Glycerol as a chemical chaperone enhances radiation-induced apoptosis in anaplastic thyroid carcinoma cells

INTRODUCTION: Anaplastic thyroid carcinoma, which is one of the most aggressive, malignant tumors in humans, results in an extremely poor prognosis despite chemotherapy and radiotherapy. The present study was designed to evaluate therapeutic effects of radiation by glycerol on p53-mutant anaplastic thyroid carcinoma cells (8305c cells). To examine the effectiveness of glycerol in radiation induced lethality for anaplastic thyroid carcinoma 8305c cells, we performed colony formation assay and apoptosis analysis. RESULTS: Apoptosis was analyzed with Hoechst 33342 staining and DNA ladder formation assay. 8305c cells became radiosensitive when glycerol was added to culture medium before X-ray irradiation. Apoptosis was induced by X-rays in the presence of glycerol. However, there was little apoptosis induced by X-ray irradiation or glycerol alone. The binding activity of whole cell extracts to bax promoter region was induced by X-rays in the presence of glycerol but not by X-rays alone. CONCLUSION: These findings suggest that glycerol is effective against radiotherapy of p53-mutant thyroid carcinomas

Blood flow velocity in the anterior humeral circumflex artery and tear size can predict synovitis severity in patients with rotator cuff tears

Background Rotator cuff tears are often associated with synovitis, but the ability of noninvasive ultrasonography to predict the severity of synovitis remains unclear. We investigated whether ultrasound parameters, namely peak systolic velocity in the anterior humeral circumflex artery and Doppler activity in the glenohumeral joint and subacromial space, reflect synovitis severity. Methods A total of 54 patients undergoing arthroscopic rotator cuff repair were selected. Doppler ultrasound was used to measure peak systolic velocity in the anterior humeral circumflex artery and Doppler activity in the glenohumeral joint and subacromial space, and these values were compared with the intraoperative synovitis score in univariate and multivariate analyses. Results Univariate analyses revealed that tear size, peak systolic velocity in the anterior humeral circumflex artery, and Doppler activity in the glenohumeral joint were associated with synovitis in the glenohumeral joint (P=0.02, P<0.001, P=0.02, respectively). In the subacromial space, tear size, peak systolic velocity in the anterior humeral circumflex artery, and Doppler activity in the subacromial space were associated with synovitis severity (P=0.02, P<0.001, P=0.02, respectively). Multivariate analyses indicated that tear size and peak systolic velocity in the anterior humeral circumflex artery were independently associated with synovitis scores in both the glenohumeral joint and the subacromial space (all P<0.05). Conclusions These findings demonstrate that tear size and peak systolic velocity in the anterior humeral circumflex artery, which can both be measured noninvasively, are useful indicators of synovitis severity. Level of evidenceIV

Hemobilia Derived from Cystic Artery Pseudoaneurysm

Cystic artery pseudoaneurysm (CAP) is a rare disease, with small number of previous reports related to CAP. Besides, it is frequently prone to critical condition due to arterial bleeding. Here, we presented a case of ruptured CAP with acute calculus cholecystitis and its subsequent successful management with temporary endoscopic biliary drainage for obstructive jaundice and embolization for the culprit artery without cholecystectomy. Since CAP is at high risk of bleeding, intravascular treatment, which is only one currently available therapeutic option, is urgently required in the clinical sites

Efficacy of Mucosal Cutting Biopsy for the Histopathological Diagnosis of Gastric Submucosal Tumors

