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Obesity is a worldwide health concern associated with impaired physical function. It is not clear if contractile protein dysfunction contributes to the impairment of muscle function observed with obesity. The purpose of this study was to examine if diet-induced obesity affects contractile function of chemically permeabilized vastus intermedius fibres of male Sprague–Dawley rats expressing fast myosin heavy chain (MHC) IIa or slow MHC I. Rats consumed either a high-fat, high sucrose (HFHS) diet or a standard (CHOW) diet beginning as either weanlings (7-week duration: WEAN7 cohort, or 14-week duration: WEAN14 cohort) or young adults (12-week duration: ADULT12 cohort, 24-week duration: ADULT24 cohort). HFHS-fed rats had higher (P < 0.05) whole-body adiposity (derived from dual-energy X-ray absorptiometry) than CHOW-fed rats in all cohorts. Relative to CHOW diet groups, the HFHS diet was associated with impaired force production in (a) MHC I fibres in the ADULT24 cohort; and (b) MHC IIa fibres in the ADULT12 and ADULT24 cohorts combined. However, the HFHS diet did not significantly affect the Ca2+-sensitivity of force production, unloaded shortening velocity, or ratio of active force to active stiffness in any cohort. We conclude that diet-induced obesity can impair force output of permeabilized muscle fibres of adult rats. Novelty: We assessed contractile function of permeabilized skeletal muscle fibres in a rat model of diet-induced obesity. The high-fat, high-sucrose diet was associated with impaired force output of fibres expressing MHC I or MHC IIa in some cohorts of rats. Other measures of contractile function were not significantly affected by diet.

Muscle operates across a wide range of sarcomere lengths. Inorganic phosphate (Pi) diminishes force output of striated muscle, with greater influence at short relative to long sarcomere lengths in fast skeletal and cardiac muscle fibres. The purpose of this study was to fill a gap in the literature regarding the length-dependent effects of Pi on contractile function of slow skeletal muscle fibres. Permeabilized slow skeletal muscle fibres from rabbit soleus were assessed at average sarcomere lengths of 2.0, 2.4, or 2.8 μm, with and without 20 mM Pi added to activating solutions (22±1 °C). The magnitude of Pi-induced reductions in peak force (43 ± 7% at 2.0 μm, 38 ± 7% at 2.4 μm, and 31 ± 8% at 2.8 μm) and peak stiffness (41 ± 9% at 2.0 μm, 36 ± 8% at 2.4 μm, and 26 ± 9% at 2.8 μm) were length dependent. Peak stiffness was less affected by Pi than peak force. Pi diminished the Ca2+-sensitivity of the force-pCa and stiffness-pCa relationships to a greater extent at 2.8 μm than 2.0 μm. Comparable results were obtained from a cooperative model of Ca2+ and myosin binding to regulated actin. In conclusion, Pi is more detrimental to the peak force output of slow skeletal muscle fibres held at short relative to long sarcomere lengths, whereas Pi has a greater effect on the Ca2+-sensitivity of force production at long relative to short sarcomere lengths. Stiffness data suggest that Pi-induced reductions in force are primarily due to fewer bound cross-bridges, with a lesser contribution attributable to lower average force per cross-bridge.

Oculopharyngeal muscular dystrophy (OPMD) is a genetic muscle disease causing ptosis, severe swallowing difficulties and progressive limb weakness, although atypical presentations may be difficult to diagnose. Sensitive biomarkers of disease progression in OPMD are needed to enable more effective clinical trials. This study was designed to test the feasibility of using MRI to aid OPMD diagnosis and monitor OPMD progression. Twenty-five subjects with Dixon whole-body muscle MRI were enrolled: 10 patients with genetically confirmed OPMD, 10 patients with non-OPMD muscular dystrophies, and 5 controls. Using the MRI Dixon technique, muscle fat replacement was evaluated in the tongue, serratus anterior, lumbar paraspinal, adductor magnus, and soleus muscles using quantitative and semi-quantitative rating methods. Changes were compared with muscle strength testing, dysphagia severity, use of gait aids, and presence of dysarthria. Quantitative MRI scores of muscle fat replacement in the tongue could differentiate OPMD from other muscular dystrophies and from controls. Moreover, fat fraction in the tongue correlated with clinical severity of dysphagia. This study provides preliminary support for the use of Dixon-based quantitative MRI images as outcome measures for monitoring disease progression in clinical trials and provides rationale for future prospective studies aimed at methodological refinement and covariate identification.

