Large-scale prospective genome-wide association study of oxaliplatin in stage II/III colon cancer and neuropathy.

BACKGROUND: The severity of oxaliplatin (L-OHP)-induced peripheral sensory neuropathy (PSN) exhibits substantial interpatient variability, and some patients suffer from long-term, persisting PSN. To identify single-nucleotide polymorphisms (SNPs) predicting L-OHP-induced PSN using a genome-wide association study (GWAS) approach. PATIENTS AND METHODS: A large prospective GWAS including 1379 patients with stage II/III colon cancer who received L-OHP-based adjuvant chemotherapy (mFOLFOX6/CAPOX) under the phase II (JOIN/JFMC41) or the phase III (ACHIVE/JFMC47) trial. Firstly, GWAS comparison of worst grade PSN (grade 0/1 versus 2/3) was carried out. Next, to minimize the impact of ambiguity in PSN grading, extreme PSN phenotypes were selected and analyzed by GWAS. SNPs that could predict time to recovery from PSN were also evaluated. In addition, SNPs associated with L-OHP-induced allergic reactions (AR) and time to disease recurrence were explored. RESULTS: No SNPs exceeded the genome-wide significance (P < 5.0 × 10-8) in either GWAS comparison of worst grade PSN, extreme PSN phenotypes, or time to recovery from PSN. An association study focusing on AR or time to disease recurrence also failed to reveal any significant SNPs. CONCLUSION: Our results highlight the challenges of utilizing SNPs for predicting susceptibility to L-OHP-induced PSN in daily clinical practice.

Randomized clinical trial of extensive intraoperative peritoneal lavage versus standard treatment for resectable advanced gastric cancer (CCOG 1102 trial).

BACKGROUND: A survival benefit of extensive intraoperative peritoneal lavage (EIPL) has been reported in patients with gastric cancer with positive peritoneal cytology. The hypothesis of this study was that EIPL may reduce peritoneal recurrence in patients with advanced gastric cancer who undergo surgery with curative intent. METHODS: This was an open-label, multi-institutional, randomized, phase 3 trial to assess the effects of EIPL versus standard treatment after curative gastrectomy for resectable gastric cancer of T3 status or above. The primary endpoint was disease-free survival (DFS); secondary endpoints were overall survival, peritoneal recurrence-free survival and incidence of adverse events. RESULTS: Between July 2011 and January 2014, 314 patients were enrolled from 15 institutions and 295 patients were analysed (145 and 150 in the EIPL and no-EIPL groups respectively). The 3-year DFS rate was 63·9 (95 per cent c.i. 55·5 to 71·2) per cent in the EIPL group and 59·7 (51·3 to 67·1) per cent in the control group (hazard ratio (HR) 0·81, 95 per cent c.i. 0·57 to 1·16; P = 0·249). The 3-year overall survival rate was 75·0 (67·1 to 81·3) per cent in the EIPL group and 73·7 (65·9 to 80·1) per cent in the control group (HR 0·91, 0·60 to 1·37; P = 0·634). Peritoneal recurrence-free survival was not significantly different between the two groups (HR 0·92, 0·62 to 1·36; P = 0·676). No intraoperative complications related to EIPL were observed. CONCLUSION: EIPL did not improve survival or peritoneal recurrence in patients who underwent gastrectomy for advanced gastric cancer. Registration number: 000005907 (http://www.umin.ac.jp/ctr/index.htm).

