Chromosomal Microdeletions and Genes\u27 Functions: A Cluster of Chromosomal Microdeletions and the Deleted Genes\u27 Functions

Hypotonia-cystinuria syndrome (HCS) is a recessive disorder caused by microdeletions of SLC3A1 and PREPL on chromosome 2p21. Patients present with generalized hypotonia at birth, failure to thrive, growth retardation and cystinuria type I. While the initially described HCS families live in small regions in Belgium and France, we have now identified HCS alleles in patients and carriers from the Netherlands, Italy, Canada and United States of America. Surprisingly, among the nine deletions detected in those patients, only one novel deletion was found. Furthermore, one previously described deletion was found six times, another twice. Finally, we have investigated the frequency of both deletions using a random Belgian cohort. Given the global occurrence, HCS should be considered in the differential diagnosis of neonatal hypotonia

The tumor suppressor Scrib interacts with the zyxin-related protein LPP, which shuttles between cell adhesion sites and the nucleus

BACKGROUND: At sites of cell adhesion, proteins exist that not only perform structural tasks but also have a signaling function. Previously, we found that the Lipoma Preferred Partner (LPP) protein is localized at sites of cell adhesion such as focal adhesions and cell-cell contacts, and shuttles to the nucleus where it has transcriptional activation capacity. LPP is a member of the zyxin family of proteins, which contains five members: ajuba, LIMD1, LPP, TRIP6 and zyxin. LPP has three LIM domains (zinc-finger protein interaction domains) at its carboxy-terminus, which are preceded by a proline-rich pre-LIM region containing a number of protein interaction domains. RESULTS: To catch the role of LPP at sites of cell adhesion, we made an effort to identify binding partners of LPP. We found the tumor suppressor protein Scrib, which is a component of cell-cell contacts, as interaction partner of LPP. Human Scrib, which is a functional homologue of Drosophila scribble, is a member of the leucine-rich repeat and PDZ (LAP) family of proteins that is involved in the regulation of cell adhesion, cell shape and polarity. In addition, Scrib displays tumor suppressor activity. The binding between Scrib and LPP is mediated by the PDZ domains of Scrib and the carboxy-terminus of LPP. Both proteins localize in cell-cell contacts. Whereas LPP is also localized in focal adhesions and in the nucleus, Scrib could not be detected at these locations in MDCKII and CV-1 cells. Furthermore, our investigations indicate that Scrib is dispensable for targeting LPP to focal adhesions and to cell-cell contacts, and that LPP is not necessary for localizing Scrib in cell-cell contacts. We show that all four PDZ domains of Scrib are dispensable for localizing this protein in cell-cell contacts. CONCLUSIONS: Here, we identified an interaction between one of zyxin's family members, LPP, and the tumor suppressor protein Scrib. Both proteins localize in cell-cell contacts. This interaction links Scrib to a communication pathway between cell-cell contacts and the nucleus, and implicates LPP in Scrib-associated functions

PAX3 Expression in Normal Skin Melanocytes and Melanocytic Lesions (Naevi and Melanomas)

Background Cutaneous Malignant Melanoma is an aggressive form of skin cancer, arising in cutaneous melanocytes. The transcription factor PAX3 regulates melanocyte specification from neural crest cells during development but expression in differentiated melanocytes is uncertain. By contrast it is frequently found in melanomas and naevi and is a marker for melanoma staging and detection. In this study we analysed the expression of PAX3 across the spectrum of melanocytic cells, from normal melanocytes to cells of benign and malignant lesions to better assess its function in these various tissues. Pax3 and PAX3 (italicized) refer to the mouse and human gene, respectively; whereas Pax3 and PAX3 (non-italicized) refer to the corresponding mouse and human protein. Methodology and Principal Findings PAX3 expression was analysed by immunohistochemistry and qRT-PCR. Immunofluorescence was used for co-expression with differentiation, migration and survival markers. As expected PAX3 expression was observed in naevi and melanoma cells. It was also found in melanocytes of normal skin where it co-expressed with melanocyte markers, MITF and MLANA. Co-expression with its downstream target, antiapoptotic factor BCL2L1 confirms PAX3 as a cell survival regulator. PAX3 was also co-expressed with melanoma cell migration marker MCAM in dermal naevi and melanoma cell nests, but this downstream target of PAX3 was not present in normal epidermal melanocytes, suggesting differential roles for PAX3 in normal epidermal melanocytes and melanoma cells. Most interestingly, a proportion of PAX3-positive epidermal melanocytes in normal skin show HES1 and Ki67 co-expression, indicating their less differentiated proliferative phenotype. Conclusions and Significance Our results suggest that a previously identified role for PAX3, that of regulator of an undifferentiated plastic state, may operate in melanocytes of normal skin. This role, possibly required for cellular response to environmental stimuli, may contribute to formation and development of melanocytic lesions in which PAX3 expression is prominent

Hémorragies sous anticoagulants oraux en gériatrie : résultats d’une étude observationnelle.

