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The phosphorylation state of αB-crystallin accumulated in the brains of two patients with Alexander's disease (one infantile and one juvenile type) was determined by means of SDS-PAGE or isoelectric focusing of soluble and insoluble fractions of brain extracts and subsequent western blot analysis with specific antibodies against αB-crystallin and each of three phosphorylated serine residues. The level of mammalian small heat shock protein of 25–28 kDa (Hsp27) in the same fraction was also estimated by western blot analysis. The majority of αB-crystallin was detected in the insoluble fraction of brain homogenates and phosphorylation was preferentially observed at Ser-59 in both cases. A significant level of phosphorylation at Ser-45 but not Ser-19 was also detected. Hsp27 was found at considerable levels in the insoluble fractions. αB-crystallin and phosphorylated forms were detected in the cerebrospinal fluid of patient with the juvenile type. αB-crystallin and phosphorylated forms were also detectable at considerable levels in the insoluble fraction of brain homogenates from patients with Alzheimer's disease and aged controls. The phosphorylation site was mostly at Ser-59 in all cases. Immunohistochemically, αB-crystallin was stained in Rosenthal fibers in brains of patients with Alexander's disease and their peripheral portions were immunostained with antibodies recognizing phosphorylated Ser-59. These results indicate that the major phosphorylation site in αB-crystallin in brains of patients with Alexander's disease or Alzheimer's disease as well as in aged controls is Ser-59. [ABSTRACT FROM AUTHOR]

Study Objectives: This study was performed to compare the results of accelerated exercise following mild hyperventilation and a standard acetylcholine (ACh) test for the induction of coronary artery spasm in patients with drug-induced coronary artery spasm.Methods and Results: The subjects were 74 patients with angiographically confirmed coronary artery spasm who were examined using accelerated exercise (ie, exercise that was accelerated every minute according to the protocol of Bruce and Horsten) following mild hyperventilation and who were not receiving any medication. ACh was injected in incremental doses of 20 microg and 50 microg into the right coronary artery and incremental doses of 20 microg, 50 microg, and 100 microg into the left coronary artery. Positive coronary spasm was defined as > or =99% luminal narrowing. Accelerated exercise following a mild hyperventilation test was as useful for detecting evidence of ischemia as was an ACh test (48 patients [64.9%] vs 49 patients [66.2%], respectively; not significant). No difference was observed between ischemic changes on ECG as a result of the newly combined method and the occurrence of ACh-induced spasm. ACh-induced coronary vasospasm occurred in 61 patients (82.4%). In the remaining 13 patients, intracoronary administration of ergonovine provoked coronary spasms. No serious irreversible complications were detected as a result of this newly combined method.Conclusions: The effectiveness of our newly combined procedure is equivalent to that of an ACh test to diagnose patients with coronary artery spasm. [ABSTRACT FROM AUTHOR]

The compact EAS Extensive Air Shower (EAS) array (200 m2) and the Linsley method have been used with the aim to observe the primary energy spectrum. The spectral indexes αproton and αiron are obtained as − 2.46 ± 0.17 and − 3.08 ± 0.24, respectively, in the primary energy region of 1016eV − 1018.5eV in the single observation of the compact EAS array. Additionally, αproton and αiron are obtained as − 3.12 ± 0.13 and − 3.52 ± 0.17, respectively, in the same primary energy region in the observation by restricting the zenith angle of EAS events.

Abstract Background The tumour suppressor phosphatase and tensin homolog (PTEN) is an important negative regulator of cell-survival signaling. To evaluate the correlation between PTEN expression and clinicopathological characteristics of colorectal cancer patients with and without liver metastases, we investigated PTEN expression in primary colorectal cancer and colorectal cancer liver metastases. Methods Sixty-nine pairs of primary colorectal cancer and corresponding liver metastasis specimens were analyzed immunohistochemically, and the correlation between immunohistochemical findings and clinicopathological factors was investigated. Seventy primary colorectal cancer specimens from patients without liver metastases were used as controls. Results PTEN was strongly expressed in 44 (62.9%) colorectal cancer specimens from patients without liver metastases. In contrast, PTEN was weakly expressed in 52 (75.4%) primary colorectal cancer specimens from patients with liver metastases, and was absent in liver metastases. Weak PTEN expression in colorectal cancer tissues was significantly associated with advanced TNM stage (p < 0.01) and lymph node metastasis (p < 0.05). PTEN expression was significantly stronger in primary colorectal cancer specimens from patients without liver metastases. Furthermore, among colorectal cancer patients with liver metastases, the 5-year survival rate was significantly higher in patients with positive PTEN expression compared to those with negative PTEN expression (p = 0.012). Conclusion Our results suggest that loss of PTEN expression is involved with colorectal cancer aggressive capacity and that diagnostic evaluation of PTEN expression may provide valuable prognostic information to aid treatment strategies for colorectal cancer patients.

Abstract Background Granulocyte-colony stimulating factor (G-CSF)-producing cancer has been reported to occur in various organs, especially the lung. However, G-CSF-producing colorectal cancer (CRC) has never been reported in the English literature. Case presentation A 57-year-old man was admitted for the surgical removal of a rectal cancer. Some hepatic tumors in the liver were revealed concurrently, and their appearance suggested multiple liver metastases. Low anterior resection was performed. with the help of histopathological examination and immunohistochemical studies, we diagnosed this case to be an undifferentiated carcinoma of the rectum. After the operation, the white blood cell (WBC) count increased gradually to 81,000 cells/μL. Modified-FOLFOX6 therapy was initiated to treat the liver metastases, but there was no effect, and peritoneal dissemination had also occurred. The serum level of G-CSF was elevated to 840 pg/mL (normal range, Conclusion This is the first case of G-CSF-producing rectal cancer, and its prognosis was very poor.

Abstract Background Alpha-fetoprotein (AFP)-producing gastric cancer is known to frequently cause multiple liver metastases and to have an extremely poor prognosis. Case presentation A 64-year-old Japanese man admitted to our hospital was diagnosed with gastric cancer with liver metastases. He underwent a total gastrectomy with splenectomy, and pathological stage IV disease according to the classification proposed by the Japanese Gastric Cancer Association was assigned. The histological diagnosis was poorly differentiated adenocarcinoma, and tumor production of AFP was confirmed by immunohistochemical staining. Following surgery, the patient received combination chemotherapy consisting of TS-1 and paclitaxel. Initially, AFP levels decreased dramatically and computed tomography (CT) revealed regression of liver metastases. However, multiple new liver metastases appeared and serum AFP levels increased after 5 months. A regimen of 5-FU plus paclitaxel followed by paclitaxel monotherapy was used next. Serum AFP levels once again decreased and CT showed regression or disappearance of liver metastases. The patient currently has a very good quality of life, and is receiving weekly paclitaxel monotherapy as an outpatient. No progression of liver metastases has been observed to date. Conclusion We consider this rare case to have significant value with respect to treatment of AFP-producing gastric cancer with multiple liver metastases, and propose that combining surgery with chemotherapeutic agents such as paclitaxel may lead to a better prognosis in such cases.

Abstract Background The transmembrane protein c-kit is a receptor tyrosine kinase (KIT) and KIT is expressed in solid tumors and hematological malignancies such as gastrointestinal stromal tumor (GIST), small-cell lung cancer and chronic myelogenous leukemia (CML). KIT plays a critical role in cell proliferation and differentiation and represents a logical therapeutic target in GIST and CML. In pancreatic cancer, c-kit expression has been observed by immunohistochemical techniques. In this study, we examined the influence of c-kit expression on proliferation and invasion using five pancreatic cancer cell lines. In addition, the inhibitory effect of imatinib mesylate on stem cell factor (SCF)-induced proliferation and invasion was evaluated. Finally, we also analyzed KIT and SCF expression in pancreatic cancer tissues using immunohistochemistry and correlated the results with clinical features. Results RT-PCR revealed that two pancreatic cancer cell lines, PANC-1 and SW1990, expressed c-kit mRNA. By Western blot analysis, c-kit protein was also present in those lines. In KIT-positive pancreatic cancer cell lines, proliferation and invasion were significantly enhanced by addition of SCF. In contrast, SCF did not enhance proliferation and invasion in the three KIT-negative lines (BxPC-3, Capan-2 and MIA PaCa-2). 5 μM imatinib mesylate significantly inhibited SCF-enhanced proliferation to the same extent compared with the control. Similarly, SCF-enhanced invasive ability was significantly inhibited by 5 μM imatinib mesylate. KIT was expressed in 16 of 42 clinical specimens by immunohistochemistry, and KIT expression was significantly related to venous system invasion. Furthermore, patients expressing both KIT and SCF had a somewhat lower survival. Conclusion Our results demonstrated that the SCF-KIT pathway enhanced the proliferation and invasiveness in KIT-positive pancreatic cancer cell lines and that the enhanced proliferation and invasion were inhibited by imatinib mesylate. We propose that inhibitors of c-kit tyrosine kinase receptor have the potential to slow the progression of KIT-positive pancreatic cancers.

Discusses clinical characteristics and possible mechanism of paroxysmal atrial fibrillation (AF) induced by intracoronary injection of acetycholine (ACh). ACh-induced paroxysmal AF in the right coronary artery testing; Effectiveness of the intravenous administration of disopyramide; Incidence rate for antiarrhythmic agents required in patients with ischemic heart disease.

This study sought to clarify major complications associated with acetylcholine testing. Serious major complications, such as sustained ventricular tachycardia, shock, and cardiac tamponade were determined in 4 of 715 patients (0.56%), but no cases of death or irreversible complications occurred. The spasm provocation test using acetylcholine should be performed carefully, although it is considered a safe and reliable method. [ABSTRACT FROM AUTHOR]

This study examines the incidence of spasm by intracoronary injection of acetylcholine in Japanese patients who underwent coronary angiography. The subjects were 685 consecutive patients (477 men, mean age 63.2 +/- 7.5 years) who were studied with an acetylcholine test. Acetylcholine was injected in incremental doses of 20, 50, and 80 microg into the right coronary artery and 20, 50, and 100 microg into the left coronary artery. Spasm was defined as total or subtotal occlusion. Coronary vasospasm was determined in 221 patients (32.3%). Spasm occurred often during effort and rest in patients with angina (25 of 51, 49.0%), exertional angina (25 of 74, 33.8%), recent myocardial infarction (30 of 80, 37.5%), healed myocardial infarction (14 of 37, 37.8%), and especially in patients with rest angina (83 of 124, 66.9%), whereas spasm was relatively uncommon in patients with nonischemic heart disease (23 of 252, 9.1%). Spasm was superimposed on significant atherosclerotic lesions in 35.9% of patients as well as on nonfixed atherosclerotic lesions in 30.8% of patients. We conclude that >9% of Japanese patients may have coronary vasospasm with intracoronary injection of acetylcholine and recommend the provocation test for evaluating coronary vasospasm if coronary angiography is undertaken. [ABSTRACT FROM AUTHOR]

Background and purpose A recent genome-wide association study has successfully identified several genetic variations in the Chr17q25 locus as susceptible genotypes for white matter hyperintensities. We report the first replication study in subjects of non- European origin. We also investigated possible associations with other asymptomatic cerebrovascular diseases and cognitive function. Methods Study subjects were 1190 general Japanese persons (66.0 ± 8.9 years old). Asymptomatic cerebrovascular damage, including lacunar infarctions, microbleeds, periventricular hyperintensity and deep and subcortical white matter hyperintensity ( DSWMH), was evaluated by brain magnetic resonance imaging. Results A polymorphism rs3744028 was significantly associated with DSWMH grade ( P = 0.015) but not periventricular hyperintensity, lacunar infarction, and microbleeds. Although age, hypertension, insulin resistance, B-type natriuretic peptide, and carotid atherosclerosis were also correlated with DSWMH, association of the genotype was independent of these environmental risk factors. In contrast, the risk allele had a protective effect against reduced cognitive function. Conclusion Susceptibility of the 17q25 locus may be conserved beyond ethnic differences. Genetic variants may have bipolar effects on brain histological and functional changes. [ABSTRACT FROM AUTHOR]

Background: The duration of, resources required for and cost of clinical trials could be reduced if a surrogate end point was to be used in place of survival. We assessed the extent to which the objective response rate (ORR) is predictive of mortality, how much difference in the ORR is needed to predict an obvious survival difference and what factors could affect the association between the two parameters during the first-line treatment of extensive disease (ED)-small-cell lung cancer (SCLC). Methods: We used the ORRs and median survival times (MSTs) from 48 phase III trials of first-line chemotherapy involving 8779 randomised patients with ED-SCLC in a linear regression analysis. The MST difference was calculated as the difference in MST between the investigational and reference arms; the ORR difference was similarly defined. Results: ORR difference between the treatment arms was modestly associated with the MST difference in the overall trials (R2 = 0.3314). In contrast, the relationship was stronger among only trials in which prophylactic cranial irradiation was given to those having an objective response to the initial chemotherapy (R2 = 0.6279). In this trial setting, large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR). Conclusions: In the first-line treatment of ED-SCLC, a favourable relationship was detected between the two parameters in the selected trial setting. Large ORR differences were needed to predict a survival benefit, clearly suggesting the need for new chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Brunner's gland hamartoma (BGH) is a benign tumor occurring in the duodenal bulb. BGH is typically asymptomatic, but it has been shown to occasionally cause anemia. The patient was a 76-year-old male. In October 2011, he was diagnosed with prostate cancer with multiple bone metastases and was referred to us for the treatment and examination of anemia. Hormonal therapy with androgen receptor antagonists and bisphosphonate administration following orchiectomy improved his symptoms. In August 2012, esophagogastroduodenoscopy (EGD) was performed due to stomach discomfort, revealing a 5 mm semi-pedunculated polyp in the duodenal bulb, Yamada-Fukutomi classification type II. Over the next 5 years, the prostate cancer treatment proceeded smoothly, and no endoscopic follow-up was conducted. In January 2017, during a health checkup, EGD revealed that the polyp in the duodenum bulb had changed morphologically with a distinct stalk measuring 10 mm. As there were no symptoms and only minimal tumor growth, a watchful waiting approach was adopted. In April 2022, due to the rapid progression of anemia, EGD was performed again, showing that the pedunculated polyp had enlarged to 20 mm in maximum diameter with an eroded surface and a stalk extending to 40 mm. Given the tumor enlargement and further examination of anemia, an endoscopic polypectomy was performed in May 2022. Histopathological examination confirmed the diagnosis of BGH. We observed a case of primary duodenal BGH during treatment for advanced prostate cancer, with endoscopic monitoring over 10 years. The morphological changes of BGH were clearly documented via EGD., Competing Interests: None., (© 2024 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Backgrounds: To the best of our knowledge, there are no reports of proteomic analysis for the identification of unknown proteins involved in resistance to anaplastic lymphoma kinase (ALK) inhibitors. In this study, we investigated the proteins involved in resistance to alectinib, a representative ALK inhibitor, through proteomic analysis and the possibility of overcoming resistance., Methods: An ALK-positive lung adenocarcinoma cell line (ABC-11) and the corresponding alectinib-resistant cell line (ABC-11/CHR2) were used. Two-dimensional difference gel electrophoresis (2D DIGE) was performed; the stained gel was scanned and the spots were analyzed using DeCyder TM2D 7.0. Mass spectrometry (MS) with the UltrafleXtreme matrix-assisted laser desorption ionization-tandem time-of-flight (MALDI-TOF/TOF) MS system was performed. For the MS/MS analysis, the samples were spotted on an AnchorChipTM 600 TF plate. The peptide masses obtained in the reflector positive mode were acquired at m/z of 400-6000. MS/MS data were searched against the NCBI protein databases. Growth inhibition was measured using an MTT assay. The isobologram and combination index were calculated based on the median-effect analysis. Western blotting was performed using antibodies, including superoxide dismutase (SOD) 1, MET, ERK, PARP, AKT, and BRCA1., Results: The 2D DIGE for ABC-11 and ABC-11/CHR2 showed different expression levels in about 2000 spots. SOD was identified from spots highly expressed in resistant strains. Western blotting also confirmed SOD1 overexpression in ABC-11/CHR2. siSOD1 enhanced the growth inhibitory effects of alectinib, increased cleaved PARP levels, and decreased pERK, pAKT, and BRCA1 levels with a combination of alectinib. In addition, the combination of LCS-1, an SOD1 inhibitor, and alectinib synergistically suppressed the growth in ABC-11/CHR2, but not in ABC-11., Conclusions: SOD1 overexpression is thought to be a mechanism for alectinib resistance, suggesting the possibility of overcoming resistance using SOD1 inhibitors., Competing Interests: Declaration of competing interest Dr. Takigawa has received grants and personal fees from Eli Lilly Japan, Daiichi-Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Boehringer-Ingelheim Japan, and Ono Pharmaceutical; grants from Kyowa Hakko Kirin, Nippon Kayaku Co. Ltd., and Takeda Pharmaceutical Co. Ltd.; and personal fees from MSD and Bristol-Myers Squibb Company Japan outside the submitted work. Dr. Ochi has received personal fees from Eli Lilly Japan K.K., Taiho Pharmaceutical Co. ltd., Chugai Pharmaceutical, Pfizer Japan Inc., Ono pharmaceutical, MSD, Bristol-Myers Squibb, Boehringer Ingelheim, and Nippon Kayaku outside the submitted work. Dr. Ichihara received honoraria from AstraZeneca K.K., Novartis, Janssen Pharmaceutical K.K., Chugai Pharmaceutical Co. Ltd. , Eli Lilly Japan K.K. , Pfizer, Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Boehringer Ingelheim. He also received research funding from Janssen Pharmaceutical K.K., Pfizer, Bristol-Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., and Takeda Pharmaceutical Co. Ltd., and research drugs from Janssen Pharmaceutical K.K., and Astelas under MTA outside the submitted work. Dr. Fukazawa has received personal fees from Boehringer-Ingelheim Japan outside the submitted work. Dr. Kiura has received grants and personal fees from Taiho Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Ono Pharmaceutical, Chugai Pharmaceutical, Nippon Kayaku Co., Ltd., Teijin Pharma Ltd., Shionogi Pharma Co., Ltd., Novartis Pharma, Takeda Pharmaceutical Co., Ltd., Kyorin Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., MSD, and Pfizer Japan Inc. and personal fees from Eli Lilly Japan, AstraZeneca, Daiichi-Sankyo Pharmaceutical, Bristol-Myers Squibb, and Nipro Pharma Co. outside the submitted work. The other authors have no conflicts of interest to declare., (Copyright © 2024 Elsevier Inc. All rights reserved.)