Second-Generation Cap Analogue Prodrugs for Targeting Aberrant Eukaryotic Translation Initiation Factor 4E (eIF4E) Activity in Drug-Resistant Melanoma.

Melanoma is the deadliest form of skin cancer with a 5-year survival rate of less than 20%. While significant strides have been made in the field of kinase-targeted and immune-based therapies for melanoma, the development of resistance to these therapeutic agents has hindered the success of treatment. Drug-resistant melanoma is particularly reliant on enhanced cap-dependent translation to drive the production of oncoproteins that promote growth and survival. The m 7 GpppX cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) is the rate-limiting factor of cap-dependent translation initiation, and its overexpression in melanoma tumors has been shown to drive resistance to BRAF V600E kinase-targeted inhibitors. These findings point to eIF4E-targeted therapies as a promising strategy to overcome drug resistance in melanoma. Herein, we build upon our previous work of developing cell-permeable cap analogue inhibitors to design second-generation cap analogues that inhibit eIF4E-mediated cap-dependent translation in drug-resistant melanoma cells.

What Measures are Effective in Trauma Screening for Young Males in Custody? A COSMIN Systematic Review.

Despite the available evidence identifying the high prevalence rates of potentially traumatic experiences in forensic populations, there is still a lack of evidence supporting the use of suitable assessment tools, especially for young males in custody. For services to identify, support, and offer trauma interventions to this cohort, practitioners require reliable and valid assessment tools. This systematic review (Open Science Framework registration: https://osf.io/r6hbk) identifies those tools able to provide valid, reliable, and comparable data for this cohort. Five electronic databases and gray literature were searched to identify relevant measures. Inclusion criteria: studies of tools to assess for trauma with males aged between 12 and 25 years-old in a custodial setting, any year of publication, and available in English. Exclusion criteria: studies that did not measure psychological trauma or include a standalone trauma scale, or report primary data. A three-step quality assessment method was used to evaluate the methodological quality and psychometric properties of the measures. Fourteen studies were selected for review (which included 12 measures). The studies sampled a total of approximately 1,768 male participants and an age range of 12 to 25 years. The studies reported on various types of psychometric evidence and due to the lack of homogeneity, a narrative synthesis was used to discuss, interpret, and evaluate each measure. The overall quality of the psychometric properties of the measures in this review showed that the currently available instruments for the assessment of trauma with young males in custody is limited but promising.

Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer.

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m7GpppX-cap at the 5' terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis, among other cancerous phenotypes. eIF4E is the rate-limiting translation factor, and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance. These findings have established eIF4E as a translational oncogene and promising, albeit challenging, anti-cancer therapeutic target. Although significant effort has been put forth toward inhibiting eIF4E, the design of cell-permeable, cap-competitive inhibitors remains a challenge. Herein, we describe our work toward solving this long-standing challenge. By employing an acyclic nucleoside phosphonate prodrug strategy, we report the synthesis of cell-permeable inhibitors of eIF4E binding to capped mRNA to inhibit cap-dependent translation.

Design of Cell-Permeable Inhibitors of Eukaryotic Translation Initiation Factor 4E (eIF4E) for Inhibiting Aberrant Cap-Dependent Translation in Cancer.

Eukaryotic translation initiation factor 4E (eIF4E) is an RNA-binding protein that binds to the m 7 GpppX-cap at the 5' terminus of coding mRNAs to initiate cap-dependent translation. While all cells require cap-dependent translation, cancer cells become addicted to enhanced translational capacity, driving the production of oncogenic proteins involved in proliferation, evasion of apoptosis, metastasis, and angiogenesis among other cancerous phenotypes. eIF4E is the rate-limiting translation factor and its activation has been shown to drive cancer initiation, progression, metastasis, and drug resistance. These findings have established eIF4E as a translational oncogene and promising, albeit challenging, anti-cancer therapeutic target. Although significant effort has been put forth towards inhibiting eIF4E, the design of cell-permeable, cap-competitive inhibitors remains a challenge. Herein, we describe our work towards solving this long-standing challenge. By employing an acyclic nucleoside phosphonate prodrug strategy, we report the synthesis of cell-permeable inhibitors of eIF4E binding to capped mRNA to inhibit cap-dependent translation.

The effects of Parachlorella kessleri cultivation on brewery wastewater.

Bioindustrial wastewaters, often characterised by high carbon and nitrogen contents, have shown promise as a valuable resource for the cultivation of beneficial microorganisms. The purpose of this study was to assess if Parachlorella kessleri could utilise brewery wastewater (Br WW) for growth and production of metabolites. P. kessleri was cultivated on different concentrations of Br WW over 14 days. Higher concentrations of Br WW led to an approximate two-fold increase in dry cell weight yielding a maximum of 12.3 g DCW/L. High glucose and nitrogen utilisation was associated with high algal biomass yields, with a 97% reduction in glucose achieved in 50% (v/v) Br WW cultures after 14 days. Assessing the benefits to P. kessleri, increases in oleic and α-linoleic acids were seen in 50 and 10% (v/v) Br WW cultures. Concentration of Br WW did not have an impact on the overall antioxidant activities of microalgal cultures, however, it did affect phenolic levels (2.4-fold increase) in 50% (v/v) Br WW cultures. This research demonstrated that P. kessleri did utilise the carbon and nitrogen content in the Br WW for growth and metabolite production, thereby reducing the nutrient load of the Br WW.

RETRACTED: Right to left ventricular volume ratio: A novel marker of disease severity in chronic thromboembolic pulmonary hypertension.

[This retracts the article DOI: 10.1016/j.ijchv.2013.10.001.].