Proteoglycans in the Control of Tumor Growth and Metastasis Formation

Proteoglycans (PGs) as a whole, or when considering their GAG chains as single entities, are emerging as key regulators of tumor progression. Expectations on using them as putative prognostic markers and potential therapeutic targets are increasing coincidentally. Due to the multitude of biological roles that they may invest and the ample spectrum of cellular processes that they may control, we still need to learn better how they regulate phenomena such as intracellular signaling, proliferation, apoptosis, motility, and drug resistance. Depending on the type, their expression pattern, and the accessibility of their molecular ligands, PGs can either promote or inhibit tumorigenesis. The structural and functional diversity of PGs coupled with their ubiquitous abundance place them at the crossroads of many critical steps within the metastatic cascade. As this phenomenon is the pivotal factor for patient survivals, particular attention should be given to the understanding of how PGs govern metastasis formation.     

Young Adults with Autism Spectrum Disorder and the Criminal Justice System

Journal of Autism and Developmental Disorders - This study describes charges, outcomes, and recidivism in both the juvenile and adult criminal justice systems (CJS) for young adults aged 17 to...     

Anti-thyroid antibodies and thyroid dysfunction in rheumatoid arthritis: Prevalence and clinical value

Objectives: The aim of this study was to assess thyroid function as well as the prevalence and clinical value of anti-thyroid antibodies in patients with rheumatoid arthritis (RA).

Methods: Seventy patients with active RA (ACR criteria), 9 males and 61 females, mean age 47 years (range 15–77) were analyzed. Anti-thyroperoxidase (TPOAb) and anti-thyroglobulin antibodies (TgAb) were tested using radioimmunoassay. Free thyroxine (FT4) and free triiodothyronine (FT3) and thyroid-stimulating hormone (TSH) serum levels were measured using electro-immunochemiluminescence (ECLIA, Elecsys Roche). Clinical variables, including tender and swollen joint count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), anti-cyclic citrullinated peptide antibody (anti-CCP) and antinuclear antibodies (ANA) were also evaluated. Statistics were performed by the SPSS statistical software for Windows.

Results: Twenty-six patients (37%) with RA were positive for TPOAb and 16 (23%) for TgAb. In 5 (7.1%) patients TSH level was slightly elevated, ranging between 4.52 and 15.65 UI/ml. The increase of TSH levels was associated with normal FT4 in 3 cases (4.2%) and with reduced FT4 in 2 cases (2.8%). One patient (1.5%) had low TSH serum value along with normal FT4. No differences in clinical and serological data between anti-thyroid positive and negative patients were observed.

Conclusion: Our study shows an increased prevalence of anti-thyroid antibodies in RA patients with a low prevalence of hormonal alterations. However, anti-thyroid antibodies do not seem to identify any peculiar RA phenotype.     

Beneath the surface: hyper-connectivity between caudate and salience regions in ADHD fMRI at rest

European Child & Adolescent Psychiatry - Attention-Deficit/Hyperactivity Disorder (ADHD) comprises disturbances in attention, emotional regulation, and reward-related processes. In spite of the...     

Does the choice of the reference model affect the results of 3D-3D superimposition procedure? A comparison of different protocols for personal identification

International Journal of Legal Medicine - In literature, 3D-3D superimposition has been widely recognized as a valid method for personal identification. However, very little information is...     

Reduced Motivation in Perinatal Fluoxetine-Treated Mice: A Hypodopaminergic Phenotype

Early life is a sensitive period, in which enhanced neural plasticity allows the developing brain to adapt to its environment. This plasticity can also be a risk factor in which maladaptive development can lead to long-lasting behavioral deficits. Here, we test how early-life exposure to the selective-serotonin-reuptake-inhibitor (SSRI), fluoxetine, affects motivation, and dopaminergic signaling in adulthood. We show for the first time that mice exposed to fluoxetine in the early postnatal period exhibit a reduction in effort-related motivation. These mice also show blunted responses to amphetamine and reduced dopaminergic activation in a sucrose reward task. Interestingly, we find that the reduction in motivation can be rescued in the adult by administering bupropion, a dopamine-norepinephrine reuptake inhibitor used as an antidepressant and a smoke cessation aid but not by fluoxetine. Taken together, our studies highlight the effects of early postnatal exposure of fluoxetine on motivation and demonstrate the involvement of the dopaminergic system in this process.SIGNIFICANCE STATEMENT The developmental period is characterized by enhanced plasticity. During this period, environmental factors have the potential to lead to enduring behavioral changes. Here, we show that exposure to the SSRI fluoxetine during a restricted period in early life leads to a reduction in adult motivation. We further show that this reduction is associated with decreased dopaminergic responsivity. Finally, we show that motivational deficits induced by early-life fluoxetine exposure can be rescued by adult administration of bupropion but not by fluoxetine.     

New Tmc1 Deafness Mutations Impact Mechanotransduction in Auditory Hair Cells

Transmembrane channel-like protein isoform 1 (TMC1) is a major component of the mechano-electrical transducer (MET) channel in cochlear hair cells and is subject to numerous mutations causing deafness. We report a new dominant human deafness mutation, TMC1 p.T422K, and have characterized the homologous mouse mutant, Tmc1 p.T416K, which caused deafness and outer hair cell (OHC) loss by the fourth postnatal week. MET channels showed decreased Ca²⁺ permeability and resting open probability, but no change in single-channel conductance or expression. Three adjacent deafness mutations are TMC1 p.L416R, p.G417R, and p.M418K, the last homologous to the mouse Beethoven that exhibits similar channel effects. All substitute a positive for a neutral residue, which could produce charge screening in the channel pore or influence binding of an accessory subunit. Channel properties were compared in mice of both sexes between dominant (Tmc1 p.T416K, Tmc1 p.D569N) and recessive (Tmc1 p.W554L, Tmc1 p.D528N) mutations of residues near the putative pore of the channel. Tmc1 p.W554L and p.D569N exhibit reduced maximum current with no effect on single-channel conductance, implying a smaller number of channels transported to the stereociliary tips; this may stem from impaired TMC1 binding to LHFPL5. Tmc1 p.D528N, located in the pore''s narrowest region, uniquely caused large reductions in MET channel conductance and block by dihydrostreptomycin (DHS). For Tmc1 p.T416K and Tmc1 p.D528N, transduction loss occurred between P15 and P20. We propose two mechanisms linking channel mutations and deafness: decreased Ca²⁺ permeability, common to all mutants, and decreased resting open probability in low Ca²⁺, confined to dominant mutations.SIGNIFICANCE STATEMENT Transmembrane channel-like protein isoform 1 (TMC1) is thought to be a major component of the mechanotransducer channel in auditory hair cells, but the protein organization and channel structure are still uncertain. We made four mouse lines harboring Tmc1 point mutations that alter channel properties, causing hair cell degeneration and deafness. These include a mouse homolog of a new human deafness mutation pT416K that decreased channel Ca²⁺ permeability by introducing a positively-charged amino acid in the putative pore. All mutations are consistent with the channel structure predicted from modeling, but only one, p.D528N near the external face of the pore, substantially reduced channel conductance and Ca²⁺ permeability and virtually abolished block by dihydrostreptomycin (DHS), strongly endorsing its siting within the pore.     

CANVAS: a late onset ataxia due to biallelic intronic AAGGG expansions

Journal of Neurology - The ataxias are a group of disorders that manifest with balance, movement, speech and visual problems. They can arise due to dysfunction of the cerebellum, the vestibular...