Charcot-Marie-Tooth disease type 2D is a hereditary axonal and glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. Here, we report a novel GARS-associated mouse neuropathy model using an adenoviral vector system that contains a neuronal-specific promoter. In this model, we found that wild-type GARS is distributed to peripheral axons, dorsal root ganglion (DRG) cell bodies, central axon terminals, and motor neuron cell bodies. In contrast, GARS containing a G240R mutation was localized in DRG and motor neuron cell bodies, but not axonal regions, in vivo. Thus, our data suggest that the disease-causing G240R mutation may result in a distribution defect of GARS in peripheral nerves in vivo. Furthermore, a distributional defect may be associated with axonal degradation in GARS-associated neuropathies.

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Charcot-Marie-Tooth disease (CMT) is the most common inherited motor and sensory neuropathy. Previous studies have found that, according to CMT patients, neuropathic pain is an occasional symptom of CMT. However, neuropathic pain is not considered to be a significant symptom associated with CMT and, as a result, no studies have investigated the pathophysiology underlying neuropathic pain in this disorder. Thus, the first animal model of neuropathic pain was developed by our laboratory using an adenovirus vector system to study neuropathic pain in CMT. To this end, glycyl-tRNA synthetase (GARS) fusion proteins with a FLAG-tag (wild type [WT], L129P and G240R mutants) were expressed in spinal cord and dorsal root ganglion (DRG) neurons using adenovirus vectors. It is known that GARS mutants induce GARS axonopathies, including CMT type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V). Additionally, the morphological phenotypes of neuropathic pain in this animal model of GARS-induced pain were assessed using several possible markers of pain (Iba1, pERK1/2) or a marker of injured neurons (ATF3). These results suggest that this animal model of CMT using an adenovirus may provide information regarding CMT as well as a useful strategy for the treatment of neuropathic pain.Graphical Abstract

Distal spinal muscular atrophy type V (dSMA-V) is a hereditary neurodegenerative axonal neuropathy and a glycyl-tRNA synthetase (GARS)-associated neuropathy that is caused by a mutation in GARS. Herein, we report a new GARSassociated neuropathy mouse model using an adenovirus vector system equipped with a neuron-specific promoter. In this model, we showed an increased number of activated microglia around the L129P mutant-expressing motor neuron cell bodies and the increased nerve injury signal in L129P mutant-expressing motor neuron cell bodies. In addition, we found that the mouse model exhibited impaired motor function caused by the L129P mutant. We propose that the neuroinflammation may be associated with motor neuron impairment in GARS-associated neuropathies.

Purpose: Although laparoscopic surgery is widely accepted in the treatment of colorectal cancer, conversion to open surgery is associated with the rate of unfavorable outcomes. The aim of this study was to determine the factors associated with open conversion from laparoscopic surgery for colorectal cancer. Methods: A total of 3,002 patients who underwent laparoscopic colectomy as an initial plan for the treatment of colorectal cancer located from the sigmoid colon to the rectum were retrospectively evaluated between January 2009 and December 2018 at Samsung Medical Center in Korea. Risk factors significantly associated with open conversion were determined using univariate and multivariate regression models. Results: Among the 3,002 patients, open conversion was performed in 120 patients (4%). Age >60 years (adjusted odds ratio [AOR], 2.370), preoperative bowel obstruction (AOR, 2.348), clinical T4 stage (AOR, 2.201), and serum carcinoembryonic antigen level >5 ng/mL (AOR, 2.289) were significantly associated with open conversion. Moreover, mucinous carcinoma was a significantly more frequent histopathologic type than adenocarcinoma (10.0% vs. 3.2%, P<0.001) in the open conversion group with an AOR of 2.549 (confidence interval, 1.259-5.159; P=0.009). Conclusion: The present study presented a novel finding, i.e. mucinous carcinoma as the histopathologic type could be an independent predictive factor for conversion from laparoscopic colectomy to open surgery. Identifying patients with mucinous carcinoma will help stratify the risk of open conversion preoperatively.