Spondylocarpotarsal synostosis syndrome: \u201cBat wings\u201d spinal fusions and \u201cladybug\u201d carpal coalitions

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Quantitative imaging techniques for the assessment of osteoporosis and sarcopenia

Bone and muscle are two deeply interconnected organs and a strong relationship between them exists in their development and maintenance. The peak of both bone and muscle mass is achieved in early adulthood, followed by a progressive decline after the age of 40. The increase in life expectancy in developed countries resulted in an increase of degenerative diseases affecting the musculoskeletal system. Osteoporosis and sarcopenia represent a major cause of morbidity and mortality in the elderly population and are associated with a significant increase in healthcare costs. Several imaging techniques are currently available for the non-invasive investigation of bone and muscle mass and quality. Conventional radiology, dual energy X-ray absorptiometry (DXA), computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound often play a complementary role in the study of osteoporosis and sarcopenia, depicting different aspects of the same pathology. This paper presents the different imaging modalities currently used for the investigation of bone and muscle mass and quality in osteoporosis and sarcopenia with special emphasis on the clinical applications and limitations of each technique and with the intent to provide interesting insights into recent advances in the field of conventional imaging, novel high-resolution techniques and fracture risk

Early Response to the Plant Toxin Stenodactylin in Acute Myeloid Leukemia Cells Involves Inflammatory and Apoptotic Signaling

Stenodactylin, a highly toxic type 2 ribosome-inactivating protein purified from the caudex of Adenia stenodactyla Harms, is a potential anticancer drug candidate. Previous studies demonstrated that stenodactylin induces apoptosis and necroptosis in treated cells, involving the production of reactive oxygen species. We analyzed the effect of stenodactylin on Raji and Ramos (Human Burkitt’s lymphoma cells) and MOLM-13 (acute myeloid leukemia cells). Moreover, we focused on the early events in MOLM-13 cells that characterize the cellular response to the toxin by whole-genome microarray analysis of gene expression. Treatment with stenodactylin induced the depurination of 28S rRNA within 4 h and increased the phosphorylation of p38 and JNK. A time-dependent activation of caspase 1, 2, 8, 9, 3/7 was also observed. Genome-wide gene expression microarray analysis revealed early changes in the expression of genes involved in the regulation of cell death, inflammation and stress response. After 4 h, a significant increase of transcript level was detectable for ATF3, BTG2, DUSP1, EGR1, and JUN. Increased upstream JUN signaling was also confirmed at protein level. The early response to stenodactylin treatment involves inflammatory and apoptotic signaling compatible with the activation of multiple cell death pathways. Because of the above described properties toward acute myeloid leukemia cells, stenodactylin may be a promising candidate for the design of new immunoconjugates for experimental cancer treatment

Aging and Imaging Assessment of Body Composition: From Fat to Facts

The aging process is characterized by the chronic inflammatory status called \u201cinflammaging\u201d, which shares major molecular and cellular features with the metabolism-induced inflammation called \u201cmetaflammation.\u201d Metaflammation is mainly driven by overnutrition and nutrient excess, but other contributing factors are metabolic modifications related to the specific body composition (BC) changes occurring with age. The aging process is indeed characterized by an increase in body total fat mass and a concomitant decrease in lean mass and bone density, that are independent from general and physiological fluctuations in weight and body mass index (BMI). Body adiposity is also re-distributed with age, resulting in a general increase in trunk fat (mainly abdominal fat) and a reduction in appendicular fat (mainly subcutaneous fat). Moreover, the accumulation of fat infiltration in organs such as liver and muscles also increases in elderly, while subcutaneous fat mass tends to decrease. These specific variations in BC are considered risk factors for the major age-related diseases, such as cardiovascular diseases, type 2 diabetes, sarcopenia and osteoporosis, and can predispose to disabilities. Thus, the maintenance of a balance rate of fat, muscle and bone is crucial to preserve metabolic homeostasis and a health status, positively contributing to a successful aging. For this reason, a detailed assessment of BC in elderly is critical and could be an additional preventive personalized strategy for age-related diseases. Despite BMI and other clinical measures, such as waist circumference measurement, waist-hip ratio, underwater weighing and bioelectrical impedance, are widely used as a surrogate measure for body adiposity, they barely reflect the distribution of body fat. Because of the great advantages offered by imaging tools in research and clinics, the attention of clinicians is now moving to powerful imaging techniques such as computed tomography, magnetic resonance imaging, dual-energy X-ray absorptiometry and ultrasound to obtain a more accurate estimation of BC. The aim of this review is to present the state of the art of the imaging techniques that are currently available to measure BC and that can be applied to the study of BC changes in the elderly, outlining advantages and disadvantages of each technique

Single-cell gene network analysis and transcriptional landscape of MYCN-amplified neuroblastoma cell lines

