S.Y. Kim

The JAK2 V617F mutation in de novo acute myelogenous leukemias

A missense somatic mutation in JAK2 gene (JAK2 V617F) has recently been reported in chronic myeloproliferative disorders, including polycythemia vera, essential thrombocythemia and myelofibrosis with myeloid metaplasia, strongly suggesting its role in the pathogenesis of myeloid disorders. As activation of JAK2 signaling is occurred in other malignancies as well, we have analysed 558 tissues from common human cancers, including colon, breast and lung carcinomas, and 143 acute adulthood leukemias by polymerase chain reaction – single strand conformation polymorphism analysis. We found three JAK2 mutations in the 113 acute myelogenous leukemias (AMLs) (2.7%), but none in other cancers. The mutations consisted of two V617F mutations and one K607N mutation. None of the AML patients with the JAK2 V617F mutation had a history of previous hematologic disorders. This is the first report on the JAK2 gene mutation in AML, and the data indicated that the JAK2 gene mutation may not only contribute to the development of chronic myeloid disorders, but also to some AMLs.

Lymph node ratio is an independent prognostic factor in patients with rectal cancer treated with preoperative chemoradiotherapy and curative resection

PURPOSEnTo evaluate the prognostic effect of lymph node ratio (LNR) in patients with locally advanced rectal cancer who were treated with curative resection after preoperative chemoradiotherapy (CRT).nnnMETHODSnBetween October 2001 and December 2007, 519 patients who had undergone curative resection of primary rectal cancer after preoperative CRT were enrolled. Of these, 154 patients were positive for lymph node (LN) metastasis and were divided into three groups according to the LNR (≤ 0.15 [n=80], 0.16-0.3 [n=44], >0.3 [n=30]) to evaluate the prognostic effect on overall survival (OS) and disease-free survival (DFS).nnnRESULTSnLNR (≤ 0.15, 0.16-0.3, and >0.3) was significantly associated with 5-year OS (90.3%, 75.1%, and 45.1%; p<0.001) and DFS (66.7%, 55.8%, and 21.9%; p<0.001) rates. In a multivariate analysis, LNR (≤ 0.15, 0.16-0.3, and >0.3) was a significant independent prognostic factor for OS (hazard ratios [HRs], 1, 3.609, and 8.197; p<0.001) and DFS (HRs, 1, 1.699, and 3.960; p<0.001). LNR had a prognostic impact on OS and DFS in patients with <12 harvested LNs, as well as in those with ≥ 12 harvested LNs (p<0.05).nnnCONCLUSIONnLNR was a significant independent prognostic predictor for OS and DFS in patients with locally advanced rectal cancer who were treated with curative resection after preoperative CRT.

The value of preoperative 18F‐FDG PET/CT for the assessing contralateral neck in head and neck cancer patients with unilateral node metastasis (N1‐3)

The purpose of this study was to determine whether preoperative 18F‐FDG PET/CT is useful in assessing contralateral lymph node metastasis in the neck.

Endoscopic resection of haemangiomas in the sinonasal cavity

OBJECTIVESnHaemangiomas do not develop as commonly in the sinonasal cavity, compared with other head and neck sites. The clinical characteristics of sinonasal cavity haemangiomas and the results for endoscopic resection have been addressed in the literature only briefly. Thus, this study aimed to evaluate these points.nnnMATERIALS AND METHODSnA retrospective chart review was undertaken of 22 patients who had undergone endoscopic excision of sinonasal cavity haemangiomas, in order to define clinical characteristics and tumour control rates.nnnRESULTS AND ANALYSISnThe most common presenting symptom was epistaxis. The most prevalent site was the inferior turbinate (45.5 per cent), followed by the maxillary sinus (18.2 per cent). No recurrence was observed in any patient.nnnCONCLUSIONnAlthough past studies have described external approach sinonasal surgery as the mainstay of treatment, our results imply that endoscopic excision of sinonasal haemangiomas yields excellent outcomes in terms of tumour control and safety.

Mandibular second molar root canal morphology and variants in a Korean subpopulation.

