FGF23, a novel muscle biomarker detected in the early stages of ALS

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane and was significantly higher around grouped atrophic fibers compared to non-atrophic fibers. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease progression offers a new direction for exploring the molecular basis and response to the underlying pathology of ALS.

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FGF23, A Novel Muscle Biomarker Detected in The Early Stages of ALS

10.21203/rs.3.rs-215167/v1 ◽

2021 ◽

Author(s):

Ying Si ◽

Mohamed Kazamel ◽

Michael Benatar ◽

Joanne Wuu ◽

Yuri Kwon ◽

...

Keyword(s):

Biomarker Discovery ◽

Clinical Symptoms ◽

Early Stage ◽

Fold Increase ◽

Progressive Increase ◽

Molecular Signature ◽

Muscle Membrane ◽

Sequencing Project ◽

Sod1g93a Mouse ◽

End Stage

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive muscle weakness. Skeletal muscle is a prime source for biomarker discovery since it is one of the earliest sites to manifest disease pathology. From a prior RNA sequencing project, we identified FGF23 as a potential muscle biomarker in ALS. Here, we validate this finding with a large collection of ALS muscle samples and found a 13-fold increase over normal controls. FGF23 was also increased in the SOD1G93A mouse, beginning at a very early stage and well before the onset of clinical symptoms. FGF23 levels progressively increased through end-stage in the mouse. Immunohistochemistry of ALS muscle showed prominent FGF23 immunoreactivity in the endomysial connective tissue and along the muscle membrane. ELISA of plasma samples from the SOD1G93A mouse showed an increase in FGF23 at end-stage whereas no increase was detected in a large cohort of ALS patients. In conclusion, FGF23 is a novel muscle biomarker in ALS and joins a molecular signature that emerges in very early preclinical stages. The early appearance of FGF23 and its progressive increase with disease advancement offers a new direction for exploring the molecular basis or response to the underlying pathology of ALS.

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Wnt antagonist FRZB is a muscle biomarker of denervation atrophy in amyotrophic lateral sclerosis

Scientific Reports ◽

10.1038/s41598-020-73845-z ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Thaddaeus Kwan ◽

Mohamed Kazamel ◽

Kristina Thoenes ◽

Ying Si ◽

Nan Jiang ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Wnt Signaling ◽

Disease Progression ◽

Molecular Signature ◽

Muscle Membrane ◽

Denervation Atrophy ◽

Muscle Denervation ◽

Variable Extent ◽

End Stage ◽

Lateral Sclerosis

Abstract Skeletal muscle and the neuromuscular junction are the earliest sites to manifest pathological changes in amyotrophic lateral sclerosis (ALS). Based on prior studies, we have identified a molecular signature in muscle that develops early in ALS and parallels disease progression. This signature represents an intersection of signaling pathways including Smads, TGF-β, and vitamin D. Here, we show that the Wnt antagonist, Frizzled Related Protein (FRZB), was increased in ALS muscle samples and to a variable extent other denervating disease but only minimally in acquired myopathies. In the SOD1G93A mouse, FRZB was upregulated in the early stages of disease (between 40 and 60 days) until end-stage. By immunohistochemistry, FRZB was predominantly localized to endomysial connective tissue and to a lesser extent muscle membrane. There was a significant increase in immunoreactivity surrounding atrophied myofibers. Because FRZB is a Wnt antagonist, we assessed β-catenin, the canonical transducer of Wnt signaling, and found increased levels mainly at the muscle membrane. In summary, we show that FRZB is part of a molecular signature of muscle denervation that may reflect disease progression in ALS. Our findings open up avenues for future investigation as to what roles FRZB and Wnt signaling might be playing in muscle denervation/reinnervation.

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Sequential fate-switches in stem-like cells drive the tumorigenic trajectory from human neural stem cells to malignant glioma

Cell Research ◽

10.1038/s41422-020-00451-z ◽

2021 ◽

Author(s):

Xiaofei Wang ◽

Ran Zhou ◽

Yanzhen Xiong ◽

Lingling Zhou ◽

Xiang Yan ◽

...

