Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

Purpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and Methods In this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. Results AZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. Conclusion Taken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.

Tiul1 and TGIF are Involved in Downregulation of TGFβ1-induced IgA Isotype Expression

TGF-β1 is well known to induce Ig germ-line α (GLα) transcription and subsequent IgA isotype class switching recombination (CSR). Homeodomain protein TG-interacting factor (TGIF) and E3-ubiquitin ligases TGIF interacting ubiquitin ligase 1 (Tiul1) are implicated in the negative regulation of TGF-β signaling. In the present study, we investigated the roles of Tiul1 and TGIF in TGFβ1-induced IgA CSR. We found that over-expression of Tiul1 decreased TGFβ1-induced GLα promoter activity and strengthened the inhibitory effect of Smad7 on the promoter activity. Likewise, overexpression of TGIF also diminished GLα promoter activity and further strengthened the inhibitory effect of Tiul1, suggesting that Tiul1 and TGIF can down-regulate TGFβ1-induced GLα expression. In parallel, overexpression of Tiul1 decreased the expression of endogenous IgA CSR-predicitive transcripts (GLTα, PSTα, and CTα) and TGFβ1-induced IgA secretion, but not GLTγ3 and IgG3 secretion. Here, over-expressed TGIF further strengthened the inhibitory effect of Tiul1. These results suggest that Tiul1 and TGIF act as negatively regulators in TGFβ1-induced IgA isotype expression

Differentiation of Recently Infarcted Myocardium from Chronic Myocardial Scar: The Value of Contrast-Enhanced SSFP-Based Cine MR Imaging

The purpose of this study is to demonstrate whether the signal intensity (SI) of myocardial infarction (MI) on contrast enhanced (CE)-cine MRI is useful for differentiating recently infarcted myocardium from chronic scar. This study included 24 patients with acute MI (36-84 years, mean age: 57) and 19 patients with chronic MI (44-80 years, mean age: 64). The diagnosis of acute MI was based on the presence of typical symptoms, i.e. elevation of the cardiac enzymes and the absence of any remote infarction history. The diagnosis of chronic MI was based on a history of MI or coronary artery disease of more than one month duration and on the absence of any recent MI within the previous six months. Retrospectively, the ECG-gated breath-hold cine imaging was performed in the short axis plane using a segmented, balanced, turbo-field, echo-pulse sequence two minutes after the administration of Gd-DTPA at a dose of 0.2 mmol/kg body weight. Delayed contrast-enhanced MRI (DCE MRI) in the same plane was performed 10 to 15 minutes after contrast administration, and this was served as the gold standard of reference. The SI of the infarcted myocardium on the CE-cine MRI was compared with that of the normal myocardium on the same image. The area of abnormal SI on the CE-cine MRI was compared with the area of hyperenhancement on the DCE MRI. The area of high SI on the CE-cine MRI was detected in 23 of 24 patients with acute MI (10 with homogenous high SI, 13 high SI with subendocardial low SI, and one with iso SI). The area of high SI on the CE-cine MRI was larger than that seen on the DCE MRI (p < 0.05). In contrast, the areas of chronic MI were seen as iso-SI with thin subendocardial low SI on the CE-cine MR in all the chronic MI patients. The presence of high SI on both the CE-cine MRI and the DCE MRI is more sensitive (95.8%) for determining the age of a MI than the presence of myocardial thinning (66.7%). This study showed the different SI patterns between recently infarcted myocardium and chronic scar on the CE-cine MRI. CE-cine MRI is thought to be quite useful for determining the age of myocardial infarction, in addition to its utility for assessing myocardial contractility

A Case of Wernicke's Encephalopathy Following Fluorouracil-based Chemotherapy

The pyrimidine antimetabolite 5-fluorouracil (5-FU) is a chemotherapeutic agent used widely for various tumors. Common side effects of 5-FU are related to its effects on the bone marrow and gastrointestinal epithelium. Neurotoxicity caused by 5-FU is uncommon, although acute and delayed forms have been reported. Wernicke's encephalopathy is an acute, neuropsychiatric syndrome resulting from thiamine deficiency, and has significant morbidity and mortality. Central nervous system neurotoxicity such as Wernicke's encephalopathy following chemotherapy with 5-FU has been reported rarely, although it has been suggested that 5-FU can produce adverse neurological effects by causing thiamine deficiency. We report a patient with Wernicke's encephalopathy, reversible with thiamine therapy, associated with 5-FU-based chemotherapy

