Primary Resistance to RET Inhibition in a RET Fusion-Positive Pancreatic Neuroendocrine Carcinoma.

We present a 54-year-old White male with a diagnosis of stage IV pancreatic neuroendocrine carcinoma. Next-generation sequencing of the tumor/blood identified a complex tumor genome, which included a rearranged during transfection (RET) gene fusion. The patient initially received cytotoxic chemotherapy with a significant radiographic response. After 4 cycles of chemotherapy, the patient was transitioned to a clinical trial using selpercatinib, a RET inhibitor, as maintenance therapy. Unfortunately, our patient developed progression of disease at the first treatment monitoring scan. Our patient suffered primary resistance to RET-targeted therapy. Proposed mechanisms of resistance include intrinsic resistance of the nuclear receptor co-activator 4-RET fusion to RET inhibition, the RET fusion representing a passenger alteration to another tumorigenic driver pathway and/or decreased efficacy of RET inhibition after platinum-based chemotherapy. Our patient's clinical course highlights the fact that "actionable" genomic alterations do not always equate to patient benefit.

A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

INTRODUCTION: Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. METHODS: De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. RESULTS: Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. CONCLUSION: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Ta+ and Nb+ + CO2: intersystem crossing in ion-molecule reactions.

The reactions of Ta+ and Nb+ with CO2 proceed only by a highly efficient oxygen atom transfer reaction to the respective oxide at room temperature in the gas phase. Although the product spin states are not determined, thermochemistry dictates that they must be different from ground state quintet Ta+ and Nb+, implying that intersystem crossing (ISC) has occurred. Recent reactive scattering experiments found dominant indirect dynamics for the reaction with Ta+ hinting at a bottleneck along the reaction path. The question on the nature of the bottleneck, whether it involves a crossing point or a transition state, could not be finally answered because theory located both close to each other. Here, we aim at shedding further light onto the impact of intersystem crossing on the reaction dynamics and ultimately the reactivity of transition metal ion reactions in the gas phase. We employ a combination of thermal kinetics for Ta+ and Nb+ with CO2 using a selected-ion flow tube (SIFT) apparatus and differential scattering cross sections for Nb+ + CO2 from crossed-beam velocity map imaging. The reaction with niobium again shows dominant indirect dynamics and in general very similar dynamics compared to Ta+ + CO2. At thermal energies, both reactions show sub-collisional rate constants with small negative temperature dependencies. Experiments are complemented by high level quantum chemical calculations of the minimum energy pathway. Statistical modelling well-reproduces the experimental thermal rate constants, and suggests that the Nb+ reaction is rate-limited by the intersystem crossing at thermal energies.

Temperature-Dependent Kinetics for the Reactions of Fen- (n = 2-17) and FexNiy- (x + y = 3-9) with O2: Comparison of Pure and Mixed Metal Clusters with Relevance to Meteor Radio Afterglows and Surface Oxidation.

Rate constants and product branching fractions were measured from 300-600 K for Fen- + O2 (n = 2-17) and for 300-500 K for FexNiy- + O2 (x + y = 3-9) using a selected-ion flow tube (SIFT) apparatus. Rate constants for 46 species are reported. All rate constants increased with increasing temperature, and several were in excess of the Langevin-Gioumousis-Stevenson (LGS) capture rate at elevated temperatures. As with previously studied transition metal anion oxidation reactions, the collision limit is treated as the sum of the LGS limit along with a hard-sphere contribution, allowing for determination of activation energies. These values are compared to each other along with previous results for Nin-. Measured rate constants for all three series (Fen-, Nin-, and FexNy-) vary over a relatively narrow range (1-5 × 10-10 cm3 s-1 at 300 K) being at least 15% of the collision rate constant. All reaction rate constants increase with temperature, described by small activation energies of 0.5-4 kJ mol-1. The data are consistent with an anticorrelation between the electron binding energy and rate constant, previously noted in other systems. The Fen- reaction produces a larger population of higher energy electrons than do the Nin- reactions, with FexNiy- producing an intermediate amount. The results suggest that the overall rate constant is limited by a small energetic barrier located at a large internuclear distance where electrostatic forces dominate, causing the potentials to be similar across systems, while the product formation is determined by the shorter-range, valence portion of the potential, which varies widely between systems.

A Common Bottleneck for Metal Oxidation by Molecular Oxygen Across Size Regimes: Kinetics of Atomic Lanthanide Cations (La+-Lu+) with O2.