Neuroblastoma (NBL) is a pediatric cancer responsible for more than 15% of cancer deaths in children, with 800 new cases each year in the United States alone. Genomic amplification of the MYC oncogene family member MYCN characterizes a subset of high-risk pediatric neuroblastomas. Several cellular models have been implemented to study this disease over the years. Two of these, SK-N-BE-2-C (BE2C) and Kelly, are amongst the most used worldwide as models of MYCN-Amplified human NBL. Here, we provide a transcriptome-wide quantitative measurement of gene expression and transcriptional network activity in BE2C and Kelly cell lines at an unprecedented single-cell resolution. We obtained 1105 Kelly and 962 BE2C unsynchronized cells, with an average number of mapped reads/cell of roughly 38,000. The single-cell data recapitulate gene expression signatures previously generated from bulk RNA-Seq. We highlight low variance for commonly used housekeeping genes between different cells (ACTB, B2M and GAPDH), while showing higher than expected variance for metallothionein transcripts in Kelly cells. The high number of samples, despite the relatively low read coverage of single cells, allowed for robust pathway enrichment analysis and master regulator analysis (MRA), both of which highlight the more mesenchymal nature of BE2C cells as compared to Kelly cells, and the upregulation of TWIST1 and DNAJC1 transcriptional networks. We further defined master regulators at the single cell level and showed that MYCN is not constantly active or expressed within Kelly and BE2C cells, independently of cell cycle phase. The dataset, alongside a detailed and commented programming protocol to analyze it, is fully shared and reusable

A History of Repeated Alcohol Intoxication Promotes Cognitive Impairment and Gene Expression Signatures of Disease Progression in the 3xTg Mouse Model of Alzheimer’s Disease

The impact of alcohol abuse on Alzheimer’s disease (AD) is poorly understood. Here, we show that the onset of neurocognitive impairment in a mouse model of AD is hastened by repeated alcohol intoxication through exposure to alcohol vapor, and we provide a comprehensive gene expression dataset of the prefrontal cortex by the single-nucleus RNA sequencing of 113,242 cells. We observed a broad dysregulation of gene expression that involves neuronal excitability, neurodegeneration, and inflammation, including interferon genes. Several genes previously associated with AD in humans by genome-wide association studies were differentially regulated in specific neuronal populations. The gene expression signatures of AD mice with a history of alcohol intoxication showed greater similarity to the signatures of older AD mice with advanced disease and cognitive impairment than did the gene expression signatures of AD mice not exposed to alcohol, suggesting that alcohol promotes transcriptional changes consistent with AD progression. Our gene expression dataset at the single-cell level provides a unique re-source for investigations of the molecular bases of the detrimental role of excessive alcohol intake in AD

Gene Co-expression Analysis Identifies Histone Deacetylase 5 and 9 Expression in Midbrain Dopamine Neurons and as Regulators of Neurite Growth via Bone Morphogenetic Protein Signaling

Parkinson’s disease is characterized by the intracellular accumulation of α-synuclein which has been linked to early dopaminergic axonal degeneration. Identifying druggable targets that can promote axonal growth in cells overexpressing α-synuclein is important in order to develop strategies for early intervention. Class-IIa histone deacetylases (HDACs) have previously emerged as druggable targets, however, it is not known which specific class-IIa HDACs should be targeted to promote neurite growth in dopaminergic neurons. To provide insight into this, we used gene co-expression analysis to identify which, if any, of the class-IIa HDACs had a positive correlation with markers of dopaminergic neurons in the human substantia nigra. This revealed that two histone deacetylases, HDAC5 and HDAC9, are co-expressed with TH, GIRK2 and ALDH1A1 in the human SN. We further found that HDAC5 and HDAC9 are expressed in dopaminergic neurons in the adult mouse substantia nigra. We show that siRNAs targeting HDAC5 or HDAC9 can promote neurite growth in SH-SY5Y cells, and that their pharmacological inhibition, using the drug MC1568, promoted neurite growth in cultured rat dopaminergic neurons. Moreover, MC1568 treatment upregulated the expression of the neurotrophic factor, BMP2, and its downstream transcription factor, SMAD1. In addition, MC1568 or siRNAs targeting HDAC5 or HDAC9 led to an increase in Smad-dependent GFP expression in a reporter assay. Furthermore, MC1568 treatment of cultured rat dopaminergic neurons increased cellular levels of phosphorylated Smad1, which was prevented by the BMP receptor inhibitor, dorsomorphin. Dorsomorphin treatment prevented the neurite growth-promoting effects of siRNAs targeting HDAC5, as did overexpression of dominant-negative Smad4 or of the inhibitory Smad7, demonstrating a functional link to BMP signaling. Supplementation with BMP2 prevented the neurite growth-inhibitory effects of nuclear-restricted HDAC5. Finally, we report that siRNAs targeting HDAC5 or HDAC9 promoted neurite growth in cells overexpressing wild-type or A53T-α-synuclein and that MC1568 protected cultured rat dopaminergic neurons against the neurotoxin, MPP+. These findings establish HDAC5 and HDAC9 as novel regulators of BMP-Smad signaling, that additionally may be therapeutic targets worthy of further exploration in iPSC-derived human DA neurons and in vivo models of Parkinson’s disease

The inhibition of the highly expressed miR-221 and miR-222 impairs the growth of prostate carcinoma xenografts in mice

MiR-221 and miR-222 are two highly homologous microRNAs whose upregulation has been recently described in several types of human tumors, for some of which their oncogenic role was explained by the discovery of their target p27, a key cell cycle regulator. We previously showed this regulatory relationship in prostate carcinoma cell lines in vitro, underlying the role of miR-221/222 as inducers of proliferation and tumorigenicity