ANTECEDENTES: Se ha descrito que un lavado peritoneal extenso intraoperatorio (extensive intraoperative peritoneal lavage, EIPL) proporciona un beneficio en la supervivencia en pacientes con cáncer gástrico con citología peritoneal positiva. La hipótesis de este estudio era que el EIPL podría disminuir la recidiva peritoneal en pacientes con cáncer gástrico avanzado sometidos a cirugía con intención curativa. MÉTODOS: Ensayo clínico fase 3, abierto, multicéntrico y aleatorizado para evaluar los efectos de un lavado peritoneal extenso intraoperatorio (EIPL) frente a tratamiento estándar tras gastrectomía curativa por cáncer gástrico ≥T3 resecable. La variable de resultado primaria fue la supervivencia libre de enfermedad (disease-free survival, DFS), y las variables de resultado secundarias fueron la supervivencia global (overall survival, OS), la supervivencia libre de recidiva peritoneal y la incidencia de efectos adversos. RESULTADOS: Entre julio de 2011 y enero de 2014, se reclutaron 314 pacientes de 15 instituciones y se analizaron los datos de 295 pacientes (145 en el grupo con EIPL y 150 en el grupo sin EIPL). La DFS a los 3 años fue 63,9% (i.c. del 95% 55,5-71,2) en el grupo con EIPL y 59,7% (i.c. del 95% 51,3-67,1) en el grupo control (cociente de riesgos instantáneos, hazard ratio, HR 0,81 (i.c. del 95% 0,57-1,16), P = 0,249). La OS a los 3 años fue 75,0% (i.c. del 95% 67,1-81,3) en el grupo con EIPL y 73,7% (i.c. del 95% 65,9-80,1) en el grupo control (HR 0,91 i.c. del 95% 0,60-1,37), P = 0,634). No se observaron diferencias estadísticamente significativas entre los dos grupos en la supervivencia libre de recidiva peritoneal (P = 0,676, HR 0,92 (i.c. del 95% 0,62-1,36). No se observaron complicaciones intraoperatorias relacionadas con EIPL. CONCLUSIÓN: El EIPL no mejoró la supervivencia o la recidiva peritoneal en pacientes sometidos a gastrectomía por cáncer gástrico avanzado.

Honeycomb micro-textures for light trapping in multi-crystalline silicon thin-film solar cells.

The liquid phase crystallization (LPC) of silicon is an emerging technology for fabricating 10 - 20 µm thin multi-crystalline silicon layers on glass. LPC silicon solar cells exhibit similar electronic performance to multi-crystalline wafer-based devices. Due to the reduced absorber thickness, however, effective measures for light trapping have to be taken. We present tailor-made micro-structures for light trapping at the LPC silicon back-side, whereby a nano-imprinted resist layer serves as a three-dimensional etching mask in subsequent reactive ion etching. Contrary to state-of-the-art random pyramid textures produced by wet-chemical etching, this method allows to produce tailor-made textures independent of grain orientation. Differently shaped micro-textures were replicated in LPC silicon. Absorptance and external quantum efficiency of periodic honeycomb patterns and random pyramids were found to be equivalent. Thus, the method enables the potential to further optimize light trapping in LPC silicon solar cells.

Si-based Mach-Zehnder wavelength/mode multi/demultiplexer for a WDM/MDM transmission system.

We propose and experimentally demonstrate a low-loss and low-crosstalk Mach-Zehnder mode/wavelength multi/demultiplexer for WDM/MDM transmission based on a Si-photonics platform. A broadband 3-dB mode divider, which is also newly devised here, makes it possible to compose a Mach-Zehnder filter for "mode" and "wavelength" simultaneously. Transmission characteristics of fabricated 3-dB mode dividers are in excellent agreement with theoretical results. Mach-Zehnder filters using the 3-dB mode divider with a free spectral range (FSR) of 20 and 1 nm are also fabricated and the modal crosstalk is less than -24 dB in the 40-nm wavelength range for the MZ filter with an FSR of 20 nm. The tuning of the peak wavelength position by the TiN heater is also demonstrated.

The importance of accounting for testing and positivity in surveillance by time and place: an illustration from HIV surveillance in Japan.

The number of tests performed is an important surveillance indicator. We illustrate this point using HIV surveillance data, focusing on Tokyo and Okinawa, two prefectures with high HIV notification rates in Japan. Restricting to data reported from local public health centres and affiliate centres where testing data are accessible, we assessed HIV surveillance data during 2007-2014, based on the annual HIV notification rate (per 100 000 population), HIV testing rate (per 100 000 population) and proportion testing HIV-positive (positivity). Nationally, testing activity and positivity showed an inverse relationship; in 2008, the testing rate peaked, but positivity was lowest. While notification rates were higher for Tokyo (median = 0.98, range = 0.89-1.33) than Okinawa (median = 0.61, range = 0.42-1.09), Okinawa had slightly higher testing rates (median = 187, range = 158-274) relative to Tokyo (median = 172, range = 163-210). Positivity was substantially lower in Okinawa (median = 0.34%, range = 0.24-0.45%) compared with Tokyo (median = 0.57%, range = 0.46-0.67%). Relative to the national testing rate (median = 85, range = 80-115) and positivity (median = 0.34%, range = 0.28-0.36%), Tokyo had higher positivity, despite more testing. In 2014 in Okinawa, all three indicators increased, providing a strong reason to be concerned as positivity increased despite more testing. Together with other information, accounting for testing and positivity improve interpretation of surveillance data to guide public health assessments.

