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MSTPubs: September 2021

Posted by on Thursday, September 30, 2021 in New Publications .

​​​​Amelioration of post-traumatic osteoarthritis via nanoparticle depots delivering small interfering RNA to damaged cartilage.
Bedingfield, SK, Colazo, JM, Yu, F. et al.
Nat Biomed Eng. 2021 Aug 19.
The progression of osteoarthritis is associated with inflammation triggered by the enzymatic degradation of extracellular matrix in injured cartilage. Here we show that a locally injected depot of nanoparticles functionalized with an antibody targeting type II collagen and carrying small interfering RNA targeting the matrix metalloproteinase 13 gene (Mmp13), which breaks down type II collagen, substantially reduced the expression of MMP13 and protected cartilage integrity and overall joint structure in acute and severe mouse models of post-traumatic osteoarthritis. MMP13 inhibition suppressed clusters of genes associated with tissue restructuring, angiogenesis, innate immune responses and proteolysis. We also show that intra-articular injections of the nanoparticles led to greater reductions in disease progression than either a single injection or weekly injections of the steroid methylprednisolone. Sustained drug retention by targeting collagen in the damaged extracellular matrix of osteoarthritic cartilage may also be an effective strategy for the treatment of osteoarthritis with other disease-modifying drugs.

Top-Down Fabricated microPlates for Prolonged, Intra-articular Matrix Metalloproteinase 13 siRNA Nanocarrier Delivery to Reduce Post-traumatic Osteoarthritis
Bedingfield, SK, Colazo, JM, Di Francesco M, Yu F, Liu DD, Di Francesco V, Himmel LE, Gupta MK, Cho H, Hasty KA, Decuzzi P, Duvall CL
ACS Nano 2021 15 (9), 14475-14491. 2021 Aug 19. doi: 10.1021/acsnano.1c04005.
Post-traumatic osteoarthritis (PTOA) associated with joint injury triggers a degenerative cycle of matrix destruction and inflammatory signaling, leading to pain and loss of function. Here, prolonged RNA interference (RNAi) of matrix metalloproteinase 13 (MMP13) is tested as a PTOA disease modifying therapy. MMP13 is upregulated in PTOA and degrades the key cartilage structural protein type II collagen. Short interfering RNA (siRNA) loaded nanoparticles (siNPs) were encapsulated in shape-defined poly(lactic-co-glycolic acid) (PLGA) based microPlates (μPLs) to formulate siNP-μPLs that maintained siNPs in the joint significantly longer than delivery of free siNPs. Treatment with siNP-μPLs against MMP13 (siMMP13-μPLs) in a mechanical load-induced mouse model of PTOA maintained potent (65–75%) MMP13 gene expression knockdown and reduced MMP13 protein production in joint tissues throughout a 28-day study. MMP13 silencing reduced PTOA articular cartilage degradation/fibrillation, meniscal deterioration, synovial hyperplasia, osteophytes, and pro-inflammatory gene expression, supporting the therapeutic potential of long-lasting siMMP13-μPL therapy for PTOA.

Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism.
Manz KM, Coleman BC, Jameson AN, Ghose DG, Patel S, Grueter BA.
Neuropsychopharmacology. 2021 Sep 20. doi: 10.1038/s41386-021-01167-3. Online ahead of print.
Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (σ1) activity, leading to the mobilization of intracellular Ca2+ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB1R). Cocaine-evoked CB1R activity occludes the expression of CB1R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.

2-Hydroxybenzylamine (2-HOBA) to prevent early recurrence of atrial fibrillation after catheter ablation: protocol for a randomized controlled trial including detection of AF using a wearable device.
O’Neill MJ, Yoneda ZT, Crawford DM, Ye F, Ao M, Pitchford LM, Rathmacher JA, Murray KT, Akers WS, Roden DM, Michaud GF, Shoemaker MB.
Trials. 2021 Aug 28;22(1):576. doi: 10.1186/s13063-021-05553-6.
Background: Although catheter ablation is an effective therapy for atrial fibrillation (AF), the most common cardiac arrhythmia encountered in clinical practice, AF ablation generates inflammation and oxidative stress in the early postoperative period predisposing to recurrence of AF. Isolevuglandins (IsoLGs) are reactive lipid mediators of oxidative stress injury that rapidly react with endogenous biomolecules to compromise their function. 2-Hydroxybenzylamine (2-HOBA), a potent small molecule scavenger of IsoLGs, sequesters the reactive species as inert adducts. This mechanism, coupled with reported safety in humans, supports the investigation of 2-HOBA as a novel therapeutic to reduce AF caused by oxidative stress, such as that which occurs after catheter ablation. Accordingly, we seek to test the hypothesis that treatment with 2-HOBA will decrease early recurrence of AF and other atrial arrhythmias following AF ablation by decreasing IsoLG adducts with native biomolecules.
Methods: The proposed trial will randomly assign 162 participants undergoing cryo- or radiofrequency catheter ablation for AF to 2-HOBA (N = 81) or placebo (N = 81). Individuals will begin the study drug 3 days prior to ablation and continue for 28 days. Participants will be given a wearable smartwatch capable of detecting and recording atrial arrhythmias. They will be instructed to record ECGs daily with additional ECGs if they experience symptoms of AF or when alerted by the smartwatch AF detection alarm. The primary clinical endpoint will be an episode of AF, atrial tachycardia, or atrial flutter lasting 30 s or more within 28 days post-AF ablation. Secondary measures will be the change in IsoLG adduct levels from blood samples collected immediately pre-ablation and post-ablation and reduction in AF burden as calculated from the smartwatch.
Discussion: The proposed trial will test the hypothesis that 2-HOBA reduces post-ablation atrial arrhythmias through sequestration of reactive IsoLG species. The results of this study may improve the understanding of the role of IsoLGs and oxidative stress in AF pathogenesis and provide evidence to advance 2-HOBA and related compounds as a new therapeutic strategy to treat AF.

