Targeting translation initiation by synthetic rocaglates for treating MYC-driven lymphomas.

MYC-driven lymphomas, especially those with concurrent MYC and BCL2 dysregulation, are currently a challenge in clinical practice due to rapid disease progression, resistance to standard chemotherapy, and high risk of refractory disease. MYC plays a central role by coordinating hyperactive protein synthesis with upregulated transcription in order to support rapid proliferation of tumor cells. Translation initiation inhibitor rocaglates have been identified as the most potent drugs in MYC-driven lymphomas as they efficiently inhibit MYC expression and tumor cell viability. We found that this class of compounds can overcome eIF4A abundance by stabilizing target mRNA-eIF4A interaction that directly prevents translation. Proteome-wide quantification demonstrated selective repression of multiple critical oncoproteins in addition to MYC in B-cell lymphoma including NEK2, MCL1, AURKA, PLK1, and several transcription factors that are generally considered undruggable. Finally, (-)-SDS-1-021, the most promising synthetic rocaglate, was confirmed to be highly potent as a single agent, and displayed significant synergy with the BCL2 inhibitor ABT199 in inhibiting tumor growth and survival in primary lymphoma cells in vitro and in patient-derived xenograft mouse models. Overall, our findings support the strategy of using rocaglates to target oncoprotein synthesis in MYC-driven lymphomas.P30 CA036727 - NCI NIH HHS; R24 GM111625 - NIGMS NIH HHS; R35 GM118173 - NIGMS NIH HHS; LB506 - Nebraska Department of Health and Human Services (Nebraska DHHS)Accepted manuscriptSupporting documentatio

MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications

The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression

Study on the Synthesis of Castor Oil-Based Plasticizer and the Properties of Plasticized Nitrile Rubber

A series of new environment-friendly plasticizers was synthesized from castor oil and used to plasticize nitrile rubber (NBR). The test results showed that tensile strength, elongation at break, and tear strength of NBR vulcanizates plasticized by castor oil-based plasticizers were found to be better than that of dioctyl phthalate (DOP). The aging test taken demonstrated that the castor oil-based plasticizers could improve the hot air and oil aging resistance of NBR vulcanizates. The thermal stability test illustrated that castor oil-based plasticizers enhanced the thermal stability of NBR vulcanizates, and the initial decomposition temperatures (T10%) were about 100 °C higher than that of DOP. In general, the studies manifested that EACO and EBCO can replace DOP to plasticize NBR and are used in fields that require high mechanical properties, aging resistance, and thermal stability. This study emphasizes the effects of sustainable, cost-effective, and high-efficiency plasticizers on NBR

Role of the Oxethyl Unit in the Structure of Vegetable Oil-Based Plasticizer for PVC: An Efficient Strategy to Enhance Compatibility and Plasticization

Developing vegetable oil-derived primary plasticizers for poly(vinyl chloride) (PVC) is still a challenge because of their insufficient compatibility. As described in this work, we report the synthesis of plasticizers through the esterification of polyethylene glycol methyl ether and dimer acid, in which dimer acid is renewable material prepared via a two-step reaction (1) the hydrolysis of fatty acids from soybean oil at 70 °C and (2) subsequent Diels−Alder reaction at 250 °C. The resulting plasticizers, dimer acid-derived polyethylene glycol methyl ether esters (DA-2n, 2n = 2, 4, 6 or 8 referring to the number of oxethyl units per molecule), were blended with PVC. It was found that the tensile properties, transparency, and thermal stability of plasticized PVC (PVC-DA-2n) increased significantly with an increase in the number of oxyethyl units. Fourier-transform infrared spectroscopy analysis revealed that its good compatibility can be attributed to the strong interaction between oxyethyl units and PVC. As the number of the oxyethyl units of plasticizer increased, the glass transition temperature (Tg) of the corresponding plasticized PVC samples decreased from 62.3 (PVC-DA-2) to 35.4 °C (PVC-DA-8). Owing to the excellent plasticization of DA-8, the performances of PVC-DA-8 were comparable or better than that of the PVC plasticized using commercial dioctyl terephthalate (DOTP). The simple but efficient method of this study provides a new avenue for the preparation of vegetable oil-based plasticizers for PVC

