% of patients, were associated with upregulation of genes involved in central nervous system function, metabolism, and AKT/mTOR signaling regulation. Loss of PTEN cytoplasmic expression was also associated with TP53 mutations, higher PTEN-targeting microRNA expression, and lower PD-L1 expression. Remarkably, low PTEN mRNA expression was associated with down-regulation of a group of genes involved in immune responses and B-cell development/differentiation, and poorer survival in DLBCL independent of AKT activation. Collectively, multi-levels of PTEN abnormalities and dysregulation may play important roles in PTEN expression and loss, and that loss of PTEN tumor-suppressor function contributes to the poor survival of DLBCL patients with AKT hyperactivation.

cAMP induces cell apoptosis in multiple myeloma and overcomes bortezomib resistance.

The acquired resistance to bortezomib represents a major obstacle for multiple myeloma (MM) treatment. Studies revealed that the treatment with cyclic adenosine monophosphate (cAMP) may be a promising strategy for MM therapy. Therefore, the present study aimed to explore the mechanism of action of cAMP in MM cells. Our results showed that 8-CPT-cAMP and bortezomib synergistically induced growth inhibition and apoptosis in MM bortezomib-resistant cell lines and primary MM cells, in which protein kinase A (PKA) activation was involved. Furthermore, 8-CPT-cAMP induced the degradation of cyclinD1 and downregulation of myeloid cell leukemia-1 (Mcl-1). Moreover, 8-CPT-cAMP enhanced endoplasmic reticulum stress caused by bortezomib. A synergy between bortezomib and cAMP was also revealed in a murine MOPC315 xenograft model, which was evidenced by the significantly inhibited tumor growth and the improved multiple cancer-related parameters by the combination of the cAMP-elevating compound forskolin and bortezomib. Taken together, this study suggests that the treatment with cAMP may be a promising strategy for enhancing the therapeutic efficacy of bortezomib in MM treatment.

Efficacy of a Chinese Herbal Medicine Compound Zhangpi Ointment against Hydroxyurea-Induced Leg Ulcers: A Prospective, Randomized, Open-Label, Controlled Clinical Trial.

Objective. The randomized controlled trial was to evaluate the efficacy of topical Chinese herbal Zhangpi Ointment for hydroxyurea-induced leg ulcers in patients with myeloproliferative neoplasms. Patients and Methods. This single-center, prospective, randomized, open-label, controlled clinical trial conducted at Shanghai Ninth People's Hospital enrolled 54 patients with hydroxyurea-induced leg ulcers. Patients were randomly assigned to the control group (n = 27) treated with chlorhexidine dressing or the intervention group (n = 27) treated with the Zhangpi Ointment. Finally, 26 patients in the control group and 23 patients in the intervention group completed 8 weeks of observation. Results. The rate of complete healing was 100% for the intervention group, which was significantly higher than that of the control group (96.15%) (P<0.05). Furthermore, the intervention group achieved a significantly higher rate of wound healing (95.56%) than the control group (69.02%) at week 4 (P<0.01). The intervention group took 34 ± 5 days to achieve complete healing while the control group took 41 ± 7 days (P < 0.01). Moreover, grade 3/4 side effects were observed in neither group. Conclusion. The Zhangpi Ointment is effective in promoting the healing of hydroxyurea-induced leg ulcers in patients with myeloproliferative neoplasms, providing a therapeutic option for a condition that is recalcitrant to conventional therapy.

Glycolytic inhibitor 2-deoxy-d-glucose suppresses cell proliferation and enhances methylprednisolone sensitivity in non-Hodgkin lymphoma cells through down-regulation of HIF-1α and c-MYC.

Metabolic reprogramming is linked to tumorigenesis, disease progression, clinical outcome and resistance to chemotherapy. However, the significance of glycolytic metabolism in non-Hodgkin lymphoma (NHL) remains unclear. Here we report that both NHL patient-samples and cell lines exhibited significant up-regulation of glycolytic metabolism. The glycolytic inhibitor 2-deoxy-d-glucose (2-DG) inhibited glucose consumption, lactic acid generation and cell proliferation and induced cell cycle arrest in NHL cell lines under both normoxia and hypoxia, and hypoxia could even enhance the inhibitory effects of 2-DG. Furthermore, 2-DG combined with methylprednisolone synergistically inhibited cell proliferation, induced cell apoptosis and cell cycle arrest, and thus increased the sensitivity of NHL cells to methylprednisolone via down-regulation of HIF-1α and c-MYC. In conclusion, these results present a novel insight into critical roles of glycolytic pathway activation in NHL progression and glucocorticoid resistance. Inhibition of the glycolytic pathway may provide a new therapeutic strategy for the treatment of NHL.