Reductive mobilization of iron by electrons

Ferritin, an iron storage protein, plays an important role in iron homeostasis. The mechanism of reductive mobilization of iron from ferritin has not been clarified yet despite many studies. The aim of this study was to assess the mechanisms of the mobilization of iron from ferritin by NADPH P-450 reductase. Nucleotide-dependent flavoenzymes generated significant mobilization of iron from ferritin. The possibility of reductive mobilization of iron from ferritin by electrons released from flavin sites or heme site of two flavoenzymes was investigated to elucidate the mediator-independent mechanisms of such reductive mobilization. The mobilization by NADPH-P450 reductase in the presence of ferricyanide increased threefold, while in the presence of cytochrome C increased thirteen-fold. These results indicate that electrons released from both flavins of NADPH-P450 reductase contribute to the reductive mobilization of iron from ferritin. The mechanism of the mobilization of iron from ferritin is discussed

Promoter-Level Transcriptome Identifies Stemness Associated With Relatively High Proliferation in Pancreatic Cancer Cells

Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a-Cre; KrasG12D; p53f/+ and Ptf1a-Cre; KrasG12D; and Brg1f/f pancreatic ductal adenocarcinomas (PDAs). The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome. Two RNA samples extracted from three individual subcutaneous tumors generated by the transplantation of PanIN or IPMN cancer cell lines were used to generate libraries and Illumina Seq, with four RNA samples in total, to depict discrete transcriptional network between IPMN and PanIN. Moreover, in IPMN cells, the transcriptome tended to be enriched for suppressive and inhibitory biological processes. In contrast, the transcriptome of PanIN cells exhibited properties of stemness. Notably, the proliferation capacity of the latter cells in culture was only minimally constrained by well-known chemotherapy drugs such as GSK690693 and gemcitabine. The various transcriptional factor network systems detected in PanIN and IPMN cells reflect the distinct molecular profiles of these cell types. Further, we hope that these findings will enhance our mechanistic understanding of the characteristic molecular alterations underlying pancreatic cancer precursors. These data may provide a promising direction for therapeutic research

Pathophysiology during ECC

Extracorporeal circulation, unlike pulsatile flow based on the beating heart, is the non-pulsatile flow through a blood pump, and the systemic circulation falls into non-physiological conditions. The living body shows various reactions to extracorporeal circulation. The pathophysiology of extracorporeal circulation includes changes in hemodynamics, coagulation, fibrinolysis, acid-base equilibrium, electrolytes, incretion, metabolism, and immune system. With advances in extracorporeal circulation technology, operability has been dramatically improved and safety has rapidly advanced as well. However, there are specific complications with extracorporeal circulation. We need to have a good knowledge of the pathophysiology and complications during extracorporeal circulation, as well as each component of the extracorporeal circulation system

SNAIL2 contributes to tumorigenicity and chemotherapy resistance in pancreatic cancer by regulating IGFBP2

Pancreatic cancer has an extremely poor prognosis because of its resistance to conventional therapies. Cancer stem cell (CSC)-targeted therapy is considered a promising approach for this disease. Epithelial-mesenchymal transition-inducing transcription factors (EMT-TFs) contribute to CSC properties in some solid tumors; however, this mechanism has not been fully elucidated in pancreatic cancer. Zinc finger protein, SNAIL2 (also known as SLUG), is a member of the SNAIL superfamily of EMT-TFs and is commonly overexpressed in pancreatic cancer. Patients exhibiting high SNAIL2 expression have a poor prognosis. In this study, we showed that the suppression of SNAIL2 expression using RNA interference decreased tumorigenicity in vitro (sphere formation assay) and in vivo (xenograft assay) in 2 pancreatic cancer cell lines, KLM1 and KMP5. In addition, SNAIL2 suppression resulted in increased sensitivity to gemcitabine and reduced the expression of CD44, a pancreatic CSC marker. Moreover, experiments on tumor spheroids established from surgically resected pancreatic cancer tissues yielded similar results. A microarray analysis revealed that the mechanism was mediated by insulin-like growth factor (IGF) binding protein 2. These results indicate that IGFBP2 regulated by SNAIL2 may represent an effective therapeutic target for pancreatic cancer

High Plasma Docosahexaenoic Acid Associated to Better Prognoses of Patients with Acute Decompensated Heart Failure with Preserved Ejection Fraction

