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It is still unclear how environmentally assisted cracking, especially sulfide stress cracking (SSC), is caused by corrosion and fracture behavior. In this study, a new in situ technique for an SSC visualization challenge was established and applied for the visualization of microcrack propagation resulting from a single pitting on the steel surface of 13% Cr martensitic stainless steel during four-point bending SSC tests and discussed by combining ex situ x-ray computed tomography (XCT) and electron backscatter diffraction (EBSD). The dynamic behavior of microcracks was visualized successfully, and the microbubbles behavior with the corrosion reaction was also captured. Regarding the relationship between internal structure and microstructure for cracking, it was found that a cavity was formed in the interior of prior to the cracks seen on the surface by XCT, and cracks by EBSD were propagated along prior austenite grain boundaries. On the basis of in situ observations and complementary ex situ analyses, the actual situation of crack on the steel surface was revealed and discussed with both corrosion and fracture over time. This approach provides an opportunity to clarify the SSC occurrence process based on actual SSC tests and contributes to the determination of phenomenological criteria. Furthermore, by combining this in situ technique with commonly known electrochemical measurements such as polarization curves, open-circuit potentials, and electrochemical impedance spectroscopy, it is possible to directly discuss various electrochemical data corresponding to corrosion and fracture behavior, including dissolution and gas evolution.

Background This phase I/II study was conducted to evaluate the efficacy, safety and pharmacokinetics of streptozocin (STZ) in Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors. Methods Twenty-two patients received up to 4 cycles of intravenous STZ at either 500 mg/m2 once daily for 5 consecutive days every 6 weeks (daily regimen) or at 1000–1500 mg/m2 once weekly for 6 weeks (weekly regimen). Tumor response was evaluated using the modified RECIST criteria ver. 1.1, and adverse events were assessed by grade according to the National Cancer Institute CTCAE (ver. 4.0). Results Fourteen (63.6%) patients completed the study protocol. No patients had complete response; partial response in 2 (9.1%), stable disease in 17 (77.3%), non-complete response/non-progressive disease in 2 (9.1%) and only 1 (4.5%) had non-evaluable disease. Excluding the latter, the response rate in the daily and weekly regimens was 6.7% (1/15) and 16.7% (1/6), respectively, with an overall response rate of 9.5% (2/21). However, the best overall response in each patient showed that the disease control rate was 100%. Adverse events occurred in all 22 patients, including 17 grade 3 adverse events in 11 patients; however, no grade 4 or 5 adverse events were reported. Prophylactic hydration and antiemetic treatment reduced the severity and incidence of nephrotoxicity, nausea and vomiting. Plasma STZ concentrations decreased rapidly after termination of infusion, with a half-life of 32–40 min. Neither repeated administration nor dose increases affected pharmacokinetic parameters. Conclusions STZ may be a useful option for Japanese patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine neoplasms (NENs) are rare neoplasms that occur in various organs and present with diverse clinical manifestations. Pathological classification is important in the diagnosis of NENs. Treatment strategies must be selected according to the status of differentiation and malignancy by accurately determining whether the neoplasm is functioning or nonfunctioning, degree of disease progression, and presence of metastasis. The newly revised Clinical Practice Guidelines for Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) comprises 5 chapters—diagnosis, pathology, surgical treatment, medical and multidisciplinary treatment, and multiple endocrine neoplasia type 1 (MEN1)/von Hippel–Lindau (VHL) disease—and includes 51 clinical questions and 19 columns. These guidelines aim to provide direction and practical clinical content for the management of GEP-NEN preferentially based on clinically useful reports. These revised guidelines also refer to the new concept of “neuroendocrine tumor” (NET) grade 3, which is based on the 2017 and 2019 WHO criteria; this includes health insurance coverage of somatostatin receptor scintigraphy for NEN, everolimus for lung and gastrointestinal NET, and lanreotide for GEP-NET. The guidelines also newly refer to the diagnosis, treatment, and surveillance of NEN associated with VHL disease and MEN1. The accuracy of these guidelines has been improved by examining and adopting new evidence obtained after the first edition was published. Supplementary Information The online version contains supplementary material available at 10.1007/s00535-021-01827-7.

