Loss of ATF6α in a Human Carcinoma Cell Line Is Compensated not by Its Paralogue ATF6β but by Sustained Activation of the IRE1 and PERK Arms for Tumor Growth in Nude Mice

To survive poor nutritional conditions, tumor cells activate the unfolded protein response, which is composed of the IRE1, PERK, and ATF6 arms, to maintain the homeostasis of the endoplasmic reticulum, where secretory and transmembrane proteins destined for the secretory pathway gain their correct three-dimensional structure. The requirement of the IRE1 and PERK arms for tumor growth in nude mice is established. Here we investigated the requirement for the ATF6 arm, which consists of ubiquitously expressed ATF6α and ATF6β, by constructing ATF6α-knockout (KO), ATF6β-KO, and ATF6α/β-double KO (DKO) in HCT116 cells derived from human colorectal carcinoma. Results showed that these KO cells grew similarly to wild-type (WT) cells in nude mice, contrary to expectations from our analysis of ATF6α-KO, ATF6β-KO, and ATF6α/β-DKO mice. We then found that the loss of ATF6α in HCT116 cells resulted in sustained activation of the IRE1 and PERK arms in marked contrast to mouse embryonic fibroblasts, in which the loss of ATF6α is compensated for by ATF6β. Although IRE1-KO in HCT116 cells unexpectedly did not affect tumor growth in nude mice, IRE1-KO HCT116 cells with ATF6α knockdown grew significantly more slowly than WT or IRE1-KO HCT116 cells. These results have unraveled the situation-dependent differential compensation strategies of ATF6α

The added value of non-contrast 3-Tesla MRI for the pre-operative localization of hyperparathyroidism

OBJECTIVE: We investigated the efficacy of non-contrast 3-Tesla MR imaging added to the combination of sestamibi with99mTc (MIBI) scintigraphy and Ultrasonography (US) for the pre-operative localization of Primary Hyperparathyroidism (PHPT) lesions. METHODS: A total of 34 parathyroid glands, including nine normal glands, were examined with MIBI, US, and non-contrast 3-Tesla MRI. MRI was performed with the acquisition of T1- and T2-weighted images and fat-suppressed T2-weighted images. We calculated the sensitivities of MIBI, US, and the 'additional' MRI, with knowledge of the former two modalities' results. RESULTS: For the diagnosis of PHPT lesions, the sensitivity values of MIBI, US, and additional MRI were 88.0% (22/25), 84.0% (21/25), and 92.0% (23/25), respectively. Normal glands were not visualized with any modality (0/9). One lesion was detected neither with US nor MRI, but only with MIBI, with the limitation that MIBI represented no more than laterality. The two glands not identified in MRI were 4 mm and 6 mm in their size, which are within the range of normal gland's size. Two lesions were not detected with US or MIBI but were visualized with the additional MRI, which indicated that the MRI contributed an 8.0% (2/25) improvement of sensitivity, compared from that of US. Fat-suppressed T2-weighted images were useful in the identification of parathyroid lesions, as these images helped to differentiate between the lesion and the adjacent tissue. CONCLUSION: Additional non-contrast 3-Tesla MRI was a useful adjunctive tool for localization of PHPT, which improved the sensitivity of the pre-operative localization of PHPT lesions. Fat-suppressed T2-weighted images contributed to their identification. LEVEL VI: Evidence from a single descriptive or qualitative study

Angiomatous Nasal Polyp Diagnosed by Preoperative Imaging and Successfully Resected by Endonasal Endoscopic Surgery: A Case Report

Angiomatous polyp is a benign, nonneoplastic nasal polyp that accounts for 4-5% of all inflammatory nasal polyps but is rarely reported in the literature. It can grow rapidly and exhibit an aggressive clinical behavior that can simulate malignant sinonasal tumor. We herein report a case of a 13-year-old boy with a rapidly growing angiomatous polyp in the nasal cavity. We had followed up the patient without significant changes for two years, but the tumor had rapidly grown in the last six months. At first, the rapid growth of the tumor and the bone erosion of the maxilla were suggestive of a malignant tumor. However, with preoperative magnetic resonance imaging (MRI) and [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography imaging findings, we established the corrective diagnosis of an angiomatous polyp. After the diagnostic imaging, we performed an endoscopic endonasal surgery and totally resected the tumor without unnecessary excessive surgery. Recognition of this disease that can mimic malignancy is important to avoid excessive surgery such as en bloc resection by craniofacial approach, and we believe that MRI findings can be helpful for the imaging diagnosis

造影ダイナミックCTとフッ素18フルオロミソニダゾール陽電子放出断層撮像法を用いた、腫瘍間質の評価および腫瘍低酸素との関連性の評価

http://pubs.rsna.org/doi/full/10.1148/radiol.2015150416京都大学0048新制・課程博士博士(医学)甲第19575号医博第4082号新制||医||1013(附属図書館)32611京都大学大学院医学研究科医学専攻(主査)教授 平岡 眞寛, 教授 YOUSSEFIAN Shohab, 教授 増永 慎一郎学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance

Normal cells produce adenosine 5′-triphosphate (ATP) mainly through mitochondrial oxidative phosphorylation (OXPHOS) when oxygen is available. Most cancer cells, on the other hand, are known to produce energy predominantly through accelerated glycolysis, followed by lactic acid fermentation even under normoxic conditions. This metabolic phenomenon, known as aerobic glycolysis or the Warburg effect, is less efficient compared with OXPHOS, from the viewpoint of the amount of ATP produced from one molecule of glucose. However, it and its accompanying pathway, the pentose phosphate pathway (PPP), have been reported to provide advantages for cancer cells by producing various metabolites essential for proliferation, malignant progression, and chemo/radioresistance. Here, focusing on a master transcriptional regulator of adaptive responses to hypoxia, the hypoxia-inducible factor 1 (HIF-1), we review the accumulated knowledge on the molecular basis and functions of the Warburg effect and its accompanying pathways. In addition, we summarize our own findings revealing that a novel HIF-1-activating factor enhances the antioxidant capacity and resultant radioresistance of cancer cells though reprogramming of the glucose metabolic pathway

Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge

Hypoxia‐inducible factor 1 (HIF‐1) is a transcriptional activator of various genes related to cellular adaptive responses to hypoxia. Dysfunctions in the regulatory systems of HIF‐1 activity have been implicated in the pathogenesis of various diseases including malignant tumors and, thus, elucidating the molecular mechanisms underlying the activation of HIF‐1 is eagerly desired for the development of novel anti‐cancer strategies. The importance of oxygen‐dependent and ubiquitin‐mediated proteolysis of the regulatory subunit of HIF‐1 (HIF‐1α) was first reported in 1997. Since then, accumulating evidence has shown that HIF‐1α may become stable and active even under normoxic conditions; for example, when disease‐associated genetic and functional alterations in some genes trigger the aberrant activation of HIF‐1 regardless of oxygen conditions. We herein review the last two decades of knowledge, since 1997, on the regulatory mechanisms of HIF‐1 activity from conventional oxygen‐ and proteolysis‐dependent mechanisms to up‐to‐the‐minute information on cancer‐associated genetic and functional alteration‐mediated mechanisms

Hyalinizing Clear Cell Carcinoma in the Sphenoid Sinus

A 39-year-old man presented with a 1-month history of headaches. Imaging revealed a mass with extensive destruction. T2-weighted imaging displayed mixture of low and sponge-like high intensities and also dark area, with FDG PET/CT showing uneven but intense accumulation. Biopsy confirmed EWSR1 rearrangement, and hyalinizing clear cell carcinoma (HCCC) was diagnosed. HCCC, recently renamed from clear cell carcinoma in the fifth edition of the World Health Organization Classification of Head and Neck Tumors, is a rare tumor. This case describes the features of T2-weighted imaging and FDG PET patterns in HCCC, possibly contributing to their consideration in the differential diagnosis

Preoperative Diagnostic Strategy for Parotid Gland Tumors Using Diffusion-Weighted MRI and Technetium-99m Pertechnetate Scintigraphy: A Prospective Study.

Fine needle aspiration cytology (FNAC) for diagnosis of a parotid gland tumor is widely used but its sensitivity is low and non-diagnostic rate is relatively high. In contrast, core needle biopsy (CNB) has a higher sensitivity and lower rate of sampling errors but has a higher risk of injury to adjacent organs such as facial nerve than FNAC. Screening of patients with parotid gland tumors to identify cases of pleomorphic adenoma (PA) and Warthin tumor (WT) may allow CNB to be confined to patients without PA and WT. We established an algorithm for preoperative diagnosis and management of parotid gland tumor using diffusion-weighted MRI and 99mTc pertechnetate scintigraphy. This algorithm was developed with the goal of maximal reduction of the number of patients in whom CNB is required. The purpose of the study is to validate our algorithm prospectively.A prospective study was conducted in 71 cases who were newly diagnosed with parotid gland tumor and 53 cases were enrolled in the study. In the algorithm, PA (high apparent diffusion coefficient (ADC) mean≥1.5×10(-3) mm(2)/s) and non-PA (low ADCmean<1.5×10(-3) mm(2)/s) cases are first distinguished based on the ADCmean on diffusion-weighed MRI. Second, among suspected non-PA cases, WT and non-WT are distinguished using technetium-99m pertechnetate scintigraphy. CNB is then performed only in probable non-PA and non-WT cases.Although CNB was only required in 40% (21/53) of all cases, we made a preoperative histopathological diagnosis with an accuracy of 87% (46/53) and we correctly diagnosed whether a tumor was benign or malignant with an accuracy of 96% (51/53). Preoperative surgical planning had to be changed during surgery in only one case (2%).Our algorithm is valuable in terms of clinical practice with highly potential for preoperative diagnosis and with less risk of CNB procedure