A period of extra-efficient force production (“boost”) followed by a decline in force (“sag”) is often observed at the onset of unfused tetanic contractions. We tested the hypothesis that in human muscle boost and sag are diminished in repeated contractions separated by short rest periods and are re-established or enhanced following long rest periods. Two sets of 3 unfused tetanic contractions were evoked in the right quadriceps muscle group of 29 participants via percutaneous stimulation of the femoral nerve. Contractions consisted of 20 pulses evoked at inter-pulse intervals of 1.25 × twitch time to peak torque. Contractions were evoked 5 s apart and sets were evoked 5 min apart. The ratio of the angular impulse of pulses 1–10 to the angular impulse of pulses 11–20 was used as the boost indicator. By this metric, boost was higher (P

NEW FINDINGS What is the central question of this study? How do contraction-induced reductions in twitch duration, without changes in twitch force, affect summation of twitch pairs into higher force contractions in skeletal muscle? What is the main finding and its importance? Abbreviating twitch duration with a brief contraction resulted in enhanced summation of fully fused twitch pairs, but impaired summation in partially fused twitch pairs even after accounting for the differences in relaxation of the first twitch. An inherent mechanism which enhances relaxation without sacrificing force generation in forceful contractions would benefit cyclic muscle activities, such as locomotion. ABSTRACT During electrically evoked contractions of skeletal muscle, the interplay between twitch duration and the time between electrical stimuli (inter-pulse interval, IPI) determines how effectively twitch forces summate into high force contractions. A brief muscle contraction can impair summation by abbreviating twitch duration, though it is not clear if these impairments occur at all physiologically relevant IPI. This study was designed to test how a brief contraction affects summation of nominally isometric twitch pairs with IPIs lasting 10-5000 ms. Left adductor pollicis muscles of human participants (n = 9) were electrically activated using stimulus pairs applied both before (Pre) and after (Post) a 10 Hz, 1.0 s contraction. Force-time records were mathematically separated into Pulse 1 (single twitch) and Pulse 2 (summated twitch) components. The ratio of Pulse 2 peak force to Pulse 1 peak force was used as our measure of summation effectiveness. Consistent with the observed decline of Pulse 1 duration at Post relative to Pre (4.7 ± 0.6%; P

Background and ObjectivesCoenzyme Q10(CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant ofCOQ7with abnormal CoQ10biosynthesis.MethodsAffected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of theCOQ7variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis.ResultsThree affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygousCOQ7c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of theCOQ7variant was demonstrated by diminished COQ7 and CoQ10levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle.DiscussionThis report describes a new neurologic phenotype ofCOQ7-related primary CoQ10deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases ofCOQ7-related CoQ10deficiency previously reported in the literature.

Magnetized Liner Inertial Fusion (MagLIF) is a magneto-inertial fusion concept that relies on fuel magnetization, laser preheat, and a magnetically driven implosion to produce fusion conditions. In MagLIF, the target is a roughly 10 mm long, 5 mm diameter, 0.5 mm thick, cylindrical beryllium shell containing ~1 mg/cm 3 D 2 gas. An axial magnetic field on the order of 10 T is applied to the target, and several kJ of laser energy is deposited into the fuel. Up to 20 MA of current is driven axially through the beryllium target, causing it to implode over approximately 100 ns. The implosion produces a ~100-μm diameter, ~8-mm tall fuel column with a burn-averaged ion temperature of several keV, that generates 10 11 -10 13 DD neutrons.

