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Background The renal tissue renin--angiotensin system is known to be activated by salt loading in salt-sensitive rats; however, the response in other organs remains unclear. Method Spontaneously hypertensive rats were subjected to normal tap water or transient high-salt-concentration water from 6 to 14 weeks of age and were thereafter given normal tap water. From 18 to 20 weeks of age, rats given water with a high salt concentration were treated with an angiotensin II type 1 receptor blocker, valsartan. Results Sustained blood pressure elevation by transient salt loading coincided with a persistent decrease in the fecal sodium content and sustained excess of the circulating volume in spontaneously hypertensive rats. Administration of valsartan sustainably reduced the blood pressure and normalized the fecal sodium levels. Notably, transient salt loading persistently induced the intestinal tissue renin--angiotensin system and enhanced sodium transporter expression exclusively in the small intestine of salt-sensitive rats, suggesting the potential connection of intestinal sodium absorption to salt sensitivity. Conclusion These results reveal the previously unappreciated contribution of the intestinal tissue renin--angiotensin system to sodium homeostasis and blood pressure regulation in the pathophysiology of salt-sensitive hypertension.

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by −3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by −17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was −7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by −13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Background/objectives Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. Methods We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. Results In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. Conclusions Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

Background/objectives Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer. Methods Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo. Results Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine. Conclusions A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.

Background Hepatic inflammatory pseudotumor (IPT) is a rare benign lesion. Because there is no specific laboratory marker or radiographic appearance, the majority of reported cases of hepatic IPT have been diagnosed after surgery or at autopsy. The etiology of hepatic IPT remains unclear but several mechanisms have been postulated such as infection or immune reaction. Case presentation A 79-year-old woman had been seeing her family doctor for hypertension, and she had been diagnosed with liver dysfunction for about 10 years. She continued attending follow-ups because of her drinking habit. Two months before her visiting our institution, further elevation of hepatobiliary enzymes was noted, and abdominal ultrasonography showed a hepatic tumor 4 cm in diameter in the lateral segment, so she was referred to our hospital. Hepatocellular carcinoma (HCC) was suspected because alpha-fetoprotein (102 ng/ml) (AFP) and lectin 3 (L3) fraction (85.4%) were elevated and the appearance on enhanced computed tomography was not inconsistent with HCC. Thus, we performed laparoscopic hepatectomy. She recovered uneventfully and was discharged on postoperative day 7. Pathological diagnosis revealed that the tumor was hepatic IPT and that the background liver condition was primary biliary cholangitis (PBC). AFP and L3 fraction decreased to normal ranges after surgery. Conclusions In 7 of 29 patients (24.1%) with reported cases of tumor markers in liver IPT, carbohydrate antigen 19-9 was elevated and AFP was elevated in 2 of 58 patients (3.4%). AFP is also frequently elevated in benign liver diseases such as hepatitis and liver cirrhosis, and L3 fraction has been used as a tumor marker for HCC with high specificity. To our knowledge, this is the first report of a case diagnosed with liver IPT in which AFP and L3 fraction increased before surgery and decreased to the normal range after resection. This confirms the rarity of hepatic IPT associated with PBC and elevated AFP and L3 fraction.

This study was performed to evaluate the surgical indication for intraductal papillary mucinous neoplasm (IPMN) advocated by the 2017 revised International Association of Pancreatology consensus guidelines (IAPCG2017). The medical records of 63 patients who underwent pancreatectomy for IPMN were retrospectively reviewed. Thirteen patients had main-duct IPMN, 25 had mixed IPMN, and 25 had branch-duct IPMN with frequencies of high-grade dysplasia or invasive carcinoma of 62, 24, and 28%, respectively. The sensitivity and specificity of high-risk stigmata for high-grade dysplasia or invasive carcinoma advocated by the IAPCG2017 were 90 and 67%, respectively. Of 17 patients with invasive carcinoma, all patients had high-risk stigmata, and 16 had an enhanced mural nodule (MN) of ≥ 5 mm. The sensitivity and specificity of a ≥ 5-mm enhanced MN for predicting invasive carcinoma were 94% and 87%, respectively. Introducing a size threshold for enhanced MNs into the assessment of high-risk stigmata increases the specificity without jeopardizing the sensitivity. The surgical indication for any type of IPMN may be determined using only a ≥ 5-mm enhanced MN. When the type of IPMN is classified strictly, about half of IPMNs are mixed type, and most are benign. The surgical indication for mixed IPMN should be reconsidered.

