No abstract

One of the biggest hurdles yet to be overcome for the continued improvement of Histone Deacetylase (HDAC) inhibitors is finding alternative motifs equipotent to the classic and ubiquitously used hydroxamic acid. The N-hydroxyl group of this motif is highly subject to sulfation/glucoronidation-based inactivation in humans; compounds containing this motif require much higher dosing in clinic to achieve therapeutic concentrations. With the goal of developing a second generation of HDAC inhibitors, lacking this hydroxamate, we designed a series of potent and selective class I HDAC inhibitors using a hydrazide motif. These inhibitors are impervious to glucuronidation and demonstrate allosteric inhibition. In vitro and ex vivo characterization of our lead analogs’ efficacy, selectivity, and toxicity profiles demonstrate they possess low nanomolar activity against models of Acute Myeloid Leukemia (AML) and are at least 100-fold more selective for AML than solid immortalized cells such as HEK293 or human peripheral blood mononuclear cells.

Multiple Myeloma (MM) is highly sensitive to disruptions in cellular protein homeostasis. Proteasome inhibitors (PIs) are initially effective in the treatment of MM, although cures are not achievable and the emergence of resistance limits the durability of responses. New therapies are needed for refractory patients, and those that combat resistance to standard of care agents would be particularly valuable. Screening of multiple chemical libraries for PI re-sensitizing compounds identified E61 as a potent enhancer of multiple PIs and MM specific activity. Using a tandem approach of click chemistry and peptide mass fingerprinting, we identified multiple protein disulfide isomerase (PDI) family members as the primary molecular targets of E61. PDIs mediate oxidative protein folding, and E61 treatment induced robust ER and oxidative stress responses as well as the accumulation of ubiquitinylated proteins. A chemical optimization program led to a new structural class of indene (exemplified by lead E64FC26), which are highly potent pan-style inhibitors of PDIs. In mice with MM, E64FC26 improved survival and enhanced the activity of bortezomib without any adverse effects. This work demonstrates the potential of E64FC26 as an

The acetylation status of lysine residues on histone proteins has long been attributed to a balance struck between the catalytic activity of histone acetyl transferases and histone deacetylases (HDAC). HDACs were identified as the sole removers of acetyl post-translational modifications (PTM) of histone lysine residues. Studies into the biological role of HDACs have also elucidated their role as removers of acetyl PTMs from lysine residues of nonhistone proteins. These findings, coupled with high-resolution mass spectrometry studies that revealed the presence of acyl-group PTMs on lysine residues of nonhistone proteins, brought forth the possibility of HDACs acting as removers of both acyl- and acetyl-based PTMs. We posited that HDACs fulfill this dual role and sought to investigate their specificity. Utilizing a fluorescence-based assay and biologically relevant acyl-substrates, the selectivities of zinc-dependent HDACs toward these acyl-based PTMs were identified. These findings were further validated using cellular models and molecular biology techniques. As a proof of principal, an HDAC3 selective inhibitor was designed using HDAC3’s substrate preference. This resulting inhibitor demonstrates nanomolar activity and >30 fold selectivity toward HDAC3 compared to the other class I HDACs. This inhibitor is capable of increasing p65 acetylation, attenuating NF-κB activation, and thereby preventing downstream nitric oxide signaling. Additionally, this selective HDAC3 inhibition allows for control of HMGB-1 secretion from activated macrophages without altering the acetylation status of histones or tubulin.

The prevalence of tickborne diseases worldwide is increasing virtually unchecked due to the lack of effective control strategies. The transmission dynamics of tickborne pathogens are influenced by the tick microbiome, tick co-infection with other pathogens, and environmental features. Understanding this complex system could lead to new strategies for pathogen control, but will require large-scale, high-resolution data. Here, we introduce Project Acari, a citizen science-based project to assay, at single-tick resolution, species, pathogen infection status, microbiome profile, and environmental conditions of tens of thousands of ticks collected from numerous sites across the United States. In the first phase of the project, we collected more than 2,400 ticks wild-caught by citizen scientists and developed high-throughput methods to process and sequence them individually. Applying these methods to 192 Ixodes scapularis ticks collected in a region with a high incidence of Lyme disease, we found that 62% were colonized by Borrelia burgdorferi, the Lyme disease pathogen. In contrast to previous reports, we did not find an association between the microbiome diversity of a tick and its probability of carrying B. burgdorferi. However, we did find undescribed associations between B. burgdorferi carriage and the presence of specific microbial taxa within individual ticks. Our findings underscore the power of coupling citizen science with highthroughput processing to reveal pathogen dynamics. Our approach can be extended for massively parallel screening of individual ticks, offering a powerful tool to elucidate the ecology of tickborne disease and to guide pathogen-control initiatives.