The clinical relevance of polyunsaturated fatty acids (PUFAs) in heart failure remains unclear. The aim of this study was to investigate the association between PUFA levels and the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). This retrospective study included 140 hospitalized patients with acute decompensated HFpEF (median age 84.0 years, 42.9% men). The patients' nutritional status was assessed, using the geriatric nutritional risk index (GNRI), and their plasma levels of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-gamma-linolenic acid (DGLA) were measured before discharge. The primary outcome was all-cause mortality. During a median follow-up of 23.3 months, the primary outcome occurred in 37 patients (26.4%). A Kaplan-Meier analysis showed that lower DHA and DGLA levels, but not EPA or AA levels, were significantly associated with an increase in all-cause death (log-rank; p < 0.001 and p = 0.040, respectively). A multivariate Cox regression analysis also revealed that DHA levels were significantly associated with the incidence of all-cause death (HR: 0.16, 95% CI: 0.06-0.44, p = 0.001), independent of the GNRI. Our results suggest that low plasma DHA levels may be a useful predictor of all-cause mortality and potential therapeutic target in patients with acute decompensated HFpEF

Establishment of patient-derived organoids and a characterization-based drug discovery platform for treatment of pancreatic cancer

BACKGROUND: Pancreatic cancer is one of the most lethal tumors. The aim of this study is to provide an effective therapeutic discovery platform for pancreatic cancer by establishing and characterizing patient-derived organoids (PDOs). METHODS: PDOs were established from pancreatic tumor surgical specimens, and the mutations were examined using a panel sequence. Expression of markers was assessed by PCR, immunoblotting, and immunohistochemistry; tumorigenicity was examined using immunodeficient mice, and drug responses were examined in vitro and in vivo. RESULTS: PDOs were established from eight primary and metastatic tumors, and the characteristic mutations and expression of cancer stem cell markers and CA19-9 were confirmed. Tumorigenicity of the PDOs was confirmed in subcutaneous transplantation and in the peritoneal cavity in the case of PDOs derived from disseminated nodules. Gemcitabine-sensitive/resistant PDOs showed consistent responses in vivo. High throughput screening in PDOs identified a compound effective for inhibiting tumor growth of a gemcitabine-resistant PDO xenograft model. CONCLUSIONS: This PDO-based platform captures important aspects of treatment-resistant pancreatic cancer and its metastatic features, suggesting that this study may serve as a tool for the discovery of personalized therapies

イワユル ビョウビョウ レンケイ ガ ソウコウ シタ ショウガイシャ ニ タイスル シュウガクテキ シカ チリョウ ニツイテ

In recent years, the oral environments of disabled people are well maintained by dental specialists for the disabled; however, because serious conditions requiring dental therapy do occur in disabled patients, we created a referral system for multidisciplinary dentistry for the disabled. In this report, we describe the successful implementation of this referral system and the treatment outcomes of disabled patients who underwent therapy by dental specialists. The patients were 12 disabled people, comprising 9 males and 3 females, who had been undergoing dental treatment in Tokushima Red Cross Hinomine Rehabilitation Center for People with Disabilities and had visited Tokushima University Hospital between January 2010 and March 2013. Their ages ranged from 14 to 71 years old, with a mean of 32.5 years old. The most common types of disabilities were hypophrenia: 7 patients (58.3%); cerebral palsy: 4 patients (33.3%), autism: 3 patients (25.0%), malformation syndrome: 2 patients (16.7%), etc. were found. The most frequent complications were epilepsy: 5 patients (41.7%); cured patent ductus arteriosus, laryngomalacia, asthma, hypertension, and ventilatory impairment were found in 1 patient (8.3%). Regarding oral diseases, chronic periodontitis and dental caries: 11 cases (91.7%), impacted wisdom teeth and persistence of deciduous teeth: 2 cases (16.7%) and oral cancer: 1 case (8.3%), were found. Concerning treatment, tooth extraction: 11 cases (91.7%), crown restoration: 5 cases (41.7%), pulpectomy: 2 cases (16.7%) and tumor resection: 1 case (8.3%), were safely performed. The procedures were performed under intravenous sedation in 6 cases, and under general anesthesia in the other 6 cases. Our referral system may contribute to the development of low-risk dentistry for the disabled