Cucurbituril Ameliorates Liver Damage Induced by Microcystis aeruginosa in a Mouse Model

Microcystis aeruginosa is a cyanobacterium that produces a variety of cyclic heptapeptide toxins in freshwater. The protective effects of the macromolecular container cucurbit[7]uril (CB7) were evaluated using mouse models of cyanotoxin-induced liver damage. Biochemical analysis of liver function was performed to gauge the extent of liver damage after exposure to cyanobacterial crude extract [CCE; LD50 = 35 mg/kg body weight; intraperitoneal (i.p.)] in the absence or presence of CB7 (35 mg/kg body weight, i.p.). CCE injection resulted in liver enlargement, potentiated the activities of alanine aminotransferase (ALT) and glutathione S-transferase (GST), increased lipid peroxidation (LPO), and reduced protein phosphatase 1 (PP1) activity. CCE-induced liver enlargement, ALT and GST activities, and LPO were significantly reduced when CB7 was coadministered. Moreover, the CCE-induced decline of PP1 activity was also ameliorated in the presence of CB7. Treatment with CB7 alone did not affect liver function, which exhibited a dose tolerance of 100 mg/kg body wt. Overall, our results illustrated that the addition of CB7 significantly reduced CCE-induced hepatotoxicity (P < 0.05).

Characterization and Fabrication of the CFM-JTE for 4H-SiC Power Device with High-Efficiency Protection and Increased JTE Dose Tolerance Window

A 13.5 kV 4H-SiC PiN rectifier with a considerable active area of 0.1 cm2 is fabricated in this paper. Charge-field-modulated junction termination extension (CFM-JTE) has been proposed for satisfying the requirement of ultra-high reverse voltage, which enlarges the JTE dose tolerance window, making it approximately 2.8 times that of the conventional two-zone JTE. Besides, the CFM-JTE can be implemented through the conventional two-zone JTE process. The measured forward current is up to 100 A @ VF = 5.2 V in the absence of carrier lifetime enhancement technology. The CFM-JTE structure accomplishes 96% of the theoretical breakdown voltage of the parallel plane junction with a relatively small terminal area of 400 μm, which contributes to achieving the Baliga’s figure of merit of 58.8 GW/cm2.

Estimating the Tolerance of Brachial Plexus to Hypofractionated Stereotactic Body Radiotherapy – A Modelling-based Approach from Clinical Experience.

Background: Brachial plexopathy (BP) is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose-response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor.Methods: Two published SBRT datasets were pooled and modeled from patients treated with SBRT at Indiana University and the Richard Roudebush VAMC from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and a probit dose response model was created with maximum likelihood parameter fitting.Results: This analysis includes a total of 89 brachial plexus Dmax values from both institutions. Among the 14 patients who developed BP, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1-72.2) in the Karolinska dataset, and Indiana had a median of 13 months (range 1-71). Both studies had a median range of 3 fractions, but in the Indiana dataset 9 patients were treated in 4 fractions and the paper did not differentiate which ones were which, so our analysis is considered to be in 3-4 fractions, which is one of the main limitations. The probit model showed that the risk of BP with Dmax of 26 Gy in 3-4 fractions is 10%, and 50% with Dmax of 70 Gy in 3 -4 fractions.Conclusions: This analysis is only a preliminary result because more details are needed, and more comprehensive datasets are needed from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

Efficacy of corticosteroid in decreasing scoliosis and extending time to loss of ambulation in a single clinic: an effectiveness trial

Purpose Pharmacologic doses of corticosteroid (CS) have been shown to ameliorate the progression of Duchenne muscular dystrophy (DMD) preserving strength, pulmonary function and ambulation as well as reducing the incidence of scoliosis. However, there are serious side effects of CS, which may impact dose tolerance. The purpose of this study was to compare the magnitude of positive CS effects on patients in our clinic to those reported in the literature. Methods We retrospectively reviewed medical records and radiographs of 142 DMD patients who were seen between 1st January 1991 and 31st December 2017. Results In total, 101 boys met study inclusion criteria. Of these 32 were steroid naïve, 37 took the recommended dose (standard of care, SOC) of Prednisone or Deflazacort, and 32 took a lower dose (LD). Following initiation of CS, both treatment groups showed an increase in weight velocity and decrease in linear growth velocity. Although there was a trend to later loss of ambulation (LOA) in the SOC group relative to the naïve group by one year, this was not significant, however, a small subgroup of boys on Deflazacort showed a 3.4 year later LOA than the naïve group. The incidence of scoliosis was reduced from 69% in the naïve, to 41% in the LD and 47% in the SOC group. Conclusions Although there was a reduction in the incidence of scoliosis, it was not as robust as seen elsewhere. Many published studies have inadequate data on scoliosis probably due to the lack of inclusion of orthopaedists in the study group. Level of evidence IV

Window of opportunity trial to characterize the safety, pharmacokinetics, and pharmacodynamics of fosciclopirox (CPX-POM) in cisplatin-ineligible muscle invasive bladder cancer patients.

