Cancer cachexia: multilevel metabolic dysfunction.

Cancer cachexia is a complex metabolic disorder marked by unintentional body weight loss or 'wasting' of body mass, driven by multiple aetiological factors operating at various levels. It is associated with many malignancies and significantly contributes to cancer-related morbidity and mortality. With emerging recognition of cancer as a systemic disease, there is increasing awareness that understanding and treatment of cancer cachexia may represent a crucial cornerstone for improved management of cancer.

NFκB and JNK pathways mediate metabolic adaptation upon ESCRT-I deficiency.

Endosomal Sorting Complexes Required for Transport (ESCRTs) are crucial for delivering membrane receptors or intracellular organelles for lysosomal degradation which provides the cell with lysosome-derived nutrients. Yet, how ESCRT dysfunction affects cell metabolism remained elusive. To address this, we analyzed transcriptomes of cells lacking TSG101 or VPS28 proteins, components of ESCRT-I subcomplex.

Generation of two induced pluripotent stem cell lines (HIMRi006-A and HIMRi007-A) from Pompe patients with infantile and late disease onset.

Here we present the generation of HIMRi006-A and HIMRi007-A Pompe disease (PD) patient derived human induced pluripotent stem cell (hiPSC) lines. HIMRi006-A represents an infantile onset disease (IOPD) phenotype caused by a homozygous c.307 T > G mutation in the GAA gene.

Quantitative muscle magnetic resonance imaging in limb-girdle muscular dystrophy type R1 (LGMDR1): A prospective longitudinal cohort study.

Limb-girdle muscular dystrophy (LGMD) type R1 (LGMDR1) is the most common subtype of LGMD in Europe. Prospective longitudinal data, including clinical assessments and new biomarkers such as quantitative magnetic resonance imaging (qMRI), are needed to evaluate the natural course of the disease and therapeutic options. We evaluated eight thigh and seven leg muscles of 13 LGMDR1 patients (seven females, mean age 36.

Sensor for Rapid In-Field Classification of Cannabis Samples Based on Near-Infrared Spectroscopy.

A rugged handheld sensor for rapid in-field classification of cannabis samples based on their THC content using ultra-compact near-infrared spectrometer technology is presented. The device is designed for use by the Austrian authorities to discriminate between legal and illegal cannabis samples directly at the place of intervention. Hence, the sensor allows direct measurement through commonly encountered transparent plastic packaging made from polypropylene or polyethylene without any sample preparation.

A Humanized and Viable Animal Model for Congenital Adrenal Hyperplasia--R484Q Mutant Mouse.

Congenital Adrenal Hyperplasia (CAH) is an autosomal recessive disorder impairing cortisol synthesis due to reduced enzymatic activity. This leads to persistent adrenocortical overstimulation and the accumulation of precursors before the blocked enzymatic step. The predominant form of CAH arises from mutations in , causing 21-hydroxylase deficiency (21-OHD).

AMPK as a mediator of tissue preservation: time for a shift in dogma?

Ground-breaking discoveries have established 5'-AMP-activated protein kinase (AMPK) as a central sensor of metabolic stress in cells and tissues. AMPK is activated through cellular starvation, exercise and drugs by either directly or indirectly affecting the intracellular AMP (or ADP) to ATP ratio. In turn, AMPK regulates multiple processes of cell metabolism, such as the maintenance of cellular ATP levels, via the regulation of fatty acid oxidation, glucose uptake, glycolysis, autophagy, mitochondrial biogenesis and degradation, and insulin sensitivity.

Virtual reality-empowered deep-learning analysis of brain cells.

Automated detection of specific cells in three-dimensional datasets such as whole-brain light-sheet image stacks is challenging. Here, we present DELiVR, a virtual reality-trained deep-learning pipeline for detecting c-Fos cells as markers for neuronal activity in cleared mouse brains. Virtual reality annotation substantially accelerated training data generation, enabling DELiVR to outperform state-of-the-art cell-segmenting approaches.

Cancer cachexia: biomarkers and the influence of age.

Cancer cachexia (Ccx) is a complex metabolic condition characterized by pronounced muscle and fat wasting, systemic inflammation, weakness and fatigue. Up to 30% of cancer patients succumb directly to Ccx, yet therapies that effectively address this perturbed metabolic state are rare. In recent decades, several characteristics of Ccx have been established in mice and humans, of which we here highlight adipose tissue dysfunction, muscle wasting and systemic inflammation, as they are directly linked to biomarker discovery.

Muscle diffusion MRI reveals autophagic buildup in a mouse model for Pompe disease.

Quantitative muscle MRI is increasingly important in the non-invasive evaluation of neuromuscular disorders and their progression. Underlying histopathotological alterations, leading to changes in qMRI parameters are incompletely unraveled. Early microstructural differences of unknown origin reflected by Diffusion MRI in non-fat infiltrated muscles were detected in Pompe patients.