Background: Early neonates of both large and small mammals are able to regenerate the myocardium through cardiomyocyte proliferation for only a short period after birth. This myocardial regenerative capacity declines in parallel with withdrawal of cardiomyocytes from the cell cycle in the first few postnatal days. No mammalian species examined to date has been found capable of a meaningful regenerative response to myocardial injury later than 1 week after birth. Methods: We examined cardiomyocyte proliferation in neonates of the marsupial opossum ( Monodelphis domestica ) by immunostaining at various times after birth. The regenerative capacity of the postnatal opossum myocardium was assessed after either apex resection or induction of myocardial infarction at postnatal day 14 or 29, whereas that of the postnatal mouse myocardium was assessed after myocardial infarction at postnatal day 7. Bioinformatics data analysis, immunofluorescence staining, and pharmacological and genetic intervention were applied to determine the role of AMPK (5′-AMP–activated protein kinase) signaling in regulation of the mammalian cardiomyocyte cell cycle. Results: Opossum neonates were found to manifest cardiomyocyte proliferation for at least 2 weeks after birth at a frequency similar to that apparent in early neonatal mice. Moreover, the opossum heart at postnatal day 14 showed substantial regenerative capacity both after apex resection and after myocardial infarction injury, whereas this capacity had diminished by postnatal day 29. Transcriptomic and immunofluorescence analyses indicated that AMPK signaling is activated in postnatal cardiomyocytes of both opossum and mouse. Pharmacological or genetic inhibition of AMPK signaling was sufficient to extend the postnatal window of cardiomyocyte proliferation in both mouse and opossum neonates as well as of cardiac regeneration in neonatal mice. Conclusions: The marsupial opossum maintains cardiomyocyte proliferation and a capacity for myocardial regeneration for at least 2 weeks after birth. As far as we are aware, this is the longest postnatal duration of such a capacity among mammals examined to date. AMPK signaling was implicated as an evolutionarily conserved regulator of mammalian postnatal cardiomyocyte proliferation.

OBJECTIVE The aim of the study was to develop a formula for predicting the probability of malignancy of mucinous cystic neoplasm (MCN) of the pancreas with ovarian-type stroma. METHODS A total of 364 patients were enrolled. A total score was calculated as the sum of the approximate integers of the odds ratios of the predictive factors identified by multivariate analysis. The relationship between the total score and pathological results was assessed. RESULTS A total of 321 patients had benign MCN and 43 had malignant MCN. Five possible predictive factors were analyzed: 56 years or older, high serum carcinoembryonic antigen level, high carbohydrate antigen 19-9 level, tumor size of 51 mm or greater, and the presence of mural nodules. The total score was significantly higher in patients with malignant MCN (median, 24; range, 0-37) compared with benign MCN (median, 5; range, 0-33; P < 0.001). Receiver operating characteristic curve analysis demonstrated that the area under the curve was 0.86, and the sensitivity and specificity of the total score for discriminating malignant MCNs were 72% and 83%, respectively, using a cut-off value of 22. CONCLUSIONS The current simple formula can predict the malignancy of MCN and may thus contribute to the adequate management of patients with MCN.

Background: Many cancers express heme oxygenase-1 ­(HO-1) at a higher frequency than healthy tissues, and this elevated expression is associated with cancer prognosis. Here, we aim to clarify the correlation between HO-1-expressing macrophage numbers and clinicopathological parameters of advanced colorectal cancer. Materials and Methods: Formalin-fixed and paraffin-embedded tissues of patients with advanced colorectal cancer were used. To detect HO-1 expression in macrophages, immunohistochemistry was performed. The number of positive cells was measured. Furthermore, HO-1 mRNA in colorectal cancer was examined by reverse transcription polymerase chain reaction. Results: Among the HO-1-negative and HO-1-positive groups, 58.02 and 85.00% of cases, respectively, were positive for lymph node metastasis. The disease-free survival (DFS) time was significantly shorter (p < 0.05) in the ­HO-1-positive group (2.44 years) than in the HO-1-negative group (4.09 years). However, according to the Cox proportional-hazards regression model, the HO-1-positive group could not be a risk factor of poor prognosis. HO-1 mRNA expression was confirmed in colorectal normal and cancer tissues. Conclusion: In this study, the correlation between HO-1-expressing macrophages and clinicopathological parameters in the tumor microenvironment of colorectal cancer was studied for the first time, and the expression was associated with lymph node metastasis and shortening of DFS.