The performance of Magnetized Liner Inertial Fusion (MagLIF) experiments is sensitive to the amount of laser energy coupled to the fuel during the preheat stage. 1 A significant source of energy loss in this process comes from the need to heat a laser entrance hole foil (LEH) located at the entrance to the target that is required to contain the gaseous fusion fuel. The energy lost to the LEH is a function of its thickness which can be reduced by cryogenically cooling the fuel, lowering the pressure required for a given fuel density. 2 To realize this, a cryogenically-cooled laser target platform was commissioned in the Pecos chamber that enables rapid testing of preheat configurations, 3 and a cryogenically-cooled MagLIF configuration was tested that symmetrically cools the liner from the top and bottom, minimizing temperature gradients across the target. These new capabilities were utilized to perform a cryogenically-cooled MagLIF experiment that demonstrated >2 kJ of preheat energy coupled to the fuel for the first time on Z.

Magnetized Liner Inertial Fusion (MagLIF) is a magneto-inertial fusion concept, which is presently being studied on the Z Pulsed Power Facility. The concept utilizes an axial magnetic field and laser heating to produce fusion-relevant conditions at stagnation despite a peak magnetically driven implosion velocity of less than 100 km/s. Initial mymargin experiments demonstrated the viability of the concept but left open questions about the amount of laser energy coupled to the fuel and the role that mix played in the stagnation conditions. In this paper, simple methodologies for estimating the laser energy coupled to the fuel and determining the stagnation pressure and mix are presented. These tools enabled comparisons across many experiments to establish performance trends, as well as allow comparisons with 2-D magnetohydrodynamics simulations. The initial experiments were affected by low laser energy coupling (0.2–0.6 kJ), which resulted in reduced neutron yields (1– $2\times 10^{12}$ ). In addition, all early experiments utilized mid-Z (aluminum) fuel-facing components. Mixing from these components had a significant impact on stagnation and increased with laser energy. Lower neutron yields (1– $3\times 10^{11}$ ) were measured with higher laser coupling (0.8–1.2 kJ), which significantly deviated from the predicted scaling. When all fuel-facing components were made from a low-Z material (beryllium), neutron production increased ( $3.2\times 10^{12}$ ) and scaled as expected with laser energy; experimental yields were approximately 40% of simulated yields. In addition, roughly I4 yield scaling was observed in experiments, where the load current was varied from 16–18 MA. These results represent the first step in experimental demonstration of stagnation performance scaling with input parameters in MagLIF.

Smith’s poetry asks questions of crime and punishment from the victims’ and perpetrators’ perspectives. In “Mugs” an easy victim reflects on the burglar of his house. In “Rehabilitation” a former prisoner returns to his prison, converted into gentrified townhouses. In “Stitched” Up the boredom, inanity, banality, and a soft pain of prison life is exposed.

Fatiguing exercise causes hydrolysis of phosphocreatine, increasing the intracellular concentration of inorganic phosphate (P(i)). P(i) diffuses into the sarcoplasmic reticulum (SR) where it is believed to forms insoluble Ca(2+) salts, thus contributing to the impairment of Ca(2+) release. Information on the P(i) entrance pathway is still lacking. In amphibian muscles endowed with isoform 3 of the RyR channel, Ca(2+) spark frequency is correlated with Ca(2+) load of the SR and can be used to monitor this variable. We studied the effects of P(i) on Ca(2+) sparks in permeabilized fibres of the frog. Relative event frequency (f/f(ref)) rose with increasing [P(i)] reaching 2.54±1.6 at 5 mM and then decreased monotonically, reaching 0.09±0.03 at [P(i)] = 80 mM. Measurement of [Ca(2+)](SR) confirmed a decrease correlated with spark frequency at high [P(i)]. A large [Ca(2+)](SR) surge was observed upon P(i) removal. Anion channels are a putative path for P(i) into the SR. We tested the effect of chloride channel blocker 9-anthracenecarboxylic acid (9AC) on P(i) entrance. 400 μM 9AC applied to the cytoplasm produced a non-significant increase in spark frequency and reduced the P(i) effects on this parameter. Fibre treatment with 2 mM 9AC in the presence of high cytoplasmic Mg(2+) suppressed P(i) effects on [Ca(2+)](SR) and spark frequency up to 55 mM P(i). These results suggest that chloride channels (or transporters) provide the main pathway of inorganic phosphate into the SR and confirm that it impairs Ca(2+) release by accumulating and precipitating with Ca(2+) inside the SR, thus contributing to myogenic fatigue.