Over recent years, new oral anticoagulant agents (NOAC) have been commercialized as a new treatment in order to prevent or treat thromboembolic events. Although the use of NOACs is easier than for vitamin K antagonists (VKA), their risk-benefit balance still raises concerns, especially in the elderly. To evaluate bleeding complications with anticoagulants agents (NOAC and VKA) among a geriatric population. A retrospective study performed in the four units of the acute geriatric department of CHU Charleroi (116 beds). All the patients who received at least one dose of oral anticoagulant (NOAC or VKA) during their hospitalization between January 1st2013 and May 31th 2014 were enrolled. Medical files of 242 patients were analyzed, and the type and severity of bleeding were recorded. Mean age was 84 ± 5.4 years old. Seventy-three percent were prescribed VKA. Rivaroxaban was the most prescribed NOAC among this population. Atrial fibrillation was the primary indication of oral anticoagulation in 73% with VKA and 94% with NOAC. Fourty-six patients presented a bleeding (38 patients (22% of patients with VKA) with VKA and 8 patients with NOAC (12% of patients with NOAC)). We found 13 major bleedings with VKA and only one with NOAC. The results of this study are encouraging concerning the utilization of NOACs in the geriatric population. However, larger studies are needed to confirm this.info:eu-repo/semantics/publishe

Molecular Markers and Chemotherapy for Advanced Salivary Cancer

Recent advances in our understanding of the molecular biology of salivary gland neoplasms have yielded diagnostic targets and potential therapeutic targets that have started to change our approach and choice of treatment strategies. Currently, these options are mainly investigated in recurrent and metastatic salivary gland cancer (SGC). Although the results of both cytotoxic and targeted molecular biological systemic therapy for locoregional recurrence and distant spread of SGC remain largely unpredictable, targeted therapy can be the treatment of choice in selected cases today. Molecular analysis is required as part of the diagnostic workup to help select patients with recurrent and metastatic SGC who may benefit from targeted or standard treatment regimens.status: publishe

Transoral Laser Microsurgery (TLM) for Glottic Cancer: Prospective Assessment of a New Pathology Workup Protocol

Background/Purpose: The value of margin status after TLM for glottic cancer is debatable, due to difficulties in specimen orientation and margin analysis. Purpose of this study was the prospective evaluation of feasibility of a new standardized technique of oriented fixation of the TLM specimen and identification of the added value on tissue processing and margin status reporting. Methods: Patients with suspicious glottic lesions undergoing TLM were included. After resection, the specimen margins were inked in the OR using different colors. Subsequently, the specimens were fixed on a pig liver carrier and sent for further processing, accompanied with photographs of the larynx pre-TLM and of the mounted specimen. Feasibility was assessed by registration of duration of specimen preparation in the OR and the lab and by procedure-specific questionnaires. Objective evaluation included assessment of margin status and proportion of evaluable margins. Chi square tests were used to make comparisons of proportions. Results: One hundred and four consecutive patients were included between May 2016 and September 2019. TLM was performed in a primary and salvage setting in 89.4 and 10.6% of patients, respectively. Mean duration of intraoperative specimen preparation was 5.1 min (SD 2.6 min). No difficulties in orientation nor fixation during intraoperative preparation were reported in 87.5 and 88.2%, respectively. Specimen orientation was judged by the pathologist as very adequate in 89.4%, with the accompanying photographs considered helpful for orientation and processing in 84.6%. Substantial difficulties in further lab processing and pathologic examination were identified in 17.7%. Deep margin evaluability was very high (98.0%) and significantly higher than the evaluability of superficial mucosal margins. Compared to our previous series published by our group (n = 142), deep margin evaluability significantly rose from 62.7 to 98.0% (p < 0.001) and true positive rate of the deep margins increased from 0 to 44.4% (p = 0.002). Discussion/Conclusion: The new and standardized technique of oriented fixation of TLM specimens on a pig liver carrier proves feasible both in the OR and lab setting and results in high margin evaluability rates, especially for the deep margin, as well as a decreased rate of false positive deep margins when compared to a historical TLM cohort.status: publishe

Salvage Transoral Laser Microsurgery for Radiorecurrent Laryngeal Cancer: Indications, Limits, and Outcomes

The aim of this report is to identify relevant literature reports on salvage transoral laser microsurgery (TLM); to consider its oncologic and functional outcomes, as well as reported complications; and to address indications and limitations of salvage TLM.status: publishe

Differential Effects of Furin Deficiency on Insulin Receptor Processing and Glucose Control in Liver and Pancreatic β Cells of Mice

The insulin receptor (IR) is critically involved in maintaining glucose homeostasis. It undergoes proteolytic cleavage by proprotein convertases, which is an essential step for its activation. The importance of the insulin receptor in liver is well established, but its role in pancreatic β cells is still controversial. In this study, we investigated the cleavage of the IR by the proprotein convertase FURIN in β cells and hepatocytes, and the contribution of the IR in pancreatic β cells and liver to glucose homeostasis. β-cell-specific Furin knockout (βFurKO) mice were glucose intolerant, but liver-specific Furin knockout (LFurKO) mice were normoglycemic. Processing of the IR was blocked in βFurKO cells, but unaffected in LFurKO mice. Most strikingly, glucose homeostasis in β-cell-specific IR knockout (βIRKO) mice was normal in younger mice (up to 20 weeks), and only mildly affected in older mice (24 weeks). In conclusion, FURIN cleaves the IR non-redundantly in β cells, but redundantly in liver. Furthermore, we demonstrated that the IR in β cells plays a limited role in glucose homeostasis

Nuclear Localization of the Autism Candidate Gene Neurobeachin and Functional Interaction with the NOTCH1 Intracellular Domain Indicate a Role in Regulating Transcription

Neurobeachin (NBEA) is an autism spectrum disorders (ASD) candidate gene. NBEA deficiency affects regulated secretion, receptor trafficking, synaptic architecture and protein kinase A (PKA)-mediated phosphorylation. NBEA is a large multidomain scaffolding protein. From N- to C-terminus, NBEA has a concanavalin A-like lectin domain flanked by armadillo repeats (ACA), an A-kinase anchoring protein domain that can bind to PKA, a domain of unknown function (DUF1088) and a BEACH domain, preceded by a pleckstrin homology-like domain and followed by WD40 repeats (PBW). Although most of these domains mediate protein-protein interactions, no interaction screen has yet been performed.status: publishe