The benefit of pancreatectomy for elderly patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. Moreover, adjuvant chemotherapy (AC) for elderly patients has not been fully evaluated. We investigated the long-term outcomes after pancreatectomy for PDAC in elderly patients with special reference to AC. The medical records of 123 patients who underwent pancreatectomy for PDAC from 2007 to 2016 were retrospectively reviewed. The patients were divided into two groups: young (

Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10–70%) and low (

Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

This study aimed to evaluate the safety and efficacy of endoscopic transpapillary pancreatic duct stent placement (ETPS) for symptomatic peripancreatic fluid collection caused by postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). ETPS was also compared with percutaneous drainage (PTD). Retrospectively 38 patients were studied who developed clinically relevant POPF. Of 38 patients, 4 underwent PTD and 11 underwent ETPS. Technical and clinical success rates of ETPS (100% and 91%, respectively) were comparable with PTD (100% and 75%, respectively). The tip of a pancreatic stent was placed over the pancreatic stump in 4 patients and draining of pus through the pancreatic stent was observed. The hospital stay after DP and the interval from intervention to discharge were significantly shorter in the ETPS group than in the PTD group. ETPS is safe and successful for managing peripancreatic fluid collection caused by POPF after DP and should be considered as a therapeutic option.

The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.

Chronic kidney disease (CKD) impairs physical performance in humans, which leads to a risk of all-cause mortality. In our previous study, we demonstrated that a reduction in muscle mitochondria rather than muscle mass was a major cause of physical decline in 5/6 nephrectomized CKD model mice. Because ghrelin administration has been reported to enhance oxygen utilization in skeletal muscle, we examined the usefulness of ghrelin for a recovery of physical decline in 5/6 nephrectomized C57Bl/6 mice, focusing on the epigenetic modification of peroxisome proliferator activated receptor gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. The mice were intraperitoneally administered acylated ghrelin (0.1 nmol/gBW; three times per week) for a month. Muscle strength and exercise endurance were measured by using a dynamometer and treadmill, respectively. Mitochondrial DNA copy number was determined by quantitative PCR. The methylation levels of the cytosine residue at 260 base pairs upstream of the translation initiation point (C-260) of PGC-1α, which has been demonstrated to decrease the expression, was evaluated by methylation-specific PCR and bisulfite genomic sequencing methods after the ghrelin administration. Ghrelin administration improved both muscle strength and exercise endurance in the mice and was associated with an increase in muscle mass and muscle mitochondrial content. Ghrelin administration decreased the methylation ratio of C-260 of PGC-1α in the skeletal muscle and increased the expression. Therefore, ghrelin administration effectively reduced the physical decline in 5/6 nephrectomized mice and was accompanied with an increased mitochondrial content through de-methylation of the promoter region of PGC-1α in the muscle.

Background Salinomycin has cytotoxic effects on various types of malignancy and induces autophagy. However, it has not been clarified whether autophagy induced by salinomycin treatment has a protective or cytotoxic role. We investigated whether salinomycin affects autophagy in pancreatic cancer cells and whether autophagy induced by salinomycin treatment has a protective or cytotoxic role in these cells. Methods We investigated the effect of salinomycin using three pancreatic cancer cell lines. We investigated effect on proliferation and the CD133 positive fraction using flow cytometry. In addition, we monitored the change in autophagic activity after salinomycin treatment using fluorescent immunostaining, western blotting, and flow cytometry. Finally, knockdown of ATG5 or ATG7 by siRNA was used to investigate the impact of autophagy inhibition on sensitivity to salinomycin. Results Salinomycin suppressed the proliferation of pancreatic cancer cells in a concentration dependent manner, and reduced the CD133 positive fraction. Salinomycin enhanced autophagy activity in these cells in a concentration dependent manner. Autophagy inhibition made pancreatic cancer cells more sensitive to salinomycin. Conclusions Our data provide the first evidence indicating that autophagy induced by salinomycin have a protective role in pancreatic cancer cells. A new therapeutic strategy of combining salinomycin, autophagy inhibitors, and anticancer drugs could hold promise for pancreatic cancer treatment.