Early results of a randomized two-by-two factorial phase II trial comparing neoadjuvant chemotherapy with two and four courses of cisplatin/S-1 and docetaxel/cisplatin/S-1 as neoadjuvant chemotherapy for locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is a promising method of improving the survival of resectable gastric cancer. Cisplatin/S-1 (CS) and docetaxel/cisplatin/S-1 (DCS) are both effective against metastatic gastric cancer. This report clarified the impact of these regimens on early endpoints, including the pathological responses, chemotherapy-related toxicities, and surgical results. METHODS: Patients with M0 and either T4 or T3 in case of junctional cancer or scirrhous type received two or four courses of cisplatin (60 mg/m2 at day 8)/S-1 (80 mg/m2 for 21 days with 1 week rest) or docetaxel (40 mg/m2 at day 1)/cisplatin (60 mg/m2 at day 1)/S-1 (80 mg/m2 for 14 days with 2 weeks rest) as NAC. Patients then underwent D2 gastrectomy and adjuvant S-1 chemotherapy for 1 year. The primary endpoint was the 3-year overall survival. RESULTS: Between October 2011 and September 2014, 132 patients were assigned to receive CS (n = 66; 33 in 2 courses and 33 in 4 courses) or DCS (n = 66; 33 in 2 courses and 33 in 4 courses). The respective major grade 3 or 4 hematological toxicities (CS/DCS) were leukocytopenia (14.1%/26.2%), neutropenia (29.7%/47.7%), anemia (14.1%/12.3%), and platelet reduction (3.1%/1.5%). The rate of pathological response, defined as a complete response or < 10% residual cancer remaining, was 19.4% in the CS group and 15.4% in the DCS group, and 15.6% in the two-course group and 19.0% in the 4-course group. The R0 resection rate was 72.7% in the CS group and 81.8% in the DCS group and 80.3% in the two-course group and the 74.2% in the four-course group. No treatment-related deaths were observed. CONCLUSIONS: Our results do not support three-drug therapy with a taxane over two-drug therapy, or any further treatment beyond two cycles as an attractive candidate for the test arm of NAC.

Artificial sweeteners and mixture of food additives cause to break oral tolerance and induce food allergy in murine oral tolerance model for food allergy.

BACKGROUND: Processed foods are part of daily life. Almost all processed foods contain food additives such as sweeteners, preservatives and colourants. From childhood, it is difficult to avoid consuming food additives. It is thought that oral tolerance for food antigens is acquired during early life. If tolerance fails, adverse immune responses to food proteins may occur. OBJECTIVE: We hypothesized that food additives prevent acquisition of oral tolerance and aimed to verify the safety of food additives. METHODS: We induced experimental oral tolerance in mice for ovalbumin (OVA), a food antigen, by previous oral treatment with OVA before sensitization with OVA injections. Food additives were administered at the induction of oral tolerance, and food allergy was induced by repeated administration of OVA. Symptoms of food allergy were defined as a change in body temperature and allergic diarrhoea. RESULTS: Saccharin sodium and a mixture of food additives inhibited acquisition of oral tolerance. Hypothermia and allergic diarrhoea with elevation of OVA-specific IgE were induced in the murine model of oral tolerance. Analyses of antigen-presenting cells in mesenteric lymph nodes showed that food additives affected their manner of migration. Additionally, food additives decreased the proportion of CD25hi regulatory T cells among CD4+ T cells in the mesenteric lymph nodes. CONCLUSIONS AND CLINICAL RELEVANCE: A large amount of food additives may prevent acquisition of oral tolerance. Intake of food additives in early life may increase the risk of food allergies.

Large-scale prospective pharmacogenomics study of oxaliplatin-induced neuropathy in colon cancer patients enrolled in the JFMC41-1001-C2 (JOIN Trial).

