Synthetic lethality by targeting the RUVBL1/2-TTT complex in mTORC1-hyperactive cancer cells

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.Despite considerable efforts, mTOR inhibitors have produced limited success in the clinic. To define the vulnerabilities of mTORC1-addicted cancer cells and to find previously unknown therapeutic targets, we investigated the mechanism of piperlongumine, a small molecule identified in a chemical library screen to specifically target cancer cells with a hyperactive mTORC1 phenotype. Sensitivity to piperlongumine was dependent on its ability to suppress RUVBL1/2-TTT, a complex involved in chromatin remodeling and DNA repair. Cancer cells with high mTORC1 activity are subjected to higher levels of DNA damage stress via c-Myc and displayed an increased dependency on RUVBL1/2 for survival and counteracting genotoxic stress. Examination of clinical cancer tissues also demonstrated that high mTORC1 activity was accompanied by high RUVBL2 expression. Our findings reveal a previously unknown role for RUVBL1/2 in cell survival, where it acts as a functional chaperone to mitigate stress levels induced in the mTORC1-Myc-DNA damage axis.NIH 1RO1CA142805National Research Foundation of Korea (NRF) grant (NRF-2017R1C1B1006072

Deterministic creation and deletion of a single magnetic skyrmion observed by direct time-resolved X-ray microscopy

Spintronic devices based on magnetic skyrmions are a promising candidate for next-generation memory applications due to their nanometre-size, topologically-protected stability and efficient current-driven dynamics. Since the recent discovery of room-temperature magnetic skyrmions, there have been reports of current-driven skyrmion displacement on magnetic tracks and demonstrations of current pulse-driven skyrmion generation. However, the controlled annihilation of a single skyrmion at room temperature has remained elusive. Here we demonstrate the deterministic writing and deleting of single isolated skyrmions at room temperature in ferrimagnetic GdFeCo films with a device-compatible stripline geometry. The process is driven by the application of current pulses, which induce spin-orbit torques, and is directly observed using a time resolved nanoscale X-ray imaging technique. We provide a current-pulse profile for the efficient and deterministic writing and deleting process. Using micromagnetic simulations, we also reveal the microscopic mechanism of the topological fluctuations that occur during this process.Comment: 27 pages, 4 figure

Chondrosarcoma of the Head and Neck

Chondrosarcoma of the head and neck region is a rare disease, representing approximately 0.1% of all head and neck neoplasms. The 5-year survival rate of chondrosarcoma is 70-80%, showing relatively good prognosis; however, it is known to progress slowly and eventually cause multiple metastases. In this study, we reviewed chondrosarcoma cases experienced at Yonsei University Medical College during the last 15 years to investigate its clinical characteristics and treatment outcome. The medical records of 8 patients who were diagnosed with chondrosarcoma of the head and neck region and underwent surgical treatment between December 1990 and December 2002 were retrospectively reviewed. The primary sites were sinus, mastoid, jugular foramen and thyroid cartilage. In all patients, the initial treatment modality was surgery, and postoperative radiation therapy was performed in 4 cases. The pathological findings showed chondrosarcoma in 7 cases and mesenchymal chondrosarcoma in 1 case. The treatment outcome resulted in 3 cases of recurrence, of which 2 cases were treated successfully and the other case expired of disease, indicating a survival rate of 87.5%. In the case that resulted in death, complete excision could not be achieved. Therefore, we concluded that wide excision is a beneficial initial treatment of this rare disease

Targeting AKT with costunolide suppresses the growth of colorectal cancer cells and induces apoptosis in vitro and in vivo