AIMnTo determine the root canal anatomy of mandibular second molars in a Korean population by analysing cone-beam computed tomography (CBCT) images.nnnMETHODOLOGYnThe CBCT images of 960 subjects were examined. The number and configuration of roots and canals were categorized according to Vertuccis and modified Meltons classifications.nnnRESULTSnOf the 1920 mandibular second molars, 41% had one root, 58% had two roots, and <1% had three roots. In the mesial roots of two-rooted molars, Vertuccis Type lV (44%) and Type II (37.75%) canals were most frequent. The prevalence of C-shaped roots was 40%, and C-shaped roots in combination with additional mesiolingual or distolingual roots were found in <1% of molars. Interestingly, O-shaped canals were detected in 0.10% of the molars. Of the C-shaped roots, the most common configuration types were Meltons Type I (66%) in the coronal region and Meltons Type III (56%) in the apical region. The prevalence of C-shaped roots was higher in females (47%) than in males (32%) (P < 0.001) and did not differ with age (P = 0.497) or tooth position (P = 0.514). Most (82%) C-shaped canals were bilateral (P < 0.001).nnnCONCLUSIONSnA high prevalence of C-shaped canals and a low incidence of three-rooted molars were observed in the mandibular second molars of the Korean subpopulation studied.

Expression of exogenous LIN28 contributes to proliferation and survival of mouse primary cortical neurons in vitro

LIN28, an RNA-binding protein, is known to be involved in the regulation of many cellular processes, such as embryonic stem cell proliferation, cell fate succession, developmental timing, and oncogenesis. In this study, we investigated the effect of constitutively expressing exogenous LIN28 on neuronal cell proliferation and viability in vitro. Plasmids containing LIN28-green fluorescent protein (GFP) or GFP were introduced into the embryonic mouse brains at E14.5 by in utero electroporation. Two days after electroporation, embryonic cortices were harvested and cultured. It was found that transfected cells stably overexpressed LIN28 in vitro. Viability curve from live cell imaging showed that the number of GFP-expressing cells decreased over time in line with naive primary cortical neurons. In contrast, the number of LIN28-GFP-overexpressing neurons initially increased and remained high at later time-points in culture than GFP-expressing cells. Double immunofluorescence showed that at an early time in culture, the number of Ki-67/GFP double-positive cells was higher in the LIN28-GFP group than that of controls. Moreover, there were significantly lower numbers of condensed nuclei/GFP- and cleaved caspase-3/GFP-positive cells in the LIN28-GFP groups compared to control GFP. Furthermore, it was confirmed that the LIN28-GFP-expressing cells at days in vitro (DIV)13 were neuronal nuclei (NeuN)-positive mature neurons. Finally, the expression of insulin-like growth factor 2 (IGF-2) was induced in LIN28-expressing primary cortical neurons, which was not detected in controls. Taken together, our results indicate that the expression of exogenous LIN28 can promote the proliferation of neural progenitor cells and exert prosurvival effect on primary cortical neurons by inhibiting caspase-dependent apoptosis, possibly via upregulation of IGF-2.

Ischemic tolerance is associated with VEGF-C and VEGFR-3 signaling in the mouse hippocampus.

The functions of vascular endothelial growth factor C (VEGF-C) and the VEGF receptor 3 (VEGFR-3) in the nervous system are not well known. In this study, we examined the role of VEGF-C and VEGFR-3 in ischemic preconditioning (IPC)-induced tolerance in the mouse hippocampus. Adult male C57BL/6 mice were subjected to either severe ischemia (SI) induced by 40 min of bilateral common carotid artery occlusion (BCCAO) with or without IPC (5-min BCCAO) or IPC only. Cerebral blood flow was measured during ischemic periods using laser Doppler flowmetry. Neuronal damage was assessed histologically, and VEGF-C and VEGFR-3 expression levels were assessed through immunostaining. Fluoro-Jade B-labeled cells were abundant in the CA1 area 7 days after SI without IPC (sham+SI group), whereas cells were rarely labeled in mice subjected to IPC followed by SI (IPC+SI group). Similarly, the number of neuronal nuclei (NeuN)-positive cells in the CA1 area was significantly lower in the sham+SI group than in the IPC+SI group. Interestingly, we found that sublethal IPC treatment induced prominent VEGF-C expression in the CA1 pyramidal neurons and VEGFR-3 expression in the stratum radiatum and stratum lacunosum moleculare after 3 days of reperfusion that were sustained for 7 days. Moreover, VEGF-C immunoreactivity was also markedly increased, whereas VEGFR-3 expression was sustained in tolerance-acquired CA1 neurons after SI. Application of a VEGFR-3 inhibitor, SAR131675, abolished the IPC-induced neuroprotection in a dose-dependent manner in the mouse hippocampus. These results suggest that VEGF-C/VEGFR-3 signaling is associated with IPC-induced hippocampal tolerance to lethal ischemia.