BACKGROUND: Peripheral sensory neuropathy (PSN) is a dose-limiting toxicity of oxaliplatin-based chemotherapy. Several genetic markers have been shown to predict oxaliplatin-induced PSN; however, results remain to be validated in a large-scale and prospective pharmacogenomics study. PATIENTS AND METHODS: Among 882 patients enrolled in the JFMC41-1001-C2 (JOIN trial), which was designed to investigate the tolerability of adjuvant-modified FOLFOX6 (mFOLFOX6) in Japanese Patients with stage II or III colon cancers undergoing curative resection, 465 patients were eligible for this pharmacogenomics analysis. Twelve single-nucleotide polymorphisms (SNPs) were selected based on published data. The effect of each genotype on time to PSN onset was evaluated in all patients (n = 465) using the Cox proportional hazard model. For the association analysis between severity of PSN and 12 SNP markers, 84 patients who failed to complete 12 cycles of mFOLFOX6 from grade 0/1 PSN group were excluded because the termination of the protocol treatment had been caused by reasons other than PSN. RESULTS: Comparison of grade 0/1 PSN with grade 2/3 PSN or grade 3 PSN showed no significant associations with any of the 12 SNP markers after adjustment for total dose of oxaliplatin. Time-to-onset analysis also failed to reveal any significant differences. CONCLUSIONS: Our large-scale and prospective pharmacogenomics study of Japanese patients receiving protocol treatment of adjuvant mFOLFOX6 could not verify a role for any of the 12 SNP markers reported as being significantly associated with PSN. Considering the OR observed in this study (range: 0.76-1.89), further evaluation of these 12 SNP markers in the context of L-OHP-induced PSN is unlikely to be clinically informative.

Tofogliflozin, A Highly Selective Inhibitor of SGLT2 Blocks Proinflammatory and Proapoptotic Effects of Glucose Overload on Proximal Tubular Cells Partly by Suppressing Oxidative Stress Generation.

Ninety percent of glucose filtered by the glomerulus is reabsorbed by a sodium-glucose cotransporter 2 (SGLT2), which is mainly expressed on S1 and S2 segment of renal proximal tubules. Since SGLT-2-mediated glucose reabsorption is increased under diabetic conditions, selective inhibition of SGLT2 is a potential therapeutic target for the treatment of diabetes. We have recently shown that an inhibitor of SGLT2 has anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing advanced glycation end products formation and oxidative stress generation in the kidney. However, the direct effects of SGLT2 inhibitor on tubular cell damage remain unclear. In this study, we investigated the effects of tofogliflozin, a highly selective inhibitor of SGLT2 on oxidative stress generation, inflammatory and proapoptotic reactions in cultured human proximal tubular cells exposed to high glucose. Tofogliflozin dose-dependently suppressed glucose entry into tubular cells. High glucose exposure (30 mM) for 4 and 24 h significantly increased oxidative stress generation in tubular cells, which were suppressed by the treatment of tofogliflozin or an antioxidant N-acetylcysteine (NAC). Monocyte chemoattractant protein-1 (MCP-1) gene expression and apoptotic cell death were induced by 4 h- and 8 day-exposure to high glucose, respectively, both of which were also blocked by tofogliflozin or NAC. The present study suggests that SGLT2-mediated glucose entry into tubular cells could stimulate oxidative stress and evoke inflammatory and proapoptotic reactions in this cell type. Blockade of glucose reabsorption in tubular cells by SGLT2 inhibitor might exert beneficial effects on tubulointerstitial damage in diabetic nephropathy.

Protective Role of PEDF-Derived Synthetic Peptide Against Experimental Diabetic Nephropathy.

