Chemopreventive effect of resveratrol and apocynin on pancreatic carcinogenesis via modulation of nuclear phosphorylated GSK3β and ERK1/2

Despite progress in clinical cancer medicine in multiple fields, the prognosis of pancreatic cancer has remained dismal. Recently, chemopreventive strategies using phytochemicals have gained considerable attention as an alternative in the management of cancer. The present study aimed to evaluate the chemopreventive effects of resveratrol (RV) and apocynin (AC) in N-Nitrosobis(2-oxopropyl)amine-induced pancreatic carcinogenesis in hamster. RV- and AC-treated hamsters showed significant reduction in the incidence of pancreatic cancer with a decrease in Ki-67 labeling index in dysplastic lesions. RV and AC suppressed cell proliferation of human and hamster pancreatic cancer cells by inhibiting the G1 phase of the cell cycle with cyclin D1 downregulation and inactivation of AKT-GSK3β and ERK1/2 signaling. Further, decreased levels of GSK3β^Ser9 and ERK1/2 phosphorylation and cyclin D1 expression in the nuclear fraction were observed in cells treated with RV or AC. Nuclear expression of phosphorylated GSK3β^Ser9 was also decreased in dysplastic lesions and adenocarcinomas of hamsters treated with RV or AC in vivo. These results suggest that RV and AC reduce phosphorylated GSK3β^Ser9 and ERK1/2 in the nucleus, resulting in inhibition of the AKT-GSK3β and ERK1/2 signaling pathways and cell cycle arrest in vitro and in vivo. Taken together, the present study indicates that RV and AC have potential as chemopreventive agents for pancreatic cancer.     

Online measurement of oxygen enables continuous noninvasive evaluation of human‐induced pluripotent stem cell (hiPSC) culture in a perfused 3D hollow‐fiber bioreactor

For clinical and/or pharmaceutical use of human‐induced pluripotent stem cells (hiPSCs), large cell quantities of high quality are demanded. Therefore, we combined the expansion of hiPSCs in closed, perfusion‐based 3D bioreactors with noninvasive online monitoring of oxygen as culture control mechanism. Bioreactors with a cell compartment volume of 3 or 17 ml were inoculated with either 10 × 10⁶ or 50 × 10⁶ cells, and cells were expanded over 15 days with online oxygen and offline glucose and lactate measurements being performed. The CellTiter‐Blue® Assay was performed at the end of the bioreactor experiments for indirect cell quantification. Model simulations enabled an estimation of cell numbers based on kinetic equations and experimental data during the 15‐day bioreactor cultures. Calculated oxygen uptake rates (OUR), glucose consumption rates (GCR), and lactate production rates (LPR) revealed a highly significant correlation (p < 0.0001). Oxygen consumption, which was measured at the beginning and the end of the experiment, showed a strong culture growth in line with the OUR and GCR data. Furthermore, the yield coefficient of lactate from glucose and the OUR to GCR ratio revealed a shift from nonoxidative to oxidative metabolism. The presented results indicate that oxygen is equally as applicable as parameter for hiPSC expansion as glucose while providing an accurate real‐time impression of hiPSC culture development. Additionally, oxygen measurements inform about the metabolic state of the cells. Thus, the use of oxygen online monitoring for culture control facilitates the translation of hiPSC use to the clinical setting.     

Primary fourth ventricular meningioma: a case report of an adult male

Primary fourth ventricular meningiomas are extremely rare and often misdiagnosed as other tumors. They have no characteristic imaging appearance on computed tomography and magnetic resonance imaging. Therefore, differentiating the lesion from common lesions in the fourth ventricle can be diagnostically challenging. In this report, we present a 25-year-old man with fourth ventricular meningioma and refer to the usefulness of diffusion-weighted imaging and apparent diffusion coefficient measurements for the differential diagnosis of fourth ventricular tumors.     

High prevalence of acetabular retroversion in both affected and unaffected hips after Legg-Calvé-Perthes disease

Background

Acetabular retroversion is observed in hips after various pediatric hip diseases. This study sought to examine the frequency of acetabular retroversion in both affected and unaffected hips after Legg-Calvé-Perthes disease and its correlation with the prominence of the ischial spine.