For safe laparoscopic gastrectomy, it is essential to secure a good visual field by employing liver retraction. We have developed a safe and easy method for liver retraction using a silicone disc, and evaluated its feasibility.We analyzed retrospectively 36 patients with gastric cancer, who underwent laparoscopic distal gastrectomy employing liver retraction by a silicone disc and needle forceps (Silicone group) or by the Penrose drain method (Penrose group) between January 2013 and July 2016. The time needed for liver retraction, complications resulting from it, and postoperative liver dysfunction were compared between the two groups.In all patients in both groups, the operation was performed successfully, obtaining an appropriate visual field. The mean time required for liver retraction was 633.8 ± 286.6 seconds in the Silicone group and 639.8 ± 328.6 seconds in the Penrose group (P = .954). Postoperative elevation of either aspartate transaminase (AST) or alanine aminotransferase (ALT) level was recognized in 13 (72.2%) of the Silicone group patients and 18 (100%) of the Penrose group patients (P = .0160). The mean AST and ALT levels in the Silicone group were significantly lower than those in the Penrose group on postoperative days 0, 1, and 3. Among intraoperative complications related to liver retraction, hemorrhage from the abdominal wall occurred in one Silicone group case and hemorrhage from liver occurred in one Penrose group case.Liver retraction using a silicone disc and needle forceps in laparoscopic gastrectomy is easy and safe, offering a good visual field and a reduced degree of liver dysfunction.

To identify non-cell-autonomous effectors of cardiomyocyte mitosis, we analyzed a transcriptomic screen of regenerating and non-regenerating neonatal hearts for differentially-expressed secreted proteins – which we hypothesized could include candidate mitogens. We identified and validated IGFBP3, which has a Janus-like stabilizing and sequestering effect on IGF growth factors, as a neonatal injury-associated secreted protein. IGFBP3 is expressed by and secreted from vascular cells in the neonatal heart after cardiac injury, notably in the infarct border zone. We found that global deletion of IGFBP3 blunted neonatal regeneration, while gain-of-function experiments using recombinant IGFBP3 and a transgenic mouse model uncovered a pro-mitotic effect of IGFBP3 on cardiomyocytes in vitro and in the adult heart. We show that site-specific expression of an IGFBP3 protease (PAPP-A2) and its inhibitor (STC2) coordinate the spatial release of IGF2 in the infarct zone to regio-selectively activate the INSR-ERK-AKT cell growth pathways in cardiomyocytes. Collectively, our work highlights the spatiotemporal orchestration of endothelial-cardiomyocyte interactions that are required for neonatal cardiac regeneration.

Mammalian cardiomyocytes maintain proliferative capacity until early neonatal stage, with most of them being arrested from the cell cycle shortly after birth. Therefore, adult mammalian heart cannot regenerate myocardial injury. Despite much attention, pharmacological approaches for the induction of cardiomyocyte proliferation and heart regeneration have yet to be successful. To induce cardiomyocyte proliferation by drug administration, we focused on benzyl isothiocyanate (BITC). Firstly, we showed that BITC induces cardiomyocyte proliferation both in vitro and in vivo through the activation of the cyclin-dependent kinase (CDK) pathway. In addition, we demonstrated that BITC treatment induces heart regeneration in the infarcted neonatal heart even after the regeneration period. Furthermore, we administered BITC to adult mice in parallel with mild hypoxia (10% O2) treatment and showed that a combination of BITC administration and mild hypoxia exposure induces cell cycle reentry in the adult heart. The present study suggests that pharmacological activation of the CDK pathway with BITC concurrently with the activation of hypoxia-related signaling pathways may enable researchers to establish a novel strategy to induce cardiac regeneration in patients with heart disease.

Nuclear lamina is a fundamental structure of the cell nucleus and regulates a wide range of molecular pathways. Defects of components of the nuclear lamina cause ageing-like physiological disorders, called laminopathy. Generally, ageing and diseases are often associated with perturbation of various time-of-day–dependent regulations, but it remains elusive whether laminopathy induces any changes of the circadian clock and physiological rhythms. Here, we demonstrated that deficiency of Lmna gene in mice caused an obvious shift of locomotor activities to the daytime. The abnormal activity profile was accompanied by a remarkable change in phase angle between the central clock in the suprachiasmatic nucleus (SCN) and the lung peripheral clocks, leaving the phase of the SCN clock unaffected by the mutation. These observations suggest that Lmna deficiency causes a change of the habitat from nocturnal to diurnal behaviours. On the other hand, molecular oscillation and its phase resetting mechanism were intact in both the Lmna-deficient cells and progeria-mimicking cells. Intriguingly, high-fat diet feeding extended the short lifespan and ameliorated the abnormalities of the behaviours and the phase of the peripheral clock in the Lmna-deficient mice. The present study supports the important contribution of the energy conditions to a shift between the diurnal and nocturnal activities.

