Surgical delivery of drug releasing poly(lactic-co-glycolic acid)/poly(ethylene glycol) paste with in vivo effects against glioblastoma

Introduction

The median survival of patients with glioblastoma multiforme (astrocytoma grade 4) remains less than 18 months despite radical surgery, radiotherapy and systemic chemotherapy. Surgical implantation of chemotherapy eluting wafers into the resection cavity has been shown to improve length of survival but the current licensed therapy has several drawbacks. This paper investigates in vivo efficacy of a novel drug eluting paste in glioblastoma.

Methods

Poly(lactic-co-glycolic acid)/poly(ethylene glycol) (PLGA/PEG) self-sintering paste was loaded with the chemotherapeutic agent etoposide and delivered surgically into partially resected tumours in a flank murine glioblastoma xenograft model.

Results

Surgical delivery of the paste was successful and practical, with no toxicity or surgical morbidity to the animals. The paste was retained in the tumour cavity, and preliminary results suggest a useful antitumour and antiangiogenic effect, particularly at higher doses. Bioluminescent imaging was not affected significantly by the presence of the paste in the tumour.

Conclusions

Chemotherapy loaded PLGA/PEG paste seems to be a promising technology capable of delivering active drugs into partially resected tumours. The preliminary results of this study suggest efficacy with no toxicity and will lead to larger scale efficacy studies in orthotopic glioblastoma models.     

Comparative effectiveness of cycling of tumor necrosis factor-α (TNF-α) inhibitors versus switching to non-TNF biologics in rheumatoid arthritis patients with inadequate response to TNF-α inhibitor using a Bayesian approach

Alternative tumor necrosis factor-α (TNF-α) inhibitors and non-TNF biologics are available as treatment options for rheumatoid arthritis patients who exhibit inadequate response to TNF-α inhibitor (TNF-IR patients). These agents have considerable efficacy compared with placebo, but head-to-head comparisons among these agents have not been performed. The objective of this study was to use Bayesian approach to compare the effectiveness of cycling TNF-α inhibitors versus switching to non-TNF biologics in TNF-IR patients. A systematic review was conducted using MEDLINE and Cochrane library. Key endpoints were the American College of Rheumatology (ACR) responses of 20/50/70 and the health assessment questionnaire (HAQ) score change at six months. Bayesian outcomes were calculated as the probability that OR is greater than one and HAQ score change difference is less than zero. Compared with TNF-α inhibitors, non-TNF biologics were associated with higher ACR response rates; in ACR20, the OR was 1.639 for abatacept [P(OR > 1) = 90.7 %], 1.871 for rituximab [P(OR > 1) = 96.2 %] and 3.52 for tocilizumab [P(OR > 1) = 99.9 %]. Similar trends were shown in the HAQ change comparison; the median differences (MD) were ?0.259 for abatacept [P(MD < 0) = 100 %], ?0.160 for rituximab [P(MD < 0) = 98.2 %], and ?0.200 for tocilizumab [P(MD < 0) = 99.3 %]. In conclusion, switching to non-TNF biologics was more effective than cycling TNF-α inhibitor in TNF-IR patients.     

Enhanced NO2 Sensing Performance of Graphene with Thermally Induced Defects

This paper demonstrates the enhanced NO₂ sensing performance of graphene with defects generated by rapid thermal annealing (RTA). A high temperature of RTA (300–700 °C) was applied to graphene under an argon atmosphere to form defects on sp² carbon lattices. The density of defects proportionally increased with increasing the RTA temperature. Raman scattering results confirmed significant changes in sp² bonding. After 700 °C RTA, I_D/I_G, I_2D/I_G, and FWHM (full width at half maximum)(G) values, which are used to indirectly investigate carbon-carbon bonds’ chemical and physical properties, were markedly changed compared to the pristine graphene. Further evidence of the thermally-induced defects on graphene was found via electrical resistance measurements. The electrical resistance of the RTA-treated graphene linearly increased with increasing RTA temperature. Meanwhile, the NO₂ response of graphene sensors increased from 0 to 500 °C and reached maximum (R = ~24%) at 500 °C. Then, the response rather decreased at 700 °C (R = ~14%). The results imply that rich defects formed at above a critical temperature (~500 °C) may damage electrical paths of sp² chains and thus deteriorate NO₂ response. Compared to the existing functionalization process, the RTA treatment is very facile and allows precise control of the NO₂ sensing characteristics, contributing to manufacturing commercial low-cost, high-performance, integrated sensors.     

The effect of electron density in furan pendant group on thermal-reversible Diels–Alder reaction based self-healing properties of polymethacrylate derivatives

Herein, we discuss the effect of electron density in a furan pendant group on the thermally reversible Diels–Alder (DA) reaction based self-healing efficiency in polymethacrylate derivatives. First, the furan-functionalized polymethacrylates (rPFMA and dPFMA) having different electron density in the furan pendant groups were prepared through free-radical polymerization. The healing efficiency of rPFMA, which was expected to have high healing efficiency due to the high reactivity of DA reaction originating from the electron density in the furan moiety, was shown to be 95.89% in the first and 69.86% in the second healing process, respectively, where it is higher than that of dPFMA having relatively low electron density in the furan moiety. To illustrate these results, kinetic tests of the DA reaction for rPFMA64 and dPFMA64 were performed, where the reactivity of the DA reaction for rPFMA64 was much higher than that for dPFMA64. This could be explained by the electron density in the furan pendant groups which controls the reactivity of DA reaction having a major effect on the efficiency of self-healing performance in furan-functionalized polymethacrylates.

