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BACKGROUND: Chronic kidney disease (CKD) is associated with increased risk of coronary heart disease. However, information regarding the histopathologic characteristics of coronary atherosclerosis in individuals with CKD is scarce. This study investigated the relationship between CKD and severity of coronary atherosclerosis in population-based autopsy samples. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 126 individuals randomly selected from 844 consecutive population-based autopsy samples. PREDICTOR: Estimated glomerular filtration rate (eGFR) calculated using the 6-variable Modification of Diet in Renal Disease (MDRD) Study equation. OUTCOMES: Severity of atherosclerosis in 3 main coronary arteries, including atherosclerotic lesion types defined using the American Heart Association classification; stenosis rates; and coronary calcified lesions. MEASUREMENTS: The relationship between CKD and severity of coronary atherosclerosis was evaluated using generalized estimating equation methods. RESULTS: Frequencies of advanced atherosclerotic lesions increased gradually as eGFR decreased (33.6%, 41.7%, 52.3%, and 52.8% for eGFRs > or = 60, 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively; P for trend = 0.006). This relationship was substantially unchanged even after adjustment for potential confounding factors (ORs, 1.40 [95% CI, 0.76-2.55], 2.02 [95% CI, 0.99-4.15], and 3.02 [95% CI, 1.22-7.49] for eGFRs of 45-59, 30-44, and <30 mL/min/1.73 m(2), respectively). Frequencies of calcified lesions of coronary arteries also increased gradually with lower eGFRs (P for trend = 0.02). Hypertension and diabetes were associated with increased risk of advanced coronary atherosclerosis and calcification of coronary arteries in individuals with decreased eGFR. LIMITATIONS: Cross-sectional study, absence of data for proteinuria, and extremely high proportion of aged people. CONCLUSIONS: The autopsy findings presented here suggest that CKD is associated significantly with severity of coronary atherosclerosis. Patients with CKD should be considered a high-risk population for advanced coronary atherosclerosis. [ABSTRACT FROM AUTHOR]

BACKGROUND: Narrow-band imaging (NBI) is a novel illumination technology for endoscopy that enhances vasculature of the GI tract. OBJECTIVE: The aim was to elucidate whether NBI colonoscopy can identify dysplasia in patients with ulcerative colitis (UC). DESIGN: Cross-sectional study of eligible patients. SETTING: Single center. PATIENTS: 46 patients with UC. INTERVENTIONS: Apparently flat mucosa at each segment and visible protruding lesions were observed by magnifying NBI colonoscopy. The surface structure was classified into honeycomb-like, villous, or tortuous pattern. The grade of dysplasia was determined in the specimens obtained from protrusions and from flat mucosa. MAIN OUTCOME MEASUREMENTS: The positive predictive value of conventional and NBI colonoscopy for the diagnosis of dysplasia. RESULTS: A total of 296 sites (20 protruding lesions and 276 flat areas) were examined by NBI colonoscopy. The surface pattern was determined to be honeycomb like in 161 sites, villous in 85 sites, and tortuous in 50 sites. Five dysplastic lesions were detected in 3 patients. A patient had 3 dysplastic lesions and the other 2 had a dysplastic lesion each. The positive rate of dysplasia was higher in protrusions (2/20 sites, 10%) than in flat mucosa (3/276 sites, 1.1%, P = .038; however, correction for the multiple testing of data removes this significance). When the surface pattern was taken into account, the rate of positive dysplasia was higher in the tortuous pattern (4/50 sites, 8%) than in the honeycomb-like or villous patterns (1/246 sites, 0.4%, P = .003). LIMITATIONS: Uncontrolled study. CONCLUSIONS: The tortuous pattern determined by NBI colonoscopy may be a clue for the identification of dysplasia during surveillance for UC. [ABSTRACT FROM AUTHOR]

The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBβ) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA , RAS , PDPK1 , and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy. [ABSTRACT FROM AUTHOR]