The oxidation reaction greatly alters characteristics of various cellular components. In exchange for efficient energy production, mitochondrial aerobic respiration substantially increases the risk of excess oxidation of cellular biomolecules such as lipids, proteins, nucleic acids, and numerous small molecules. To maintain a physiologically balanced cellular reduction-oxidation (redox) state, cells utilize a variety of molecular machineries including cellular antioxidants and protein degradation complexes such as the ubiquitin-proteasome system or autophagy. In the past decade, biomolecular liquid-liquid phase separation (LLPS) has emerged as a subject of great interest in the biomedical field, as it plays versatile roles in the maintenance of cellular homeostasis. With regard to redox homeostasis, LLPS arose as a major player in both well-characterized and newly emerging redox pathways. LLPS is involved in direct redox imbalance sensing, signal transduction, and transcriptional regulation. Also, LLPS is at play when cells resist redox imbalance through metabolic switching, translational remodeling, activating the DNA damage response, and segregation of vulnerable lipids and proteins. On the other hand, chronic accumulation of phase-separated molecular condensates such as lipid droplets and amyloid causes neurotoxic outcomes. In this review we enumerate recent progress on understanding how cells utilize LLPS to deal with oxidative stress, especially related to cell survival or pathogenesis, and we discuss future research directions for understanding biological phase separation in cellular redox regulation.

Recent interest in understanding cardiomyocyte cell-cycle has been driven by potential therapeutic applications in cardiomyopathy. However, despite recent advances, cardiomyocyte mitosis remains a poorly understood process. For example, it is unclear how sarcomeres are disassembled during mitosis to allow abscission of daughter cardiomyocytes. Here we identify adducin as a regulator of sarcomere disassembly during mammalian cardiomyocyte mitosis. α/γ-adducins are selectively expressed in neonatal mitotic cardiomyocytes, and their levels decline precipitously thereafter. Cardiomyocyte-specific overexpression of various splice isoforms and phosphoforms of α-adducin in-vitro and in-vivo identified Thr445/Thr480 phosphorylation of a short isoform of α adducin as a potent inducer of neonatal cardiomyocyte sarcomere disassembly. Concomitant overexpression of this α-adducin variant along with γ-adducin resulted in stabilization of the adducin complex and persistent sarcomere disassembly in adult mice, which is mediated by interaction with α-actinin. These results highlight an important mechanism for coordination of cytoskeletal morphological changes during cardiomyocyte mitosis.

Objective This study assessed whether neoadjuvant chemoradiotherapy (CRT) with S-1 increases the R0 resection rate in borderline resectable pancreatic cancer (BRPC). Summary background data Although a multidisciplinary approach that includes neoadjuvant treatment has been shown to be a better strategy for BRPC than upfront resection, a standard treatment for BRPC has not been established. Methods A multicenter, single-arm, phase II study was performed. Patients who fulfilled the criteria for BRPC received S-1 (40 mg/m bid) and concurrent radiotherapy (50.4 Gy in 28 fractions) before surgery. The primary endpoint was the R0 resection rate. At least 40 patients were required, with a one-sided α = 0.05 and β = 0.05 and expected and threshold values for the primary endpoint of 30% and 10%, respectively. Results Fifty-two patients were eligible, and 41 were confirmed to have definitive BRPC by a central review. CRT was completed in 50 (96%) patients and was well tolerated. The rate of grade 3/4 toxicity with CRT was 43%. The R0 resection rate was 52% among the 52 eligible patients and 63% among the 41 patients who were centrally confirmed to have BRPC. Postoperative grade III/IV adverse events according to the Clavien-Dindo classification were observed in 7.5%. Among the 41 centrally confirmed BRPC patients, the 2-year overall survival rate and median overall survival duration were 58% and 30.8 months, respectively. Conclusions S-1 and concurrent radiotherapy appear to be feasible and effective at increasing the R0 resection rate and improving survival in patients with BRPC. Trial registration UMIN000009172.

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.

Background It is yet a mystery whether dendritic cells (DCs) contact cancer stem cells (CSCs) and uptake CSC antigens in intrahepatic cholangiocarcinoma (ICC). The aim of this study was to examine the histological relationship between tumour cells expressing CSC markers and DCs infiltrating ICC. In addition, clinicopathological factors, including progression-free survival (PFS) and overall survival (OS), were compared between cases with many and few CSC marker-positive cells. Materials and methods Resected tissue sections of 22 cases with ICC were used for immunostaining to detect DC infiltration into ICC tumour nests positive for CD1a, DC-SIGN, DEC205, DC-LAMP, and CD123 and to detect ICC tumour cells positive for CSC markers such as CD44v9, EpCAM, and Sox9. The relationship between the number of CSC marker-positive cells and ICC clinicopathological factors was examined by Kaplan-Meier method and univariate and multivariate analyses using the Cox proportional hazards model. Results CD1a+ immature DCs infiltrated ICC tumour nests significantly more than the other types of DCs. Furthermore, they were frequently localized within CD44v9− and EpCAMhigh ICC tumour nests. According to Kaplan-Meier method, PFS and OS were longer in the Sox9high group than in the Sox9low group, and according to both univariate and multivariate analyses, Sox9 expression was an independent factor. Conclusion The present study first demonstrated that CD1a+ immature DCs frequently infiltrated CD44v9− and EpCAMhigh ICC tumour nests, suggesting the possibility of cell-to-cell contact between epithelial type immature DCs and CSCs in ICC. Furthermore, it was suggested that Sox9 expression in ICC may be a prognostic factor.

