Development of CD33-Targeted Dual Drug-Loaded Nanoparticles for the Treatment of Pediatric Acute Myeloid Leukemia.

Paediatric acute myeloid leukemia (AML) is a heterogeneous hematological malignancy still heavily reliant on traditional chemotherapeutic approaches. Combination treatments have shown to be a superior approach, but their success is often hindered by side effects and different drugs' pharmacokinetics. Here, we investigated ABT-737 and Purvalanol A as a potential drug pairing for pediatric AML and described the development of CD33-targeted polymeric nanoparticles (NPs) to enable their simultaneous targeted codelivery.

The pseudo-caspase FLIP(L) regulates cell fate following p53 activation.

p53 is the most frequently mutated, well-studied tumor-suppressor gene, yet the molecular basis of the switch from p53-induced cell-cycle arrest to apoptosis remains poorly understood. Using a combination of transcriptomics and functional genomics, we unexpectedly identified a nodal role for the caspase-8 paralog and only human pseudo-caspase, FLIP(L), in regulating this switch. Moreover, we identify FLIP(L) as a direct p53 transcriptional target gene that is rapidly up-regulated in response to Nutlin-3A, an MDM2 inhibitor that potently activates p53.

A revised model of TRAIL-R2 DISC assembly explains how FLIP(L) can inhibit or promote apoptosis.

The long FLIP splice form FLIP(L) can act as both an inhibitor and promoter of caspase-8 at death-inducing signalling complexes (DISCs) formed by death receptors such as TRAIL-R2 and related intracellular complexes such as the ripoptosome. Herein, we describe a revised DISC assembly model that explains how FLIP(L) can have these opposite effects by defining the stoichiometry (with respect to caspase-8) at which it converts from being anti- to pro-apoptotic at the DISC. We also show that in the complete absence of FLIP(L), procaspase-8 activation at the TRAIL-R2 DISC has significantly slower kinetics, although ultimately the extent of apoptosis is significantly greater.

Repurposing of Cetuximab in antibody-directed chemotherapy-loaded nanoparticles in EGFR therapy-resistant pancreatic tumours.

The anti-Epidermal Growth Factor Receptor (EGFR) antibody Cetuximab (CTX) has demonstrated limited anti-cancer efficacy in cells overexpressing EGFR due to activating mutations in RAS in solid tumours, such as pancreatic cancer. The utilisation of antibodies as targeting components of antibody-drug conjugates, such as trastuzumab emtansine (Kadcyla), demonstrates that antibodies may be repurposed to direct therapeutic agents to antibody-resistant cancers. Here we investigated the use of CTX as a targeting agent for camptothecin (CPT)-loaded polymeric nanoparticles (NPs) directed against KRAS mutant CTX-resistant cancer cells.

Aquatic noise pollution: implications for individuals, populations, and ecosystems.

Anthropogenically driven environmental changes affect our planet at an unprecedented scale and are considered to be a key threat to biodiversity. According to the World Health Organization, anthropogenic noise is one of the most hazardous forms of anthropogenically driven environmental change and is recognized as a major global pollutant. However, crucial advances in the rapidly emerging research on noise pollution focus exclusively on single aspects of noise pollution, e.

Changes in the acoustic environment alter the foraging and sheltering behaviour of the cichlid Amititlania nigrofasciata.

Anthropogenic noise can affect behaviour across a wide range of species in both terrestrial and aquatic environments. However, behaviours might not be affected in isolation. Therefore, a more holistic approach investigating how environmental stressors, such as noise pollution, affect different behaviours in concert is necessary.

Screening for hypothyroidism in Down syndrome using the capillary thyroid stimulating hormone method.

Objectives: To analyze data from the Scottish capillary thyroid stimulating hormone (TSH) screening program for hypothyroidism in Down syndrome to identify a threshold for capillary TSH elevation below which low venous free thyroxine (fT4) (<9 pmol/L) and/or frank venous TSH elevation (>10 mU/L) range is unlikely.

Study Design: Review of proformas prospectively submitted on all children with Down syndrome referred via the screening program between 2003 and 2013.

Results: Ninety-nine patients with Down syndrome (50 females, 49 males) were identified, 76 school-age (≥ 5 years) and 23 preschool (<5 years), mean (range) age at referral 9.

Anthropogenic noise affects behavior across sensory modalities.

Many species are currently experiencing anthropogenically driven environmental changes. Among these changes, increasing noise levels are specifically a problem for species using acoustic signals (i.e.

Enhanced antitumor activity of the photosensitizer meso-Tetra(N-methyl-4-pyridyl) porphine tetra tosylate through encapsulation in antibody-targeted chitosan/alginate nanoparticles.

meso-Tetra(N-methyl-4-pyridyl) porphine tetra tosylate (TMP) is a photosensitizer that can be used in photodynamic therapy (PDT) to induce cell death through generation of reactive oxygen species in targeted tumor cells. However, TMP is highly hydrophilic, and therefore, its ability to accumulate intracellularly is limited. In this study, a strategy to improve TMP uptake into cells has been investigated by encapsulating the compound in a hydrogel-based chitosan/alginate nanoparticle formulation.

Experimentally increased noise levels change spatial and singing behaviour.

The reasons why animal populations decline in response to anthropogenic noise are still poorly understood. To understand how populations are affected by noise, we must understand how individuals are affected by noise. By modifying the acoustic environment experimentally, we studied the potential relationship between noise levels and both spatial and singing behaviour in the European robin (Erithacus rubecula).

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia.

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression.

Vorinostat/SAHA-induced apoptosis in malignant mesothelioma is FLIP/caspase 8-dependent and HR23B-independent.

Introduction: Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence. The caspase 8 inhibitor FLIP is an anti-apoptotic protein over-expressed in several cancer types including MPM. The histone deacetylase (HDAC) inhibitor Vorinostat (SAHA) is currently being evaluated in relapsed mesothelioma.

Conatumumab (AMG 655) coated nanoparticles for targeted pro-apoptotic drug delivery.

Colloidal nanoparticle drug delivery systems have attracted much interest for their ability to enable effective formulation and delivery of therapeutic agents. The selective delivery of these nanoparticles to the disease site can be enhanced by coating the surface of the nanoparticles with targeting moieties, such as antibodies. In this current work, we demonstrate that antibodies on the surface of the particles can also elicit key biological effects.

c-FLIP: a key regulator of colorectal cancer cell death.

c-FLIP is an inhibitor of apoptosis mediated by the death receptors Fas, DR4, and DR5 and is expressed as long (c-FLIP(L)) and short (c-FLIP(S)) splice forms. We found that small interfering RNA (siRNA)-mediated silencing of c-FLIP induced spontaneous apoptosis in a panel of p53 wild-type, mutant, and null colorectal cancer cell lines and that this apoptosis was mediated by caspase-8 and Fas-associated death domain. Further analyses indicated the involvement of DR5 and/or Fas (but not DR4) in regulating apoptosis induced by c-FLIP siRNA.

Chemotherapy and TRAIL-mediated colon cancer cell death: the roles of p53, TRAIL receptors, and c-FLIP.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently attracted attention as a potential therapeutic agent in the treatment of cancer. We assessed the roles of p53, TRAIL receptors, and cellular Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP) in regulating the cytotoxic effects of recombinant TRAIL (rTRAIL) alone and in combination with chemotherapy [5-fluorouracil (5-FU), oxaliplatin, and irinotecan] in a panel of colon cancer cell lines. Using clonogenic survival and flow cytometric analyses, we showed that chemotherapy sensitized p53 wild-type, mutant, and null cell lines to TRAIL-mediated apoptosis.