Imaging Findings of Castleman's Disease Localized in the Axilla: A Case Report

Castleman's disease is a rare benign lymphoproliferative disorder of uncertain origin which most commonly involves the mediastinum but rarely affects the axilla. We report a case of localized Castleman's disease involving the axillary lymph node. Mammography revealed a well-defined, homogeneously dense ovoid mass, 3 cm in size, in the left axilla, while gray-scale ultrasonography (US) demonstrated a well-defined, uniformly hypoechoic ovoid mass with good through transmission. Peripheral hypervascularity was observed at power Dopper US, and early rapid homogeneous enhancement at contrast-enhanced dynamic CT

Calcified Carcinoma of the Gallbladder with Calcified Nodal Metastasis Presenting as a Porcelain Gallbladder: A Case Report

Porcelain gallbladder is regarded as a risk factor of gallbladder cancer. A porcelain gallbladder with calcified regional lymph nodes was found using computed tomography (CT) and magnetic resonance imaging (MRI) in a 43-year-old man who presented with nausea, vomiting, and abdominal pain. His cholecystectomy specimen showed diffuse wall thickening and contained small gallstones. Histological examination revealed diffuse infiltrative adenocarcinoma with extensive intratumoral calcification (calcified carcinoma). The majority of the calcified material was located within or replaced the tumor glands, and was not found in the stroma. A lymph node was totally replaced with a calcified metastatic adenocarcinoma. To the best of our knowledge, only one case of calcified lymph node metastasis from a calcified carcinoma of the gallbladder has been previously reported in the literature. We herein add a case of calcified carcinoma of the gallbladder with calcified lymph node metastasis, presenting as a porcelain gallbladder on CT and MRI

Clinical effectiveness of the sequential 4-channel NMES compared with that of the conventional 2-channel NMES for the treatment of dysphagia in a prospective double-blind randomized controlled study

Background To date, conventional swallowing therapies and 2-channel neuromuscular electrical stimulation (NMES) are standard treatments for dysphagia. The precise mechanism of 2-channel NMES treatment has not been determined, and there are controversies regarding the efficacy of this therapy. The sequential 4-channel NMES was recently developed and its action is based on the normal contractile sequence of swallowing-related muscles. Objective To evaluate and compare the rehabilitative effectiveness of the sequential 4-channel NMES with that of conventional 2-channel NMES. Methods In this prospective randomized case–control study, 26 subjects with dysphagia were enrolled. All participants received 2- or 4-channel NMES for 2–3weeks (minimal session: 7 times, treatment duration: 300–800min). Twelve subjects in the 4-channel NMES group and eleven subjects in the 2-channel NMES group completed the intervention. Initial and follow-up evaluations were performed using the videofluoroscopic dysphagia scale (VDS), the penetration-aspiration scale (PAS), the MD Anderson dysphagia inventory (MDADI), the functional oral intake scale (FOIS), and the Likert scale. Results The sequential 4-channel NMES group experienced significant improvement in their VDS (oral, pharyngeal, and total), PAS, FOIS, and MDADI (emotional, functional, and physical subsets) scores, based on their pretreatment data. VDS (oral, pharyngeal, and total) and MDADI (emotional and physical subsets) scores, but not PAS and FOIS scores, significantly improved in the 2-channel NMES group posttreatment. When the two groups were directly compared, the 4-channel NMES group showed significant improvement in oral and total VDS scores. Conclusions The sequential 4-channel NMES, through its activation of the suprahyoid and thyrohyoid muscles, and other infrahyoid muscles mimicking physiological activation, may be a new effective treatment for dysphagia. Trial registration: clinicaltrial.gov, registration number: NCT03670498, registered 13 September 2018, https://clinicaltrials.gov/ct2/show/NCT03670498?term=NCT03670498&draw=2&rank=1 .This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI18C1169). This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Min‑ istry of Science, ICT and Future Planning (NRF- NRF-2016R1D1A1B03935130)

Prevalence of Bartonella henselae and Bartonella clarridgeiae in cats and dogs in Korea

Blood, saliva, and nail samples were collected from 54 dogs and 151 cats and analyzed for the presence of Bartonella henselae with a novel nested polymerase chain reaction (PCR) method. Bartonella (B.) henselae was detected in feral cat blood (41.8%), saliva (44.1%), and nail (42.7%) samples. B. henselae was also detected in pet cat blood (33.3%), saliva (43.5%), and nail (29.5%) samples and in pet dog blood (16.6%), saliva (18.5%), and nail (29.6%) samples. Nine samples were infected with B. clarridgeiae and 2 were co-infected with B. henselae and B. clarridgeiae of blood samples of dogs. This report is the first to investigate the prevalence of B. henselae and B. clarridgeiae in dogs and cats in Korea, and suggests that dogs and cats may serve as potential Bartonella reservoirs