Identification of two variants of Acinetobacter baumannii 17978 with distinct genotypes and phenotypes.
Wijers CDM, Pham L, Menon S, Boyd KL, Noel HR, Skaar E, Gaddy JA, Palmer LD, Noto MJ.
Infect Immun. 2021 Aug 30:IAI0045421. doi: 10.1128/IAI.00454-21. Online ahead of print.
Acinetobacter baumannii is a nosocomial pathogen that exhibits substantial genomic plasticity. Here, the identification of two variants of A. baumannii ATCC 17978 that differ based on the presence of a 44 kb accessory locus, which was named AbaAL44 (“A. baumannii accessory locus 44 kb”), is described. Analyses of existing deposited data suggest that both variants are found in published studies of A. baumannii ATCC 17978 and that ATCC-derived laboratory stocks are comprised of a mix of these two variants. Yet, each variant exhibits distinct interactions with the host in vitro and in vivo. Infection with the variant that harbors AbaAL44 (Ab 17978 UN) results in decreased bacterial burdens and increased neutrophilic lung inflammation in a mouse model of pneumonia, and affects the production of IL-1β and IL-10 by infected macrophages. AbaAL44 harbors putative pathogenesis genes including those predicted to encode for a type I pilus cluster, a catalase, and a cardiolipin synthase. The accessory catalase increases A. baumannii resistance to oxidative stress and neutrophil-mediated killing in vitro. The accessory cardiolipin synthase plays a dichotomous role by promoting bacterial uptake and increasing IL-1β production by macrophages, but also enhancing bacterial resistance to cell envelope stress. Collectively, these findings highlight the phenotypic consequences of A. baumannii’s genomic dynamism through the evolution of two variants of a common type strain with distinct infection-related attributes.

An updated, computable MEDication-Indication resource for biomedical research.
Zheng NS, Kerchberger VE, Borza VA, Eken HN, Smith JC, Wei WQ.
Sci Rep. 2021 Sep 23;11(1):18953. doi: 10.1038/s41598-021-98579-4.

Dissecting Monomer-Dimer Equilibrium of an RNase P Protein Provides Insight Into the Synergistic Flexibility of 5′ Leader Pre-tRNA Recognition.
Zeng D, Abzhanova A, Brown BP, Reiter NJ.
Front Mol Biosci. 2021 Sep 3;8:730274. doi: 10.3389/fmolb.2021.730274. eCollection 2021.

Validation of Group-wise Registration for Surface-based Functional MRI Analysis.
Yu C, Liu Y, Cai LY, Kerley CI, Xu K, Taylor WD, Kang H, Shafer AT, Beason-Held LL, Resnick SM, Landman BA, Lyu I.
Proc SPIE Int Soc Opt Eng. 2021 Feb 15;11596:115961X. doi: 10.1117/12.2580771.

Pharmacological read-through of R294X Mecp2 in a novel mouse model of Rett syndrome.
Merritt JK, Collins BE, Erickson KR, Dong H, Neul JL.
Hum Mol Genet. 2020 Aug 29;29(15):2461-2470. doi: 10.1093/hmg/ddaa102.

Group B streptococcal infection of the genitourinary tract in pregnant and non-pregnant patients with diabetes mellitus: an immunocompromised host or something more?
Nguyen LM, Omage JI, Noble K, McNew KL, Moore DJ, Aronoff DM, Doster RS.
Am J Reprod Immunol. 2021 Sep 27. doi: 10.1111/aji.13501. Online ahead of print.

The relationship between white matter microstructure and self-perceived cognitive decline.
Archer DB, Moore EE, Pamidimukkala U, Shashikumar N, Pechman KR, Blennow K, Zetterberg H, Landman BA, Hohman TJ, Jefferson AL, Gifford KA.
Neuroimage Clin. 2021 Aug 28;32:102794. doi: 10.1016/j.nicl.2021.102794. Online ahead of print.

Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes.
Yoneda ZT, Anderson KC, Quintana JA, O’Neill MJ, Sims RA, Glazer AM, Shaffer CM, Crawford DM, Stricker T, Ye F, Wells Q, Stevenson LW, Michaud GF, Darbar D, Lubitz SA, Ellinor PT, Roden DM, Shoemaker MB.
JAMA Cardiol. 2021 Sep 8. doi: 10.1001/jamacardio.2021.3370. Online ahead of print.

Growth Arrest Specific-6 and Axl Coordinate Inflammation and Hypertension.
Van Beusecum JP, Ruggeri Barbaro N, Smart CD, Patrick DM, Loperena R, Zhao S, de la Visitacion N, Ao M, Xiao L, Shibao CA, Harrison DG.
Circ Res. 2021 Sep 27. doi: 10.1161/CIRCRESAHA.121.319643. Online ahead of print.

Lactate activation of α-cell KATP channels inhibits glucagon secretion by hyperpolarizing the membrane potential and reducing Ca2+ entry.
Zaborska KE, Dadi PK, Dickerson MT, Nakhe AY, Thorson AS, Schaub CM, Graff SM, Stanley JE, Kondapavuluru RS, Denton JS, Jacobson DA.
Mol Metab. 2020 Dec;42:101056. doi: 10.1016/j.molmet.2020.101056. Epub 2020 Jul 28.

Chapter Eleven – Proteomic biomarker technology for cancer immunotherapy
Fankhauser R, DePatie N, Berryman R, Lucero OM, Kulkarni RP.
Engineering Technologies and Clinical Translation, Academic Press, 2022,
Pages 357-397, ISBN 9780323909495,