BACKGROUND Rapid urinary trypsinogen-2 dipstick test and levels of urinary trypsinogen-2 and trypsinogen activation peptide (TAP) concentration have been reported as prognostic markers for the diagnosis of acute pancreatitis. AIM To reconfirm the validity of all these markers in the diagnosis of acute pancreatitis by undertaking a multi-center study in Japan. METHODS Patients with acute abdominal pain were recruited from 17 medical institutions in Japan from April 2009 to December 2012. Urinary and serum samples were collected twice, at enrollment and on the following day for measuring target markers. The diagnosis and severity assessment of acute pancreatitis were assessed based on prognostic factors and computed tomography (CT) Grade of the Japanese Ministry of Health, Labour, and Welfare criteria. RESULTS A total of 94 patients were enrolled during the study period. The trypsinogen-2 dipstick test was positive in 57 of 78 patients with acute pancreatitis (sensitivity, 73.1%) and in 6 of 16 patients with abdominal pain but without any evidence of acute pancreatitis (specificity, 62.5%). The area under the curve (AUC) score of urinary trypsinogen-2 according to prognostic factors was 0.704, which was highest in all parameter. The AUC scores of urinary trypsinogen-2 and TAP according to CT Grade were 0.701 and 0.692, respectively, which shows higher than other pancreatic enzymes. The levels of urinary trypsinogen-2 and TAP were significantly higher in patients with extended extra-pancreatic inflammation as evaluated by CT Grade. CONCLUSION We reconfirmed urinary trypsinogen-2 dipstick test is useful as a marker for the diagnosis of acute pancreatitis. Urinary trypsinogen-2 and TAP may be considered as useful markers to determine extra-pancreatic inflammation in acute pancreatitis.

Highlights • Acute pancreatitis is one of complication of pancreaticoduodenectomy. • Delayed severe acute pancreatitis which needs intensive care is very rare. • Necrosectomy effective treated abdominal abscess, but it is important to avoid injury to surrounding organs. • Clinicians should be aware that severe pancreatitis chould occur even after pancreatectomy., Introduction Acute pancreatitis is a known complication of pancreaticoduodenectomy (PD). However, no reports in the literature describe a late delayed severe acute pancreatitis. We report a case of acute pancreatitis 5 years after PD in a patient who needed intensive care for his complication. Presentation of case A 64-years-old man presented with upper abdominal pain and reported a history of PD 5 years prior to presentation. Contrast-enhanced computed tomography revealed an edematous pancreatic remnant with inflammation of the surrounding tissue, and he was diagnosed with acute pancreatitis. His condition worsened, and he was transferred to our hospital the following day. He was admitted to the intensive care unit to manage respiratory and circulatory insufficiency. Although his condition improved, an abdominal abscess was identified, and necrosectomy was performed on day 43 of hospitalizaiton. We carefully removed as much necrotic tissue as was possible without injury to the pancreaticojejunal anastomosis and the ascending colon. Inflammation gradually subsided, and he was discharged on day 111 of hospitalization. The last drain was removed in day 133 of admission to our hospital. Pancreatitis and abdominal abscess have not recurred until the time of writing this paper. Discussion Delayed severe acute pancreatitis is rare. Necrosectomy can treat an abdominal abscess; however it is important to avoid injury to other organs. Conclusion Clinicians should be aware that severe acute pancreatitis can occur after PD.

This is the first report of terahertz (THz) radiation from intrinsic Josephson junction devices made of solid Bi 2 Sr 2 CaCu 2 O 8+δ thin films. It is shown that in situ laser trimming of the current lead structure could activate initially THz inactive devices. The trimming increased inductive reactance and improved RF isolation of intrinsic Josephson junctions. It is considered that the RF isolation is a key component to maintain a cavity resonance within intrinsic Josephson junctions essential to create THz waves from solid Bi-2212 film IJJ devices.

