Connexins orchestrate progression of breast cancer metastasis to the brain by promoting FAK activation.

Brain metastasis is a complication of increasing incidence in patients with breast cancer at advanced disease stage. It is a severe condition characterized by a rapid decline in quality of life and poor prognosis. There is a critical clinical need to develop effective therapies to prevent and treat brain metastases.

NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy.

Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC/BCL2 B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2.

Notch regulates Th17 differentiation and controls trafficking of IL-17 and metabolic regulators within Th17 cells in a context-dependent manner.

Th17 cells play critical roles in host defense and autoimmunity. Emerging data support a role for Notch signaling in Th17 cell differentiation but whether it is a positive or negative regulator remains unclear. We report here that T cell-specific deletion of Notch receptors enhances Th17 cell differentiation in the gut, with a corresponding increase in IL-17 secretion.

Acidic tumor microenvironment abrogates the efficacy of mTORC1 inhibitors.

Background: Blocking the mechanistic target of rapamycin complex-1 (mTORC1) with chemical inhibitors such as rapamycin has shown limited clinical efficacy in cancer. The tumor microenvironment is characterized by an acidic pH which interferes with cancer therapies. The consequences of acidity on the anti-cancer efficacy of mTORC1 inhibitors have not been characterized and are thus the focus of our study.

Combined CSL and p53 downregulation promotes cancer-associated fibroblast activation.

Stromal fibroblast senescence has been linked to ageing-associated cancer risk. However, density and proliferation of cancer-associated fibroblasts (CAFs) are frequently increased. Loss or downmodulation of the Notch effector CSL (also known as RBP-Jκ) in dermal fibroblasts is sufficient for CAF activation and ensuing keratinocyte-derived tumours.

Cellular hallmarks reveal restricted aerobic metabolism at thermal limits.

All organisms live within a given thermal range, but little is known about the mechanisms setting the limits of this range. We uncovered cellular features exhibiting signature changes at thermal limits in Caenorhabditis elegans embryos. These included changes in embryo size and shape, which were also observed in Caenorhabditis briggsae, indicating evolutionary conservation.

Long-term intravital immunofluorescence imaging of tissue matrix components with epifluorescence and two-photon microscopy.

Besides being a physical scaffold to maintain tissue morphology, the extracellular matrix (ECM) is actively involved in regulating cell and tissue function during development and organ homeostasis. It does so by acting via biochemical, biomechanical, and biophysical signaling pathways, such as through the release of bioactive ECM protein fragments, regulating tissue tension, and providing pathways for cell migration. The extracellular matrix of the tumor microenvironment undergoes substantial remodeling, characterized by the degradation, deposition and organization of fibrillar and non-fibrillar matrix proteins.

Nanoparticle conjugation of CpG enhances adjuvancy for cellular immunity and memory recall at low dose.

In subunit vaccines, strong CD8(+) T-cell responses are desired, yet they are elusive at reasonable adjuvant doses. We show that targeting adjuvant to the lymph node (LN) via ultrasmall polymeric nanoparticles (NPs), which rapidly drain to the LN after intradermal injection, greatly enhances adjuvant efficacy at low doses. Coupling CpG-B or CpG-C oligonucleotides to NPs led to better dual-targeting of adjuvant and antigen (codelivered on separate NPs) in cross-presenting dendritic cells compared with free adjuvant.

Role of lymphatic vessels in tumor immunity: passive conduits or active participants?

Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity.

The Notch pathway: hair graying and pigment cell homeostasis.

The Notch signaling pathway is an essential cell-cell interaction mechanism, which regulates processes such as cell proliferation, cell fate decisions, differentiation or stem cell maintenance. Pigmentation in mammals is provided by melanocytes, which are derived from the neural crest, and by the retinal pigment epithelium (RPE), which is part of the optic cup and hence orginates from neuroectoderm. The importance of functional Notch signaling in melanocytes has been unveiled recently.

Few crucial links assure checkpoint efficiency in the yeast cell-cycle network.

Motivation: The ability of cells to complete mitosis with high fidelity relies on elaborate checkpoint mechanisms. We study S- and M-phase checkpoint responses in silico in the budding yeast with a stochastic dynamical model for the cell-cycle. We aim to provide an unbiased functional classification of network interactions that reflect the contribution of each link to checkpoint efficiency in the presence of cellular fluctuations.

Circadian clocks go in vitro: purely post-translational oscillators in cyanobacteria.

Recent findings about the core of the circadian oscillator in cyanobacteria are challenging the dogma that such clocks are driven through transcriptional-translational feedback regulation. Instead, the master pacemaker is independent of both transcription and translation, and consists of self-sustained oscillations in the phosphorylation status of the KaiC protein in vivo. Using a minimal cocktail of three recombinant proteins with adenosine triphosphate, the core clock was even reproduced in vitro.

UVA radiation-induced oxidative damage to lipids and proteins in vitro and in human skin fibroblasts is dependent on iron and singlet oxygen.

This study describes the damage that occurs to lipids and proteins that have been irradiated in vitro or in human skin fibroblasts with physiological doses of UVA radiation. Thiobarbituric acid-reactive species were formed from phosphatidylcholine after UVA radiation in vitro. By using iron chelators, this process was shown to involve iron.

Caudalization by the amphibian organizer: brachyury, convergent extension and retinoic acid.

Caudalization, which is proposed to be one of two functions of the amphibian organizer, initiates posterior pathways of neural development in the dorsalized ectoderm. In the absence of caudalization, dorsalized ectoderm only expresses the most anterior (archencephalic) differentiation. In the presence of caudalization, dorsalized ectorderm develops various levels of posterior neural tissues, depending on the extent of caudalization.