Endothelial Notch1 signaling in white adipose tissue promotes cancer cachexia.

Cachexia is a major cause of morbidity and mortality in individuals with cancer and is characterized by weight loss due to adipose and muscle tissue wasting. Hallmarks of white adipose tissue (WAT) remodeling, which often precedes weight loss, are impaired lipid storage, inflammation and eventually fibrosis. Tissue wasting occurs in response to tumor-secreted factors.

Development of a peptide drug restoring AMPK and adipose tissue functionality in cancer cachexia.

Cancer cachexia is a severe systemic wasting disease that negatively affects quality of life and survival in patients with cancer. To date, treating cancer cachexia is still a major unmet clinical need. We recently discovered the destabilization of the AMP-activated protein kinase (AMPK) complex in adipose tissue as a key event in cachexia-related adipose tissue dysfunction and developed an adeno-associated virus (AAV)-based approach to prevent AMPK degradation and prolong cachexia-free survival.

Dysregulation of Metabolism and Proteostasis in Skeletal Muscle of a Presymptomatic Pompe Mouse Model.

Pompe disease is a rare genetic metabolic disorder caused by mutations in acid-alpha glucoside (GAA) leading to pathological lysosomal glycogen accumulation associated with skeletal muscle weakness, respiratory difficulties and cardiomyopathy, dependent from the GAA residual enzyme activity. This study aimed to investigate early proteomic changes in a mouse model of Pompe disease and identify potential therapeutic pathways using proteomic analysis of skeletal muscles from pre-symptomatic Pompe mice. For this purpose, quadriceps samples of Gaa mutant (Pompe) and wildtype mice, at the age of six weeks, were studied with three biological replicates for each group.

Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status.

Objectives: Cancer is considered an emerging diabetes complication, with higher incidence and worse prognosis in patients with diabetes. Cancer is frequently associated with cachexia, a systemic metabolic disease causing wasting. It is currently unclear how diabetes affects the development and progression of cachexia.

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post-COVID-19 condition.

Background And Purpose: Post-COVID-19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case-control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC.

Methods: Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age- and sex-matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi-echo spin-echo sequence for quantitative water mapping reflecting putative edema, and a diffusion-weighted spin-echo echo-planar imaging sequence to assess microstructural alterations.

Quantitative muscle MRI captures early muscle degeneration in calpainopathy.

To evaluate differences in qMRI parameters of muscle diffusion tensor imaging (mDTI), fat-fraction (FF) and water T2 time in leg muscles of calpainopathy patients (LGMD R1/D4) compared to healthy controls, to correlate those findings to clinical parameters and to evaluate if qMRI parameters show muscle degeneration in not-yet fatty infiltrated muscles. We evaluated eight thigh and seven calf muscles of 19 calpainopathy patients and 19 healthy matched controls. MRI scans were performed on a 3T MRI including a mDTI, T2 mapping and mDixonquant sequence.

Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells.

Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved.

Nuclear Receptors in Energy Metabolism.

Nuclear receptors are master regulators of energy metabolism through the conversion of extracellular signals into gene expression signatures. The function of the respective nuclear receptor is tissue specific, signal and co-factor dependent. While normal nuclear receptor function is central to metabolic physiology, aberrant nuclear receptor signaling is linked to various metabolic diseases such as type 2 diabetes mellitus, obesity, or hepatic steatosis.

Obesity and cancer-extracellular matrix, angiogenesis, and adrenergic signaling as unusual suspects linking the two diseases.

Obesity is an established risk factor for several human cancers. Given the association between excess body weight and cancer, the increasing rates of obesity worldwide are worrisome. A variety of obesity-related factors has been implicated in cancer initiation, progression, and response to therapy.

A Novel MATLAB®-Algorithm-Based Video Analysis to Quantitatively Determine Solution Creeping in Intact Pharmaceutical Glass Vials.

During the filling process of a biopharmaceutical drug product (DP), a liquid DP film might creep up the inner vial wall which is barely discernible, appears as milky-white haze after lyophilisation and is known as fogging. Creeping and fogging are mainly dependent on the primary packaging material surface and its hydration, vial preparation process as well as DP composition. The occurrence of both can impede visual inspection and might lead to DP rejection.

Angpt2/Tie2 autostimulatory loop controls tumorigenesis.

Invasive nonfunctioning (NF) pituitary neuroendocrine tumors (PitNETs) are non-resectable neoplasms associated with frequent relapses and significant comorbidities. As the current therapies of NF-PitNETs often fail, new therapeutic targets are needed. The observation that circulating angiopoietin-2 (ANGPT2) is elevated in patients with NF-PitNET and correlates with tumor aggressiveness prompted us to investigate the ANGPT2/TIE2 axis in NF-PitNETs in the GH3 PitNET cell line, primary human NF-PitNET cells, xenografts in zebrafish and mice, and in MENX rats, the only autochthonous NF-PitNET model.