The patient was a 70-year-old woman in whom examination revealed a high level of carbohydrate antigen 19-9. Abdominal ultrasonography and computed tomography (CT) revealed a multilocular cystic lesion compressing the gallbladder. CT indicated the presence of a multilocular cystic tumor (67 × 68 × 72 mm) in contact with the right hepatic lobe. Intraoperative findings indicated that the cyst diameter was 8.5 × 6.0 cm, and the cyst was continuous with the gallbladder. The gallbladder was resected along with the cyst. The cyst was multilocular and originated from the cystic duct and gallbladder wall. The cyst wall contained cuboidal to columnar mucin-producing epithelial cells and ovarian-like stroma (OS). The final diagnosis was mucinous cystic neoplasm (MCN) of the gallbladder with low-grade dysplasia. In the 2010 WHO classification of tumors of the digestive system, MCN have been newly defined as a type of hepatobiliary tract epithelial neoplasms. MCN of the gallbladder with OS is extremely rare. Only three cases have been published in the literature. The presence of OS is necessary for diagnosis of MCN.

In this paper, the authors discuss process planning for the lateral extrusion of a pipe with a lost core. In this process, maximum longitudinal length of the bulged part is restricted by the balance of the extrusion speed of the material and the lost core. In the free bulging condition, longitudinal length is limited to the pipe radius, because the extrusion speed of the core is slower than that of the pipe material when the longitudinal length of the bulged part is longer. The authors designed a two-stage forming process using the transit shape of a truncated cone to solve this problem. The dimensions of the truncated cone were estimated through trial-and-error using a commercial FEM simulator and considering the stretch effect for wrinkles of the pipe by deformation and traveling of the lost core. Finally, the authors conducted experiments to confirm the design’s validity. As a result, a longer longitudinal length of the bulged part than the pipe radius was successfully obtained.

Objective We sought to identify clinicopathological characteristics of high-grade pancreatic intraepithelial neoplasia (PanIN)/carcinoma in situ to facilitate screening for pancreatic ductal adenocarcinoma. Methods We evaluated PanIN lesions in 173 consecutive autopsy cases with no evidence of pancreatic ductal adenocarcinoma and/or intraductal papillary mucinous neoplasm (mean age, 80.5 years) by submitting the entire pancreas for microscopic examination. Results PanIN-3 was found in 4% of examined cases, whereas PanIN-1 and PanIN-2 were present in 77% and 28%, respectively. PanIN-3 was more frequently identified in patients with diabetes mellitus and/or older age. PanIN-3 lesions were always multifocal, and the number of PanIN-3 foci was positively associated with those of PanIN-1 or PanIN-2. PanIN-3 was located more frequently in the pancreatic body and tail than in the head and predominantly involved small interlobular/intralobular ducts rather than the main duct. Notably, 71% of pancreata with PanIN-3 showed cystic changes in PanIN-3 and lower grade PanIN lesions. PanIN-3 was also accompanied by higher grade extralobular fibrosis. Conclusions We found that 4% of the examined pancreata harbored PanIN-3 lesions that were associated with several unique clinicopathological features. The cystic change along with fibrotic pancreatic parenchyma may be detected by imaging studies such as endoscopic ultrasound.

OBJECTIVES This study aimed to clarify clinicopathological features of pancreatic cysts. METHODS Pancreata from 280 autopsies (median, 83 years; male, 146; female, 134) were sectioned every 5 mm. Cysts (

In this study, decomposition products of glycidyl palmitate (GP) of fatty acids heated at high temperature such as deep frying were investigated. When GP and tripalmitin (TP) were heated at 180 and 200 °C, they were decreased with heating time. The weight of GP was less than that of TP, although both GP and TP were converted to polar compounds after heating. The decomposition rate of GP was higher than TP. Both GP and TP produced considerable amounts of hydrocarbons and aldehydes during heating. Aldehydes produced from GP and TP included saturated aldehydes with carbon chain length of 3–10, while hydrocarbons consisted of carbon chain length of 8–15. It was observed that major hydrocarbons produced from GP during heating were pentadecane. Moreover, the level of carbon dioxide (CO2) released from GP was higher than that of TP. It was suggested that fatty acids in GE might be susceptible to decarboxylation. From these results, GP might be quickly decomposed to hydrocarbons, aldehydes and CO2 besides polar compounds by heating, in comparison with TP.

