Identification of Small GTPases That Phosphorylate IRF3 through TBK1 Activation Using an Active Mutant Library Screen

Interferon regulatory factor 3 (IRF3) integrates both immunological and non-immunological inputs to control cell survival and death. Small GTPases are versatile functional switches that lie on the very upstream in signal transduction pathways, of which duration of activation is very transient. The large number of homologous proteins and the requirement for site-directed mutagenesis have hindered attempts to investigate the link between small GTPases and IRF3. Here, we constructed a constitutively active mutant expression library for small GTPase expression using Gibson assembly cloning. Small-scale screening identified multiple GTPases capable of promoting IRF3 phosphorylation. Intriguingly, 27 of 152 GTPases, including ARF1, RHEB, RHEBL1, and RAN, were found to increase IRF3 phosphorylation. Unbiased screening enabled us to investigate the sequence-activity relationship between the GTPases and IRF3. We found that the regulation of IRF3 by small GTPases was dependent on TBK1. Our work reveals the significant contribution of GTPases in IRF3 signaling and the potential role of IRF3 in GTPase function, providing a novel therapeutic approach against diseases with GTPase overexpression or active mutations, such as cancer.

A Rare Case of Synchronous Pleomorphic Adenoma and Lobular Capillary Hemangioma of Nasal Septum / 대한이비인후과학회지

Pleomorphic adenoma is the most common benign tumor of major salivary gland, but it rarely originates from the nasal cavities. Meanwhile, the lobular capillary hemangioma, known as pyogenic granuloma, is also a benign tumor of unclear etiology unusually found in the sinonasal area. Little is known about cases where pleomorphic adenoma and lobular capillary hemangioma originate simultaneously in the nasal cavity. Here, we report a case of 63-year-old female with pleomorphic adenoma and lobular capillary hemangioma simultaneously arising from the nasal septum. After endoscopic tumor resection, there was no recurrence or complication during the follow-up.

Effects of a low-FODMAP enteral formula on diarrhea on patients in the intensive care unit

BACKGROUND/OBJECTIVES@#A dietary restriction on the intake of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) has been reported to be effective in the treatment of gastrointestinal (GI) tract complications. Enteral nutrition (EN) is widely used for patients who cannot obtain their nutritional requirements orally, but many studies have reported EN complications, especially diarrhea, in up to 50% of patients. @*SUBJECTS/METHODS@#We performed a single-center, non-randomized, controlled trial to determine the effects of a low-FODMAP enteral formula on GI complications in patients in intensive care units (ICUs). Patients in the ICU who needed EN (n = 66) were alternately assigned to the low-FODMAP group (n = 33) or the high-FODMAP group (n = 33). @*RESULTS@#Anthropometric and biochemical parameters were measured, and stool assessment was performed using King's Stool Chart. We excluded patients who received laxatives, GI motility agents, proton pump inhibitors, antifungal agents, and antibiotics other than β-lactams. There were no differences in GI symptoms during 7 days of intervention, including bowel sound, abdominal distension, and vomiting between the 2 groups. However, diarrhea was more frequent in the high-FODMAP group (7/33 patients) than the lowFODMAP group (1/33 patients) (P = 0.044). @*CONCLUSIONS@#Our results suggest that a low-FODMAP enteral formula may be a practical therapeutic approach for patients who exhibit enteral formula complications. Our study warrants further randomized clinical trials and multicenter trials.

Malignant rhabdoid tumor of the kidney in an adult with loss of INI1 expression and mutation in the SMARCB1 gene

A 57-year-old man with left flank pain was referred to our institute. Computed tomography scans revealed two enhancing masses in the left kidney. The clinical diagnosis was renal cell carcinoma (RCC). He underwent a radical nephrectomy with an adrenalectomy. Two well-circumscribed solid masses in the hilum and the lower pole (4.5 × 3.5 cm and 7.0 × 4.1 cm) were present. Poorly cohesive uniform round to polygonal epithelioid cells making solid sheets accounted for most of the tumor area. The initial diagnosis was RCC, undifferentiated with rhabdoid features. As the tumor showed loss of INI1 expression and a mutation in the SMARCB1 gene on chromosome 22, the revised diagnosis was a malignant rhabdoid tumor (MRT) of the kidney. To date, only a few cases of renal MRT in adults have been reported. To the best of our knowledge, this is the first report of MRT in the native kidney of an adult demonstrating a SMARCB1 gene mutation, a hallmark of MRT.

Visual Field Defect after Taking Atorvastatin/Ezetimibe, a Case Study

Atorvastatin is one of the most widely prescribed medications for dyslipidemia treatment. In Korea, post combined therapy with ezetimibe, a 73-year-old woman was reported by a community pharmacy to have experienced visual field defect, which recovered after drug discontinuation. She had never experienced this symptom before, and several studies have reported an association between use of statins and visual disorders such as blurred vision, diplopia, and cataract. Blockage of cholesterol accumulation, oxidative stress, or myopathy is expected to be a cause of this symptom. Naranjo scale, Korean causality assessment algorithm (Ver.2), and World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria were the three tools used to determine causality between the visual disorder and atorvastatin. The results represent ‘probable’, ‘certain’, and ‘probable/likely’ causality, respectively. Our results, in combination with a review of literature, indicate that ocular adverse effects are highly likely related to atorvastatin.