A silver-catalyzed coupling reaction of quinones with aryl disulfides for the synthesis of quinonyl aryl thioethers is described. In the presence of AgOAc (0.2 equiv)/dppp (0.24 equiv) as the catalyst, (NH4)2S2O8 (3.0 equiv) as the oxidant, and Bu4NBF4 (1.0 equiv) as the additive, the reaction is simple, provides high yield (up to 88% yield), and possesses a broad substrate scope. The reaction is believed to proceed via direct activation of disulfides evidenced by observation of a metathesis reaction between two different disulfides placed together under the reaction conditions and 13C NMR spectroscopy analysis.

Study Design: Systematic Review. Objectives: To review the literature surrounding the cost-effectiveness of implanting spinal cord stimulators for failed back surgery syndrome. Methods: A systematic review was conducted inclusive of all publications in the Medline database and Cochrane CENTRAL trials register within the last 10 years (English language only) assessing the cost-effectiveness of Spinal Cord Stimulator device implantation (SCSdi) in patients with previous lumbar fusion surgery. Results: The majority of reviewed publications that analyzed cost-effectiveness of SCSdi compared to conventional medical management (CMM) or re-operation in patients with failed back surgery syndrome (FBSS) showed an overall increase in direct medical costs; these increased costs were found in nearly all cases to be offset by significant improvements in patient quality of life. The cost required to achieve these increases in quality adjusted life years (QALY) falls well below $25 000/QALY, a conservative estimate of willingness to pay. Conclusions: The data suggest that SCSdi provides both superior outcomes and a lower incremental cost: effectiveness ratio (ICER) compared to CMM and/or re-operation in patients with FBSS. These findings are in spite of the fact that the majority of studies reviewed were agnostic to the type of device or innervation utilized in SCSdi. Newer devices utilizing burst or higher frequency stimulation have demonstrated their superiority over traditional SCSdi via randomized clinical trials and may provide lower ICERs.

OBJECTIVEQuality of life (QOL) is an important endpoint measure of cancer treatment. The authors’ goal was to evaluate QOL trajectories and prognostic value in cancer patients treated with stereotactic radiosurgery (SRS) for brain metastases.METHODSPatients who underwent Gamma Knife radiosurgery (GKRS) between January 2016 and November 2019 were prospectively evaluated for QOL using the EQ-5D-3L questionnaire before SRS and at follow-up visits. Only patients who had pre-SRS and at least 1 post-SRS QOL assessment were considered.RESULTSFifty-four cancer patients underwent 109 GKRS procedures. The first post-SRS visit was at a median of 2.59 months (range 0.13–21.08 months), and the last post-SRS visit was at 14.72 months (range 2.52–45.21 months) after SRS. There was no statistically significant change in the EQ-5D index score (p = 0.539) at the first compared with last post-SRS visit. The proportion of patients reporting some problems on the EQ-5D dimension of self-care increased during the course of follow-up from 9% (pre-SRS visit) to 18% (last post-SRS visit; p = 0.03). The proportion of patients reporting problems on the EQ-5D dimensions of mobility, usual activities, pain/discomfort, and anxiety/depression remained stable during the course of follow-up (p ≥ 0.106). After adjusting for clinical variables, a higher recursive partitioning analysis (RPA) class (i.e., worse prognostic category) was independently associated with greater odds for EQ-5D index score deterioration (p = 0.050). Upfront whole-brain radiation therapy predicted deterioration of the EQ-5D self-care (p = 0.03) and usual activities (p = 0.024) dimensions, while a greater number of lesions predicted deterioration of the EQ-5D anxiety/depression dimension (p = 0.008). A lower pre-SRS EQ-5D index was associated with shorter survival independently from clinical and demographic variables (OR 18.956, 95% CI 2.793–128.64; p = 0.003).CONCLUSIONSQOL is largely preserved in brain metastasis patients treated with SRS. Higher RPA class, upfront whole-brain radiation therapy, and greater intracranial disease burden are independent predictors of post-SRS QOL deterioration. Worse pre-SRS QOL predicts shorter survival. Assessment of QOL is recommended in brain metastasis patients managed with SRS.