Background: Gastrointestinal stromal tumors occur frequently. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is performed commonly for diagnosis. However, the success rate of histological diagnosis is insufficient when the submucosal tumor (SMT) is small. Recently, another technique, mucosal cutting biopsy (MCB) has been reported. The aim of this study is to evaluate the efficacy and safety of MCB. Method: Between January 2012 and August 2018, MCB and EUS-FNA were performed 16 and 31 times for diagnosing gastric SMT. The diagnostic rate, the rate of successful immunohistochemistry, and the safety were reviewed. Difficult locations for EUS-FNA were also evaluated. Results: The mean SMT sizes measured on MCB and EUS-FNA were 21.2 and 36.2 mm. The diagnostic rates of MCB and EUS-FNA were almost the same (88 vs. 81%), but successful immunohistochemistry was significantly higher in the MCB group (93 vs. 59%, p = 0.03). In the subgroup of SMTs &#x3c; 20 mm, the successful histological diagnosis rate from EUS-FNA was relatively low. There were no complications. Failures of EUS-FNA were more frequent in the middle third of the stomach. Conclusions: MCB was an effective procedure for diagnosing gastric SMT, especially in the case of small SMTs located at the middle third of the stomach

Epithelial EP4 plays an essential role in maintaining homeostasis in colon

Colonic epithelial cells comprise the mucosal barrier, and their dysfunction promotes microbial invasion from the gut lumen and induces the development of intestinal inflammation. The EP4 receptor is known to mediate the protective effect of prostaglandin (PG) E2 in the gastrointestinal tract; however, the exact role of epithelial EP4 in intestinal pathophysiology remains unknown. In the present study, we aimed to investigate the role of epithelial EP4 in maintaining colonic homeostasis by characterizing the intestinal epithelial cell-specific EP4 knockout (EP4 cKO) mice. Mice harboring the epithelial EP4 deletion showed significantly lower colonic crypt depth and lower numbers of secretory cell lineages, as well as impaired epithelial cells in the colon. Interestingly, EP4-deficient colon epithelia showed a higher number of apoptotic cells. Consistent with the defect in mucosal barrier function of colonic epithelia and secretory cell lineages, EP4 cKO colon stroma showed enhanced immune cell infiltration, which was accompanied by increased production of inflammatory cytokines. Furthermore, EP4-deficient colons were susceptible to dextran sulfate sodium (DSS)-induced colitis. Our study is the first to demonstrate that epithelial EP4 loss resulted in potential "inflammatory" status under physiological conditions. These findings provided insights into the crucial role of epithelial PGE2/EP4 axis in maintaining intestinal homeostasis

Significant contribution of subseafloor microparticles to the global manganese budget

Ferromanganese minerals are widely distributed in subseafloor sediments and on the seafloor in oceanic abyssal plains. Assessing their input, formation and preservation is important for understanding the global marine manganese cycle and associated trace elements. However, the extent of ferromanganese minerals buried in subseafloor sediments remains unclear. Here we show that abundant (108–109 particles cm−3) micrometer-scale ferromanganese mineral particles (Mn-microparticles) are found in the oxic pelagic clays of the South Pacific Gyre (SPG) from the seafloor to the ~100 million-year-old sediments above the basement. Three-dimensional micro-texture, and major and trace element compositional analyses revealed that these Mn-microparticles consist of poorly crystalline ferromanganese oxides precipitating from bottom water. Based on our findings, we extrapolate that 1.5–8.8 × 1028 Mn-microparticles, accounting for 1.28–7.62 Tt of manganese, are globally present in oxic subseafloor sediments. This estimate is at least two orders of magnitude larger than the manganese budget for nodules and crusts on the seafloor. Subseafloor Mn-microparticles thus contribute significantly to the global manganese budget.This study was supported in part by the Japan Society for the Promotion of Science (JSPS) Strategic Fund for Strengthening Leading-Edge Research and Development (to JAMSTEC and F.I.), the JSPS Funding Program for Next Generation World-Leading Researchers (GR102 to F.I.), JSPS Grant-in-Aid for Scientific Research (24687004 and 15H05608 to Y.M., 25871219 to G.-I.U., 15H02810 to R.W., 18H04134, 17H06458 and 17H04582 to Y.T., and 26251041 to F.I.), JSPS Grant-in-Aid for JSPS Fellows (14J00199 to G.-I.U.), and Ministry of Education, Culture, Sports, Science, and Technology (MEXT) Fund Leading Initiative for Excellent Young Researchers (to Kochi University and G.-I.U.)