TPS604 Background: Fosciclopirox (Ciclopirox Prodrug, CPX-POM) is being developed for the treatment of non-muscle invasive and muscle invasive (MIBC) bladder cancer. CPX-POM selectively delivers its active metabolite, ciclopirox (CPX), to the entire urinary tract following systemic administration. In a validated, chemical carcinogen mouse model of bladder cancer, CPX-POM treatment results in significant decreases in bladder weight, a clear migration to lower stage tumors, dose-dependent reductions in Ki67 and PCNA staining, and inhibition of Notch 1 and Wnt signaling. The safety, dose tolerance, pharmacokinetics and pharmacodynamics of IV CPX-POM have recently been characterized in 19 patients with advanced solid tumors (CPX-POM-001, NCT03348514). The safety and dose tolerance of IV CPX-POM was characterized across a dose range of 30 to 1200 mg/m2. The CPX-POM Recommended Phase 2 Dose (PR2D) of 900 mg/m2 administered IV over 20 minutes on Days 1-5 every 21 days was selected. Methods: Twelve cisplatin ineligible MIBC patients (Stage >T2, NO-N1, M0), scheduled for radical cystectomy (RC) will be enrolled in this window of opportunity study. Patients will receive two 21-day treatment cycles followed by RC within 14 days of completion of the second cycle. Safety and tolerability assessments will be made based on observed adverse and serious adverse events, physical examination, vital signs, electrocardiogram, clinical laboratory tests, and concomitant medications. Assessment of complete and partial pathologic response will be determined at RC. Ki67, Notch and Wnt signaling, and CD8+ lymphocyte tumor infiltration will be determined by immunohistochemistry. An unbiased approach to characterizing CPX-POM mechanisms of action will also be employed using RNAseq and ChIPseq. Serial blood (plasma) and complete urine specimens will be collected on Days 5-6 of Cycle 1 for determination of drug and metabolite concentrations by LC-MS/MS. Plasma and urine steady-state pharmacokinetics of CPX-POM, CPX and ciclopirox glucuronide will be characterized. Urine ß-glucuronidase activity is also being determined by ELISA. Clinical trial information: NCT03348514.

Safety, dose tolerance, pharmacokinetics, and pharmacodynamics of fosciclopirox (CPX-POM) in patients with advanced solid tumors.

518 Background: Fosciclopirox (CPX-POM) is being developed for the treatment of non-muscle invasive and muscle invasive bladder cancer. CPX-POM selectively delivers its active metabolite, ciclopirox (CPX), to the entire urinary tract following systemic administration. In a chemical carcinogen mouse model of bladder cancer, CPX-POM treatment resulted in significant decreases in bladder weight, migration to lower stage tumors, inhibition of cell proliferation as well as Notch 1 and Wnt signaling pathways. Methods: Study CPX-POM-001 (NCT03348514) is US multi-site, Phase I, open-label, dose escalation study characterizing the safety, dose tolerance, pharmacokinetics (PK) and pharmacodynamics of IV CPX-POM in advanced solid tumor patients. The PK of CPX-POM, CPX and ciclopirox glucuronide (CPX-G), were characterized in plasma and urine. Circulating biomarkers of Wnt and Notch, IL-6, IL-8 and VEGF were determined. Results: Nineteen patients were enrolled in the study. The starting dose of 30 mg/m2 was administered once daily on Days 1-5 of each 21-day treatment cycle. Doses were escalated to 1200 mg/m2. The MTD was determined to be 900 mg/m2. Overall, the number of treatment-related AE's tended to increase in frequency with dose, nausea and vomiting being the most common. Grade 3 confusion was observed in the 1200 mg/m2 cohort. Four AE's of Grade 1 confusion at 600 and 900 mg/m2. There was no evidence of QTc prolongation or other ECG abnormality. One patient in the 240 mg/m2 dose cohort, with a diagnosis of indolent primary fallopian tube tumor, achieved a partial response per RECIST 1.1. Metabolism of CPX-POM was rapid and complete. The clearance of CPX was dose proportional and time-independent. At MTD, steady-state 24-hour urine CPX concentrations of 215 µM were achieved. Evidence of Notch and Wnt inhibition was observed. Conclusions: IV CPX-POM was well tolerated with treatment-related AEs primarily CNS-related. At MTD, systemic and urinary CPX exposures exceeding in vitro IC50 values by several-fold. The 900 mg/m2 dose is currently being evaluated in an expansion cohort study in cisplatin-ineligible muscle invasive bladder cancer patients scheduled for cystectomy. Clinical trial information: NCT03348514.

Surgery treatment for early radiation ulcer developed after endovascular intervention

Delayed radiation damage to soft tissue and its treatment are described in detail. In the majority of cases the development of late radiation injuries were resulted from the radiation therapy of cancer. Early radiation injuries rarely occur. Most of early radiation-induced pathologic changes result from occupational radiation exposure or violation of radiation safety regulations. Nowadays we witness widespread clinical use of endovascular interventions, that can last for many hours. Concurrently, publications of research groups reported on complications in patients underwent endovascular procedures have appeared. The reported complications can be a result of increas-ing radiation dose to normal tissue over dose tolerance limits. The article presents a case of the successful treatment of early radiation ulcer on the left shoulder blade developed as a result of coronography followed by transluminal balloon angioplasty and stenting of the ramus interven-tricularis anterior (RIVA). Fibrotic tissue and radiation ulcer were excised en bloc with a cuff of healthy tissue followed by single-stage plasty with interpolated thoracodorsal musculocutaneous flap. Due to the given treatment we managed to restore the patient’s health status and improve his quality of life.