Keyword(s):

Malignant Glioma ◽

Single Cell ◽

De Novo ◽

Early Stage ◽

Lineage Tracing ◽

Human Neural Stem Cells ◽

Transcriptional Reprogramming ◽

Neural Stem Progenitor Cells ◽

Human Gbm ◽

End Stage

AbstractGlioblastoma (GBM) is an incurable and highly heterogeneous brain tumor, originating from human neural stem/progenitor cells (hNSCs/hNPCs) years ahead of diagnosis. Despite extensive efforts to characterize hNSCs and end-stage GBM at bulk and single-cell levels, the de novo gliomagenic path from hNSCs is largely unknown due to technical difficulties in early-stage sampling and preclinical modeling. Here, we established two highly penetrant hNSC-derived malignant glioma models, which resemble the histopathology and transcriptional heterogeneity of human GBM. Integrating time-series analyses of whole-exome sequencing, bulk and single-cell RNA-seq, we reconstructed gliomagenic trajectories, and identified a persistent NSC-like population at all stages of tumorigenesis. Through trajectory analyses and lineage tracing, we showed that tumor progression is primarily driven by multi-step transcriptional reprogramming and fate-switches in the NSC-like cells, which sequentially generate malignant heterogeneity and induce tumor phenotype transitions. We further uncovered stage-specific oncogenic cascades, and among the candidate genes we functionally validated C1QL1 as a new glioma-promoting factor. Importantly, the neurogenic-to-gliogenic switch in NSC-like cells marks an early stage characterized by a burst of oncogenic alterations, during which transient AP-1 inhibition is sufficient to inhibit gliomagenesis. Together, our results reveal previously undercharacterized molecular dynamics and fate choices driving de novo gliomagenesis from hNSCs, and provide a blueprint for potential early-stage treatment/diagnosis for GBM.

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Whole brain atlas-based diffusion kurtosis imaging parameters for evaluation of minimal hepatic encephalopathy

The Neuroradiology Journal ◽

10.1177/19714009211026924 ◽

2021 ◽

pp. 197140092110269

Author(s):

Prateek Gupta ◽

Sameer Vyas ◽

Teddy Salan ◽

Chirag Jain ◽

Sunil Taneja ◽

...

Keyword(s):

Hepatic Encephalopathy ◽

Clinical Symptoms ◽

Early Stage ◽

Imaging Techniques ◽

Clinical Stage ◽

Minimal Hepatic Encephalopathy ◽

Brain Atlas ◽

Diffusion Kurtosis Imaging ◽

Whole Brain ◽

Diffusion Kurtosis

Background and purposes Minimal hepatic encephalopathy (MHE) has no recognizable clinical symptoms, but patients have cognitive and psychomotor deficits. Hyperammonemia along with neuroinflammation lead to microstructural changes in cerebral parenchyma. Changes at conventional imaging are detected usually at the overt clinical stage, but microstructural alterations by advanced magnetic resonance imaging techniques can be detected at an early stage. Materials and methods Whole brain diffusion kurtosis imaging (DKI) data acquired at 3T was analyzed to investigate microstructural parenchymal changes in 15 patients with MHE and compared with 15 age- and sex-matched controls. DKI parametric maps, namely kurtosis fractional anisotropy (kFA), mean kurtosis (MK), axial kurtosis (AK) and radial kurtosis (RK), were evaluated at 64 white matter (WM) and gray matter (GM) regions of interest (ROIs) in the whole brain and correlated with the psychometric hepatic encephalopathy score (PHES). Results The MHE group showed a decrease in kFA and AK across the whole brain, whereas MK and RK decreased in WM ROIs but increased in several cortical and deep GM ROIs. These alterations were consistent with brain regions involved in cognitive function. Significant moderate to strong correlations (–0.52 to –0.66; 0.56) between RK, MK and kFA kurtosis metrics and PHES were observed. Conclusion DKI parameters show extensive microstructural brain abnormalities in MHE with minor correlation between the severity of tissue damage and psychometric scores.

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A novel variant in the COL4A3 gene: etiology of Alport syndrome type 2 in a 38-year-old male with suspected hereditary kidney disease

Advances in Laboratory Medicine / Avances en Medicina de Laboratorio ◽

10.1515/almed-2021-0058 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Paula Sienes Bailo ◽

José Luis Bancalero Flores ◽

Raquel Lahoz Alonso ◽

María Santamaría González ◽

Alex Gutiérrez Dalmau ◽

...