Approximately 50% of prostate cancers are associated with gene fusions of the androgen-regulated gene TMPRSS2 to the oncogenic erythroblast transformation-specific (ETS) transcription factor ERG. The three-dimensional proximity of TMPRSS2 and ERG genes, in combination with DNA breaks, facilitates the formation of TMPRSS2-ERG gene fusions. However, the origins of DNA breaks that underlie gene fusion formation in prostate cancers are far from clear. We demonstrate a role for inflammation-induced oxidative stress in the formation of DNA breaks leading to recurrent TMPRSS2-ERG gene fusions. The transcriptional status and epigenetic features of the target genes influence this effect. Importantly, inflammation-induced de novo genomic rearrangements are blocked by homologous recombination (HR) and promoted by non-homologous end-joining (NHEJ) pathways. In conjunction with the association of proliferative inflammatory atrophy (PIA) with human prostate cancer, our results support a working model in which recurrent genomic rearrangements induced by inflammatory stimuli lead to the development of prostate cancer.

The adult mammalian heart is incapable of regeneration following cardiomyocyte loss, which underpins the lasting and severe effects of cardiomyopathy. Recently, it has become clear that the mammalian heart is not a post-mitotic organ. For example, the neonatal heart is capable of regenerating lost myocardium, and the adult heart is capable of modest self-renewal. In both of these scenarios, cardiomyocyte renewal occurs via the proliferation of pre-existing cardiomyocytes, and is regulated by aerobic-respiration-mediated oxidative DNA damage. Therefore, we reasoned that inhibiting aerobic respiration by inducing systemic hypoxaemia would alleviate oxidative DNA damage, thereby inducing cardiomyocyte proliferation in adult mammals. Here we report that, in mice, gradual exposure to severe systemic hypoxaemia, in which inspired oxygen is gradually decreased by 1% and maintained at 7% for 2 weeks, results in inhibition of oxidative metabolism, decreased reactive oxygen species production and oxidative DNA damage, and reactivation of cardiomyocyte mitosis. Notably, we find that exposure to hypoxaemia 1 week after induction of myocardial infarction induces a robust regenerative response with decreased myocardial fibrosis and improvement of left ventricular systolic function. Genetic fate-mapping analysis confirms that the newly formed myocardium is derived from pre-existing cardiomyocytes. These results demonstrate that the endogenous regenerative properties of the adult mammalian heart can be reactivated by exposure to gradual systemic hypoxaemia, and highlight the potential therapeutic role of hypoxia in regenerative medicine.

Objective The aim of the study was to clarify the correlation between the microenvironmental factors and histological grade in intraductal papillary mucinous neoplasm (IPMN). Methods We investigated 65 IPMNs resected at Yamagata University Hospital between 2000 and 2011, and all cases were categorized to low-inter (including low- and intermediate-grade dysplasia) and high-inv (including high-grade dysplasia and IPMN with an associated invasive carcinoma) groups. We compared between the 2 groups pathologically with regard to fibrosis and the expression of alpha-smooth muscle actin (α-SMA), periostin, and galectin-1 in the periductal stroma of IPMN. Results There were 41 low-inter and 24 high-inv. The subtype was categorized as 22 main duct type (MD-IPMN) and 43 branch duct type (BD-IPMN). The degree of fibrosis and the expression of α-SMA, periostin, and galectin-1 were significantly higher in high-inv than in low-inter within BD-IPMNs. Multivariate logistic regression analysis indicated that high expression of α-SMA (odds ratio, 13.802; 95% confidence interval, 1.108-171.893; P = 0.0414) was a significant independent related factor of high-inv in BD-IPMN. Conclusions Stromal fibrosis and expression of α-SMA, periostin, and galectin-1 are more marked in high-inv than in low-inter within BD-IPMNs, and they could become new markers for determining the indications for surgery in BD-IPMN.

Background It is well known that pancreatic ductal adenocarcinoma (PDAC) is accompanied with pancreatic atrophy and fibrosis. We previously reported the correlation between pancreatic volume and body surface area (BSA) and significant reduction of BSA-adjusted pancreatic volume in pancreatic cancer patients. We evaluated potential correlation between BSA-adjusted pancreatic volume and PDAC prognosis. Methods The study subjects were 48 pancreatic cancer patients received pancreatectomy at our department from June 2006 to September 2012. Pancreatic volumetry was retrospectively performed using the images obtained from multidetector computed tomography before the surgery. BSA-adjusted pancreatic volumes were calculated and analyzed for potential correlation with the prognosis. Results Average BSA-adjusted pancreatic volume among 48 cases was 35.4 ± 11.9 ml/m(2) . Types of surgery included 24 cases with pancreaticoduodenectomy and 24 cases with distal pancreatectomy. The cases with BSA-adjusted pancreatic volume less than 40 ml/m(2) had significantly poorer prognosis compared to the cases of 40 ml/m(2) and greater (3-year survival rate: 32.4% vs. 64.3%). Statistical analysis identified four prognosis factors, i.e. BSA-adjusted pancreatic volume less than 40 ml/m(2) , postoperative adjuvant chemotherapy, lymph node metastasis and lymphatic invasion. Conclusions This study demonstrated BSA-adjusted pancreatic volume as a prognosis factor for PDAC and the volume of 40 ml/m(2) is considered to be the cutoff value.

