A Novel Brain PET Radiotracer for Imaging Alpha Synuclein Fibrils in Multiple System Atrophy.

Abnormal α-synuclein (α-syn) aggregation characterizes α-synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy (MSA). However, no suitable positron emission tomography (PET) radiotracer for imaging α-syn in PD and MSA exists currently. Our structure-activity relationship studies identified 4-methoxy-N-(4-(3-(pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)phenyl)benzamide (4i) as a PET radiotracer candidate for imaging α-syn. In vitro assays revealed high binding of 4i to recombinant α-syn fibrils (inhibition constant (Ki) = 6.1 nM) and low affinity for amyloid beta (Aß) fibrils in Alzheimer's disease (AD) homogenates. However, [3H]4i also exhibited high specific binding to AD, progressive supranuclear palsy, and corticobasal degeneration tissues as well as PD and MSA tissues, suggesting notable affinity to tau. Nevertheless, the specific binding to pathologic α-syn aggregates in MSA post-mortem brain tissues was significantly higher than in PD tissues. This finding demonstrated the potential use of [11C]4i as a PET tracer for imaging α-syn in MSA patients. Nonhuman primate PET studies confirmed good brain uptake and rapid washout for [11C]4i.

In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [3H]1 provided KD (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [18F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Binding assays with [3H]21 provided KD (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [18F]21 demonstrated a higher brain penetration than [18F]1 and rapid clearance from normal brain tissues. We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.

The Role of the Hand Surgery Consultant in the Care of the Basketball Athlete.

Basketball presents several characteristics that distinguishes it from other contact sports and can influence the manner by which a Team Physician and Hand Surgery Consultant interact. An abbreviated list of pathologies that affect the basketball athlete and the approach to their evaluation and treatment by a Hand Surgeon are described in context of return-to-play.

The Role of the Hand Surgery Consultant in the Care of the Amateur and Professional Golfer.

Golf is unique in this compendium of sports-related hand and wrist injury management. It is the only sport where the ball is stationary and there is no opponent against whom the player is defending. This distinctive sport dates to the 15th century in Scotland and is one of the oldest sports, but it is one where technology has changed many of the fundamental elements-from the "playing field (through advanced in agronomy) and the equipment (club and ball technology).

The Role of the Hand Surgery Consultant in the Management of the High School and Collegiate Athlete.

For the purpose of this article, we will not use individual sports as the primary delineator; however, the two different levels of play: High School and Collegiate. We plan to share insight that we have gained through decades of practice treating High School sports and collegiate athletes. This article offers readers reliable guidance on not only treating the athlete's hand but understanding the person as a whole and the struggles at each level of play.

Lessons Learned in the Care of the Professional Athlete.

The role of an experienced Hand Surgery Consultant within the complete care matrix for a professional sports organization has evolved in my 3-decade career. Granted, hand injuries may have been demoted in this population where ACL tears, shoulder dislocations, and Lisfranc injuries seem to have much greater visibility, but our experience has told us that Hand injuries often contribute to the most surgeries per team/per season and can result in significant man-game loss of service. In my 30 years as a Consultant, Team Physician and/or Medical Director in all 4 major North American-based Leagues (as well as for "itinerant" independent contractor sports of golf, tennis, and motorsports), we have cared for well over 2000 athletes. This privilege has provided us with unparalleled exposure to the locker rooms, training rooms, and clubhouses for almost every team in professional-level competition and many elite-level collegiate programs. My goal in assembling this volume was to highlight the skilled and experienced colleagues who have contributed so much to the surgical science of caring for the hand and wrist in the professional athlete and furthering the logic of having a Hand Surgeon on "speed dial" for our fellow Team Physicians who want to provide optimal care for their athletes. Regrettably, until recently, the limited number of us who had significant involvement in this cohort probably fell short of engaging in scientific inquiry and publishing our observations or series. I will accept more than my share of that shortcoming, but as these practices have expanded in number and the exposure went from anecdotal to voluminous, our community started to communicate within Hand Surgery ranks, but now we want to share our knowledge with all professional involved in elite athlete care. This collection is not meant to be an exhaustive review of individual pathologies. Fortunately, valued colleagues have done a laudable job of chronicling the common-to-complex pathologies that we see in sports coverage This publication is styled less from the "what" and "how" standpoint, aimed instead at providing Team Physicians with the "when" and "why" of optimizing their player's outcomes through collaboration with their Hand Specialist.

The Role of the Hand Surgery Consultant in the Care of the Baseball Athlete.