Pigment epithelium-derived factor (PEDF) is a glycoprotein with complex neuroprotective, anti-angiogenic, and anti-inflammatory properties, all of which could potentially be exploited as a therapeutic option for vascular complications in diabetes. We have previously shown that PEDF-derived synthetic peptide, P5-3 (FIFVLRD) has a comparable ability with full PEDF protein to inhibit rat corneal neovascularization induced by chemical cauterization. However, the effects of PEDF peptide on experimental diabetic nephropathy remain unknown. To address the issue, we modified P5-3 to stabilize and administered the modified peptide (d-Lys-d-Lys-d-Lys-Gln-d-Pro-P5-3-Cys-amide, 0.2 nmol/day) or vehicle to streptozotocin-induced diabetic rats (STZ-rats) intraperitoneally by an osmotic mini pump for 2 weeks. We further examined the effects of modified peptide on human proximal tubular cells. Renal PEDF expression was decreased in STZ-rats. Although the peptide administration did not affect blood glucose or blood pressure, it decreased urinary excretion levels of 8-hydroxy-2'-deoxyguanosine, an oxidative stress marker, and reduced plasminogen activator inhibitor-1 (PAI-1) gene expression, and suppressed glomerular expansion in the diabetic kidneys. High glucose or advanced glycation end products stimulated oxidative stress generation and PAI-1 gene expression in tubular cells, all of which were significantly suppressed by 10 nM modified P5-3 peptide. Our present study suggests that PEDF-derived synthetic modified peptide could protect against experimental diabetic nephropathy and inhibit tubular cell damage under diabetes-like conditions through its anti-oxidative properties. Supplementation of modified P5-3 peptide may be a novel therapeutic strategy for diabetic nephropathy.

Sulforaphane reduces advanced glycation end products (AGEs)-induced inflammation in endothelial cells and rat aorta.

BACKGROUND AND AIMS: Advanced glycation end products (AGEs)-receptor RAGE interaction evokes oxidative stress and inflammatory reactions, thereby being involved in endothelial cell (EC) damage in diabetes. Sulforaphane is generated from glucoraphanin, a naturally occurring isothiocyanate found in widely consumed cruciferous vegetables, by myrosinase. Sulforaphane has been reported to protect against oxidative stress-mediated cell and tissue injury. However, effects of sulforaphane on AGEs-induced vascular damage remain unclear. METHODS AND RESULTS: In this study, we investigated whether and how sulforaphane could inhibit inflammation in AGEs-exposed human umbilical vein ECs (HUVECs) and AGEs-injected rat aorta. Sulforaphane treatment for 4 or 24 h dose-dependently inhibited the AGEs-induced increase in RAGE, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecular-1 (VCAM-1) gene expression in HUVECs. AGEs significantly stimulated MCP-1 production by, and THP-1 cell adhesion to, HUVECs, both of which were prevented by 1.6 µM sulforaphane. Sulforaphane significantly suppressed oxidative stress generation and NADPH oxidase activation evoked by AGEs in HUVECs. Furthermore, aortic RAGE, ICAM-1 and VCAM-1 expression in AGEs-injected rats were increased, which were suppressed by simultaneous infusion of sulforaphane. CONCLUSION: The present study demonstrated for the first time that sulforaphane could inhibit inflammation in AGEs-exposed HUVECs and AGEs-infused rat aorta partly by suppressing RAGE expression through its anti-oxidative properties. Inhibition of the AGEs-RAGE axis by sulforaphane might be a novel therapeutic target for vascular injury in diabetes.

Empagliflozin, an Inhibitor of Sodium-Glucose Cotransporter 2 Exerts Anti-Inflammatory and Antifibrotic Effects on Experimental Diabetic Nephropathy Partly by Suppressing AGEs-Receptor Axis.

Advanced glycation end products (AGEs) and receptor RAGE play a role in diabetic nephropathy. We have previously shown that increased glucose uptake into proximal tubular cells via sodium-glucose cotransporter 2 (SGLT2) stimulates oxidative stress generation and RAGE expression, thereby exacerbating the AGE-induced apoptosis in this cell type. However, the protective role of SGLT2 inhibition against the AGE-RAGE-induced renal damage in diabetic animals remains unclear. In this study, we investigated the effects of empagliflozin, SGLT2 inhibitor on AGE-RAGE axis, inflammatory and fibrotic reactions, and tubular injury in the kidney of streptozotocin-induced diabetic rats.Administration of empagliflozin for 4 weeks significantly improved hyperglycemia and HbA1c, and decreased expression levels of AGEs, RAGE, 8-hydroxydeoxyguanosine (8-OHdG), and F4/80, markers of oxidative stress and macrophages, respectively, in the diabetic kidney. Although empagliflozin did not reduce albuminuria, it significantly decreased urinary excretion levels of 8-OHdG and L-fatty acid binding protein, a marker of tubular injury. Moreover, inflammatory and fibrotic gene expression such as monocyte chemoattractant protein-1, intercellular adhesion molecule-1, plasminogen activator inhibitor-1, transforming growth factor-ß, and connective tissue growth factor was enhanced in the diabetic kidney, all of which were prevented by empagliflozin. The present study suggests that empagliflozin could inhibit oxidative, inflammatory and fibrotic reactions in the kidney of diabetic rats partly via suppression of the AGE-RAGE axis. Blockade of the increased glucose uptake into renal proximal tubular cells by empagliflozin might be a novel therapeutic target for tubulointerstitial damage in diabetic nephropathy.