Cetuximab, an approved anti-EGFR receptor monoclonal antibody, is used for the treatment of metastatic cancer, often in conjunction with cytotoxic chemotherapy. It is also employed as a radiosensitizer in the context of definitive radiation therapy for locally advanced cases. However, overcoming resistance to cetuximab, whether intrinsic or acquired, represents a significant challenge in clinical practice. In preclinical studies, the identification of tyrosine 821 (Y821) on the C-terminal of AXL has been linked to resistance to both cetuximab and radiation therapy via signaling through the tyrosine kinase c-Abl. Blocking c-Abl signaling with the tyrosine kinase inhibitor imatinib restored sensitivity to cetuximab and radiotherapy, ultimately resulting in complete tumor regression without recurrence in models of head and neck cancer. In this clinical trial, we aim to translate these promising preclinical findings into clinical practice through a window-of-opportunity trial that evaluates the effects of combining cetuximab with imatinib in head and neck cancer patients. This is a window-of-opportunity study conducted at a single center, involving patients diagnosed with head and neck squamous cell carcinoma who are undergoing treatment with surgery, radiation, or chemoradiation. A total of 15 patients will be recruited for this study. Participants will initially undergo a medical history review and physical examination and provide written informed consent. To be eligible, subjects must have sufficient tumor volume to allow for a minimum of two core research biopsies. The first research biopsy will be performed at baseline prior to therapy to analyze Ki67 and potential markers of sensitivity to cetuximab and imatinib. Simultaneously with the first research biopsy, research-related blood samples will be collected to assess circulating tumor cells through the course of the trial. Subjects will receive two doses of cetuximab as follows: a loading dose of 400 mg/m2 on Day 1 and 250 mg/m2 on Day 8. In addition, they will take 400 mg of imatinib orally daily for a period ranging from a minimum of 8 days to a maximum of 14 days before undergoing definitive surgery or definitive radiation/chemoradiation. Following the combined treatment with imatinib and cetuximab, subjects will undergo a second research blood draw and a research biopsy. The administration of imatinib will be discontinued 1-3 days prior to the second research biopsy. For patients undergoing surgical resection, this second research biopsy will be obtained during the surgical procedure. Patients will return for follow-up visits at 1, 3, and 12 months after completing definitive therapy to assess toxicities, monitor adverse events, and collect blood samples. Enrollment in the study is ongoing. NCT05816785 TBD TBD [ABSTRACT FROM AUTHOR]

Abstract: In order to study film-boiling phenomena in saturated superfluid helium (He IIs) under a microgravity environment, a very compact visualization setup was designed and fabricated at High Energy Accelerator Research Organization (KEK). It consists of a cryostat, a vacuum pump, a high-speed video camera and electrical circuits for measurement. The cryostat in the setup is equipped with optical windows for the visualization of film boiling in He IIs. The setup was tested to verify its thermal and safety performance under a microgravity environment using a 10m free-drop tower at the Hokkaido Center of the National Institute of Advanced Industrial Science and Technology (AIST). Successful system operation from 1.94 to 2.05K under microgravity conditions below 1×10−3 g was confirmed. The design and test results are described in this technical note. [ABSTRACT FROM AUTHOR]

Chronic inhibition of nitric oxide synthase by N(omega)-nitro- L-arginine methyl ester (L-NAME) causes progressive renal injury with systemic hypertension and interstitial macrophage infiltration. We have previously shown that there is local activation of the renin-angiotensin-aldosterone system in the renal cortex as a major pathogenic feature of macrophage infiltration. In this study, we measured the effects of the aldosterone antagonist, spironolactone, on renal injury in L-NAME-treated male Wistar rats. After 12 weeks of L-NAME-treatment, rats had increased systolic blood pressure, urinary protein excretion, and serum creatinine and histological analysis showed glomerulosclerosis, interstitial fibrosis, and macrophage infiltration. Treatment with spironolactone significantly prevented these renal changes, whereas treatment with hydralazine had no effect. The cortical expression of osteopontin was significantly elevated in L-NAME-treated rats, and expression of its mRNA significantly correlated with the number of infiltrating macrophages and degree of interstitial fibrosis. Spironolactone treatment markedly suppressed osteopontin expression. Our results suggest that reduced nitric oxide bioavailability caused renal inflammation and fibrosis through an aldosterone receptor-dependent mechanism associated with osteopontin expression independent of its systemic hemodynamic effects. [ABSTRACT FROM AUTHOR]