Kinetics of the lanthanide cations (Ln+ = La+-Lu+ excluding Pm+) reacting with molecular oxygen were measured in a selected-ion flow tube apparatus from 300 to 600 K. Where exothermic, these reactions occur efficiently, producing LnO+ + O. The reactions display positive temperature dependences consistent with Arrhenius equation behavior and show small activation energies (0-2 kJ mol-1) that are strongly correlated to promotion energies of the Ln+ atoms. Reanalysis of literature data on neutral Ln + O2 reactions show a similar correlation with slightly larger activation energies (0-10 kJ mol-1). The data are explained by a common mechanism controlling oxidation by molecular oxygen in these systems, as well as in gas-phase reactions of transition metal and posttransition metal cluster anions, neutral clusters deposited on surfaces, and for oxygen incident on metal surfaces. It is posited that across these systems, the height of an early barrier along the reaction coordinate is predictable based on knowledge of the electronic states of the reactants and may be used to either promote or inhibit oxygen activation.

Two state reactivity (TSR) and hydrogen tunneling reaction kinetics measured in the Co+ mediated decomposition of CH3CHO.

The electronic structure of a transition metal atom allows it to act as a catalytic active site by providing lower energy alternative pathways in chemical transformations. We have identified and kinetically characterized three such pathways in the title reaction. One is an adiabatic pathway that occurs on a single potential energy surface described within the Born-Oppenheimer approximation. A second pathway opens microseconds into the reaction as a portion of the reacting population competitively transitions from triplet to singlet multiplicity to circumvent energetic barriers on the triplet surface. These pathways are single- and two-state reactive (SSR and TSR) where the Co+ cation mediates an oxidative addition/reductive elimination sequence of the CH3CHO molecule. The third observed reaction pathway is the aldehyde hydrogen tunneling through an Eyring barrier to form high-spin products. First-order rate constants for the adiabatic and nonadiabatic energy lowered pathways, and the hydrogen tunneling pathway, are each measured using the single photon initiated dissociative rearrangement reaction (SPIDRR) experimental technique. We believe that this is the first experimental study where such disparate dynamic features (SSR, TSR, and H-tunneling) are disentangled in a system's chemistry, attributing specific rate constant values to each effect and quantifying the various competitions. Moreover, multi-reference CASSCF/CASPT2 calculations indicate that structures with covalent Co-H bonds are present exclusively along the excited singlet surface. This phenomenon significantly reduces these structures' energy relative to their triplet counterparts, thus enabling the surface crossing and spin inversion that cause the observed two-state reactivity.

Kinetics for the Reactions of Ar+, O2+, and NO+ with Isoprene (2-Methyl-1,3-butadiene) as a Function of Temperature (300-500 K).

Rate constants and product branching fractions were measured for reactions of Ar+, O2+, and NO+ with isoprene (2-methyl-1,3-butadiene C5H8) as a function of temperature. The rate constants are large (∼2 × 10-9 cm3 s-1) and increase with temperature, exceeding the ion-dipole/induced dipole capture rate. Adding a hard sphere term to the collision rate provides a more useful upper limit and predicts the positive temperature dependences. Previous kinetic energy-dependent rate constants show a similar trend. NO+ reacts only by non-dissociative charge transfer. The more energetic O2+ reaction has products formed through both non-dissociative and dissociative charge transfer, or possibly through an H atom transfer. The very energetic Ar+ has essentially only dissociative products; assumption of statistical behavior in the dissociation reasonably reproduces the product branching fractions.

Electron and Ar+ interaction with Mo(CO)6 at thermal energies; energetic limit on removal of 5 ligands from Mo(CO)6.

The rate constant for electron attachment to Mo(CO)6 was determined to be ka = 2.4 ± 0.6 × 10-7 cm3 s-1 at 297 K in a flowing-afterglow Langmuir-probe experiment. The sole anion product is Mo(CO)5-. A small decline in ka was observed up to 450 K, and decomposition was apparent at higher temperatures. The charge transfer reaction of Ar+ with Mo(CO)6 is exothermic by 7.59 ± 0.03 eV, which appears to be sufficient to remove the first 5 ligands from Mo(CO)6+.

Measurement of time dependent product branching ratios indicates two-state reactivity in metal mediated chemical reactions.

