Inhibition of Amyloid-ß Aggregation by Cobalt(III) Schiff Base Complexes: A Computational and Experimental Approach.

Coordination complexes have emerged as prominent modulators of amyloid aggregation via their interaction with the N-terminal histidine residues of amyloid-ß (Aß). Herein, we report the synthesis and characterization of a novel cobalt(III) Schiff base complex with methylamine axial ligands, and we present both computational and experimental data demonstrating the reduction of ß-sheet formation by this complex. The computations include molecular dynamics simulations of both monomeric and pentameric Aß, which demonstrate decreased formation of ß-sheet structures, destabilization of preformed ß-sheets, and suppression of aggregation. These results are consistent with a dose dependence in experimental bulk aggregation data using thioflavin T fluorescence, and overall this study demonstrates useful drug activity of the cobalt complex.

Process improvement in thyroid fine needle aspiration: Standardizing number of smears for enhanced adequacy and diagnosis.

Fine-needle aspiration (FNA) is a safe, cost-effective diagnostic procedure used in the evaluation of thyroid nodules. The number of thyroid FNAs has dramatically increased over the past few years. In the absence of standardized procedures regarding the number of needle passes needed for diagnosis and the lack of clarity on the use of conventional smears (CS) versus liquid-based preparations (LBP), the demand of thyroid FNAs has led to increased workload on cytology laboratories, which can negatively affect patient safety. We implemented a standardized two needle passes for CS and collection of all needle rinses and additional pass material in CytoRich Red for ThinPrep LBP and compared the non-diagnostic and diagnostic rates before and after this intervention. There were 290 pre-intervention cases and 348 post-intervention cases; of which, there were 17 (5.9%) non-diagnostic cases of the pre-intervention group and 27 (7.8) non-diagnostic cases of the post-intervention group. There was no statistically significant difference in non-diagnostic and diagnostic rates before and after the change (p = 0.347 by two-tailed Z test).

Spinal calcifying pseudoneoplasms of the neuraxis: A case report and review of the literature.

Calcifying pseudoneoplasms of the neuraxis (CAPNON) are rare, non-neoplastic, slow-growing tumors that can present anywhere throughout the central nervous system. While the etiology of these lesions remains unknown, the mainstay of treatment is surgical excision. We describe a case of CAPNON at our institution in a 66 year-old female patient who presented with 5 months of pain and burning sensation in her thigh. On MRI, an intradural extramedullary lesion was identified at the level of T11-T12. The mass was surgically excised and the patient reported resolution of her symptoms by her six week follow-up appointment. We reviewed 79 spinal CAPNON cases, covering all cases reported in the literature thus far. In summary, we find that spinal CAPNON are most commonly lumbar and extradural in location, with pain as the most common presenting symptom. Lesions are well-defined and hypointense on T1 and T2 MRI sequence. The majority of cases had favorable surgical outcomes with near complete resolution of pain and associated symptoms.

Integrating Multisector Molecular Characterization into Personalized Peptide Vaccine Design for Patients with Newly Diagnosed Glioblastoma.

PURPOSE: Outcomes for patients with glioblastoma (GBM) remain poor despite multimodality treatment with surgery, radiation, and chemotherapy. There are few immunotherapy options due to the lack of tumor immunogenicity. Several clinical trials have reported promising results with cancer vaccines. To date, studies have used data from a single tumor site to identify targetable antigens, but this approach limits the antigen pool and is antithetical to the heterogeneity of GBM. We have implemented multisector sequencing to increase the pool of neoantigens across the GBM genomic landscape that can be incorporated into personalized peptide vaccines called NeoVax. PATIENTS AND METHODS: In this study, we report the findings of four patients enrolled onto the NeoVax clinical trial (NCT0342209). RESULTS: Immune reactivity to NeoVax neoantigens was assessed in peripheral blood mononuclear cells pre- and post-NeoVax for patients 1 to 3 using IFNγ-ELISPOT assay. A statistically significant increase in IFNγ producing T cells at the post-NeoVax time point for several neoantigens was observed. Furthermore, a post-NeoVax tumor biopsy was obtained from patient 3 and, upon evaluation, revealed evidence of infiltrating, clonally expanded T cells. CONCLUSIONS: Collectively, our findings suggest that NeoVax stimulated the expansion of neoantigen-specific effector T cells and provide encouraging results to aid in the development of future neoantigen vaccine-based clinical trials in patients with GBM. Herein, we demonstrate the feasibility of incorporating multisector sampling in cancer vaccine design and provide information on the clinical applicability of clonality, distribution, and immunogenicity of the neoantigen landscape in patients with GBM.