The phenotypic changes in parathyroid cells after successful renal transplantation remain to be elucidated. We compared 10 diffuse and 11 nodular hyperplastic parathyroid glands from five renal allograft recipients with persistent hyperparathyroidism, with five diffuse and 13 nodular hyperplasia from seven uremic patients on hemodialysis, and 13 normal glands. Comparisons included expressions of both vitamin D receptor (VDR) and calcium-sensing receptor (CaSR), proliferative activity (Ki67), and apoptosis (TUNEL). Immunoreactivity was assessed semiquantitatively and expressed as labeling index. The area/cell was also measured to assess cellular hypertrophy. The labeling indexes of VDR (587±71; mean±s.e.m.) and CaSR (45.0±2.8) in recipients’ diffuse hyperplasia were significantly higher than those in uremic diffuse hyperplasia (224±44, 29.3±2.3, respectively) (P<0.01, each). However, these expressions remained low in recipients’ nodular hyperplasia (42±8, 11.8±1.4, respectively). Ki67 labeling index in recipients’ nodular hyperplasia (7±1) was significantly smaller than in uremic patients (24±6, P<0.01). TUNEL labeling index in recipients’ diffuse hyperplasia (30±5) was the highest among the groups. The cell volume tended to be smaller in both patterns of hyperplasia in allograft recipients compared with uremic patients. Our results suggest that the phenotypic change in parathyroid cells after renal transplantation depends on the pattern of hyperplasia, where it is normalized only in diffuse hyperplastic glands in which the number of cells also regresses with significant induction of apoptosis.Kidney International (2006) 70, 363–370. doi:10.1038/sj.ki.5001549; published online 31 May 2006 [ABSTRACT FROM AUTHOR]

Abstract: Polypyrrole was deposited at selected areas on aluminum by anodizing, laser irradiation, and electrolytic polymerization, and the application of the technique for fabricating micro-actuators was attempted. Aluminum specimens covered with porous type anodic oxide films were irradiated with a pulsed Nd-YAG laser to remove the oxide films locally, and then thin Ni layers were deposited at areas where film had been removed. Polypyrrole could be successfully deposited only on the Ni layer by anodic polarization of the specimens in pyrrole monomer solution, and a polypyrrole/Ni bilayer structure could be obtained by dissolution of the aluminum substrate and anodic oxide film in NaOH solutions. The bilayer structure was found to be inactive to doping and dedoping of ions during anodic and cathodic polarization. A three-layer structure, nitrocellulose/Ni/polypyrrole, fabricated by electrolytic polymerization after nitrocellulose coating on a Ni layer detached from the aluminum substrate, showed ion-doping and -dedoping activity, suggesting the possibility of fabricating micro-actuators in this manner. [Copyright &y& Elsevier]

Early 1,25-dihydroxyvitamin D3 (VD3) therapy during the course of renal failure prevents the downregulation of VD3 receptor (VDR), calcium-sensing receptor (CaSR) or p21, and the parathyroid (PT) growth. We hypothesized that VD3 could restore the decreased expressions of VDR and CaSR, and cause regression in enlarged PT glands. 5/6 nephrectomized rats fed high-phosphorus diet were killed at 1, 3, 5, or 7 days and at 2, 3, 4, 8, or 12 weeks. VD3-treated rats were given VD3 intraperitoneally for 1, 2, 3, or 4 weeks, starting 8 weeks after 5/6 nephrectomy. PT glands were weighed and subjected to immunohistochemical analyses for VDR, CaSR, p21, Ki67, and Tdt-mediated dUTP nick end-labeling (TUNEL) assay. The area per cell was measured as the parameter of cell size. The expression of VDR and p21 began to decrease at day 1, and Ki67 increased at day 3, but decreased thereafter. There was a significant increase in PT gland weight to week 12 with the increase of cell size. VD3 treatment significantly increased both VDR and CaSR expressions 2 weeks after the start of injection, and reduced the PT gland weight at week 3 with significant increase of TUNEL-positive cells and decrease of cell size. Our results suggest that PT growth in uremic rats involves both PT cell proliferation and hypertrophy, in association with the reduction of VDR, CaSR, and p21 expressions. In addition, VD3 treatment could reverse PT hyperplasia and hypertrophy via restoration of these proteins.Kidney International (2006) 69, 464–470. doi:10.1038/sj.ki.5000090; published online 4 January 2006 [ABSTRACT FROM AUTHOR]

