Heavy Water (D2O) Containing Preservation Solution Reduces Hepatic Cold Preservation and Reperfusion Injury in an Isolated Perfused Rat Liver (IPRL) Model

Background: Heavy water (D2O) has many biological effects due to the isotope effect of deuterium. We previously reported the efficacy of D2O containing solution (Dsol) in the cold preservation of rat hearts. Here, we evaluated whether Dsol reduced hepatic cold preservation and reperfusion injury. Methods: Rat livers were subjected to 48-hour cold storage in University of Wisconsin (UW) solution or Dsol, and subsequently reperfused on an isolated perfused rat liver. Graft function, injury, perfusion kinetics, oxidative stress, and cytoskeletal integrity were assessed. Results: In the UW group, severe ischemia and reperfusion injury (IRI) was shown by histopathology, higher liver enzymes leakage, portal resistance, and apoptotic index, oxygen consumption, less bile production, energy charge, and reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio (versus control). The Dsol group showed that these injuries were significantly ameliorated (versus the UW group). Furthermore, cytoskeletal derangement was progressed in the UW group, as shown by less degradation of alpha-Fodrin and by the inactivation of the actin depolymerization pathway, whereas these changes were significantly suppressed in the Dsol group. Conclusion: Dsol reduced hepatic IRI after extended cold preservation and subsequent reperfusion. The protection was primarily due to the maintenance of mitochondrial function, cytoskeletal integrity, leading to limiting oxidative stress, apoptosis, and necrosis pathways

Comparison of two small animal PET prototypes for off-line range verification in carbon beam irradiation

Small animal studies in the carbon ion therapy field are still necessary to understand cancer cell behavior deeply and to explore new medical applications. For precise irradiation with dose monitoring for small animals, PET measurement of positron emitters produced via fragmentation reactions is desired. This study compared our two recently developed small animal PET prototypes with different performance characteristics. The first is a total body small-animal (TBS) PET prototype with a high sensitivity of 16.7% at the center, while the spatial resolution is limited to about 2 mm. The second is a crosshair light sharing (CLS) PET prototype having sub-millimeter spatial resolution while the sensitivity at the center is limited to 1.0%. Both are compact mobile scanners, which can be moved to an irradiation room at the Heavy-Ion Medical Accelerator in Chiba (HIMAC) for offline PET measurement. Also, they have sufficient axial length for measuring a rat\u27s total body at one time. In this study, cylindrical phantoms of 4 cm diameter and 10 cm length made of polymethyl methacrylate (PMMA) were irradiated with a 290 MeV/u 12C beam (1.2×109 pps) for 16 s. A brass collimator and a PMMA range shifter of 90 mm thickness were placed upstream to adjust the beam shape and the Bragg peak position to the phantom center. Off-line PET measurement start times after the end of irradiation and the measurement times were 5 min and 20 min for TBS PET and 6 min and 30 min for CLS PET, respectively. As a result, peaks in images obtained by TBS and CLS PET prototypes were observed respectively at 4 mm and 3 mm upstream from the Bragg peak position. The obtained image of the CLS PET was significantly noisier than that of TBS PET, although the measurement time of CLS PET was longer. The high sensitivity of the TBS PET prototype is preferred in cases where the number of produced positron emitters is limited.IEEE NSS MIC 202

Hypofractionated Proton Beam Therapy for cT1-2N0M0 Non-small Cell Lung Cancer Patients With Interstitial Lung Disease

Background/Aim: To evaluate the outcomes of proton beam therapy (PBT) for early-stage non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD). Patients and Methods: Between 2002 and 2017, 110 patients receiving hypofractionated PBT for cT1-2N0M0 NSCLC were reviewed.Results: Of the 110 patients, 17 were diagnosed with ILD. The median follow-up period was 37.8 months. No significant difference in the 1-year cumulative rate of grade ≥2 pneumonitis was observed between patients with and those without ILD (17.6% vs. 14.1%, p=0.708). The lung doses were significantly lower in patients with than in those without ILD among patients without grade ≥2 neumonitis. There were no significant differences in overall survival or local recurrence-free rates according to the presence of ILD. Conclusion: PBT appears to be a feasible and effective treatment for cT1-2N0M0 NSCLC inpatients with ILD, but the lung dose should be strictly reduced