For several decades, the influence of Two State Reactivity (TSR) has been implicated in a host of reactions, but has lacked a stand-alone, definitive experimental kinetic signature identifying its occurrence. Here, we demonstrate that the measurement of a temporally dependent product branching ratio is indicative of spin inversion and is a kinetic signature of TSR. This is caused by products exiting different hypersurfaces with different rates and relative exothermicities. The composite measurement of product intensities with the same mass but with different multiplicities yield biexponential temporal dependences with the sampled product ratio changing in time. These measurements are made using the single photon initiated dissociative rearrangement reaction (SPIDRR) technique which identifies TSR but further determines the kinetic parameters for reaction along the original ground electronic surface in competition with spin inversion and its consequent TSR.

Insight into hydrogen production through molecular simulation of an electrode-ionomer electrolyte system.

In this work, we examine metal electrode-ionomer electrolyte systems at high voltage (negative surface charge) and at high pH to assess factors that influence hydrogen production efficiency. We simulate the hydrogen evolution electrode interface investigated experimentally in the work of Bates et al. [J. Phys. Chem. C 119, 5467 (2015)] using a combination of first principles calculations and classical molecular dynamics. With this detailed molecular information, we explore the hypotheses posed in the work of Bates et al. In particular, we examine the response of the system to increased bias voltage and oxide coverage in terms of the potential profile, changes in solvation and species concentrations away from the electrode, surface concentrations, and orientation of water at reactive surface sites. We discuss this response in the context of hydrogen production.

Prehospital Cervical Spine Motion: Immobilization Versus Spine Motion Restriction.

OBJECTIVE: This study aims to evaluate the efficacy of two different spinal immobilization techniques on cervical spine movement in a simulated prehospital ground transport setting. METHODS: A counterbalanced crossover design was used to evaluate two different spinal immobilization techniques in a standardized environment. Twenty healthy male volunteers (age = 20.9 ± 2.2 yr) underwent ambulance transport from a simulated scene to a simulated emergency department setting in two separate conditions: utilizing traditional spinal immobilization (TSI) and spinal motion restriction (SMR). During both transport scenarios, participants underwent the same simulated scenario. The main outcome measures were cervical spine motion (cumulative integrated motion and peak range of motion), vital signs (heart rate, blood pressure, oxygen saturation), and self-reported pain. Vital signs and pain were collected at six consistent points throughout each scenario. RESULTS: Participants experienced greater transverse plane cumulative integrated motion during TSI compared to SMR (F1,57 = 4.05; P = 0.049), and greater transverse peak range of motion during participant loading/unloading in TSI condition compared to SMR (F1,57 = 17.32; P < 0.001). Pain was reported by 40% of our participants during TSI compared to 25% of participants during SMR (χ2 = 1.29; P = 0.453). CONCLUSIONS: Spinal motion restriction controlled cervical motion at least as well as traditional spinal immobilization in a simulated prehospital ground transport setting. Given these results, along with well-documented potential complications of TSI in the literature, SMR is supported as an alternative to TSI. Future research should involve a true patient population.

Electromyographical Comparison of Muscle Activation Patterns Across Three Commonly Performed Kettlebell Exercises.

Lyons, BC, Mayo, JJ, Tucker, WS, Wax, B, and Hendrix, RC. Electromyographical comparison of muscle activation patterns across 3 commonly performed kettlebell exercises. J Strength Cond Res 31(9): 2363-2370, 2017-The purpose of this study was to compare the muscle activation patterns of 3 different kettlebell (KB) exercises using electromyography (EMG). Fourteen resistance-trained subjects completed a 1-arm swing (Swing), 1-arm swing style snatch (Snatch), and a 1-arm clean (Clean) using a self-selected 8 to 10 repetition maximum load for each exercise. Trial sessions consisted of subjects performing 5 repetitions of each KB exercise. Mean EMG was used to assess the muscle activation of the biceps brachii, anterior deltoid, posterior deltoid, erector spinae (ES), vastus lateralis (VL), biceps femoris, contralateral external oblique (EO), and gluteus maximus during each lift using surface electrodes. The mean EMG was normalized using maximal voluntary contractions obtained from manual muscle testing. Repeated-measures analysis of variance revealed a significant difference in the muscle activation patterns of the ES (Swing > Snatch), EO (Snatch, Clean > Swing), and VL (Swing > Clean) across the 3 KB exercises. We conclude that although the KB Swing, Snatch, and Clean are total body exercises, they place different demands on the ES, contralateral EO, and the VL. Therefore, KBs represent an authentic alternative for lifters, and the Swing, Snatch, and Clean are not redundant exercises.

Head and Trunk Acceleration During Intermediate Transport on Medical Utility Vehicles.

OBJECTIVE: To compare head and trunk acceleration during transport on 2 medical utility vehicles. DESIGN: Within subject. SETTING: Controlled laboratory. PARTICIPANTS: Nineteen male volunteers (21.8 ± 1.4 years, 176.5 ± 5.5 cm, 90.3 ± 16.1 kg). INTERVENTIONS: Participants were secured to a spineboard and stretcher on the Husqvarna HUV 4421DXL ambulance (HUV) and modified John Deere Gator TH (Gator) and driven over synthetic field turf transitioning to concrete slab (interval 1) and concrete slab transitioning to natural grass (interval 2). Three-dimensional (x, y, and z) accelerometers recorded head and trunk acceleration. At each data point, acceleration of the trunk was subtracted from the acceleration of the head and the peak acceleration difference was determined. Independent variables were vehicle (HUV, Gator) and interval (interval 1, interval 2). MAIN OUTCOME MEASURES: The average peak acceleration differences in 3 directions (x, y, z) were analyzed using a 2-factor within analysis of variance (P ≤ 0.05). RESULTS: For x, Gator in interval 2 (28.34 ± 7.45 m/s/s) was greater than HUV in interval 2 (21.87 ± 6.28 m/s/s), and HUV (11.05 ± 3.29 m/s/s) and Gator (12.56 ± 4.32 m/s/s) in interval 1. The HUV in interval 2 was greater than HUV and Gator in interval 1. For z, Gator in interval 2 (22.12 ± 4.8 m/s/s) was greater than HUV in interval 2 (15.21 ± 2.84 m/s/s), and HUV (9.51 ± 3.01 m/s/s) and Gator (12.5 ± 3.78 m/s/s) in interval 1. The HUV in interval 2 was greater than HUV and Gator in interval 1. Gator in interval 1 was greater than HUV in interval 1. CONCLUSIONS: Varying head and trunk accelerations exist in healthy spine-boarded participants during transport on medical utility vehicles dependent on surface and vehicle type. CLINICAL RELEVANCE: Intermediate transport vehicles vary in their ability to mitigate perturbations conveyed to the patient from the terrain travelled over.

The Acute Effects of Hold-Relax Proprioceptive Neuromuscular Facilitation With Vibration Therapy on Glenohumeral Internal-Rotation Deficit.

CONTEXT: Clinicians use various stretching techniques to prevent the onset of and treat glenohumeral internal-rotation deficit (GIRD). It is unknown which stretching technique is the most effective. OBJECTIVE: To investigate the acute effects of hold-relax proprioceptive neuromuscular facilitation (PNF) with and without vibration therapy on internal rotation in individuals with GIRD. DESIGN: 2-within (stretch × time) comparison with repeated measures. SETTING: Controlled laboratory. PARTICIPANTS: 11 male current and former overhead athletes (19.8 ± 1.4 y, 184.5 ± 4.5 cm, 91.8 ± 11.6 kg) who presented with GIRD. INTERVENTIONS: At 3 separate sessions, participants performed 1 of 3 randomly assigned stretches: hold-relax PNF (PNF), hold-relax PNF in combination with a whole-body-vibration unit set at 30 Hz (PNF-V), and static stretch (SS). Pretest and posttest maximum passive glenohumeral internal-rotation measurements were taken with a digital protractor. MAIN OUTCOME MEASURES: The dependent variables were the mean glenohumeral internal-rotation measurements taken at the pretest and posttest. The influence of stretch (PNF, PNF-V, and SS) and time (pretest and posttest) on mean glenohumeral internal rotation was compared using a 3 × 2 factorial ANOVA with repeated measures on both variables (P ≤ .05). RESULTS: There was a stretch-by-time interaction (F2,20 = 34.697, P < .001). Post hoc testing revealed that the PNF posttest (73.0° ± 10.4°) was greater than the PNF pretest (60.0° ± 11.8°), the PNF-V posttest (74.7° ± 10.0°) was greater than the PNF-V pretest (57.4° ± 10.4°), and the SS posttest (67.0° ± 10.7°) was greater than the SS pretest (60.1° ± 9.4°). When comparing the posttest values, the PNF-V posttest was greater than the SS posttest. CONCLUSIONS: All 3 stretches (PNF, PNF-V, and SS) resulted in acute increases in glenohumeral internal rotation in individuals presenting with GIRD. The PNF-V stretch resulted in the greatest increase and would be the most clinically beneficial for patients with GIRD.

Highlights and discoveries from the Chandra X-ray Observatory.

