Specifics of Porous Polymer and Xenogeneic Matrices and of Bone Tissue Regeneration Related to Their Implantation into an Experimental Rabbit Defect.

This paper provides a study of two bone substitutes: a hybrid porous polymer and an osteoplastic matrix based on a bovine-derived xenograft. Both materials are porous, but their pore characteristics are different. The osteoplastic matrix has pores of 300-600 µm and the hybrid polymer has smaller pores, generally of 6-20 µm, but with some pores up to 100 µm across. SEM data confirmed the porometry results and demonstrated the different structures of the materials. Therefore, both materials were characterized by an interconnected porous structure and provided conditions for the adhesion and vital activity of human ASCs in vitro. In an experimental model of rabbit shin bone defect, it was shown that, during the 6-month observation period, neither of the materials caused negative reactions in the experimental animals. By the end of the observation period, restoration of the defects in animals in both groups was completed, and elements of both materials were preserved in the defect areas. Data from morphological examinations and CT data demonstrated that the rate of rabbit bone tissue regeneration with the hybrid polymer was comparable to that with the osteoplastic matrix. Therefore, the hybrid polymer has good potential for use in further research and improvement in biomedical applications.

Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer.

PURPOSE: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting. PATIENTS AND METHODS: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms. RESULTS: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). CONCLUSION: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.

An Open-Source Pipeline for Processing Direct Infusion Mass Spectrometry Data of the Human Plasma Metabolome.

Direct infusion mass spectrometry (DIMS) is growing in popularity as an effective method for the screening of biological samples in clinical metabolomics. Being quick to execute, DIMS generally requires special skills when interpreting the results of measurements. By inspecting the similarities between two-dimensional electrospray ionization with quadrupole time-of-flight (ESI-QTOF) and matrix-assisted laser desorption/ionization (MALDI) mass spectra, the pipeline for processing QTOF mass spectra using open-source packages (MALDIquant, MSnbase and MetaboAnalystR) was tested. Previously, all algorithmic workflows have relied on the application of software either provided by a vendor or privately developed by enthusiasts. Here, we computationally examined two ways of interpreting the DIMS results of human blood metabolomic profiling. The studied spectra were acquired using ESI-QTOF maXis Impact II (Bruker Daltonics, Billerica, MA, USA), then pre-processed using COMPASS/DataAnalysis commercial software and mapped onto the metabolites using in-lab-developed MatLab scripts. Alternatively, in this work we used the open-source packages MALDIquant, for spectrum pre-processing, and MetaboAnalystR, for data interpretation, instead of the low-availability commercial and home-made tools. Using a set of 100 plasma samples (20 from volunteers with normal body mass index and 80 from patients at different stages of obesity), we observed a high degree of concordance in annotated metabolic pathways between the proprietary DataAnalysis/MatLab pipeline and our freely available solution.

Comparison of Biomarker Assays for EGFR: Implications for Precision Medicine in Patients with Glioblastoma.

PURPOSE: Patients with glioblastoma (GBM) have a poor prognosis and are in desperate need of better therapies. As therapeutic decisions are increasingly guided by biomarkers, and EGFR abnormalities are common in GBM, thus representing a potential therapeutic target, we systematically evaluated methods of assessing EGFR amplification by multiple assays. Specifically, we evaluated correlation among fluorescence in situ hybridization (FISH), a standard assay for detecting EGFR amplification, with other methods.Experimental Design: Formalin-fixed, paraffin-embedded tumor samples were used for all assays. EGFR amplification was detected using FISH (N = 206) and whole-exome sequencing (WES, N = 74). EGFR mRNA expression was measured using reverse transcription-polymerase chain reaction (RT-PCR, N = 206) and transcriptome profiling (RNAseq, N = 64). EGFR protein expression was determined by immunohistochemistry (IHC, N = 34). Significant correlations among various methods were determined using Cohen's kappa (κ = 0.61-0.80 defines substantial agreement) or R 2 statistics. RESULTS: EGFR mRNA expression levels by RNA sequencing (RNAseq) and RT-PCR were highly correlated with EGFR amplification assessed by FISH (κ = 0.702). High concordance was also observed when comparing FISH to WES (κ = 0.739). RNA expression was superior to protein expression in delineating EGFR amplification. CONCLUSIONS: Methods for assessing EGFR mRNA expression (RT-PCR, RNAseq) and copy number (WES), but not protein expression (IHC), can be used as surrogates for EGFR amplification (FISH) in GBM. Collectively, our results provide enhanced understanding of available screening options for patients, which may help guide EGFR-targeted therapeutic approaches.

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations.

Patients enrolled in clinical trials for traumatic brain injury (TBI) may present with heterogeneous features over a range of injury severity, such as diffuse axonal injury, ischemia, edema, hemorrhage, oxidative damage, mitochondrial and metabolic dysfunction, excitotoxicity, inflammation, and other pathophysiological processes. To determine whether combination therapies might be more effective than monotherapy at attenuating moderate TBI or promoting recovery, the National Institutes of Health funded six preclinical studies in adult and immature male rats to evaluate promising acute treatments alone and in combination. Each of the studies had a solid rationale for its approach based on previous research, but only one reported significant improvements in long-term outcomes across a battery of behavioral tests. Four studies had equivocal results because of a lack of sensitivity of the outcome assessments. One study demonstrated worse results with the combination in comparison with monotherapies. While specific research findings are reported elsewhere, this article provides an overview of the study designs, insights, and recommendations for future research aimed at therapy development for TBI.

Dietary choline supplementation improves behavioral, histological, and neurochemical outcomes in a rat model of traumatic brain injury.

Novel pharmacological approaches that safely and effectively lessen the degree of neurological impairment following traumatic brain injury (TBI) are sorely needed. Non-invasive approaches that could be used over an extended periods of time might be particularly useful. Previous studies from our lab have hypothesized that TBI-induced decreases in hippocampal and cortical alpha7 neuronal nicotinic cholinergic receptor (nAChR) expression might contribute to cognitive impairment that follows brain injury. The purpose of this study was to determine whether the low-potency, but selective alpha7 nAChR agonist choline might be a useful treatment for improvement of neurological outcome in a rat model of TBI. Male Sprague-Dawley rats were exposed to control or choline-supplemented diets for 2 weeks prior to experimental brain injury (1.5-mm cortical contusion injury) and throughout the recovery phase. Dietary choline supplementation resulted in a modest degree of improvement in spatial memory as assessed in the Morris water maze test. In addition, choline treatment resulted in significant cortical tissue sparing, reduced brain inflammation, and normalized some TBI-induced deficits in nAChR expression. The results of this study suggest that alpha7 nAChR agonists may be useful drugs to enhance recovery following brain injury.