Objective:Intermittent fasting (IF) has benefits in increasing insulin sensitivity and lowering body weight. However, the underlining mechanism for the beneficial effects has not been elucidated so far.Design and method:Mice were subjected to a severe IF regimen, in which they were fasted for 72 hou

The clinical importance of intraoperative peritoneal cytology in patients with pancreatic cancer remains incompletely understood.Peritoneal washing samples were collected from 411 consecutive patients with pancreatic ductal adenocarcinoma from 1996 to 2014. Of the 411 patients, 335 underwent macroscopically curative resection and 76 with noncurative factors did not undergo resection. We compared long-term outcomes between patients with positive cytology (cytology+) and those with negative cytology (cytology-) and investigated the importance of clinicopathologic factors.Of 335 patients with curative resection, 300 (89.6%) were cytology- and 35 (10.4%) were cytology+. The median overall survival of cytology+ patients was less than that of cytology- patients (16 vs 31 months, respectively; P .0001). The median overall survival of cytology+ patients with noncurative factors was significantly worse than that of cytology+ patients with curative resection (6.9 vs 16.0 months, respectively; P = .0023). The median disease-free survival of cytology+ patients was less than that of cytology- patients (6.5 vs 16 months, respectively; P .0001). In the multivariate analysis, cytology+ was an independent prognostic factor for overall survival and disease-free survival.Cytology+ without noncurative factors was a predictive factor for a poor prognosis. Therefore, it is important to regard patients with pancreatic cancer characterized by cytology+ as a special group that may warrant more aggressive adjuvant therapy.

This paper presents a glitchy-clock generator integrated in FPGA for evaluating fault injection attacks and their countermeasures on cryptographic modules. The proposed generator exploits clock management capabilities, which are common in modern FPGAs, to generate clock signal with temporal voltage spike. The shape and timing of the glitchy-clock cycle are configurable at run time. The proposed generator can be embedded in a single FPGA without any external instrument (e.g., a pulse generator and a variable power supply). Such integration enables reliable and reproducible fault injection experiments. In this paper, we examine the characteristics of the proposed generator through experiments on Side-channel Attack Standard Evaluation Board (SASEBO). The result shows that the timing of the glitches can be controlled at the step of about 0.17ns. We also demonstrate its application to the safe-error attack against an RSA processor.

This paper presents a glitchy-clock generator integrated in FPGA for evaluating fault injection attacks and their countermeasures on cryptographic modules. The proposed generator exploits clock management capabilities, which are common in modern FPGAs, to generate clock signal with temporal voltage spike. The shape and timing of the glitchy-clock cycle are configurable at run time. The proposed generator can be embedded in a single FPGA without any external instrument (e.g., a pulse generator and a variable power supply). Such integration enables reliable and reproducible fault injection experiments. In this paper, we examine the characteristics of the proposed generator through experiments on Side-channel Attack Standard Evaluation Board (SASEBO). The result shows that the timing of the glitches can be controlled at the step of about 0.17 ns. We also demonstrate its application to the safe-error attack against an RSA processor.

Objective:Intermittent fasting (IF) has been shown to have benefits in increasing insulin sensitivity, stress resistance and lowering blood pressure. However, the underlining mechanism for the beneficial effects has not been elucidated yet.Design and method:Mice were subjected to a severe IF regimen

In this paper, we present an efficient countermeasure against fault sensitivity analysis (FSA) based on configurable delay blocks (CDBs). FSA is a new type of fault attack, which exploits the relationship between fault sensitivity (FS) and secret information. Previous studies reported that it could break cryptographic modules equipped with conventional countermeasures against differential fault analysis (DFA), such as redundancy calculation, masked and–or, and wave dynamic differential logic. The proposed countermeasure can thwart both DFA and FSA attacks based on setup time violation faults. The proposed ideas are to use a CDB as a time base for detection and to combine the technique with Li’s countermeasure concept that removes the dependency between FSs and secret data. The postmanufacture configuration of the CDBs allows minimization of the overhead in operating frequency that comes from manufacture variability. In this paper, we also present an implementation of the proposed countermeasure in application-specified integrated circuit, and describe its configuration method. We then investigate the hardware overhead of the proposed countermeasure for an advanced encryption standard processor and demonstrate its validity through an experiment.

