Typical bulbar ALS can be linked to GARS mutation.

Background: Amyotrophic lateral sclerosis is the most frequent motor neuron disorders (MND) in adults. The role of genetic factors is worldwide accepted, and currently, more than 30 genes have been linked to this disease. Genetics was also the matter of numerous studies in distal hereditary motor neuropathies (dHMN). GARS is classically linked to a predominant dHMN and, until now, no mutation has been described in GARS in other MND. Case Report: We report the case of a 70-year-old woman who developed a classical bulbar ALS phenotype. Owing to his familial history of ALS, a genetic screening was performed excluding the main genes linked to ALS and revealing a heterozygous missense mutation in GARS gene with a high probability of pathogenicity. Conclusion: This first description of mutation in GARS in ALS, extends once more the genetic overlap between ALS and other MND.

Causative Genes in Amyotrophic Lateral Sclerosis and Protein Degradation Pathways: a Link to Neurodegeneration.

Amyotrophic lateral sclerosis (ALS) is a disease caused by the degeneration of motor neurons (MNs) leading to progressive muscle weakness and atrophy. Several molecular pathways have been implicated, such as glutamate-mediated excitotoxicity, defects in cytoskeletal dynamics and axonal transport, disruption of RNA metabolism, and impairments in proteostasis. ALS is associated with protein accumulation in the cytoplasm of cells undergoing neurodegeneration, which is a hallmark of the disease. In this review, we focus on mechanisms of proteostasis, particularly protein degradation, and discuss how they are related to the genetics of ALS. Indeed, the genetic bases of the disease with the implication of more than 30 genes associated with familial ALS to date, together with the important increase in understanding of endoplasmic reticulum (ER) stress, proteasomal degradation, and autophagy, allow researchers to better understand the mechanisms underlying the selective death of motor neurons in ALS. It is clear that defects in proteostasis are involved in this type of cellular degeneration, but whether or not these mechanisms are primary causes or merely consequential remains to be clearly demonstrated. Novel cellular and animal models allowing chronic expression of mutant proteins, for example, are required. Further studies linking genetic discoveries in ALS to mechanisms of protein clearance will certainly be crucial in order to accelerate translational and clinical research towards new therapeutic targets and strategies.

The MAP3K ZAK, a novel modulator of ERK-dependent migration, is upregulated in colorectal cancer.

Often described as a mediator of cell cycle arrest or as a pro-apoptotic factor in stressful conditions, the MAP3K ZAK (Sterile alpha motif and leucine zipper-containing kinase) has also been proven to positively regulate epidermal growth factor receptor (EGFR) and WNT signaling pathways, cancer cell proliferation and cellular neoplastic transformation. Here, we show that both isoforms of ZAK, ZAK-α and ZAK-ß are key factors in cancer cell migration. While ZAK depletion reduced cell motility of HeLa and HCT116 cells, its overexpression triggered the activation of all three mitogen-activated protein kinases (MAPKs), extracellular signal-regulated kinase (ERK), c-JUN N-terminal kinase (JNK) and p38, as well as an increase in cell motion. On the contrary, the kinase-dead mutants, ZAK-α K45M and ZAK-ß K45M, were not able to provoke such events, and instead exerted a dominant-negative effect on MAPK activation and cell migration. Pharmacological inhibition of ZAK by nilotinib, preventing ZAK-autophosphorylation and thereby auto-activation, led to the same results. Activated by epidermal growth factor (EGF), we further showed that ZAK constitutes an essential element of the EGF/ERK-dependent cell migration pathway. Using public transcriptomic databases and tissue microarrays, we finally established that, as strong factors of the EGFR signaling pathway, ZAK-α and/or ZAK-ß transcripts and protein(s) are frequently upregulated in colorectal adenoma and carcinoma patients. Notably, gene set enrichment analysis disclosed a significant correlation between ZAK+ colorectal premalignant lesions and gene sets belonging to the MAPK/ERK and motility-related signaling pathways of the reactome database, strongly suggesting that ZAK induces such pro-tumoral reaction cascades in human cancers.

Response to chemotherapy is not related to chromosome instability in synovial sarcoma.

BACKGROUND: Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy. PATIENTS AND METHODS: The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen. RESULTS: Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity. CONCLUSION: The absence of significant association between response to chemotherapy and genomic complexity suggests that the prognostic value of chromosome instability in SS is independent of response to chemotherapy; mechanisms leading to metastatic relapse of SS are intrinsic to the biology of the tumor and current cytotoxic drugs are only poorly efficient to prevent it.

[Arthroscopic treatment of lateral epicondylitis: a prospective study on 14 cases]. / Traitement arthroscopique de l'épicondylite latérale : étude prospective à propos de 14 cas.

Lateral epicondylitis of the elbow is a relatively common pathology and would involve 1-3% of the overall population. Lack of consensus on surgical techniques reflects the difficulty of understanding and treating this disease. Our prospective study reports the results of its arthroscopic treatment on 14 patients operated on between 2009 and 2012. The mean follow-up was 7.15 months. All patients underwent a well conducted medical treatment for an average of 32.5 months. The operation was carried out under regional anesthesia in an outpatient. The technique included a time of joint exploration, joint capsulotomy and a transverse division of the pathological tendon of extensor carpi radialis brevis (ECRB) and extensor digitorum communis (EDC). The value on the visual analogic scale (VAS) at rest and during exercise increased from 2.85 to 0.43 and from 7.71 to 2.43, respectively, then remained stable over time. Professional activity was resumed on average at 9.1 weeks. Neither intraoperative nor postoperative complications were found. No laxity was observed. The Mayo Clinic and DASH scores were significantly improved from 52.14 to 92.5 and from 54.11 to 9.7, respectively. Overall, we observed 11 very good and three good results. Although our prospective series has a few patients and limited follow-up, our results are better or similar than those reported in the literature on pain relief and functional recovery. In contrast, the average recovery of professional activity was longer. Elbow arthroscopy, less invasive than open procedures, and allowing further joint exploration, seems an excellent alternative technique in this indication.

[Treatment of rheumatoid swan neck deformity by tenodesis of proximal interphalangeal joint with a half flexor digitorum superficialis tendon. About 23 fingers at 61 months follow-up]. / Traitement des déformations des doigts longs en col-de-cygne dans les affections rhumatismales par ténodèse de l'articulation interphalangienne proximale à l'aide d'un hémi-tendon fléchisseur superficiel. À propos de 23 doigts à 61 mois de recul.

OBJECTIVES: Surgical treatment of finger swan neck deformities is versatile. We aimed to assess the outcome of PIP tenodesis on unfixed deformities, in patients suffering from rheumatoid arthritis. METHODS: Twenty-three PIP tenodeses were performed on eight patients, using half of a superficialis flexor digitorum tendon sutured to A2 pulley through a volar approach. Postoperative splinting, in 20° of PIP flexion, was maintained for 4 weeks. The patients were assessed retrospectively, at a mean period of 61 months. RESULTS: The PIP flexion gained 26°. On the other hand, a 4°-flexion contraction was induced. The mean postoperative flexion reached 65°. The PIP hyperextension was corrected by 33°. In one same patient, the correction was insufficient for the four fingers. The DIP lack of extension was totally corrected in 70% of the cases and partially in 30%. Each patient had functional improvement. Nineteen good and excellent, and four fair results were reported. No major complication was observed. CONCLUSION: This tenodesis seems to be reliable and to give good long-term results. It is our intervention of choice for rheumatoid flexible swan-neck deformity.