Liver proteomics identifies a disconnect between proteins associated with de novo lipogenesis and triglyceride storage.

De novo lipogenesis (DNL) has been implicated in the development and progression of liver steatosis. Hepatic DNL is strongly influenced by dietary macronutrient composition with diets high in carbohydrate increasing DNL while diets high in fat decrease DNL. The enzymes in the core DNL pathway have been well characterized; however, less is known about other liver proteins that play accessory or regulatory roles.

High-content analysis of proteostasis capacity in cellular models of amyotrophic lateral sclerosis (ALS).

Disrupted proteome homeostasis (proteostasis) in amyotrophic lateral sclerosis (ALS) has been a major focus of research in the past two decades. However, the proteostasis processes that become disturbed in ALS are not fully understood. Obtaining more detailed knowledge of proteostasis disruption in association with different ALS-causing mutations will improve our understanding of ALS pathophysiology and may identify novel therapeutic targets and strategies for ALS patients.

Hepatic lipid droplet-associated proteome changes distinguish dietary-induced fatty liver from glucose tolerance in male mice.

Fatty liver is characterized by the expansion of lipid droplets (LDs) and is associated with the development of many metabolic diseases. We assessed the morphology of hepatic LDs and performed quantitative proteomics in lean, glucose-tolerant mice compared with high-fat diet (HFD) fed mice that displayed hepatic steatosis and glucose intolerance as well as high-starch diet (HStD) fed mice who exhibited similar levels of hepatic steatosis but remained glucose tolerant. Both HFD- and HStD-fed mice had more and larger LDs than Chow-fed animals.

ALS-linked CCNF variant disrupts motor neuron ubiquitin homeostasis.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders that share pathological features, including the aberrant accumulation of ubiquitinated protein inclusions within motor neurons. Previously, we have shown that the sequestration of ubiquitin (Ub) into inclusions disrupts Ub homeostasis in cells expressing ALS-associated variants superoxide dismutase 1 (SOD1), fused in sarcoma (FUS) and TAR DNA-binding protein 43 (TDP-43). Here, we investigated whether an ALS/FTD-linked pathogenic variant in the CCNF gene, encoding the E3 Ub ligase Cyclin F (CCNF), also perturbs Ub homeostasis.

Proteostasis impairment and ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disease that results from the loss of both upper and lower motor neurons. It is the most common motor neuron disease and currently has no effective treatment. There is mounting evidence to suggest that disturbances in proteostasis play a significant role in ALS pathogenesis.

Ubiquitin Homeostasis Is Disrupted in TDP-43 and FUS Cell Models of ALS.

A major feature of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitin (Ub) into intracellular inclusions. This sequestration of Ub may reduce the availability of free Ub, disrupting Ub homeostasis and ultimately compromising cellular function and survival. We previously reported significant disturbance of Ub homeostasis in neuronal-like cells expressing mutant SOD1.

Cancer in the news: Bias and quality in media reporting of cancer research.

Cancer research in the news is often associated with sensationalised and inaccurate reporting, which may give rise to false hopes and expectations. The role of study selection for cancer-related news stories is an important but less commonly acknowledged issue, as the outcomes of primary research are generally less reliable than those of meta-analyses and systematic reviews. Few studies have investigated the quality of research that makes the news and no previous analyses of the proportions of primary and secondary research in the news have been found in the literature.

Mercury, methylmercury and long-chain polyunsaturated fatty acids in selected fish species and comparison of approaches to risk-benefit analysis.

Fish (n = 281) of six species, caught in New Zealand waters, were analysed for total mercury (t-Hg), methylmercury (MeHg) and the long-chain polyunsaturated fatty acids, eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA). Mean t-Hg and MeHg concentrations for the six species were in the range 0.06-0.

-Alkylisatin-Loaded Liposomes Target the Urokinase Plasminogen Activator System in Breast Cancer.

The urokinase plasminogen activator and its receptor (uPA/uPAR) are biomarkers for metastasis, especially in triple-negative breast cancer. We prepared anti-mitotic -alkylisatin (-AI)-loaded liposomes functionalized with the uPA/uPAR targeting ligand, plasminogen activator inhibitor type 2 (PAI-2/SerpinB2), and assessed liposome uptake in vitro and in vivo. Receptor-dependent uptake of PAI-2-functionalized liposomes was significantly higher in the uPA/uPAR overexpressing MDA-MB-231 breast cancer cell line relative to the low uPAR/uPAR expressing MCF-7 breast cancer cell line.

MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer.

In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost.

The pivotal role of ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration.

Ubiquitin-activating enzyme E1, UBA1, functions at the apex of the enzymatic ubiquitylation cascade, catalysing ubiquitin activation. UBA1 is thus of fundamental importance to the modulation of ubiquitin homeostasis and to all downstream ubiquitylation-dependent cellular processes, including proteolysis through the ubiquitin-proteasome system and selective autophagy. The proteasome-dependent and -independent functions of UBA1 contribute significantly to a range of processes crucial to neuronal health.

Lipid droplet-associated kinase STK25 regulates peroxisomal activity and metabolic stress response in steatotic liver.

Nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are emerging as leading causes of liver disease worldwide and have been recognized as one of the major unmet medical needs of the 21st century. Our recent translational studies in mouse models, human cell lines, and well-characterized patient cohorts have identified serine/threonine kinase (STK)25 as a protein that coats intrahepatocellular lipid droplets (LDs) and critically regulates liver lipid homeostasis and progression of NAFLD/NASH. Here, we studied the mechanism-of-action of STK25 in steatotic liver by relative quantification of the hepatic LD-associated phosphoproteome from high-fat diet-fed knockout mice compared with their wild-type littermates.

The Ubiquitin Proteasome System Is a Key Regulator of Pluripotent Stem Cell Survival and Motor Neuron Differentiation.

The ubiquitin proteasome system (UPS) plays an important role in regulating numerous cellular processes, and a dysfunctional UPS is thought to contribute to motor neuron disease. Consequently, we sought to map the changing ubiquitome in human iPSCs during their pluripotent stage and following differentiation to motor neurons. Ubiquitinomics analysis identified that spliceosomal and ribosomal proteins were more ubiquitylated in pluripotent stem cells, whilst proteins involved in fatty acid metabolism and the cytoskeleton were specifically ubiquitylated in the motor neurons.

Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer.

Background: The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.

Using Narratives to Teach Students Enrolled in Science and Medical Science Bachelor's Degree Programs.

Introduction: Narratives (as opposed to stories) can assess multiple facets of the same problem through the viewpoints of different characters.

Methods: Narratives related to three cancer patients, from diagnosis to cure or death, were used to teach seven cancer-related themes in a Cancer Pathology course offered to third-year medical science and science (college) undergraduates.

Results: The majority of students preferred narrative-based learning compared with traditional learning methods because they felt that it improved their learning experience and retention of information.

Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer.

Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1).

Heterogeneity of fatty acid metabolism in breast cancer cells underlies differential sensitivity to palmitate-induced apoptosis.

Breast cancer (BrCa) metabolism is geared toward biomass synthesis and maintenance of reductive capacity. Changes in glucose and glutamine metabolism in BrCa have been widely reported, yet the contribution of fatty acids (FAs) in BrCa biology remains to be determined. We recently reported that adipocyte coculture alters MCF-7 and MDA-MB-231 cell metabolism and promotes proliferation and migration.

Dissecting Multi-protein Signaling Complexes by Bimolecular Complementation Affinity Purification (BiCAP).

The assembly of protein complexes is a central mechanism underlying the regulation of many cell signaling pathways. A major focus of biomedical research is deciphering how these dynamic protein complexes act to integrate signals from multiple sources in order to direct a specific biological response, and how this becomes deregulated in many disease settings. Despite the importance of this key biochemical mechanism, there is a lack of experimental techniques that can facilitate the specific and sensitive deconvolution of these multi-molecular signaling complexes.

SOD1 aggregation alters ubiquitin homeostasis in a cell model of ALS.

A hallmark of amyotrophic lateral sclerosis (ALS) pathology is the accumulation of ubiquitylated protein inclusions within motor neurons. Recent studies suggest the sequestration of ubiquitin (Ub) into inclusions reduces the availability of free Ub, which is essential for cellular function and survival. However, the dynamics of the Ub landscape in ALS have not yet been described.

The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia.

Primary cilia are crucial for signal transduction in a variety of pathways, including hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The ubiquitin-proteasome system (UPS) component UBR5 was previously identified as a putative positive regulator of ciliogenesis in a functional genomics screen.

Towards clinical translation of ligand-functionalized liposomes in targeted cancer therapy: Challenges and opportunities.

The development of therapeutic resistance to targeted anticancer therapies remains a significant clinical problem, with intratumoral heterogeneity playing a key role. In this context, improving the therapeutic outcome through simultaneous targeting of multiple tumor cell subtypes within a heterogeneous tumor is a promising approach. Liposomes have emerged as useful drug carriers that can reduce systemic toxicity and increase drug delivery to the tumor site.

Improving the Delivery of SOD1 Antisense Oligonucleotides to Motor Neurons Using Calcium Phosphate-Lipid Nanoparticles.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting the upper and lower motor neurons in the motor cortex and spinal cord. Abnormal accumulation of mutant superoxide dismutase I (SOD1) in motor neurons is a pathological hallmark of some forms of the disease. We have shown that the orderly progression of the disease may be explained by misfolded SOD1 cell-to-cell propagation, which is reliant upon its active endogenous synthesis.

Correction: Insulin and diet-induced changes in the ubiquitin-modified proteome of rat liver.

[This corrects the article DOI: 10.1371/journal.pone.

Adipocyte-Tumor Cell Metabolic Crosstalk in Breast Cancer.

The tumor stroma is a heterogeneous ecosystem comprising matrix, fibroblasts, and immune cells and has an important role in cancer progression. Adipocytes constitute a major component of breast stroma, and significant emerging evidence demonstrates a reciprocal metabolic adaptation between stromal adipocytes and breast cancer (BC) cells. Recent observations promote a model where adipocytes respond to cancer cell-derived endocrine and paracrine signaling to provide metabolic substrates, which in turn drive enhanced cancer cell proliferation, invasion, and treatment resistance.