DNA aptamer raised against advanced glycation end products (AGEs) improves glycemic control and decreases adipocyte size in fructose-fed rats by suppressing AGE-RAGE axis.

Advanced glycation end products (AGEs) decrease adiponectin expression and suppress insulin signaling in cultured adipocytes through the interaction with a receptor for AGEs (RAGE) via oxidative stress generation. We have recently found that high-affinity DNA aptamer directed against AGE (AGE-aptamer) prevents the progression of experimental diabetic nephropathy by blocking the harmful actions of AGEs in the kidney. This study examined the effects of AGE-aptamer on adipocyte remodeling, AGE-RAGE-oxidative stress axis, and adiponectin expression in fructose-fed rats. Although AGE-aptamer treatment by an osmotic mini pump for 8 weeks did not affect serum insulin levels, it significantly decreased average fasting blood glucose and had a tendency to inhibit body weight gain in fructose-fed rats. Furthermore, AGE-aptamer significantly suppressed the increase in adipocyte size and prevented the elevation in AGEs, RAGE, and an oxidative stress marker, 8-hydroxydeoxyguanosine (8-OHdG), levels in adipose tissues of fructose-fed rats at 14-week-old, while it restored the decrease in adiponectin mRNA levels. Our present study suggests that AGE-aptamer could improve glycemic control and prevent adipocyte remodeling in fructose-fed rats partly by suppressing the AGE-RAGE-mediated oxidative stress generation. AGE-aptamer might be a novel therapeutic strategy for fructose-induced metabolic derangements.

Structure of a zinc oxide ultra-thin film on Rh(100).

The structural parameters of ultra-thin zinc oxide films on Rh(100) are investigated using low-energy electron diffraction intensity (LEED I-V) curves, scanning tunneling microscopy (STM), and first-principles density functional theory (DFT) calculations. From the analysis of LEED I-V curves and DFT calculations, two optimized models A and B are determined. Their structures are basically similar to the planer h-BN ZnO(0001) structure, although some oxygen atoms protrude from the surface, associated with an in-plane shift of Zn atoms. From a comparison of experimental STM images and simulated STM images, majority and minority structures observed in the STM images represent the two optimized models A and B, respectively.

Bazedoxifene blocks AGEs-RAGE-induced superoxide generation and MCP-1 level in endothelial cells.

Advanced glycation endproducts (AGEs) and their receptor (RAGE) play a role in vascular complications in diabetes. We have previously shown that 17ß-estradiol at 10 nmol/l, a nearly identical plasma concentration to that during mid-pregnancy, up-regulates RAGE expression in endothelial cells. The finding might suggest the involvement of 17ß-estradiol in the deterioration of vascular complications in diabetes during pregnancy. However, the effects of the selective estrogen receptor modulator, bazedoxifene, on oxidative and inflammatory reactions in AGEs-exposed endothelial cells remain unknown. In this study, we addressed the issue. Ten nmol/l 17ß-estradiol increased RAGE and monocyte chemoattractant protein-1 (MCP-1) gene and protein expression in human umbilical vein endothelial cells (HUVECs), both of which were blocked by 10 nmol/l bazedoxifene. Bazedoxifene at 10 nmol/l also significantly inhibited the AGEs-induced superoxide generation, RAGE and MCP-1 gene and protein expression in HUVECs. The present study suggests that blockade of the AGEs-RAGE axis by bazedoxifene might be a novel therapeutic target for preventing vascular damage in diabetes, especially in postmenopausal women.

Radiation therapy for extramammary Paget's disease: treatment outcomes and prognostic factors.