The approach to the care of baseball athletes and organizations is influenced by 2 factors that distinguish it from other sports: the number of contests and the number of players. America's pastime is a marathon that can (if successful in the regular season and postseason play) stretch over a 10-months, 162+-game schedule. In addition, unlike other major North American sports, baseball's "feeder system" is the highly-structured Minor League Baseball. This is in contradistinction to caring for 15 basketball players who arrive at the professional level through collegiate (or even high school) play or 20 hockey players that may have had an NCAA experience or come through the Junior Leagues in Canada. Even though a 53-man football roster can keep a Hand Surgery Consultant busy, it is still a limited professional level cohort that is one-third to one-fourth of the size of baseball's and is played across less than 20 contests. Granted, every sport has its own culture-which is why we have developed this format for this publication-but planning for the scope of baseball care is also influenced by the unique pace and intensity of the interactions, that is why it is called a "clubhouse," rather than a "locker room". With these fundamentals shared, let us expand on what our experience has taught us about the care for athletes that are engaged in batting, throwing, receiving, and colliding on the diamond.

Screening of σ2 Receptor Ligands and In Vivo Evaluation of 11C-Labeled 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline for Potential Use as a σ2 Receptor Brain PET Tracer.

In this study, a panel of 46 compounds containing five different scaffolds known to have high σ2 receptor affinity were screened. 6,7-Dimethoxy-2-[4-(4-methoxyphenyl)butan-2-yl]-1,2,3,4-tetrahydroisoquinoline [(±)-7] (Ki for σ1 = 48.4 ± 7.7 nM, and Ki for σ2 = 0.59 ± 0.02 nM) and its desmethyl analogue, (±)-8 (Ki for σ1 = 108 ± 35 nM, and Ki for σ2 = 4.92 ± 0.59 nM), showed excellent binding affinity and subtype selectivity for σ2 receptors. In vitro cell binding indicated that σ2 receptor binding of [11C]-(±)-7 and [11C]-(±)-8 was dependent on TMEM97 protein expression. In PET studies, the peak brain uptake of [11C]-(±)-7 (8.28 ± 2.52%ID/cc) was higher than that of [11C]-(±)-8 (4.25 ± 0.97%ID/cc) with specific distribution in the cortex and hypothalamus. Brain uptake or tissue binding was selectively inhibited by ligands with different σ2 receptor binding affinities. The results suggest [11C]-(±)-7 can be used as a PET radiotracer for imaging the function of σ2 receptors in central nervous system disorders.

PARP Targeted Alpha-Particle Therapy Enhances Response to PD-1 Immune-Checkpoint Blockade in a Syngeneic Mouse Model of Glioblastoma.

We have previously demonstrated potent antitumor effects of PARP targeted alpha-therapy with astatine-211-MM4 ([211At]MM4) in neuroblastoma preclinical models, although differential sensitivity suggests it is unlikely to be curative as a single-agent in all tumor types. Alpha-particle induced DNA damage can elicit an immune response that results in T-cell activation against tumor cells; however, tumor cells can evade immune surveillance through expression of programmed death ligand 1 (PD-L1). Therefore, we investigated the effects of α particle therapy in combination with immune-checkpoint blockade using astatine-211-MM4 and anti-programmed death receptor 1 (anti-PD-1) immunotherapy in a syngeneic mouse model of glioblastoma. We characterized the sensitivity of four human glioblastoma cell lines to [211At]MM4 in vitro. To evaluate [211At]MM4 treatment effects on hematological tissues, complete blood counts were performed after a single dose at 12, 24, or 36 MBq/kg. In vivo efficacy was evaluated in a syngeneic mouse model of glioblastoma using GL26 glioblastoma cells in CB57BL/6J mice treated with either 36 MBq/kg [211At]MM4, anti-PD-1 antibody, or a combination of the two. Following a single dose of [211At]MM4, lymphocytes are significantly decreased compared to control at both 72 h and 1 week following treatment followed by recovery of counts by 2 weeks. However, neutrophils showed an increase with all dose levels of [211At]MM4 exhibiting higher levels than control. The average best tumor responses for combination, anti-PD-1, and [211At]MM4 were 100%, 83.6%, and 58.2% decrease in tumor volume, respectively. Average progression free intervals for combination, anti-PD-1, [211At]MM4, and control groups was 65, 36.4, 23.2, and 3 days, respectively. The percentages of disease-free mice at the end of the study for combination and anti-PD-1 were 100% and 60%, while [211At]MM4 and control groups were both 0%. In summary, combination therapy was more effective than either single agent in all response categories analyzed, highlighting the potential for PARP targeted alpha-therapy to enhance PD-1 immune-checkpoint blockade.

Metallaphotoredox aryl and alkyl radiomethylation for PET ligand discovery.