Sulfated Hyaluronan Binds to Heparanase and Blocks Its Enzymatic and Cellular Actions in Carcinoma Cells

We examined whether sulfated hyaluronan exerts inhibitory effects on enzymatic and biological actions of heparanase, a sole endo-beta-glucuronidase implicated in cancer malignancy and inflammation. Degradation of heparan sulfate by human and mouse heparanase was inhibited by sulfated hyaluronan. In particular, high-sulfated hyaluronan modified with approximately 2.5 sulfate groups per disaccharide unit effectively inhibited the enzymatic activity at a lower concentration than heparin. Human and mouse heparanase bound to immobilized sulfated hyaluronan. Invasion of heparanase-positive colon-26 cells and 4T1 cells under 3D culture conditions was significantly suppressed in the presence of high-sulfated hyaluronan. Heparanase-induced release of CCL2 from colon-26 cells was suppressed in the presence of sulfated hyaluronan via blocking of cell surface binding and subsequent intracellular NF-κB-dependent signaling. The inhibitory effect of sulfated hyaluronan is likely due to competitive binding to the heparanase molecule, which antagonizes the heparanase-substrate interaction. Fragment molecular orbital calculation revealed a strong binding of sulfated hyaluronan tetrasaccharide to the heparanase molecule based on electrostatic interactions, particularly characterized by interactions of (−1)- and (−2)-positioned sulfated sugar residues with basic amino acid residues composing the heparin-binding domain-1 of heparanase. These results propose a relevance for sulfated hyaluronan in the blocking of heparanase-mediated enzymatic and cellular actions

Empagliflozin in Patients with Chronic Kidney Disease

Background The effects of empagliflozin in patients with chronic kidney disease who are at risk for disease progression are not well understood. The EMPA-KIDNEY trial was designed to assess the effects of treatment with empagliflozin in a broad range of such patients. Methods We enrolled patients with chronic kidney disease who had an estimated glomerular filtration rate (eGFR) of at least 20 but less than 45 ml per minute per 1.73 m(2) of body-surface area, or who had an eGFR of at least 45 but less than 90 ml per minute per 1.73 m(2) with a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 200. Patients were randomly assigned to receive empagliflozin (10 mg once daily) or matching placebo. The primary outcome was a composite of progression of kidney disease (defined as end-stage kidney disease, a sustained decrease in eGFR to < 10 ml per minute per 1.73 m(2), a sustained decrease in eGFR of & GE;40% from baseline, or death from renal causes) or death from cardiovascular causes. Results A total of 6609 patients underwent randomization. During a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 432 of 3304 patients (13.1%) in the empagliflozin group and in 558 of 3305 patients (16.9%) in the placebo group (hazard ratio, 0.72; 95% confidence interval [CI], 0.64 to 0.82; P < 0.001). Results were consistent among patients with or without diabetes and across subgroups defined according to eGFR ranges. The rate of hospitalization from any cause was lower in the empagliflozin group than in the placebo group (hazard ratio, 0.86; 95% CI, 0.78 to 0.95; P=0.003), but there were no significant between-group differences with respect to the composite outcome of hospitalization for heart failure or death from cardiovascular causes (which occurred in 4.0% in the empagliflozin group and 4.6% in the placebo group) or death from any cause (in 4.5% and 5.1%, respectively). The rates of serious adverse events were similar in the two groups. Conclusions Among a wide range of patients with chronic kidney disease who were at risk for disease progression, empagliflozin therapy led to a lower risk of progression of kidney disease or death from cardiovascular causes than placebo