BACKGROUND: Extramammary Paget's disease (EMPD) is a relatively rare malignancy, and there are few reports related to radiation therapy. In the present study, we investigated the outcome of radiation therapy for EMPD. PATIENTS AND METHODS: Forty-one patients with EMPD in the genitalia underwent radiation therapy with curative intent. Fifteen patients had regional lymph node metastases before radiation therapy, but none had distant metastasis. Total doses of 45-80.2 Gy (median, 60 Gy) were delivered to tumor sites in 23-43 fractions (median, 33 fractions). RESULTS: At a median follow-up period of 41 months, 16 patients had developed recurrences, including 5 with local progression within the radiation field and 12 with lymph node or/and distant metastases outside the radiation field. The local progression-free and disease-free rates were 88% and 55% at 3 years, and 82% and 46% at 5 years, respectively. Nine patients died at 6-73 months after irradiation; the causes of death were tumor progression in five patients, infectious pneumonia in two, renal failure in one and old age in one. The overall and cause-specific survival rates were 93% and 96% at 3 years, and 68% and 84% at 5 years, respectively. Tumor invasion into the dermis and regional lymph node metastasis were significant prognostic factors for both distant metastasis and survival. No therapy-related toxicities of grade ≥3 were observed. CONCLUSIONS: Radiation therapy is safe and effective for patients with EMPD. It appeared to contribute to prolonged survival owing to good tumor control, and to be a promising curative treatment option.

Olmesartan blocks advanced glycation end products-induced vcam-1 gene expression in mesangial cells by restoring Angiotensin-converting enzyme 2 level.

Advanced glycation end products (AGEs) and their receptor (RAGE) system are involved in diabetic nephropathy. Angiotensin-converting enzyme 2 (ACE 2) plays a protective role against cardiovascular and renal injury by stimulating the production of angiotensin-(1-7) [Ang-(1-7)], an antagonist of angiotensin II (Ang II). However, effects of the AGEs-RAGE axis on ACE 2 expression in mesangial cells remain unknown. We examined here the role of ACE 2 in the AGEs-RAGE-induced mesangial cell damage and investigated whether olmesartan, one of the Ang II type 1 receptor blockers (ARB), prevented the deleterious effects of AGEs via restoration of ACE 2 and Ang-(1-7) level. AGEs significantly increased superoxide generation, upregulated RAGE mRNA level, and decreased ACE 2 gene expression and Ang-(1-7) production in mesangial cells, all of which were blocked by olmesartan, but not by a different type of ARB, azilsartan. An antioxidant, N-acetylcysteine or RAGE-antibodies also restored the decrease in ACE 2 mRNA level in AGEs-exposed mesangial cells. Moreover, olmesartan, but not azilsartan completely inhibited the AGEs-induced increase in vascular cell adhesion molecule-1 (VCAM-1) mRNA level in mesangial cells, which was abolished by the treatment with A-779, an antagonist of Ang-(1-7) receptor, Mas receptor. Our present study suggests that olmesartan could block the AGEs-induced VCAM-1 gene induction in mesangial cells by restoring the downregulated ACE 2 levels and subsequently stimulating the Ang-(1-7)-Mas receptor axis. Restoration of ACE 2 levels and blockade of renin-angiotensin system by olmesartan might be a promising strategy for the treatment of diabetic nephropathy.

Linagliptin blocks renal damage in type 1 diabetic rats by suppressing advanced glycation end products-receptor axis.

Advanced glycation end products (AGEs) and their receptor (RAGE) play a role in diabetic nephropathy. We have recently found that linagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP-4) suppresses the AGE-induced oxidative stress generation and intercellular adhesion molecule-1 (ICAM-1) gene expression in endothelial cells. However, whether linagliptin could have beneficial effects on experimental diabetic nephropathy in a glucose-lowering independent manner remains unknown. To address the issue, this study examined the effects of linagliptin on renal damage in streptozotocin-induced diabetic rats. Serum levels of DPP-4 were significantly elevated in diabetic rats compared with control rats. Although linagliptin treatment for 2 weeks did not improve hyperglycemia in diabetic rats, linagliptin significantly reduced AGEs levels, RAGE gene expression, and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative stress in the kidney of diabetic rats. Furthermore, linagliptin significantly reduced albuminuria, renal ICAM-1 mRNA levels, and lymphocyte infiltration into the glomeruli of diabetic rats. Our present study suggests that linagliptin could exert beneficial effects on diabetic nephropathy partly by blocking the AGE-RAGE-evoked oxidative stress generation in the kidney of streptozotocin-induced diabetic rats. Inhibition of DPP-4 by linagliptin might be a promising strategy for the treatment of diabetic nephropathy.