Methods

We retrospectively investigated the version and morphological features of the acetabulum using pelvic radiographs after Legg-Calvé-Perthes disease (107 affected hips treated non-operatively and 72 unaffected hips from the contralateral side). The diagnosis of acetabular retroversion was made based on the presence of a positive cross-over sign on anteroposterior pelvic radiographs. The correlation between the presence of a positive cross-over sign and modified Stulberg classes, the onset age of Legg-Calvé-Perthes disease, radiographic parameters for acetabular dysplasia and the prominence of the ischial spine were examined.

Results

The prevalence of a positive cross-over sign was 49.5 % (45 of 91 hips) in affected hips and 45.8 % (33 of 72 hips) in unaffected hips. Hips with a positive cross-over sign were significantly coexistent bilaterally. The prevalence of prominence of the ischial spine in the positive cross-over sign group was 71.4 % in the affected side and 81.8 % in the unaffected side, indicating a significant correlation between the cross-over sign and the prominence of the ischial spine in both affected and unaffected hips. The positive cross-over sign did not have any correlation with the parameters for acetabular dysplasia and the onset age, however, had a significant correlation with the severity of the femoral head deformity.

Conclusions

High prevalence of acetabular retroversion in both affected and unaffected hips after Legg-Calvé-Perthes disease was demonstrated. Symmetric acetabular deformity and the coexistence of prominence of the ischial spine suggested the effects of the Legg-Calvé-Perthes disease lesions on the skeletal development of the whole pelvis. Further follow-up is needed to clarify the pathological significance of acetabular retroversion after Legg-Calvé-Perthes disease.     

An annular pancreas associated with carcinoma of the papilla of Vater: report of a case

An annular pancreas is an uncommon congenital anomaly that usually presents early in childhood. Malignancy in the setting of an annular pancreas is unusual. We herein report a case of annular pancreas with carcinoma of the papilla of Vater. A 59-year-old man presented with epigastric discomfort and was referred to us after gastroduodenal endoscopy showed a tumor of the papilla of Vater. Preoperative imaging showed the pancreatic parenchyma encircling the descending duodenum and a tumor at the papilla of Vater. A pancreaticoduodenectomy was performed for the annular pancreas and the ampullary tumor. Histological examination confirmed a complete annular pancreas and carcinoma in situ of the papilla of Vater. We also provide a review of the reported cases of an annular pancreas with periampullary neoplasms and discuss the clinical characteristics of this anomaly.     

A case of adefovir-induced membranous nephropathy related to hepatitis B caused by lamivudine-resistant virus after liver transplant due to Byler’s disease

We report on how adefovir-induced membranous nephropathy related to hepatitis B was caused by lamivudine-resistant virus after a liver transplant due to Byler’s disease. In 1980, a 2-year-old girl was diagnosed with Byler’s disease (familial progressive familial intrahepatic cholestasis). In 1994 (at the age of 14 years) she underwent a liver transplant with her father as the donor. In 2003, hematuria and proteinuria appeared and shortly afterwards her renal function rapidly decreased. A renal biopsy showed atypical membranous nephropathy, which suggested the possibility of a secondary renal disease. The patient had suffered from chronic hepatitis type B (HBV). In 2001 she was administered lamivudine which is an antiviral drug; it was around this time that hematuria and proteinuria appeared as well as an increase of the virus titer. We believed the HBV-related membranous nephropathy was the cause of the virus titer and the renal histology. We concluded that the patient’s condition had become resistant to lamivudine medication. Therefore, in February 2004 we administered adefovir, a new drug at the time, to treat the HBV. In April 2004, the HB virus titer decreased and the hematuria and proteinuria decreased. The patient’s renal function also showed improvement. HBV-associated nephropathy is caused by HBV antigen deposition in the glomeruli. Generally the first choice of treatment is antivirus therapy. There are many reports demonstrating that administration of interferon and lamivudine are effective; however, there are few reports that show adefovir as an effective treatment for HBV-associated nephropathy.     

