The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders.

This review article focuses on the Contactin (CNTN) subset of the Immunoglobulin supergene family (IgC2/FNIII molecules), whose components share structural properties (the association of Immunoglobulin type C2 with Fibronectin type III domains), as well as a general role in cell contact formation and axonal growth control. IgC2/FNIII molecules include 6 highly related components (CNTN 1-6), associated with the cell membrane via a Glycosyl Phosphatidyl Inositol (GPI)-containing lipid tail. Contactin 1 and Contactin 2 share ~50 (49.38)% identity at the aminoacid level. They are components of the cell surface, from which they may be released in soluble forms. They bind heterophilically to multiple partners in cis and in trans, including members of the related L1CAM family and of the Neurexin family Contactin-associated proteins (CNTNAPs or Casprs). Such interactions are important for organising the neuronal membrane, as well as for modulating the growth and pathfinding of axon tracts. In addition, they also mediate the functional maturation of axons by promoting their interactions with myelinating cells at the nodal, paranodal and juxtaparanodal regions. Such interactions also mediate differential ionic channels (both Na(+) and K(+)) distribution, which is of critical relevance in the generation of the peak-shaped action potential. Indeed, thanks to their interactions with Ankyrin G, Na(+) channels map within the nodal regions, where they drive axonal depolarization. However, no ionic channels are found in the flanking Contactin1-containing paranodal regions, where CNTN1 interactions with Caspr1 and with the Ig superfamily component Neurofascin 155 in cis and in trans, respectively, build a molecular barrier between the node and the juxtaparanode. In this region K(+) channels are clustered, depending upon molecular interactions with Contactin 2 and with Caspr2. In addition to these functions, the Contactins appear to have also a role in degenerative and inflammatory disorders: indeed Contactin 2 is involved in neurodegenerative disorders with a special reference to the Alzheimer disease, given its ability to work as a ligand of the Alzheimer Precursor Protein (APP), which results in increased Alzheimer Intracellular Domain (AICD) release in a γ-secretase-dependent manner. On the other hand Contactin-1 drives Notch signalling activation via the Hes pathway, which could be consistent with its ability to modulate neuroinflammation events, and with the possibility that Contactin 1-dependent interactions may participate to the pathogenesis of the Multiple Sclerosis and of other inflammatory disorders

Role of biomechanical assessment in rotator cuff tear repair: Arthroscopic vs mini-open approach

BACKGROUND Rotator cuff (RC) tears are one of the most frequent pathologies within the shoulder girdle. Hand dominance and older age are associated with RC tears. Two different surgical procedures, the mini-open (MO) and all-arthroscopic (AA) approach, represented the standard of treatment. AIM To compare the clinical and biomechanical outcomes of two surgical techniques (AA vs MO procedure) performed to address the painful shoulder syndrome with partial or total supraspinatus tendon tear. METHODS Eighty-eight participants, 50 following RC repair with AA and 38 with MO approach, were recruited in the present cross-sectional case-control study (ORTHO-SHOULDER, Prot. 0054602). All patients underwent postoperative clinical evaluation for pain (Visual analogic scale), impairment, and disability (disability of the arm, shoulder, and hand) and limitation in daily activity (Constant-Murley score). Patients\u2019 shoulder mobility was also assessed in our Laboratory of Functional Movement through a wearable inertial sensor and surface electromyography to monitor kinematics and muscle activity during the movement on the frontal (abduction/adduction) and sagittal (flexion-extension) planes. RESULTS No statistically significant differences between the two procedures were observed in either main clinical score or range of motion. A significant increase in velocity during the movement execution and a higher contribution of upper trapezius muscles were found in the AA group compared with MO patients. CONCLUSION In terms of clinical scores, our findings were in line with previous results. However, the use of technology-based assessment of shoulder mobility has revealed significant differences between the two techniques in terms of mean velocity and pattern of muscle activation

Oral dysplastic complications after HSCT: Single case series of multidisciplinary evaluation of 80 patients