Within 40 years of the detection of the first extra-solar x-ray source in 1962, NASA's Chandra X-ray Observatory has achieved an increase in sensitivity of 10 orders of magnitude, comparable to the gain in going from naked-eye observations to the most powerful optical telescopes over the past 400 years. Chandra is unique in its capabilities for producing sub-arcsecond x-ray images with 100-200 eV energy resolution for energies in the range 0.08 < E < 10 keV, locating x-ray sources to high precision, detecting extremely faint sources, and obtaining high-resolution spectra of selected cosmic phenomena. The extended Chandra mission provides a long observing baseline with stable and well-calibrated instruments, enabling temporal studies over timescales from milliseconds to years. In this report we present a selection of highlights that illustrate how observations using Chandra, sometimes alone, but often in conjunction with other telescopes, have deepened, and in some instances revolutionized, our understanding of topics as diverse as protoplanetary nebulae; massive stars; supernova explosions; pulsar wind nebulae; the superfluid interior of neutron stars; accretion flows around black holes; the growth of supermassive black holes and their role in the regulation of star formation and growth of galaxies; impacts of collisions, mergers, and feedback on growth and evolution of groups and clusters of galaxies; and properties of dark matter and dark energy.

Nitrate in shallow groundwater associated with residential land use in central Florida.

The primary objective of this study was to quantify the effects of residential fertilizer use on groundwater quality, which have not been well defined by field-scale investigations. Concentrations of constituents associated with fertilizer use were monitored in shallow groundwater in residential areas in Orange and Seminole Counties of Central Florida. The study area is within the Wekiva River basin, a river that is primarily spring fed. Sampling locations were selected to represent land in residential use for more than 5 yr and to avoid septic systems and areas recently used for citrus production. Twenty-six wells were installed in the surficial aquifer, screened within approximately 3 m of the water table, which was encountered between 0.3 and 11.5 m below land surface. Of these wells, 24 were in residential areas, scattered over an area of about 2600 ha, and two were in nearby undeveloped areas. Samples were collected four times between October 2008 and July 2009. Concentrations of nitrate plus nitrite nitrogen (NO-N) averaged 2.0 ± 0.2 mg L in the residential areas and were significantly higher ( < 0.01) than observed in undeveloped areas (0.3 ± 0.1 mg L). Groundwater was also analyzed for stable isotopes of nitrogen and oxygen and has been analyzed for bacteria (by others), which corroborated that these wells were not affected by human or animal waste. Levels of NO-N in the residential areas are primarily attributed to residential fertilizer use, considering the control for and exclusion of other plausible sources.

IL-7R expression and IL-7 signaling confer a distinct phenotype on developing human B-lineage cells.

IL-7 is an important cytokine for lymphocyte differentiation. Similar to what occurs in vivo, human CD19⁺ cells developing in human/murine xenogeneic cultures show differential expression of the IL-7 receptor α (IL-7Rα) chain (CD127). We now describe the relationship between CD127 expression/signaling and Ig gene rearrangement. In the present study, < 10% of CD19⁺CD127⁺ and CD19⁺CD127⁻ populations had complete VDJ(H) rearrangements. IGH locus conformation measurements by 3D FISH revealed that CD127⁺ and CD127⁻ cells were less contracted than pediatric BM pro-B cells that actively rearrange the IGH locus. Complete IGH rearrangements in CD127⁺ and CD127⁻ cells had smaller CDR3 lengths and fewer N-nucleotide insertions than pediatric BM B-lineage cells. Despite the paucity of VDJ(H) rearrangements, microarray analysis indicated that CD127⁺ cells resembled large pre-B cells, which is consistent with their low level of Ig light-chain rearrangements. Unexpectedly, CD127⁻ cells showed extensive Ig light-chain rearrangements in the absence of IGH rearrangements and resembled small pre-B cells. Neutralization of IL-7 in xenogeneic cultures led to an increase in Ig light-chain rearrangements in CD127⁺ cells, but no change in complete IGH rearrangements. We conclude that IL-7-mediated suppression of premature Ig light-chain rearrangement is the most definitive function yet described for IL-7 in human B-cell development.

Comparison of Muscle Activity During a Ring Muscle Up and a Bar Muscle Up.