BACKGROUND: Colorectal cancer (CRC) is a clinically challenging malignant tumor worldwide. As a natural product and sesquiterpene lactone, Costunolide (CTD) has been reported to possess anticancer activities. However, the regulation mechanism and precise target of this substance remain undiscovered in CRC. In this study, we found that CTD inhibited CRC cell proliferation in vitro and in vivo by targeting AKT. METHODS: Effects of CTD on colon cancer cell growth in vitro were evaluated in cell proliferation assays, migration and invasion, propidium iodide, and annexin V-staining analyses. Targets of CTD were identified utilizing phosphoprotein-specific antibody array; Costunolide-sepharose conjugated bead pull-down analysis and knockdown techniques. We investigated the underlying mechanisms of CTD by ubiquitination, immunofluorescence staining, and western blot assays. Cell-derived tumour xenografts (CDX) in nude mice and immunohistochemistry were used to assess anti-tumour effects of CTD in vivo. RESULTS: CTD suppressed the proliferation, anchorage-independent colony growth and epithelial-mesenchymal transformation (EMT) of CRC cells including HCT-15, HCT-116 and DLD1. Besides, the CTD also triggered cell apoptosis and cell cycle arrest at the G2/M phase. The CTD activates and induces p53 stability by inhibiting MDM2 ubiquitination via the suppression of AKT's phosphorylation in vitro. The CTD suppresses cell growth in a p53-independent fashion manner; p53 activation may contribute to the anticancer activity of CTD via target AKT. Finally, the CTD decreased the volume of CDX tumors without of the body weight loss and reduced the expression of AKT-MDM2-p53 signaling pathway in xenograft tumors. CONCLUSIONS: Our project has uncovered the mechanism underlying the biological activity of CTD in colon cancer and confirmed the AKT is a directly target of CTD. All of which These results revealed that CTD might be a new AKT inhibitor in colon cancer treatment, and CTD is worthy of further exploration in preclinical and clinical trials.1

Incidentally detected breast lesions on chest CT with US correlation: a pictorial essay

With the increasing use of computed tomography (CT), incidental breast lesions are detected more frequently. When interpreting chest CT findings, it is important for radiologists to carefully review the breast to recognize any abnormal findings that could affect patient management. The purpose of this study is to discuss incidental breast lesions on chest CT with ultrasonography correlation that may be encountered in routine clinical practice

Comparison of 0.05% cyclosporine and 3% diquafosol solution for dry eye patients: a randomized, blinded, multicenter clinical trial

Background This study is aim to compare the clinical effectiveness between the two most prominent dry eye disease (DED)-specific eye drops, 0.05% cyclosporine (CN) and 3% diquafosol (DQ). Methods This is a multi-centered, randomized, masked, prospective clinical study. A total of 153 DED patients were randomly allocated to use CN twice per day or DQ six times daily. Cornea and conjunctival staining scores (NEI scale), tear break-up time (TBUT), Schirmer test scores, and ocular surface disease index (OSDI) score were measured at baseline, 4 and 12 weeks after treatment. Results At 12 weeks after treatment, NEI scaled scores were significantly reduced from the baseline by − 6.60 for CN and − 6.63 for DQ group (all P < 0.0001, P = 0.9739 between groups). TBUT and Schirmer values for CN were significantly improved from the baseline at 4 and 12 weeks (P = 0.0034, P < 0.0001 for TBUT, P = 0.0418, P = 0.0031 for Schirmer test). However, for DQ, TBUT showed significant improvement at 12 weeks only (P = 0.0281). Mean OSDI score differences from the baseline to 12 weeks were improved by − 13.03 ± 19.63 for CN and − 16.11 ± 20.87 for DQ, respectively (all P < 0.0001, P = 0.854 between groups). Regarding drug compliance, the mean instillation frequency of CN was less than that of DQ (P < 0.001). There were no statistically significant intergroup differences in safety evaluation. Conclusions The level of improvement regarding NEI, TBUT, and OSDI scores were not significantly different between the two treatment groups. However, with regards to the early improvement of TBUT and patient compliance, patients using CN improved faster and with greater adherence to drug usage than did those treated with DQ. Trial registration KCT0002180, retrospectively registered on 23 December 2016.This study was supported by an unrestricted educational grant from Taejoon Pharm (Seoul, Korea), which affords funding only, but has not any other contribution to our research

A case of necrotizing pancreatitis subsequent to transcatheter arterial chemoembolization in a patient with hepatocellular carcinoma

Necrotizing pancreatitis is one of the rare complications of transcatheter arterial chemoembolization (TACE). Necrotizing pancreatitis after TACE may result from the development of ischemia caused by regurgitation of embolic materials into the vessels supplying the pancreas. We report a case of post-TACE necrotizing pancreatitis with abscess formation in a patient with hepatocellular carcinoma. The patient had suffered hepatic artery injury due to repetitive TACE; during his 25th TACE procedure he had submitted to selective catheterization of the feeding vessel from the dorsal pancreatic artery with a cytotoxic agent and Gelfoam particles. The patient complained of abdominal pain after the TACE procedure, and a CT scan led to a diagnosis of necrotizing pancreatitis with abscess formation. The pancreatic abscess progressed despite general management of the pancreatitis, including antibiotics. Percutaneous catheter drainage was performed, and the symptoms of the patient improved