Herein, we discuss the effect of electron density in a furan pendant group on the thermally reversible Diels–Alder (DA) reaction based self-healing efficiency in polymethacrylate derivatives.     

Change in the Recurrence Pattern and Predictors over Time after Complete Cure of Hepatocellular Carcinoma

Background/AimsWe investigated changes in recurrence rates and significant recurrence predictors over time after complete cure of hepatocellular carcinoma (HCC).MethodsA total of 1,491 patients with first-time diagnosis of Barcelona Clinic Liver Cancer stage A HCC, completely cured by treatment between 2007 and 2016, were recruited from two Korean tertiary institutes.ResultsThe mean age of the population (1,144 men and 347 women) was 58.6 years. Of the total population, 914 patients (61.3%) had liver cirrhosis. Nine-hundred and forty-one (63.1%) and 550 (36.9%) patients were treated with surgical resection and radiofrequency ablation (RFA), respectively. One-year cumulative incidences of HCC recurrence were 14.3%, 9.9%, and 5.1% from the time of treatment, 3 years after treatment, and 5 years after treatment, respectively. Upon multivariate analysis, multiple tumors, maximal tumor size ≥3 cm, and high Model for End-Stage Liver Disease scores were independently associated with increased HCC recurrence risk from the time of treatment and 1 and 2 years after curative treatment (all p<0.05, except for maximal tumor size ≥3 cm for recurrence 2 years after treatment). Meanwhile, liver cirrhosis and RFA were independently associated with the increased HCC recurrence risk for almost all time points (liver cirrhosis all p<0.05; RFA all p<0.005 except for recurrence from 5 years after treatment).ConclusionsThe recurrence rate of HCC after curative treatment gradually decreased over time. Two years after treatment, when tumor-related factors lose their prognostic implications, may be used as a cutoff to define the boundary between early and late recurrence of HCC. (Gut Liver 2021;15-429)     

Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen

Using the CD40 system, in vitro proliferation of hairy cell leukemia (HCL) was examined in 43 patients. In this culture system, cells were stimulated by interleukin-4 (IL-4) and anti-CD40 monoclonal antibodies (MoAbs) that were added in soluble form or were cross-linked via their Fc part using Fc gamma RII-transfected mouse fibroblast cells. Proliferation was induced and confirmed by 3H-thymidine incorporation in 14 cases and by the presence of metaphases in 42 cases. 3H-thymidine incorporation showed a heterogeneous pattern: cross-linking of anti- CD40 gave the highest proliferation in 8 cases; in 11 cases, stimulation with anti-CD40 MoAbs alone, without cross-linking also resulted in proliferation; the addition of IL-4 further enhanced 3H- thymidine incorporation in 5 cases, but suppressed this phenomenon in 5 other cases. The CD40 system proved to be very effective in obtaining cytogenetic data. With a success rate of 42 of 43 patients tested, we found clonal abnormalities in 8 cases (19%) and nonclonal abnormalities with involvement of one or two abnormal metaphases in another 7 cases. The chromosomes most frequently involved in the abnormal karyotypes, both structurally and numerically, were chromosomes 5, 7, and 14. By fluorescence-activated cell-sorting analysis of the cultured cells, and by immunophenotypic analysis of metaphase spreads, T-cell growth could be excluded and the HCL-lineage confirmed. Stimulation via the CD40 antigen is an excellent tool for growing hairy cell leukemia cells.     

Inhibition and complexation of activated protein C by two major inhibitors in plasma

To determine the major physiologic inhibitors of activated protein C (APC), plasma was incubated with APC or with Protac C and subjected to immunoblotting. APC:inhibitor complexes gave two major bands reacting with antiprotein C antibodies when immunoblotted on nondenaturing gels, and additional minor bands that varied between serum and plasma. Formation of one of the two major bands of APC:inhibitor complex, but not the other, was stimulated by heparin and only this band reacted with antibodies to the previously described APC inhibitor that is here designated PCI-1. Plasma immunodepleted of PCI-1 formed complexes with APC as visualized with antiprotein C but not anti-PCI-1 antibodies, and exhibited heparin-independent inhibition of APC activity, providing evidence for the existence of a second major physiologic APC inhibitor, PCI-2. Formation of APC:PCI-2 complexes in PCI-1-depleted plasma paralleled inhibition of APC amidolytic activity. PCI-2 was separated from PCI-1 and partially purified using column chromatography. PCI-2 formed inactive complexes of approximately 110,000 molecular weight (mol wt) with APC suggesting PCI-2 has an approximate mol wt of 50,000. Thus, inhibition of APC in plasma involves two major distinct 50,000 mol wt inhibitors, the heparin-dependent PCI-1 and the heparin- independent PCI-2.