A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer

The Kelch-like ECH-associated protein 1 (KEAP1)–nuclear factor E2-related factor 2 (NRF2)pathway has a central role in cellular antioxidant defense. NRF2 activation due to KEAP1 or NRF2 mutations occurs frequently in many cancers, suggesting that NRF2 inhibition could be a promising therapeutic strategy. However, no potent NRF2 inhibitors are clinically available to date. To develop potent NRF2 inhibitors for therapeutic purpose, we screened ~4000 clinical compounds and determined clobetasol propionate (CP) as the most potent NRF2 inhibitor. Mechanistically, CP prevented nuclear accumulation and promoted β-TrCP-dependent degradation of NRF2 in a glucocorticoid receptor- and a glycogen synthase kinase 3 (GSK3)-dependent manner. As a result, CP induced oxidative stress and strongly suppressed the anchorage-independent growth of tumors with KEAP1 mutation, but not with the wild-type KEAP1. Further, CP alone or in combination with rapamycin strongly inhibited the in vitro and in vivo growth of tumors harboring mutations in KEAP1 or both KEAP1 and LKB1 that are frequently observed in lung cancer. Thus, CP could be a repurposed therapeutic agent for cancers with high NRF2 activity. We also proposed that the use CP and rapamycin in combination could be a potential therapeutic strategy for tumors harboring both KEAP1 and LKB1 mutations.

Association between dental pain and depression in Korean adults using the Korean National Health and Nutrition Examination Survey

The purpose of this study was to evaluate the relationships between the prevalence of depression and dental pain using a well characterised, nationally representative, population-based study. This study analysed data from the 2012 Korea National Health and Nutrition Examination Survey (n = 4886). Oral health status was assessed using the oral health questionnaire, and oral examination was performed by trained dentists. Depression was defined as the participant having been diagnosed as depression during the previous year. Logistic regression was applied to estimate adjusted odds ratios (AOR) and 95% confidence intervals (CI), controlling for a range of covariates. Results demonstrated that participants included in root canal treatment is necessary showed higher prevalence of self-reported dental pain; in particular, participants with depression presented more dental pain than those without depression. After adjusting for sociodemographic factors, self-reported dental pain increased in participants with depression. The AOR (95% CI) for having self-reported dental pain was 1·58 (1·08-2·33) in dentists diagnosis of no dental pain/depression group, 1·62 (1·32-1·98) in dentists diagnosis of dental pain/no depression group and 2·84 (1·10-7·37) in dentists diagnosis of dental pain/depression group. It was concluded that depression was associated with dental pain after adjustment for potential confounders in Korean adults. Thus, dentists should consider the possible presence of psychopathology when treating patients with dental pain.

Chronic Rejection in a Small Bowel Transplant with Successful Revision of the Allograft by Segmental Resection: Case Report

An 8-year-old girl was admitted for severe electrolyte imbalance and for hyponatremic seizure. In July 2005, at 3 years of age, she underwent isolated small-bowel transplantation of 100 cm ileum from her father. Her own bowel was only 50 cm of proximal jejunum which had been directly connected to the anus due to extended total aganglionosis. The graft was placed into the middle of her remaining bowel, using the splenic artery and vein as feeding vessels with saving of the spleen. Daclizumab induction and tacrolimus monotherapy were applied for immunosuppression. Two acute cellular rejection episodes, E on day 10 and 4 years after transplantation, were successfully treated with OKT-3 and recombinant antithymocyte globulin, respectively. However, because of intermittent bowel dysfunction, she was hospitalized several times for hydration and metabolic care. On admission, her abdomen was moderately distended, and a simple abdominal film showed a fixed dilated loop. Colonoscopy could not pass the narrowed lumen, with stiffness at the anastomosis between the graft and the distal bowel. Endoscopic biopsy at the entrance to the stricture showed a nonspecific inflammatory reaction with fibrosis. Similar findings on a gastrograffin enema suggested chronic rejection (CR). On laparotomy, an irregularly narrowed fibrotic loop was noticed at the distal part of the graft, proximal to the anastomosis. We performed a 20-cm segmental resection with an end-to-end anastomosis. Histopathologic findings showed CR with fibrosis and hyalinization of the entire bowel wall and vessel walls with mild cellular infiltrations. She recovered in 10 days. The graft may have been saved, but intermittent requirement of hydration over the following months suggested progressive graft dysfunction. A case of segmental involvement of CR with subsequent successful graft salvage by partial resection is rare in the literature.