Context-dependent functions of pattern recognition receptors in cancer.

The immune system plays a critical role in shaping all facets of cancer, from the early initiation stage through to metastatic disease and resistance to therapy. Our understanding of the importance of the adaptive arm of the immune system in antitumour immunity has led to the implementation of immunotherapy with immune checkpoint inhibitors in numerous cancers, albeit with differing efficacy. By contrast, the clinical utility of innate immunity in cancer has not been exploited, despite dysregulated innate immunity being a feature of at least one-third of all cancers associated with tumour-promoting chronic inflammation.

Selective Targeting of Protein Kinase C (PKC)-θ Nuclear Translocation Reduces Mesenchymal Gene Signatures and Reinvigorates Dysfunctional CD8 T Cells in Immunotherapy-Resistant and Metastatic Cancers.

Protein kinase C (PKC)-θ is a serine/threonine kinase with both cytoplasmic and nuclear functions. Nuclear chromatin-associated PKC-θ (nPKC-θ) is increasingly recognized to be pathogenic in cancer, whereas its cytoplasmic signaling is restricted to normal T-cell function. Here we show that nPKC-θ is enriched in circulating tumor cells (CTCs) in patients with triple-negative breast cancer (TNBC) brain metastases and immunotherapy-resistant metastatic melanoma and is associated with poor survival in immunotherapy-resistant disease.

Decrease in Plasma miR-27a and miR-221 After Concussion in Australian Football Players.

Introduction: Sports-related concussion (SRC) is a common form of brain injury that lacks reliable methods to guide clinical decisions. MicroRNAs (miRNAs) can influence biological processes involved in SRC, and measurement of miRNAs in biological fluids may provide objective diagnostic and return to play/recovery biomarkers. Therefore, this prospective study investigated the temporal profile of circulating miRNA levels in concussed male and female athletes.

Using UV-Responsive Nanoparticles to Provide Control of Growth Factor Delivery and a More Constant Release Profile from a Hydrogel Environment.

Nanoparticles are popular delivery vehicles, but their diffusional release results in inconstant drug delivery. Here, we flatten the delivery profile into a more constant, zero-order profile. Brain-derived neurotrophic factor (BDNF) is attached to photoactive titanium dioxide nanoparticles and loaded into a nanofibrous self-assembling peptide (SAP) hydrogel.

Horizontal Transposon Transfer and Its Implications for the Ancestral Ecology of Hydrophiine Snakes.

Transposable elements (TEs), also known as jumping genes, are sequences able to move or copy themselves within a genome. As TEs move throughout genomes they often act as a source of genetic novelty, hence understanding TE evolution within lineages may help in understanding environmental adaptation. Studies into the TE content of lineages of mammals such as bats have uncovered horizontal transposon transfer (HTT) into these lineages, with squamates often also containing the same TEs.

The therapeutic potential of RNA Polymerase I transcription inhibitor, CX-5461, in uterine leiomyosarcoma.

Background: Uterine leiomyosarcoma is a rare aggressive smooth muscle cancer with poor survival rates. RNA Polymerase I (Pol I) activity is elevated in many cancers supporting tumour growth and prior studies in uterine leiomyosarcoma revealed enlarged nucleoli and upregulated Pol I activity-related genes. This study aimed to investigate the anti-tumour potential of CX-5461, a Pol I transcription inhibitor currently being evaluated in clinical trials for several cancers, against the human uterine leiomyosarcoma cell line, SK-UT-1.

Complementary effects of Orthosiphon stamineus standardized ethanolic extract and rosmarinic acid in combination with gemcitabine on pancreatic cancer.

Background: Pancreatic cancer is one of the most notorious cancers and is known for its highly invasive characteristics, drug resistance, and metastatic progression. Unfortunately, many patients with advanced pancreatic cancer become insensitive towards gemcitabine treatment. Orthosiphon stamineus (O.

Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway.

Cell death plays an important role during pathogen infections. Here, we report that interferon-γ (IFNγ) sensitizes macrophages to Toll-like receptor (TLR)-induced death that requires macrophage-intrinsic death ligands and caspase-8 enzymatic activity, which trigger the mitochondrial apoptotic effectors, BAX and BAK. The pro-apoptotic caspase-8 substrate BID was dispensable for BAX and BAK activation.

Evaluation of Innate Lymphoid Cells and Dendritic Cells Following Viral Vector Vaccination.

Recently, we have shown that fate of a vaccine is determined by the cytokine milieu in the innate immune compartment at the early stage of vaccination. Specifically, 24 h post-delivery, level of innate lymphoid cell type 2 (ILC2)-derived IL-13/IL-13Rα2 are the master regulators of DC and also different ILC subsets responsible for modulating the downstream immune outcomes. Here, we provide step-by-step details how to assess different ILC and DC subsets in lung and muscle following intranasal and intramuscular viral vector vaccination, respectively, using multi-color flow cytometry and confocal microscopy.

Neutrophil extracellular traps and their histones promote Th17 cell differentiation directly via TLR2.

Neutrophils perform critical functions in the innate response to infection, including through the production of neutrophil extracellular traps (NETs) - web-like DNA structures which are extruded from neutrophils upon activation. Elevated levels of NETs have been linked to autoimmunity but this association is poorly understood. By contrast, IL-17 producing Th17 cells are a key player in various autoimmune diseases but are also crucial for immunity against fungal and bacterial infections.