Oral squamous cell carcinoma (OSCC) is the most common secondary solid malignancy after hematopoietic stem‐cell transplantation (HSCT). OSCC following HSCT is frequently preceded by chronic graft‐versus‐host disease (cGVHD). The aim of this study was to describe a cohort of post‐HSCT patients and to evaluate the onset of oral epithelial dysplasia and/or OSCC over time. In this retrospective cohort study, we present a cohort of hematological patients that underwent HSCT. Demographic variables, clinical hematological data, data regarding acute graft‐versus‐host disease (aGVHD) and cGVHD, and oral clinical features were analyzed. We focused on clinicopathological features of a subgroup of 22 patients with oral cGVHD and OSCC after HSCT. Among 80 included patients, 46 patients (57,5%) developed aGVHD and 39 patients (48,7%) developed cGVHD. Oral mucosa was involved in 17 patients with aGVHD (36,9%) and in 22 patients (56,4%) with cGVHD. Out of a total of 22 oral biopsies, roughly 40% revealed mild to moderate dysplasia, and 32 % were OSCC. In the absence of international agreement on the best timing of oral follow‐up after HSCT, it is mandatory to establish a close multidisciplinary evaluation in order to prevent the onset of HSCT-related OSCC and to reduce post‐transplant mortality due to secondary tumors

The Cerebellar Dopaminergic System

In the central nervous system (CNS), dopamine (DA) is involved in motor and cognitive functions. Although the cerebellum is not been considered an elective dopaminergic region, studies attributed to it a critical role in dopamine deficit-related neurological and psychiatric disorders [e.g., Parkinson's disease (PD) and schizophrenia (SCZ)]. Data on the cerebellar dopaminergic neuronal system are still lacking. Nevertheless, biochemical studies detected in the mammalians cerebellum high dopamine levels, while chemical neuroanatomy studies revealed the presence of midbrain dopaminergic afferents to the cerebellum as well as wide distribution of the dopaminergic receptor subtypes (DRD1-DRD5). The present review summarizes the data on the cerebellar dopaminergic system including its involvement in associative and projective circuits. Furthermore, this study also briefly discusses the role of the cerebellar dopaminergic system in some neurologic and psychiatric disorders and suggests its potential involvement as a target in pharmacologic and non-pharmacologic treatments

Metabolomic Approaches for Detection and Identification of Biomarkers and Altered Pathways in Bladder Cancer

Metabolomic analysis has proven to be a useful tool in biomarker discovery and the molecular classification of cancers. In order to find new biomarkers, and to better understand its pathological behavior, bladder cancer also has been studied using a metabolomics approach. In this article, we review the literature on metabolomic studies of bladder cancer, focusing on the different available samples (urine, blood, tissue samples) used to perform the studies and their relative findings. Moreover, the multi-omic approach in bladder cancer research has found novel insights into its metabolic behavior, providing excellent start-points for new diagnostic and therapeutic strategies. Metabolomics data analysis can lead to the discovery of a “signature pathway” associated with the progression of bladder cancer; this aspect could be potentially valuable in predictions of clinical outcomes and the introduction of new treatments. However, further studies are needed to give stronger evidence and to make these tools feasible for use in clinical practice

Distinct Cis Regulatory Elements Govern the Expression of TAG1 in Embryonic Sensory Ganglia and Spinal Cord

Cell fate commitment of spinal progenitor neurons is initiated by long-range, midline-derived, morphogens that regulate an array of transcription factors that, in turn, act sequentially or in parallel to control neuronal differentiation. Included among these are transcription factors that regulate the expression of receptors for guidance cues, thereby determining axonal trajectories. The Ig/FNIII superfamily molecules TAG1/Axonin1/CNTN2 (TAG1) and Neurofascin (Nfasc) are co-expressed in numerous neuronal cell types in the CNS and PNS – for example motor, DRG and interneurons - both promote neurite outgrowth and both are required for the architecture and function of nodes of Ranvier. The genes encoding TAG1 and Nfasc are adjacent in the genome, an arrangement which is evolutionarily conserved. To study the transcriptional network that governs TAG1 and Nfasc expression in spinal motor and commissural neurons, we set out to identify cis elements that regulate their expression. Two evolutionarily conserved DNA modules, one located between the Nfasc and TAG1 genes and the second directly 59 to the first exon and encompassing the first intron of TAG1, were identified that direct complementary expression to the CNS and PNS, respectively, of the embryonic hindbrain and spinal cord. Sequential deletions and point mutations of the CNS enhancer element revealed a 130bp element containing three conserved E-boxes required for motor neuron expression. In combination, these two elements appear to recapitulate a major part of the pattern of TAG1 expression in the embryonic nervous system

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients