Synthesis and photochemical properties of caged peroxides for photocontrol of cellular oxidative stress.

We developed a caged hydroperoxide, BhcTBHP, releasing prooxidant TBHP under blue light irradiation. MitoTBHP with triphenylphosphonium at position 7 triggered selective oxidative stress and membrane depolarization in mitochondria upon photoirradiation. This study presents a powerful tool for studying redox signaling and oxidative stress in living cells.

Hypoxia-Induced CD36 Expression in Gastric Cancer Cells Promotes Peritoneal Metastasis via Fatty Acid Uptake.

BACKGROUND: The lipid scavenger receptor cluster of differentiation 36 (CD36) has been shown to have a pro-metastatic function in several cancers. Adipose tissue, a favorable site for peritoneal metastasis (PM) from gastric cancer (GC), promotes this process by providing free fatty acids (FFAs); however, the role of CD36 in PM progression from GC remains to be elucidated. MATERIALS AND METHODS: We evaluated CD36 expression in the GC cells under various conditions. CD36 overexpressing (CD36OE) MKN45 cells were prepared and their migration and invasive properties were assessed. A PM mouse model was used to investigate the biological effects of palmitic acid (PA) and CD36. Furthermore, we examined the clinical role of CD36 expression in 82 human PM samples by immunohistochemical staining. RESULTS: Hypoxia markedly increased CD36 expression in GC cells. In normoxia, only CD36OE MKN45 cells treated with PA showed an increase in migration and invasion abilities. An increased expression of active Rac1 and Cdc42 was observed, which decreased following etomoxir treatment. Conversely, hypoxia increased those capacities of both vector and CD36OE MKN45 cells. In a mouse model transplanted with CD36OE MKN45 cells, more peritoneal tumors were observed in the high-fat diet group than those in the normal diet group. In clinical samples, 80% of PM lesions expressed CD36, consistent with hypoxic regions, indicating a significant association with prognosis. CONCLUSION: Our findings indicate that a hypoxia in the peritoneal cavity induces CD36 expression in GC cells, which contributes to PM through the uptake of FFAs.

Crosstalk between cancer-associated fibroblasts and immune cells in peritoneal metastasis: inhibition in the migration of M2 macrophages and mast cells by Tranilast.

BACKGROUND: The role of tumor-stroma interactions in tumor immune microenvironment (TME) is attracting attention. We have previously reported that cancer-associated fibroblasts (CAFs) contribute to the progression of peritoneal metastasis (PM) in gastric cancer (GC), and M2 macrophages and mast cells also contribute to TME of PM. To elucidate the role of CAFs in TME, we established an immunocompetent mouse PM model with fibrosis, which reflects clinical features of TME. However, the involvement of CAFs in the immunosuppressive microenvironment remains unclear. In this study, we investigated the efficacy of Tranilast at modifying this immune tolerance by suppressing CAFs. METHODS: The interaction between mouse myofibroblast cell line LmcMF and mouse GC cell line YTN16 on M2 macrophage migration was investigated, and the inhibitory effect of Tranilast was examined in vitro. Using C57BL/6J mouse PM model established using YTN16 with co-inoculation of LmcMF, TME of resected PM treated with or without Tranilast was analyzed by immunohistochemistry. RESULTS: The addition of YTN16 cell-conditioned medium to LmcMF cells enhanced CXCL12 expression and stimulated M2 macrophage migration, whereas Tranilast inhibited the migration ability of M2 macrophages by suppressing CXCL12 secretion from LmcMF. In PM model, Tranilast inhibited tumor growth and fibrosis, M2 macrophage, and mast cell infiltration and significantly promoted CD8 + lymphocyte infiltration into the tumor, leading to apoptosis of cancer cells by an immune response. CONCLUSION: Tranilast improved the immunosuppressive microenvironment by inhibiting CAF function in a mouse PM model. Tranilast is thus a promising candidate for the treatment of PM.

Nonbacterial Thrombotic Endocarditis Associated with Acute Promyelocytic Leukemia: An Autopsy Case Report.

Valve vegetation is one of the most fearful findings for physicians. The first diagnosis that comes to their mind is infective endocarditis (IE), but it can also be noninfective; nonbacterial thrombotic endocarditis (NBTE). NBTE can be even more challenging than IE for physicians because of the wide range of differential diagnoses such as malignancies, autoimmune disorders and human immunodeficiency virus. A 45-year-old woman presented at the emergency room with a sudden onset of dysarthria and right-sided hemiplegia. Laboratory data showed her blood counts and coagulation test were mostly normal and the magnetic resonance imaging detected a high-signal-intensity change in her left brain. An echocardiogram found a vegetation-like structure on her atrial valve. We highly suspected IE leading to cerebral embolism. The clot was successfully removed by our neurosurgeons and anticoagulation therapy was started concurrently. Her state of consciousness improved, but then she suffered a brain hemorrhage and died. The autopsy revealed that the cause of her vegetation was acute promyelocytic leukemia (APL). Based on these findings, it is important to remember that APL can be the cause of NBTE even if the blood count and coagulation tests are almost normal.

The Association between the Establishment of a General Internal Medicine Department and an Increased Number of Blood Cultures in Other Departments: An Interrupted Time Series Analysis.

Objective The establishment of a department of general internal medicine (GIM) has been shown to improve the clinical outcomes among patients treated in GIM departments but the effect on practice patterns in other departments remains unclear. We evaluated the association between the establishment of a GIM department and the use of blood cultures, an indicator of quality of care of infectious diseases, in other departments. Methods This study was conducted between 2013 and 2017 in a community hospital which established a new GIM department in 2015, with a mandate to improve the quality of care of the hospital including infectious disease management. The primary outcome was the change in the number of blood culture episodes per calendar month in other departments before and after establishment of the GIM department. The secondary outcome was the change in the blood culture episodes per month, indexed to 1,000 patient-days, during the same time. Using 2015 as the phase-in period, interrupted time series analyses were used to evaluate the change in the outcome variables. Results In departments other than GIM, there were 284 blood cultures prior to the establishment of the GIM department (2013-2014) and 853 afterwards (2016-2017). The number of blood culture episodes in other departments increased by 10.7 (95%CI: 0.39-21.0, p=0.042) per calendar month after the establishment of the GIM department; blood culture episodes/calendar month/1,000 patient-days increased by 0.55 (95%CI: 0.03-1.07 p=0.037). Conclusion These results indicate that a GIM department in a community hospital can improve the quality of care in other departments.

Switchable synthesis of cyclic carbamates by carbon dioxide fixation at atmospheric pressure.

The base-promoted switchable synthesis of five- and six-membered cyclic carbamates using atmospheric pressure carbon dioxide as the C1 source was developed. The chemoselectivity of products was simply controlled by changing bases and solvents. The reaction proceeds effectively under mild conditions, affording valuable cyclic carbamates. Experimental results and DFT studies revealed the reaction mechanism.

Use of esophageal stent for the treatment of postoperative gastrointestinal-airway fistula after esophagectomy.

A gastrointestinal-airway fistula (GAF) after esophagectomy is a very serious postoperative complication that can cause severe respiratory complications due to digestive juice inflow. Generally, GAF is managed by invasive surgical treatment; less-invasive treatment has yet to be established. We performed esophageal stent placement (ESP) in three cases of GAF after esophagectomy. We assessed the usefulness of ESP through our clinical experience. All GAFs were successfully managed by ESP procedures. After the procedure, the stent positioning and expansion were appropriately evaluated by radiological assessments over time. The stent was removed after endoscopic confirmation of fistula closure on days 8, 23, and 71. Only one patient with a long-term indwelling stent developed a manageable secondary gastrobronchial fistula as a procedure-related complication. In conclusion, ESP was shown to be a less-invasive and effective therapeutic modality for the treatment of GAF.

Integrated Cognitive Architecture for Robot Learning of Action and Language.

The manner in which humans learn, plan, and decide actions is a very compelling subject. Moreover, the mechanism behind high-level cognitive functions, such as action planning, language understanding, and logical thinking, has not yet been fully implemented in robotics. In this paper, we propose a framework for the simultaneously comprehension of concepts, actions, and language as a first step toward this goal. This can be achieved by integrating various cognitive modules and leveraging mainly multimodal categorization by using multilayered multimodal latent Dirichlet allocation (mMLDA). The integration of reinforcement learning and mMLDA enables actions based on understanding. Furthermore, the mMLDA, in conjunction with grammar learning and based on the Bayesian hidden Markov model (BHMM), allows the robot to verbalize its own actions and understand user utterances. We verify the potential of the proposed architecture through experiments using a real robot.

Tocilizumab-resistant TAFRO Syndrome Complicated by Type II Respiratory Failure.

A 66-year-old man with a several year history of thrombocytopenia, pleural effusion and ascites, anasarca, and organomegaly presented with general fatigue, appetite loss, dyspnea with type II respiratory failure. The precise history of the patient and the re-evaluation of lymph node and bone marrow biopsies conducted by the previous physician indicated TAFRO syndrome. The patient's laboratory data improved for a year with tocilizumab, but then worsened to the point that the patient required artificial ventilation due to the deterioration of type II respiratory failure. The replacement of tocilizumab with rituximab yielded a steady improvement, but it was necessary to address the patient's persistent respiratory failure. Peripheral nerve disorder might have been involved with the patient's respiratory failure.

Thoracoscopic Surgery in a Patient with Multiple Esophageal Carcinomas after Surgery for Esophageal Achalasia.

We present a case in which we used a thoracoscopic approach for resection of multiple esophageal carcinomas diagnosed 33 years after surgery for esophageal achalasia. A 68-year-old Japanese man had been diagnosed with esophageal achalasia and underwent surgical treatment 33 years earlier. He was examined at our hospital for annual routine checkup in which upper gastrointestinal endoscopy showed a "0-IIb+IIa" lesion in the middle esophagus. Iodine staining revealed multiple irregularly shaped iodine-unstained areas, the diagnosis of which was esophageal carcinoma. Thoracoscopic subtotal esophagectomy was performed. Esophageal carcinoma may occur many years after surgery for esophageal achalasia, even if the passage symptoms have improved. So, long-term periodic follow-up is necessary for detection of carcinoma at an earlier stage.

Impact of preoperative ultrasonography findings on the patency rate of vascular access in Japanese hemodialysis patients.

BACKGROUND: Although ultrasonography before a vascular access (VA) operation has become popular in recent years, benchmarks for the diameter or blood flow of arteries or veins are not defined in Japan. The objective of the present study is to analyze the relationship between preoperative US findings and the patency rate of VA in Japanese hemodialysis patients. METHODS: 139 patients with end stage kidney disease were enrolled in this study. They had been given primary radiocephalic arteriovenous fistula (AVF) from February 2009 to December 2010 at the Juntendo University Hospital and were followed up over 2 years. We defined the interval from the time of AVF creation until first access thrombosis or any intervention to maintain or restore blood flow as patency time (primary patency). We examined the correlation between the 2-year primary patency rate of VA and the diameter of the radial artery (RA), brachial artery (BA), or cephalic vein at an anastomosis presumptive region by US, the blood flow of RA or BA, as measured by US, age, gender, and primary kidney diseases. RESULTS: The average patency term was 448.6 ± 271.3 days, with the 1-year and 2-year patency rate as 64.0 and 51.2 %, respectively. The patency rate was significantly lower in elderly patients over the age of 75 and in patients with diabetes mellitus. US findings of 2.0 mm or less in the RA diameter also resulted in a noticeably low patency rate. A multivariate analysis indicated that those factors were risk factors for early VA failure. CONCLUSIONS: Preoperative US findings of the diameter of RA may involve the patency rate of VA, making it appears that an RA of 2.0 mm or more in diameter at an anastomosis region may be more effective for the improvement in the patency rate of VA.

B-type (brain) natriuretic peptide and pruritus in hemodialysis patients.

INTRODUCTION AND OBJECTIVE: While pruritus is a common complication in hemodialysis patients, the pathophysiological mechanisms remain obscure. Recently, B-type (brain) natriuretic peptide (BNP) has been defined as an itch-selective neuropeptide in pruriceptive neurons in mice, and higher serum levels of BNP are frequently observed in hemodialysis patients. The objective of the present study was to evaluate the role of serum BNP in pruritus in patients undergoing hemodialysis. PATIENTS AND METHODS: The current cross-sectional study was performed on 43 patients undergoing maintenance hemodialysis. A visual analog scale (VAS) measuring the general severity of pruritus (values from 0 to 10, with higher values indicating more severe pruritus) in daytime and at night was self-reported by patients. Each patient's background and laboratory tests, including serum BNP in the post-hemodialysis period, were collected. The correlation between VAS and clinical parameters was evaluated. RESULTS: Both daytime and nighttime VAS scores in diabetic patients were significantly less than those in nondiabetic patients. Multiple regression analysis revealed that pruritus in daytime was worsened by serum BNP (ß=2.0, t=2.4, P=0.03), calcium (ß=4.4, t=5.2, P<0.0001), and ß2-microglobulin (ß=2.0, t=3.0, P=0.007), while it was eased by age (ß=-2.2, t=-3.2, P=0.0004). Nocturnal pruritus was severe in nondiabetic patients (ß=1.7, t=3.8, P=0.0005) and weakened by the total iron binding capacity (ß=-2.9, t=-3.1, P=0.004). CONCLUSION: It is suggested that a higher level of serum BNP increases the pruritus of hemodialysis patients in daytime and that diabetic patients are less sensitive to itch, especially at nighttime.

FOLFIRI plus bevacizumab as a first-line treatment for Japanese patients with metastatic colorectal cancer: a JACCRO CC-03 multicenter phase II study.

PURPOSE: The purpose of this multicenter phase II study was to evaluate the efficacy and safety of a combination of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FOLFIRI) plus bevacizumab as first-line chemotherapy in Japanese patients with metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer were eligible for enrollment. On day 1 of a 14-day cycle, patients received bevacizumab 5 mg/kg, irinotecan 150 mg/m², and L-leucovorin 200 mg/m² as an intravenous infusion, followed by 5-FU 400 mg/m² as an intravenous bolus and then 5-FU 2,400 mg/m² as an 46-h intravenous infusion. This treatment cycle was repeated. The primary endpoint was progression-free survival (PFS). RESULTS: We enrolled 40 patients, but one withdrew consent before starting treatment. The remaining 39 patients received a total of 509 cycles of FOLFIRI plus bevacizumab (median 11 per patient; range 1-30). The median PFS was 11.5 months, the median overall survival (OS) was 22.0 months, and the 1-year OS rate was 81.8 %. All 39 patients had adverse events. Grade 3 or 4 neutropenia and stomatitis occurred in 21 (53.9 %) and 4 (10.3 %) patients, respectively. CONCLUSION: Our results suggest that FOLFIRI plus bevacizumab is a clinically effective regimen with a manageable toxicity profile as first-line chemotherapy in patients with metastatic colorectal cancer.

Hydroalkoxylation of unactivated olefins with carbon radicals and carbocation species as key intermediates.

A unique Markovnikov hydroalkoxylation of unactivated olefins with a cobalt complex, silane, and N-fluoropyridinium salt is reported. Further optimization of reaction conditions yielded high functional group tolerance and versatility of alcoholic solvent employed, including methanol, i-propanol, and t-butanol. Use of trifluorotoluene as a solvent made the use of alcohol in stoichiometric amount possible. Mechanistic insight into this novel catalytic system is also discussed. Experimental results suggest that catalysis involves both carbon radical and carbocation intermediates.

[A case that showed an improved quality of life for rectal gastrointestinal stromal tumor patient treated with cytoreductive surgery].

A 49-year-old man was admitted to another hospital with the complaint of difficulty in defecating. He underwent laparotomy, and investigation of the biopsy revealed a huge intraperitoneal tumor. He began to take imatinib in April 2008 following a diagnosis of gastrointestinal stromal tumor (GIST), but the tumor increased in size. He was referred to our hospital for oral administration of sunitinib to reduce the tumor size. The tumor was 30 cm in diameter, and there were several peritoneal metastases around the liver. He began to take sunitinib in February 2009. The tumor increased in size from August 2010 but a partial remission was noted. We performed cytoreductive surgery in April 2011 as palliative care, but the tumor size increased again in October. We performed cytoreductive surgery again, but he died in December 2011. Although cytoreductive surgery for GIST is a potential treatment option, we suggest supportive care.

Administration of anti-vascular endothelial growth factor antibody following hepatectomy does not inhibit remnant liver regeneration or growth of remnant metastases.

In addition to the use of chemotherapeutic agents for the prevention of multiple liver metastases from colorectal cancer, the anti-vascular endothelial growth factor (VEGF) antibody, bevacizumab, is often used, and its effectiveness has been established. By contrast, it has been reported that the use of bevacizumab prior to or following surgery delays wound healing or liver regeneration. In this study, we investigated whether the administration of bevacizumab following hepatectomy inhibits remnant liver regeneration or the growth of remnant metastases. Mice were partially hepatectomized (31% of the liver was removed), transplanted with the murine colorectal cancer cell line, CT26, in the remnant lobe, and intraperitoneally injected with bevacizumab (4 mg/kg) for a total of 6 times. Serum VEGF levels were measured on day 1 following surgery, and each lobe of the liver was weighed on day 14. Serum VEGF levels in non-hepatectomized, tumor-bearing mice exceeded those in their non-tumor-bearing counterparts; however, the administration of bevacizumab did not reduce the serum VEGF levels. The volume of the liver lobe of the hepatectomized, CT26-transplanted and non-CT26-transplanted mice was 1,349.6 and 735.5 mg, respectively, indicating rapid growth of the CT26 transplant (p=0.023). The volume of the CT26-transplanted lobe of the bevacizumab-administered mice was 1,379.0 mg, which was not significantly different from that (1,349.6 mg) of the non-bevacizumab-administered mice. The volume of the remnant lobe of the bevacizumab-administered mice was 1,051.0 mg, which did not significantly differ from that (957.3 mg) of the non-bevacizumab-administered mice. The administration of bevacizumab following hepatectomy did not delay remnant liver regeneration, and did not suppress the growth of metastases in the remnant lobes or remnant liver regeneration.

Combination therapy of gemcitabine or oral S-1 with the anti-VEGF monoclonal antibody bevacizumab for pancreatic neuroendocrine carcinoma.

We previously reported that the administration of bevacizumab for pancreatic neuroendocrine tumors inhibited angiogenesis in the host, resulting in tumor growth inhibition. In light of these results, we compared the effect of bevacizumab/gemcitabine/S-1 combination therapy vs. bevacizumab monotherapy. The QGP-1 pancreatic neuroendocrine carcinoma cell line and the BxPC-3 ductal cell carcinoma cell line were transplanted into the subcutaneous tissue of mice, and the mice were treated for 3 weeks with bevacizumab [50 mg/kg intraperitoneally (i.p.) twice weekly], gemcitabine (240 mg/kg i.p. once weekly) and S-1 (10 mg/kg orally five times weekly). The antitumor effect and side effects were evaluated by measuring the tumor volume and weight and by changes in body weight, respectively. The tumor volume became smaller (from the maximum volume) in the group treated with bevacizumab, gemcitabine and S-1 (BGS) and the group treated with bevacizumab and gemcitabine (BG). A significant difference was noted in the tumor weight between the BG group and the group treated with bevacizumab alone. A relatively significant decrease in the body weight was observed in the BGS and BG groups. We conclude that gemcitabine is appropriate as a drug used in combination with bevacizumab for pancreatic neuroendocrine tumors.

Computed tomography virtual endoscopy with angiographic imaging for the treatment of type IV-A choledochal cyst.

Type IV-A choledochal cysts (CCs) are a congenital biliary anomaly which involve dilatation of the extrahepatic and intrahepatic bile ducts. We present the case of a 30-year-old woman with type IV-A CC, on whom three-dimensional computed tomography (3D CT) and virtual endoscopy were performed. 3D CT revealed partial dilatation in the posterior branch of the intrahepatic bile duct and a relative stricture between it and the extrahepatic bile duct. Virtual endoscopy showed that this stricture was membrane-like and separated from the surrounding blood vessels. Based on these image findings, complete cyst resection, bile duct plasty for the stricture, and hepaticojejunostomy were safely performed. To the best of our knowledge, there are no reports of imaging by virtual endoscopy of the biliary tract which show the surrounding blood vessels running along the bile duct.