Keyword(s):

Kidney Disease ◽

Alport Syndrome ◽

Clinical Symptoms ◽

Molecular Testing ◽

Syndrome Type ◽

Variant Of Uncertain Significance ◽

Type Iv ◽

Novel Variant ◽

End Stage

ABSTRACT Objectives Patients with Alport syndrome develop progressive kidney function deterioration, sensorineural hearing loss, and ocular abnormalities. This condition is caused by mutations in COL4A5 (X-linked inheritance), COL4A3 and COL4A4 (autosomal dominant or recessive inheritance), and encoding type IV collagen α3, α4, and α5, respectively. If left untreated, clinical symptoms progress from microscopic hematuria to proteinuria, progressive kidney failure, and end-stage kidney disease. At present, kidney transplantation is the only effective approach. Next-generation sequencing is the method of choice for the diagnosis of this condition. Case presentation We report the case of a young man with chronic kidney disease who eventually underwent transplantation. Molecular testing made it possible to determine the etiology of his clinical symptoms and autosomal recessive Alport syndrome type 2. The patient was found to be a compound heterozygote for two missense variants (trans configuration) in the COL4A3 gene: A likely pathogenic variant c.4981C>T (p.Arg1661Cys) in exon 52 inherited from the mother (described elsewhere), and another variant of uncertain significance, c.943G>A (p.Gly315Ser), in exon 17 inherited from the father that has not been previously reported in the literature or found in relevant databases. Conclusions Following genetic confirmation, genetic counseling was provided to the patient and his direct relatives.

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Identification of Novel Biomarker for Early Detection of Diabetic Nephropathy

Biomedicines ◽

10.3390/biomedicines9050457 ◽

2021 ◽

Vol 9 (5) ◽

pp. 457

Author(s):

Kyeong-Seok Kim ◽

Jin-Sol Lee ◽

Jae-Hyeon Park ◽

Eun-Young Lee ◽

Jong-Seok Moon ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Early Stage ◽

Kidney Injury ◽

Diabetic Patients ◽

High Morbidity ◽

Neutrophil Gelatinase Associated Lipocalin ◽

Zucker Diabetic Fatty Rats ◽

Kidney Injury Molecule 1 ◽

Stage Renal Disease ◽

End Stage

Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus. After development of DN, patients will progress to end-stage renal disease, which is associated with high morbidity and mortality. Here, we developed early-stage diagnostic biomarkers to detect DN as a strategy for DN intervention. For the DN model, Zucker diabetic fatty rats were used for DN phenotyping. The results revealed that DN rats showed significantly increased blood glucose, blood urea nitrogen (BUN), and serum creatinine levels, accompanied by severe kidney injury, fibrosis and microstructural changes. In addition, DN rats showed significantly increased urinary excretion of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Transcriptome analysis revealed that new DN biomarkers, such as complementary component 4b (C4b), complementary factor D (CFD), C-X-C motif chemokine receptor 6 (CXCR6), and leukemia inhibitory factor (LIF) were identified. Furthermore, they were found in the urine of patients with DN. Since these biomarkers were detected in the urine and kidney of DN rats and urine of diabetic patients, the selected markers could be used as early diagnosis biomarkers for chronic diabetic nephropathy.

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Abdominal irradiation increases inflammatory cytokine expression and activates NF-κB in rat ileal muscularis layer

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00094.2003 ◽

2003 ◽

Vol 285 (3) ◽

pp. G556-G565 ◽

Cited By ~ 56

Author(s):

C. Linard ◽

A. Ropenga ◽

M. C. Vozenin-Brotons ◽

A. Chapel ◽

D. Mathe

Keyword(s):