The muscle up (MU) is a variation of a common gymnastics movement that combines a pull up and a dip. It can be performed on a bar (BMU) or a set of rings (RMU). The difference in upper extremity muscle recruitment (MR) between BMU and RMU has not been evaluated. Therefore, the purpose of this study was to compare the MR of select muscles during BMU and RMU. Ten active males (27.6 ± 7.9 years) performed 5 repetitions of BMU and RMU in randomized order. Muscle recruitment of the upper (UT) and lower trapezius (LT), serratus anterior (SA), pectoralis major (PM), latissimus dorsi (LD), triceps brachii (TB), biceps brachii (BB), and forearm flexors (FF) was assessed using electromyography. A 2 × 2 ANOVA (ring vs bar, pull phase vs push phase) with repeated measures was performed for each muscle. Least significant differences post hoc tests were performed when a significant interaction effect occurred. The RMU significantly elicited more muscle activation in the UT (p = 0.007), BB (p = 0.001), and FF (p = 0.001) during the pull phase. The RMU also significantly elicited more muscle activation in the TB (p = 0.025) and BB (p = 0.001) during the push phase. These results suggest that the instability of the RMU primarily increases the required recruitment of the upper limbs but does not significantly change the recruitment of the shoulder stabilizers. Appropriate upper limb development is needed to perform the RMU and the BMU may be a better technique to learn first due to its lower difficulty.

The Effects of Wearing a Portable Media Armband on Muscle Activation of the Biceps Brachii.

Portable media armbands are commonly used among the physically active population. Their effect on muscle function has not been established. The purpose of this study was to determine if muscle activation of the biceps brachii is influenced by wearing a portable media armband during an elbow flexion exercise. Eighteen participants (11 males: age = 22.5 ± 2.1 years, height = 178.3 ± 5.2 cm, mass = 85.0 ± 6.5 kg; 7 females: age = 22.9 ± 2.5 years, height = 168.3 ± 5.7 cm, mass = 72.3 ± 12.2 kg) with no history of upper extremity injury volunteered for the study. Participants performed elbow flexion trials with a hand-held dumbbell with and without wearing a portable media armband. Dumbbell weight was determined by an 8-10 repetition maximum, and the condition was counterbalanced. The average concentric and eccentric phases for five trials for each condition were normalized to a maximum voluntary isometric contraction using electromyography. The independent variable was condition (with-PMAB and without-PMAB). The dependent variable was the muscle activation of the biceps brachii. Mean data for each condition were analyzed using separate paired-samples t-tests for the concentric and eccentric phases (p < 0.05). Statistical analysis revealed a significant difference for the concentric phase (t17 = 2.905; p = 0.010). The with-PMAB condition elicited greater muscle activation (72.57 ± 36.31%) compared to the without-PMAB (63.67 ± 26.2%), with a medium effect size (d = 0.69). There was no statistical difference for the eccentric phase (t17 = 1.964; p = 0.066), and a small effect size (d = 0.46). The increase in muscle activation during the concentric phase is likely due to a change in the muscle properties due to the compressive force applied to the muscle fibers by the portable media armband.

An Excellent Response of Microsatellite Instability-High Pancreatic Adenocarcinoma to Pembrolizumab Treatment: The Role of Circulating Tumor DNA Testing.

The role of circulating tumor DNA (ctDNA) is expanding in oncology practices, and it is increasingly being used for targeted therapies and disease monitoring. It is minimally invasive and provides data from both primary and secondary sites of disease. Herein, we report a unique case of a patient with microsatellite instability-high (MSI-H) pancreatic adenocarcinoma (PDAC) treated with neoadjuvant chemotherapy and pembrolizumab who achieved a pathologically confirmed complete resolution of the tumor. A 75-year-old female was diagnosed with pancreatic adenocarcinoma (PDAC) in the uncinate process with aortocaval and retrocrural adenopathy. Next-generation sequencing was obtained via ctDNA testing, and the patient was initiated on cytotoxic chemotherapy while awaiting results. ctDNA revealed MSI-H status, and pembrolizumab was added to the cytotoxic chemotherapy regimen. At follow-up after five cycles of treatment, excellent treatment response was noted on magnetic resonance imaging (MRI) of the abdomen, demonstrating the resolution of the pancreatic mass and adenopathy. Six months of neoadjuvant treatment was given in total, after which the patient underwent resection with curative intent and achieved a complete pathological response with no evidence of disease. The role of ctDNA testing in directing treatment and influencing follow-up has already demonstrated great value. In our case, ctDNA adequately replaced conventional tissue biopsy, alleviating the burden of invasive testing on the patient. This is of great value, especially for patients with non-resectable tumors as well as in several other clinical scenarios. Our case also contributes to the growing body of literature demonstrating the role of immune-directed therapy for MSI-H PDAC.