Rapid In Vivo Fixation and Isolation of Translational Complexes from Eukaryotic Cells.

Rapid responses involving fast redistribution of messenger(m)RNA and alterations of mRNA translation are pertinent to ongoing homeostatic adjustments of the cells. These adjustments are critical to eukaryotic cell survivability and 'damage control' during fluctuating nutrient and salinity levels, temperature, and various chemical and radiation stresses. Due to the highly dynamic nature of the RNA-level responses, and the instability of many of the RNA:RNA and RNA:protein intermediates, obtaining a meaningful snapshot of the cytoplasmic RNA state is only possible with a limited number of methods.

Uncovering the impacts of alternative splicing on the proteome with current omics techniques.

The high-throughput sequencing of cellular RNAs has underscored a broad effect of isoform diversification through alternative splicing on the transcriptome. Moreover, the differential production of transcript isoforms from gene loci has been recognized as a critical mechanism in cell differentiation, organismal development, and disease. Yet, the extent of the impact of alternative splicing on protein production and cellular function remains a matter of debate.

The Antiviral Drug Efavirenz in Breast Cancer Stem Cell Therapy.

Although many breast cancer therapies show initial success in the treatment of the primary tumour, they often fail to eliminate a sub-population of cells known as cancer stem cells (CSCs). These cells are recognised for their self-renewal properties and for their capacity for differentiation often leading to chemo/radio-resistance. The antiviral drug Efavirenz has been shown to be effective in eliminating triple-negative breast cancer cells, and here we examine its effect on breast CSCs.

Translational control in cell ageing: an update.

Cellular ageing is one of the main drivers of organismal ageing and holds keys towards improving the longevity and quality of the extended life. Elucidating mechanisms underlying the emergence of the aged cells as well as their altered responses to the environment will help understanding the evolutionarily defined longevity preferences across species with different strategies of survival. Much is understood about the role of alterations in the DNA, including many epigenetic modifications such as methylation, in relation to the aged cell phenotype.

STAT3-YAP/TAZ signaling in endothelial cells promotes tumor angiogenesis.

The nuclear translocation and activity of the cotranscriptional activators YAP and TAZ (YAP/TAZ) in endothelial cells (ECs) are crucial during developmental angiogenesis. Here, we studied the role of YAP/TAZ signaling in ECs in tumor angiogenesis and found that the expression of and downstream target genes in ECs correlated with tumor vascularization in human colorectal carcinomas and skin melanoma. Treatment with the YAP/TAZ inhibitor verteporfin reduced vessel density and tumor progression in a mouse colorectal cancer (CRC) model.

Translation complex stabilization on messenger RNA and footprint profiling to study the RNA responses and dynamics of protein biosynthesis in the cells.

During protein biosynthesis, ribosomes bind to messenger (m)RNA, locate its protein-coding information, and translate the nucleotide triplets sequentially as codons into the corresponding sequence of amino acids, forming proteins. Non-coding mRNA features, such as 5' and 3' untranslated regions (UTRs), start sites or stop codons of different efficiency, stretches of slower or faster code and nascent polypeptide interactions can alter the translation rates transcript-wise. Most of the homeostatic and signal response pathways of the cells converge on individual mRNA control, as well as alter the global translation output.

Comparing Objective Perimetry, Matrix Perimetry, and Regional Retinal Thickness in Mild Diabetic Macular Edema.

Purpose: To compare per-region macular sensitivity and delay from objective perimetry with Matrix perimetry and retinal thickness in mild diabetic macular edema (DMO).

Methods: Thirty-three patients with type 2 diabetes (T2D) aged 59.2 ± 10.

PGRMC1 Promotes Progestin-Dependent Proliferation of Breast Cancer Cells by Binding Prohibitins Resulting in Activation of ERα Signaling.

In previous studies, we reported that progesterone receptor membrane component 1 (PGRMC1) is implicated in progestin signaling and possibly associated with increased breast cancer risk upon combined hormone replacement therapy. To gain mechanistic insight, we searched for potential PGRMC1 interaction partners upon progestin treatment by co-immunoprecipitation and mass spectrometry. The interactions with the identified partners were further characterized with respect to PGRMC1 phosphorylation status and with emphasis on the crosstalk between PGRMC1 and estrogen receptor α (ERα).

From Progenitors to Progeny: Shaping Striatal Circuit Development and Function.

Understanding how neurons of the striatum are formed and integrate into complex synaptic circuits is essential to provide insight into striatal function in health and disease. In this review, we summarize our current understanding of the development of striatal neurons and associated circuits with a focus on their embryonic origin. Specifically, we address the role of distinct types of embryonic progenitors, found in the proliferative zones of the ganglionic eminences in the ventral telencephalon, in the generation of diverse striatal interneurons and projection neurons.

Current and Emerging Molecular Therapies for Head and Neck Squamous Cell Carcinoma.

Head and neck cancer affects nearly 750,000 patients, with more than 300,000 deaths annually. Advances in first line surgical treatment have improved survival rates marginally particularly in developed countries, however survival rates for aggressive locally advanced head and neck cancer are still poor. Recurrent and metastatic disease remains a significant problem for patients and the health system.

Running to save sight: The effects of exercise on retinal health and function.

The benefits of exercise to human health have long been recognised. However, only in the past decade have researchers started to discover the molecular benefits that exercise confers, especially to the central nervous system (CNS). These discoveries include the magnitude of molecular messages that are communicated from skeletal muscle to the CNS.