Positron emission tomography (PET) radioligands (radioactively labelled tracer compounds) are extremely useful for in vivo characterization of central nervous system drug candidates, neurodegenerative diseases and numerous oncology targets1. Both tritium and carbon-11 radioisotopologues are generally necessary for in vitro and in vivo characterization of radioligands2, yet there exist few radiolabelling protocols for the synthesis of either, inhibiting the development of PET radioligands. The synthesis of such radioligands also needs to be very rapid owing to the short half-life of carbon-11. Here we report a versatile and rapid metallaphotoredox-catalysed method for late-stage installation of both tritium and carbon-11 into the desired compounds via methylation of pharmaceutical precursors bearing aryl and alkyl bromides. Methyl groups are among the most prevalent structural elements found in bioactive molecules, and so this synthetic approach simplifies the discovery of radioligands. To demonstrate the breadth of applicability of this technique, we perform rapid synthesis of 20 tritiated and 10 carbon-11-labelled complex pharmaceuticals and PET radioligands, including a one-step radiosynthesis of the clinically used compounds [11C]UCB-J and [11C]PHNO. We further outline the direct utility of this protocol for preclinical PET imaging and its translation to automated radiosynthesis for routine radiotracer production in human clinical imaging. We also demonstrate this protocol for the installation of other diverse and pharmaceutically useful isotopes, including carbon-14, carbon-13 and deuterium.

Structure-activity relationship studies and bioactivity evaluation of 1,2,3-triazole containing analogues as a selective sphingosine kinase-2 inhibitors.

Sphingosine kinase (SphK) is primarily responsible for the production of Sphingosine-1-phosphate (S1P) that plays an important role in many biological and pathobiological processes including cancer, inflammation, neurological and cardiovascular disorders. Most research has focused on developing inhibitors of SphK1 rather than inhibitors of the other isoform SphK2 which has great importance in several pathophysiologic pathways. Exploration of new analogues for improving the potency and selectivity of SphK2 inhibitors is critical. We now have designed, synthesized, and evaluated eighteen new 1,2,3-triazole analogues for their SphK2 inhibitory activity using a ADP-Glo kinase assay, and explored their in vivo anti-tumor bioactivity. Several compounds including 21c, 21e, 21g, 25e-h, 29a-c have high selectivity for SphK2 over SphK1; compound 21g displayed the highest potency with an IC50 value of 0.23 µM. In addition, three compounds 21a, 21b, and 25b have high anti-tumor activity against U-251 MG human glioblastoma cells. Molecular modeling study was performed to elucidate the polar head group and 1,2,3-triazole pharmacophore impact on the SphK2 selectivity.

Identification of a nanomolar affinity α-synuclein fibril imaging probe by ultra-high throughput in silico screening.

Small molecules that bind with high affinity and specificity to fibrils of the α-synuclein (αS) protein have the potential to serve as positron emission tomography (PET) imaging probes to aid in the diagnosis of Parkinson's disease and related synucleinopathies. To identify such molecules, we employed an ultra-high throughput in silico screening strategy using idealized pseudo-ligands termed exemplars to identify compounds for experimental binding studies. For the top hit from this screen, we used photo-crosslinking to confirm its binding site and studied the structure-activity relationship of its analogs to develop multiple molecules with nanomolar affinity for αS fibrils and moderate specificity for αS over Aß fibrils. Lastly, we demonstrated the potential of the lead analog as an imaging probe by measuring binding to αS-enriched homogenates from mouse brain tissue using a radiolabeled analog of the identified molecule. This study demonstrates the validity of our powerful new approach to the discovery of PET probes for challenging molecular targets.

Underwater acoustic surface waves on a periodically perforated metal plate.

Acoustic surface waves are supported at the surface of appropriately structured elastic materials. Here the excitation and propagation of the lowest-order surface mode supported by a square array of open-ended cavities on a metal plate submerged in water is demonstrated. This mode, which has a half-wavelength character in the cavity, arises due to inter-cavity interaction by evanescent diffraction of the pressure field, and forms a band from zero-frequency to an asymptotic limit frequency. The authors perform an acoustic characterization of the pressure field close to the surface of the perforated plate in the 60-100 kHz frequency range; sound is pulsed from a fixed point-like acoustic source, and the evolution of the acoustic field across the sample surface is measured as a function of time and space with a traversing detector. Using Fourier analysis, the dispersion is imaged between points of high-symmetry (Γ,X,M) and at planes in momentum-space at fixed frequencies. Beaming of acoustic energy on the surface over a narrow frequency band was observed, caused by the anisotropic mode dispersion of the acoustic surface wave on the square lattice. The measured dispersion shows good agreement with the predictions of a numerical model.