Evaluation of Antiemetic Therapy for Breakthrough Nausea and Vomiting in Patients with Hematopoietic Stem Cell Transplantation

BACKGROUND: The patients receiving hematopoietic stem cell transplantation (HSCT) are known to have a high incidence of breakthrough nausea and vomiting due to the conditioning regimen. The purpose of this study was to evaluate the adequacy of antiemetic therapy for breakthrough nausea and vomiting in patients receiving HSCT and to propose an effective treatment regimen. METHODS: We retrospectively reviewed the electronic medical records of 109 adult patients. The collected data were used to identify (1) antiemetic and dosing regimens prescribed for controlling breakthrough nausea and vomiting, (2) the rate of patients who developed breakthrough nausea and vomiting, and (3) the percent of antiemetics prescribed on the day of symptom onset. Based on the National Comprehensive Cancer Network guideline, we assessed the suitability of antiemetics for breakthrough nausea and vomiting, and prescription timing. RESULTS: All patients were prescribed pro re nata antiemetics. About 40.0%, 41.4%, and 18.6% of patients were using one, two, and three or more additional drugs for breakthrough nausea and vomiting, respectively. The most frequently administered drugs were intravenous metoclopramide (43.8%) and granisetron patch (36.2%). Breakthrough nausea and vomiting occurred in 87 patients (79.1%) and they developed symptoms 320 cases. About 220 cases (68.8%) were treated with additional antiemetics on the day of symptom onset and the rate of symptom resolution was only 10.3% (9 patients). CONCLUSION: The breakthrough nausea and vomiting in patients receiving HSCT occurred very frequently and was hard to control, thus requiring more rapid and aggressive treatments.

A Pyloric Gland-Phenotype Ovarian Mucinous Tumor Resembling Lobular Endocervical Glandular Hyperplasia in a Patient with Peutz-Jeghers Syndrome

We describe an ovarian mucinous neoplasm that histologically resembles lobular endocervical glandular hyperplasia (LEGH) containing pyloric gland type mucin in a patient with Peutz-Jeghers syndrome (PJS). Although ovarian mucinous tumors rarely occur in PJS patients, their pyloric gland phenotype has not been clearly determined. The histopathologic features of the ovarian mucinous tumor were reminiscent of LEGH. The cytoplasmic mucin was stained with periodic acid-Schiff reaction after diastase treatment but was negative for Alcian blue pH 2.5, suggesting the presence of neutral mucin. Immunohistochemically, the epithelium expressed various gastric markers, including MUC6, HIK1083, and carbonic anhydrase-IX. Multiple ligation-dependent probe amplification detected a germline heterozygous deletion mutation at exons 1–7 of the STK11 gene (c.1-?_920+?del) in peripheral blood leukocytes and mosaic loss of heterozygosity in ovarian tumor tissue. Considering that LEGH and/or gastric-type cervical adenocarcinoma can be found in patients with PJS carrying germline and/or somatic STK11 mutations, our case indicates that STK11 mutations have an important role in the proliferation of pyloric-phenotype mucinous epithelium at various anatomical locations.

Diagnostic Significance of Cellular Neuroglial Tissue in Ovarian Immature Teratoma

BACKGROUND: Immature teratoma (IT) is a tumor containing immature neuroectodermal tissue, primarily in the form of neuroepithelial tubules. However, the diagnosis of tumors containing only cellular neuroglial tissue (CNT) without distinct neuroepithelial tubules is often difficult, since the histological characteristics of immature neuroectodermal tissues remain unclear. Here, we examined the significance of CNT and tried to define immature neuroectodermal tissues by comparing the histological features of neuroglial tissues between mature teratoma (MT) and IT. METHODS: The histological features of neuroglial tissue, including the cellularity, border between the neuroglial and adjacent tissues, cellular composition, mitotic index, Ki-67 proliferation rate, presence or absence of tissue necrosis, vascularity, and endothelial hyperplasia, were compared between 91 MT and 35 IT cases. RESULTS: CNTs with a cellularity grade of ≥ 2 were observed in 96% of IT cases and 4% of MT cases (p < .001); however, CNT with a cellularity grade of 3 in MT cases was confined to the histologically distinct granular layer of mature cerebellar tissue. Moreover, CNT in IT exhibited significantly higher rates of Ki-67 proliferation, mitoses, and necrosis than those in MT (p < .001). Furthermore, an infiltrative border of neuroglial tissue and glomeruloid endothelial hyperplasia were significantly more frequent in IT cases than in MT cases (p < .001). CONCLUSIONS: Our results suggest that if CNT with a cellularity grade of ≥ 2 is not a component of cerebellar tissue, such cases should be diagnosed as IT containing immature neuroectodermal tissue, particularly if they exhibit an infiltrative border, mitoses, necrosis, and increased Ki-67 proliferation.

Pancreatic Lymphoma Masquerading as Autoimmune Pancreatitis / 대한췌담도학회지

Accurate diagnosis of autoimmune pancreatitis (AIP) is important to clinicians since it is difficult to differentiate AIP from pancreatic malignancies. Furthermore, unlike pancreatic malignancies, AIP has dramatic response to steroids. A 61-years-old man presented with acute pancreatitis. Imaging studies showed two separate pancreatic masses, irregular narrowing of main pancreatic duct, and a renal mass that highly suggested AIP. Endoscopic ultrasound-guided core needle biopsy of the pancreatic masses and ultrasound-guided biopsy of the renal mass revealed peripheral T-cell lymphoma. The patient is currently undergoing chemotherapy. We present a case of pancreatic lymphoma masquerading as AIP with literature review.