Diffusion basis spectrum imaging as an adjunct to conventional MRI leads to earlier diagnosis of high-grade glioma tumor progression versus treatment effect.

Background: Following chemoradiotherapy for high-grade glioma (HGG), it is often challenging to distinguish treatment changes from true tumor progression using conventional MRI. The diffusion basis spectrum imaging (DBSI) hindered fraction is associated with tissue edema or necrosis, which are common treatment-related changes. We hypothesized that DBSI hindered fraction may augment conventional imaging for earlier diagnosis of progression versus treatment effect. Methods: Adult patients were prospectively recruited if they had a known histologic diagnosis of HGG and completed standard-of-care chemoradiotherapy. DBSI and conventional MRI data were acquired longitudinally beginning 4 weeks post-radiation. Conventional MRI and DBSI metrics were compared with respect to their ability to diagnose progression versus treatment effect. Results: Twelve HGG patients were enrolled between August 2019 and February 2020, and 9 were ultimately analyzed (5 progression, 4 treatment effect). Within new or enlarging contrast-enhancing regions, DBSI hindered fraction was significantly higher in the treatment effect group compared to progression group (P = .0004). Compared to serial conventional MRI alone, inclusion of DBSI would have led to earlier diagnosis of either progression or treatment effect in 6 (66.7%) patients by a median of 7.7 (interquartile range = 0-20.1) weeks. Conclusions: In the first longitudinal prospective study of DBSI in adult HGG patients, we found that in new or enlarging contrast-enhancing regions following therapy, DBSI hindered fraction is elevated in cases of treatment effect compared to those with progression. Hindered fraction map may be a valuable adjunct to conventional MRI to distinguish tumor progression from treatment effect.

Cobalt(III) Schiff base complexes stabilize non-fibrillar amyloid-ß aggregates with reduced toxicity.

The aggregation of amyloid-ß (Aß) is believed to be foundational to the pathogenesis of Alzheimer's disease (AD). In vitro aggregation kinetics have been shown to correlate with rates of disease progression in both AD patients and animal models, thus proving to be a useful metric for testing Aß-targeted therapeutics. Here we present evidence of cobalt(III) Schiff base complex ([Co(acetylacetonate)(NH3)2]Cl; Co(III)-sb) modulation of Aß aggregation kinetics by a variety of complementary techniques. These include Thioflavin T (ThT) fluorescence, circular dichroism (CD) spectroscopy, transmission electron microscopy (TEM), and atomic force microscopy (AFM). Our data was fitted to kinetic rate laws using a mathematical model developed by Knowles et al. in order to extract mechanistic information about the effect of Co(III)-sb on aggregation kinetics. Our analysis revealed that Co(III)-sb alters Aß aggregation by decreasing the polymerization rate and increasing the nucleation rate, suggesting that Co(III)-sb causes Aß to rapidly stabilize oligomeric species with reduced elongation into mature fibrils. This result was corroborated by TEM and AFM of Aß aggregates in vitro. We also demonstrate that Aß aggregate mixtures produced in the presence of Co(III)-sb exhibit decreased cytotoxicity compared to untreated samples.

Cobalt-Schiff Base Complexes: Preclinical Research and Potential Therapeutic Uses.

The use of metals in medicine has grown impressively in recent years as a result of greatly advanced understanding of biologically active metal complexes and metal-containing proteins. One landmark in this area was the introduction of cisplatin and related derivatives as anticancer drugs. As the body of literature continues to expand, it is necessary to inspect sub-classes of this group with more acute detail. This chapter will review preclinical research of cobalt complexes coordinated by Schiff base ligands. Cobalt-Schiff base complexes have a wide variety of potential therapeutic functions, including as antimicrobials, anticancer agents, and inhibitors of protein aggregation. While providing a broad introduction to this class of agents, this chapter will pay particular attention to agents for which mechanisms of actions have been studied. Appropriate methods to assess activity of these complexes will be reviewed, and promising preclinical complexes in each of the following therapeutic areas will be highlighted: antimicrobial, antiviral, cancer therapy, and Alzheimer's disease.