Inflammatory Cytokine ◽

Intestinal Inflammation ◽

Clinical Symptoms ◽

Early Stage ◽

Cytokine Expression ◽

Mrna Levels ◽

Activator Protein 1 ◽

Γ Irradiation ◽

Control Tissue ◽

Anti Inflammatory

The small bowel is an important dose-limiting organ in abdominal radiotherapy because irradiation can cause acute enteritis that, in turn, leads to progressively reduced motility and finally, in a later phase, to fibrosis. Because these clinical symptoms may be caused by the early stage of an inflammatory process, we characterized the radiation-induced intestinal inflammation in rats. Abdominal γ-irradiation (10-Gy) induced a cascade of inflammatory events characterized by an early (6 h after exposure) increase in IL-1β, TNF-α, and IL-6 mRNA levels in the rat ileal muscularis layer. IL-8 [a cytokine-induced neutrophil chemoattractant (CINC)] mRNA appeared later (at 3 days). The expression of TGF-β (a profibrotic cytokine) was higher in irradiated than control tissue at day 1, whereas IL-10 (an anti-inflammatory cytokine) expression vanished completely. Despite strong IL-1ra expression, the IL-1ra/IL-1β ratio, which is an indicator of inflammatory balance, was -41% at day 1 in irradiated compared with control tissue. The nuclear transcription factors NF-κB and activator protein-1 (AP-1) govern transcription of these genes, directly or indirectly. Although expression of the subunits of NF-κB (p65, p50) and AP-1 (c- fos, c- jun) did not increase, irradiation caused a rapid and persistent translocation of p65 and p50. An imbalance between proinflammatory and anti-inflammatory mediators may contribute to perpetuating intestinal inflammation, thus making it chronic.

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Diet, nutrients and metabolism: cogs in the wheel driving Alzheimer's disease pathology?

British Journal Of Nutrition ◽

10.1017/s0007114515000926 ◽

2015 ◽

Vol 113 (10) ◽

pp. 1499-1517 ◽

Cited By ~ 19

Author(s):

Rhona Creegan ◽

Wendy Hunt ◽

Alexandra McManus ◽

Stephanie R. Rainey-Smith

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Symptoms ◽

Aged Care ◽

Ageing Population ◽

People With Dementia ◽

Stage Disease ◽

Custodial Care ◽

Global Statistics ◽

End Stage

Alzheimer's disease (AD), the most common form of dementia, is a chronic, progressive neurodegenerative disease that manifests clinically as a slow global decline in cognitive function, including deterioration of memory, reasoning, abstraction, language and emotional stability, culminating in a patient with end-stage disease, totally dependent on custodial care. With a global ageing population, it is predicted that there will be a marked increase in the number of people diagnosed with AD in the coming decades, making this a significant challenge to socio-economic policy and aged care. Global estimates put a direct cost for treating and caring for people with dementia at $US604 billion, an estimate that is expected to increase markedly. According to recent global statistics, there are 35·6 million dementia sufferers, the number of which is predicted to double every 20 years, unless strategies are implemented to reduce this burden. Currently, there is no cure for AD; while current therapies may temporarily ameliorate symptoms, death usually occurs approximately 8 years after diagnosis. A greater understanding of AD pathophysiology is paramount, and attention is now being directed to the discovery of biomarkers that may not only facilitate pre-symptomatic diagnosis, but also provide an insight into aberrant biochemical pathways that may reveal potential therapeutic targets, including nutritional ones. AD pathogenesis develops over many years before clinical symptoms appear, providing the opportunity to develop therapy that could slow or stop disease progression well before any clinical manifestation develops.

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Analysis of Separability of COVID-19 and Pneumonia in Chest X-ray Images by Means of Convolutional Neural Networks

Proceedings ◽

10.3390/proceedings2020054031 ◽

2020 ◽

Vol 54 (1) ◽

pp. 31

Author(s):

Joaquim de Moura ◽

Lucía Ramos ◽

Plácido L. Vidal ◽

Jorge Novo ◽

Marcos Ortega

Keyword(s):

Neural Networks ◽

Convolutional Neural Networks ◽

Clinical Symptoms ◽

Early Stage ◽

World Health ◽

Complete Analysis ◽

Screening Process ◽

X Ray ◽

Chest X Ray ◽

Health Organization

The new coronavirus (COVID-19) is a disease that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On 11 March 2020, the coronavirus outbreak has been labelled a global pandemic by the World Health Organization. In this context, chest X-ray imaging has become a remarkably powerful tool for the identification of patients with COVID-19 infections at an early stage when clinical symptoms may be unspecific or sparse. In this work, we propose a complete analysis of separability of COVID-19 and pneumonia in chest X-ray images by means of Convolutional Neural Networks. Satisfactory results were obtained that demonstrated the suitability of the proposed system, improving the efficiency of the medical screening process in the healthcare systems.

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