This paper proposes a multiple-fault injection attack based on adaptive control of fault injection timing in embedded microprocessors. The proposed method can be conducted under the black-box condition that the detailed cryptographic software running on the target device is not known to attackers. In addition, the proposed method is non-invasive, without the depackaging required in previous works, since such adaptive fault injection is performed by precisely generating a clock glitch. In this paper, we demonstrate the validity of the proposed method through an experiment on Advanced Encryption Standard (AES) software with a typical recalculation-based countermeasure on an 8-bit microprocessor. We first describe the proposed method to inject two kinds of faults, designed to obtain a faulty output available for differential fault analysis and to avoid a conditional branch for the countermeasure, respectively. We then show an experimental result that the faulty output can be obtained by circumventing countermeasure without using information from the detailed instruction sequence. Furthermore, we proposed a countermeasure against our attack, which prevents the attackers from calling the output routine through skipping the branch or branch test instruction.

This paper qualitatively explores the relations between two kinds of side-channel leakages, i.e., the fault sensitivity (FS) and the power consumption. The FS is a relatively new active side-channel leakage, while the power consumption is one of the earliest researched passive side-channel leakage. These two side-channels are closely related with regard to both the security evaluation and the countermeasure proposal. This paper experimentally answers the following important issues such as the relationship between these two side-channels, whether they share the same leakage function and whether they can be protected by the same countermeasure. Based on two FPGA AES implementations without countermeasures, we first confirm a high correlation between the power consumption and the FS. Then, we construct the leakage profiles for the FS and the power consumption to explain the detailed relations between them. We also confirm a successful key recovery using the FS profile as the leakage model for power consumption. Based on these discoveries, we believe that FSA can be used as an evaluation tool to find the first-order leakage with less data-complexity, and it is more reasonable to achieve the countermeasures against FSA and power analysis from different design levels.

In this paper, we present an efficient countermeasure against Fault Sensitivity Analysis (FSA) based on a configurable delay blocks (CDBs). FSA is a new type of fault attack which exploits the relationship between fault sensitivity and secret information. Previous studies reported that it could break cryptographic modules equipped with conventional countermeasures against Differential Fault Analysis (DFA) such as redundancy calculation, Masked AND-OR and Wave Dynamic Differential Logic (WDDL). The proposed countermeasure can detect both DFA and FSA attacks based on setup time violation faults. The proposed ideas are to use a CDB as a time base for detection and to combine the technique with Li's countermeasure concept which removes the dependency between fault sensitivities and secret data. Post-manufacture configuration of the delay blocks allows minimization of the overhead in operating frequency which comes from manufacture variability. In this paper, we present an implementation of the proposed countermeasure, and describe its configuration method. We also investigate the hardware overhead of the proposed countermeasure implemented in ASIC for an AES module and demonstrate its validity through an experiment using a prototype FPGA implementation.

This paper describes a new configuration of the channeled spectropolarimeter and its application for the spectroscopic measurement of Mueller matrix. The new configuration uses the channeled spectroscopic polarization state generator (CSPSG) consisting of a polarizer and two high-order retarders. The channeled spectropolarimeter using the CSPSG has features that up to four independent polarimetric parameters about a sample can be determined simultaneously from a single channeled spectrum and that it is almost immune to the wavefront perturbations induced by the sample. To apply the channeled spectropolarimetry for the full measurement of Mueller matrix, the CSPSG is combined with a rotating compensator spectropolarimeter. All elements of the spectroscopic Mueller matrix are determined from four channeled spectra. Its feature is that it requires only one rotating component for the full Mueller matrix measurement.