Flow regulation manipulates contemporary seasonal sedimentary dynamics in the reservoir fluctuation zone of the Three Gorges Reservoir, China

Since the launch of the Three Gorges Dam on the Yangtze River, a distinctive reservoir fluctuation zone has been created and significantly modified by regular dam operations. Sediment redistribution within this artificial landscape differs substantially from that in natural fluvial riparian zones, due to a specific hydrological regime comprising steps of water impoundment with increasing magnitudes and seasonal water level fluctuation holding a range of sediment fluxes. This study reinterpreted post-dam sedimentary dynamics in the reservoir fluctuation zone by stratigraphy determination of a 345-cm long sediment core, and related it to impact of the hydrological regime. Seasonality in absolute grain-size composition of suspended sediment was applied as a methodological basis for stratigraphic differentiation. Sedimentary laminations with relatively higher proportions of sandy fractions were ascribed to sedimentation during the dry season when proximal subsurface bank erosion dominates source contributions, while stratigraphy with a lower proportion of sandy fractions is possibly contributed by sedimentation during the wet season when distal upstream surface erosion prevails. Chronology determination revealed non-linear and high annual sedimentation rates ranging from 21.7 to 152.1cm/yr. Although channel geomorphology may primarily determine the spatial extent of sedimentation, seasonal sedimentary dynamics was predominantly governed by the frequency, magnitude, and duration of flooding. Summer inundation by natural floods with enhanced sediment loads produced from upstream basins induced higher sedimentation rates than water impoundment during the dry season when distal sediment supply was limited. We thus conclude that flow regulation manipulates contemporary seasonal sedimentary dynamics in the reservoir fluctuation zone, though little impact on total sediment retention rate was detected. Ongoing reductions in flow and sediment supply under human disturbance may have profound implications in affecting sedimentary equilibrium in the reservoir fluctuation zone. The results herein provide insights of how big dams have disrupted the sediment conveyance processes of large scale fluvial systems

BiVO₄–Deposited MIL–101–NH₂ for Efficient Photocatalytic Elimination of Cr(VI)

In this study, a flower–like BiVO4/MIL–101–NH2 composite is synthesized by a facile and surfactant–free process. The –COO−–Bi3+ ionic bond construction was conductive to enhance the interface affinity between BiVO4 and MIL–101–NH2. Due to the highly efficient light capture and sufficient electron traps induced by oxygen vacancies and the formation of a heterostructure, the improved separation and transportation rates of charge carriers are realized. In addition, the MIL–101–NH2/BiVO4 composite is favorable for Cr(VI) photocatalytic removal (91.2%). Moreover, FNBV–3 (Fe/Bi = 0.25) also exhibited an excellent reusability after five cycles

BiVO4–Deposited MIL–101–NH2 for Efficient Photocatalytic Elimination of Cr(VI)

In this study, a flower–like BiVO4/MIL–101–NH2 composite is synthesized by a facile and surfactant–free process. The –COO−–Bi3+ ionic bond construction was conductive to enhance the interface affinity between BiVO4 and MIL–101–NH2. Due to the highly efficient light capture and sufficient electron traps induced by oxygen vacancies and the formation of a heterostructure, the improved separation and transportation rates of charge carriers are realized. In addition, the MIL–101–NH2/BiVO4 composite is favorable for Cr(VI) photocatalytic removal (91.2%). Moreover, FNBV–3 (Fe/Bi = 0.25) also exhibited an excellent reusability after five cycles

Molecular modeling investigation on mechanism of diazinon pesticide removal from water by single- and multi-walled carbon nanotubes

In this study, the mechanism of diazinon adsorption on single-walled carbon nanotubes (SWNTs), as well as multi-walled carbon nanotubes (MWNTs), was investigated using molecular modelling. Determination of the lowest energy sites of different types of carbon nanotubes (CNTs) was demonstrated. The adsorption site locator module was used for this purpose. It was found that the 5-walled CNTs are the best MWNTs for diazinon elimination from water due to their higher interactions with diazinon. In addition, the adsorption mechanism in SWNT and MWNTs was determined to be wholly adsorption on the lateral surface. It is because the geometrical size of diazinon molecules is larger than the inner diameter of SWNT and MWNTs. Furthermore, the contribution of diazinon adsorption on the 5-wall MWNTs was the highest, for the lowest diazinon concentration in the mixture