JNK pathway plays a critical role for expansion of human colorectal cancer in the context of BRG1 suppression

Tumor stem cells (TSCs), capable of self-renewal and continuous production of progeny cells, could be potential therapeutic targets. We have recently reported that chromatin remodeling regulator Brg1 is required for maintenance of murine intestinal TSCs and stemness feature of human colorectal cancer (CRC) cells by inhibiting apoptosis. However, it is still unclear how BRG1 suppression changes the underlying intracellular mechanisms of human CRC cells. We found that Brg1 suppression resulted in upregulation of the JNK signaling pathway in human CRC cells and murine intestinal TSCs. Simultaneous suppression of BRG1 and the JNK pathway, either by pharmacological inhibition or silencing of c-JUN, resulted in even stronger inhibition of the expansion of human CRC cells compared to Brg1 suppression alone. Consistently, high c-JUN expression correlated with worse prognosis for survival in human CRC patients with low BRG1 expression. Therefore, the JNK pathway plays a critical role for expansion and stemness of human CRC cells in the context of BRG1 suppression, and thus a combined blockade of BRG1 and the JNK pathway could be a novel therapeutic approach against human CRC

Pancreatic RECK inactivation promotes cancer formation, epithelial-mesenchymal transition, and metastasis

膵癌悪性化の分子機構解明 --RECK発現の低下が膵癌の浸潤・転移を引き起こす--. 京都大学プレスリリース. 2023-09-19.RECK is downregulated in various human cancers; however, how RECK inactivation affects carcinogenesis remains unclear. We addressed this issue in a pancreatic ductal adenocarcinoma (PDAC) mouse model and found that pancreatic Reck deletion dramatically augmented the spontaneous development of PDAC with a mesenchymal phenotype, which was accompanied by increased liver metastases and decreased survival. Lineage tracing revealed that pancreatic Reck deletion induced epithelial-mesenchymal transition (EMT) in PDAC cells, giving rise to inflammatory cancer-associated fibroblast–like cells in mice. Splenic transplantation of Reck-null PDAC cells resulted in numerous liver metastases with a mesenchymal phenotype, whereas reexpression of RECK markedly reduced metastases and changed the PDAC tumor phenotype into an epithelial one. Consistently, low RECK expression correlated with low E-cadherin expression, poor differentiation, metastasis, and poor prognosis in human PDAC. RECK reexpression in the PDAC cells was found to downregulate MMP2 and MMP3, with a concomitant increase in E-cadherin and decrease in EMT-promoting transcription factors. An MMP inhibitor recapitulated the effects of RECK on the expression of E-cadherin and EMT-promoting transcription factors and invasive activity. These results establish the authenticity of RECK as a pancreatic tumor suppressor, provide insights into its underlying mechanisms, and support the idea that RECK could be an important therapeutic effector against human PDAC

Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis

Jun Ueda, Akihito Harada, Takashi Urahama, Shinichi Machida, Kazumitsu Maehara, Masashi Hada, Yoshinori Makino, Jumpei Nogami, Naoki Horikoshi, Akihisa Osakabe, Hiroyuki Taguchi, Hiroki Tanaka, Hiroaki Tachiwana, Tatsuma Yao, Minami Yamada, Takashi Iwamoto, Ayako Isotani, Masahito Ikawa, Taro Tachibana, Yuki Okada, Hiroshi Kimura, Yasuyuki Ohkawa, Hitoshi Kurumizaka, Kazuo Yamagata, Testis-Specific Histone Variant H3t Gene Is Essential for Entry into Spermatogenesis, Cell Reports, Volume 18, Issue 3, 2017, Pages 593-600, ISSN 2211-1247, https://doi.org/10.1016/j.celrep.2016.12.065