Prospective Evaluation of Internalized Weight Bias and Weight Change Among Successful Weight-Loss Maintainers.

OBJECTIVE: Internalized weight bias (IWB) has been associated with weight regain after intentional weight loss, but reliance on cross-sectional data limits the understanding of this relationship. This study prospectively evaluated IWB as a predictor of weight change in a longitudinal observational study of successful weight-loss maintainers. METHODS: National Weight Control Registry participants (maintained 13.6-kg weight loss for ≥ 1 y) were asked to complete an online questionnaire including current weight and Weight Bias Internalization Scale-Modified (WBIS-M) at baseline and 12 months. RESULTS: At baseline, 1,250 of 1,643 eligible individuals completed the baseline assessment (71% female; 94% white; mean age ± SD: 52 y ± 13.1; BMI: 27 ± 5.5). The average WBIS-M score was 3.0 (± 1.3). Study completers (n = 862) reported 2.2% (± 7.8%) weight gain. Higher baseline IWB predicted weight gain among men (n = 254; t = -2.28; P = 0.02) but not women (n = 608; t = 1.22; P = 0.22). A one-point reduction in WBIS-M score at follow-up was associated with a 3.0% weight loss. CONCLUSIONS: Among weight-loss maintainers, IWB may be a risk factor for weight gain among men. Weight loss at follow-up was associated with reduced IWB in both men and women. Reliance on female-only samples may limit our understanding of IWB and its implications for weight control.

Chalcones and Five-Membered Heterocyclic Isosteres Bind to Alpha Synuclein Fibrils in Vitro.

A series of chalcone and heterocyclic isosteres, in which the enone moiety was replaced with an isoxazole and pyrazole ring system, was synthesized and their affinities for alpha synuclein (Asyn), amyloid beta (Aß), and tau fibrils were measured in vitro. The compounds were found to have a modest affinity and selectivity for Asyn versus Aß fibrils and low affinity for tau fibrils. Insertion of a double bond to increase the extendable surface area resulted in an increase in affinity and improvement in selectivity for Asyn versus Aß and tau fibrils. The results of this study indicate that compound 11 is a secondary lead compound for structure-activity relationship studies aimed at identifying a suitable compound for positron emission tomography-imaging studies of insoluble Asyn aggregates in Parkinson's disease.

Alpha Synuclein Fibrils Contain Multiple Binding Sites for Small Molecules.

The fibrillary aggregation of the protein alpha synuclein (Asyn) is a hallmark of Parkinson's disease, and the identification of small molecule binding sites on fibrils is essential to the development of diagnostic imaging probes. A series of molecular modeling, photoaffinity labeling, mass spectrometry, and radioligand binding studies were conducted on Asyn fibrils. The results of these studies revealed the presence of three different binding sites within fibrillar Asyn capable of binding small molecules with moderate to high affinity. A knowledge of the amino acid residues in these binding sites will be important in the design of high affinity probes capable of imaging fibrillary species of Asyn.

Rationale, design and pilot feasibility results of a smartphone-assisted, mindfulness-based intervention for smokers with mood disorders: Project mSMART MIND.

BACKGROUND: Although individuals with psychiatric disorders are disproportionately affected by cigarette smoking, few outpatient mental health treatment facilities offer smoking cessation services. In this paper, we describe the development of a smartphone-assisted mindfulness smoking cessation intervention with contingency management (SMI-CM), as well as the design and methods of an ongoing pilot randomized controlled trial (RCT) targeting smokers receiving outpatient psychiatric treatment. We also report the results of an open-label pilot feasibility study. METHODS: In phase 1, we developed and pilot-tested SMI-CM, which includes a smartphone intervention app that prompts participants to practice mindfulness, complete ecological momentary assessment (EMA) reports 5 times per day, and submit carbon monoxide (CO) videos twice per day. Participants earned incentives if submitted videos showed CO≤6ppm. In phase 2, smokers receiving outpatient treatment for mood disorders are randomized to receive SMI-CM or enhanced standard treatment plus non-contingent CM (EST). RESULTS: The results from the pilot feasibility study (N=8) showed that participants practiced mindfulness an average of 3.4times/day (≥3min), completed 72.3% of prompted EMA reports, and submitted 68.0% of requested CO videos. Participants reported that the program was helpful overall (M=4.85/5) and that daily mindfulness practice was helpful for both managing mood and quitting smoking (Ms=4.50/5). CONCLUSIONS: The results from the feasibility study indicated high levels of acceptability and satisfaction with SMI-CM. The ongoing RCT will allow evaluation of the efficacy and mechanisms of action underlying SMI-CM for improving cessation rates among smokers with mood disorders.