B Background: b Portal vein (PV) resection followed by interposition graft repair is sometimes necessary to complete radical resection in pancreatic malignancies. Autologous external iliac vein (EIV) has been a good candidate for this graft, but harvesting the EIV has caused, in turn, critical venous congestion and thus the swelling of the affected lower extremity. [Extracted from the article]

We studied in vitro hormonal activity of bisphenol A diglycidyl ether (BADGE) and bisphenol F diglycidyl ether (BFDGE), which are used as a material of interior coating for food cans. We also examined related compounds such as 2,2-bis[4-(3-chloro-2-hydroxypropoxy)phenyl]propane (BADGE.2HCl), and bis[4-(3-chloro-2-hydroxypropoxy)phenyl]methane (BFDGE.2HCl) etc. For this purpose, we constructed two stably transfected CHO-K1 cell lines (AR-EcoScreen for androgenic activity and c-luc for cell toxicity evaluation). One stably expresses luciferase with induction of androgen. The other stably expresses luciferase without androgen induction. Also, we have determined the androgenic and anti-androgenic effects of the test chemicals by reporter gene assay with these cell lines. None of the chemicals tested by this assay exhibited androgen agonistic activity. However, BADGE.2HCl and BFDGE.2HCl had the conspicuous antagonistic activity for androgen. These compounds had a high binding affinity for androgen receptor. Furthermore, these two compounds did not show the estrogenic activity in vitro assays. On the contrary, bisphenol A and bisphenol F exhibited anti-androgenic activity in vitro in addition to the estrogenic activity. These results suggest that these chlorohydroxy compounds of BADGE and BFDGE act as androgen antagonist through the process of binding to androgen receptor. [Copyright &y& Elsevier]

Abstract: The serious shortage of brain-dead donors leads to the use of pancreata from marginal donors, including cardiac death in Japan. We studied the islet histology of pancreas graft biopsies to investigate the adequacy of using pancreata from marginal donors. Pancreas allograft biopsy was performed originally to diagnose acute rejection (Drachenberg grade I–III) at a mean of 6 months after transplantation. The percentage of β cells showing oxidative DNA changes, replication, and apoptosis was investigated in 7 recipients of simultaneous pancreas-kidney transplantations with good graft function from marginal donors. Their causes of death were cerebrovascular with donor ages >44 years (n = 3), cardiac (n = 2), and cerebrovascular (n = 2). The percentage of β cells per islet in the transplanted pancreas (71.9 ± 3.3%) did not correlate with glycemic control or insulin secretion, but did correlated inversely with donor age (r = −0.81; P < .05). Oxidative DNA changes as revealed by 8-hydroxy-2′-deoxyguanosine (8-OHdG) staining were diffusely present in islet cells as well as in the exocrine cells of the transplanted pancreas. The percentage of 8-OHdG–positive cells per pancreas (71.8 ± 4.5%) did not correlate with glycemic levels, insulin secretion, donor age, or ischemic time. There were no Ki67-positive replicating cells or terminal deoxynucleotide transferase–mediated dUTP nick-end labeling–positive apoptotic islet cells. Transplanted pancreata from marginal donors showed preserved β cells and function despite diffuse oxidative changes. [Copyright &y& Elsevier]