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)–positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B‐cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1‐3 of FL. Reverse transcription–polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα‐positive cells strongly correlated with the width of GCs (r s = 0.81, P

Heart failure is a devastating disease that affects more than 26 million individuals worldwide and has a 5-year survival rate of less than 50%, with its development in part reflecting the inability of the adult mammalian heart to regenerate damaged myocardium. In contrast, certain vertebrate species including fish and amphibians, as well as neonatal mammals, are capable of complete cardiac regeneration after various types of myocardial injury such as resection of the ventricular apex or myocardial infarction, with this regeneration being mediated by the proliferation of cardiomyocytes, dissolution of temporary fibrosis, and revascularization of damaged tissue. In an effort to identify regulators of cardiac regeneration and to develop novel therapeutic strategies for induction of myocardial regeneration in the adult human heart, recent studies have adopted an approach based on comparative biology. These studies have pointed to cellular or tissue responses to environmental cues-including activation of the immune system, the reaction to mechanical stress, and the adoption of oxidative metabolism-as key determinants of whether the heart undergoes regeneration or nonregenerative scar formation after injury. We here summarize recent insight into the molecular mechanisms as well as environmental and systemic factors underlying cardiac regeneration based on the findings of inter- or intraspecific comparisons between regenerative and nonregenerative responses to heart injury. We also discuss how recent progress in understanding the molecular, systemic, and environmental basis of cardiac regeneration in a variety of organisms may relate to multiple scientific fields including ecology, evolutionary as well as developmental biology.

The aim of this study was to evaluate the clinicopathological features of solid pseudopapillary neoplasms (SPNs).In this retrospective study, 288 SPNs were analyzed.Overall, 214 patients (74%) were female. Distant metastases occurred in 4 patients, and splenic vein tumor thrombus occurred in 1 patient. Although imaging findings showed large (2.0 cm) SPNs with clear, regular border, and heterogeneous internal structure, small SPNs appeared as almost entirely solid. Surgical resection was performed in 278 cases. The 5-year survival rate was 98.8%. Six patients had tumor recurrence after the initial resection. The detection rate in typical pathological findings was low for small SPNs. Tumor extension to the pancreatic parenchyma was detected in greater than 70% of the cases. Tumor invasion to adjacent organs was detected in 13 cases. One was given a diagnosis of apparent high-grade malignant transformation.The proportion of male cases was higher than that in previous studies, and there were statistically significant differences in the onset age and tumor diameter between male and female patients. Therefore, women seemed to have an early occurrence of SPNs, suggesting a difference in the developmental stage between men and women. Images and pathological findings of SPNs varied according to tumor size. Our findings indicated that SPN patients have excellent survival after margin-negative surgical resection.

The forkhead box C2 (Foxc2) protein is a member of the forkhead/winged helix transcription factor family and plays an essential role in cardiovascular development. Previous studies showed that Foxc2 null mouse embryos die during midgestation or just after birth with severe cardiovascular defects, including interruption, coarctation of the aortic arch and ventricular septal defects. These are also seen in human congenital heart disease. However, the tissue specific role of Foxc2 in aortic arch remodelling is not yet fully understood. Here we show that Foxc2 is expressed in a restricted pattern in several cell populations, including the mesenchyme and endothelium of pharyngeal arch arteries, which are important for cardiovascular development. In this study, we use a conditional knockout approach to examine the tissue specific role of Foxc2 in aortic arch remodelling. We demonstrate that mouse embryos lacking Foxc2 in Nkx2.5-expressing mesenchyme and endothelium of pharyngeal arch arteries display aortic arch interruption type B and ventricular septal defects. In contrast, conditional deletion of Foxc2 in Tie2-expressing endothelial cells does not result in aortic arch or ventricular septal defects, but does result in embryonic lethality due to peripheral oedema. Our data therefore provide for a detailed understanding of the role of mesenchymal Foxc2 in aortic arch remodelling and in the development of ventricular septum.