High plasma pentosidine level is accompanied with cardiovascular events in hemodialysis patients

Background

Cardiovascular disease is a major complication in patients with end-stage renal disease (ESRD). The accumulation of advanced glycation end products (AGEs) is facilitated in these patients. The aim of this study was to investigate the relationship between circulating AGEs and cardiovascular events in hemodialysis patients.

Methods

The plasma level of pentosidine, a well-defined AGEs, was measured in 110 hemodialysis patients who were prospectively followed for 90?months. The relationship between plasma pentosidine level and cardiovascular events was assessed using Kaplan-Meier and Cox regression analysis.

Results

Thirty-nine cardiovascular events (14 coronary heart disease and 25 strokes) occurred during the follow-up period. Multivariable Cox proportional hazard analysis showed that plasma pentosidine levels (HR 1.040, 95% CI 1.022–1.058, p?p?p?Conclusion The plasma pentosidine level predicts cardiovascular events in hemodialysis patients. The effects of lowering circulating AGE levels on cardiovascular events should be examined in ESRD patients.     

Renal disease progression in autosomal dominant polycystic kidney disease

Background

Autosomal dominant polycystic kidney disease is a lifelong progressive disorder. However, how age, blood pressure, and stage of chronic kidney disease (CKD) affect the rate of kidney function deterioration is not clearly understood.

Methods

In this long-term observational case study up to 13.9?years (median observation period for slope was 3.3?years), serum creatinine was serially measured in 255 mostly adult patients. The glomerular filtration rate was estimated (eGFR) using a modified Modification of Diet in Renal Disease Study method. The total kidney volume (TKV) has been measured in 86 patients at one center since 2006.

Results

As age increased, eGFR declined significantly (P?Conclusion The declining rate of eGFR was relatively constant and did not correlate with age or eGFR after adolescence. eGFR was already low in young adult patients with hypertension. As age increased after adolescence, eGFR declined and TKV increased similarly between normal and high blood pressure groups. eGFR starts to decline in patients with normal eGFR, suggesting that the decline starts earlier than previously thought.     

A case of acute renal failure after exercise with renal hypouricemia demonstrated compound heterozygous mutations of uric acid transporter 1

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid (UA) clearance and is associated with acute renal failure (ARF). A 17-year-old Japanese male developed ARF after anerobic exercise. Renal function improved completely after approximately 2 weeks of hydration treatment. After remission, hypouricemia became evident (1.0 mg/dL) from the initial level of UA (4.8 mg/dL) and fractional excretion of uric acid (FEUA) was >50%. His parents showed normal levels of UA and FEUA. Polymerase chain reaction of a urate anion exchanger known to regulate UA level [SLC22A12 gene: UA transporter 1 (URAT1)] demonstrated compound heterozygous mutations (Q297X and R90H). Thus, we describe a Japanese male with hypouricemia complicated by anerobic exercise-induced ARF, with definite demonstration of a genetic abnormality in the responsible gene, URAT1.     

Psoriatic arthritis in two patients with an inadequate response to treatment with tocilizumab

Psoriatic arthritis (PsA) is considered as one of the seronegative spondylarthropathies. Like rheumatoid arthritis (RA), the increased production of interleukin (IL)-6 suggests a pathogenic role of IL-6 in PsA. However, whether humanized anti-IL-6 receptor antibody such as tocilizumab (TCZ) might be effective for PsA as well as RA has yet to be determined. We report herein two cases of PsA treated using TCZ. Although, TCZ treatment resulted in disappearance of serum CRP in both patients, arthritis and skin lesions were not improved despite 6-month administration of TCZ. In contrast, tumor necrosis factor (TNF) inhibitor proved effective against arthritis and skin lesions in these patients. Collectively, these findings not only indicate that IL-6 has distinct pathological roles in RA and PsA, but also suggest that TNF inhibitor therapy (but not TCZ) is effective for arthritis and skin lesions of PsA.