We present experimental results from the first systematic study of performance scaling with drive parameters for a magnetoinertial fusion concept. In magnetized liner inertial fusion experiments, the burn-averaged ion temperature doubles to 3.1 keV and the primary deuterium-deuterium neutron yield increases by more than an order of magnitude to 1.1×10^{13} (2 kJ deuterium-tritium equivalent) through a simultaneous increase in the applied magnetic field (from 10.4 to 15.9 T), laser preheat energy (from 0.46 to 1.2 kJ), and current coupling (from 16 to 20 MA). Individual parametric scans of the initial magnetic field and laser preheat energy show the expected trends, demonstrating the importance of magnetic insulation and the impact of the Nernst effect for this concept. A drive-current scan shows that present experiments operate close to the point where implosion stability is a limiting factor in performance, demonstrating the need to raise fuel pressure as drive current is increased. Simulations that capture these experimental trends indicate that another order of magnitude increase in yield on the Z facility is possible with additional increases of input parameters.

Càncer de mama precoç; Teràpia endocrina; Abemaciclib Cáncer de mama precoz; Terapia endocrina; Abemaciclib Early Breast Cancer; Endocrine Therapy; Abemaciclib PURPOSE Many patients with HR+, HER2− early breast cancer (EBC) will not experience recurrence or have distant recurrence with currently available standard therapies. However, up to 30% of patients with high-risk clinical and/or pathologic features may experience distant recurrence, many in the first few years. Superior treatment options are needed to prevent early recurrence and development of metastases for this group of patients. Abemaciclib is an oral, continuously dosed, CDK4/6 inhibitor approved for HR+, HER2− advanced breast cancer (ABC). Efficacy and safety of abemaciclib in ABC supported evaluation in the adjuvant setting. METHODS This open-label, phase III study included patients with HR+, HER2−, high-risk EBC, who had surgery and, as indicated, radiotherapy and/or adjuvant/neoadjuvant chemotherapy. Patients with four or more positive nodes, or one to three nodes and either tumor size ≥ 5 cm, histologic grade 3, or central Ki-67 ≥ 20%, were eligible and randomly assigned (1:1) to standard-of-care adjuvant endocrine therapy (ET) with or without abemaciclib (150 mg twice daily for 2 years). The primary end point was invasive disease-free survival (IDFS), and secondary end points included distant relapse–free survival, overall survival, and safety. RESULTS At a preplanned efficacy interim analysis, among 5,637 randomly assigned patients, 323 IDFS events were observed in the intent-to-treat population. Abemaciclib plus ET demonstrated superior IDFS versus ET alone (P = .01; hazard ratio, 0.75; 95% CI, 0.60 to 0.93), with 2-year IDFS rates of 92.2% versus 88.7%, respectively. Safety data were consistent with the known safety profile of abemaciclib. CONCLUSION Abemaciclib when combined with ET is the first CDK4/6 inhibitor to demonstrate a significant improvement in IDFS in patients with HR+, HER2− node-positive EBC at high risk of early recurrence. Funded and sponsored by Eli Lilly and Company. Additional support provided by National Institute for Health Research funding to the Royal Marsden and Institute of Cancer Research Biomedical Research Center.

Sandia's Z Pulsed Power Facility is able to dynamically compress matter to extreme states with exceptional uniformity, duration, and size, which are ideal for investigating fundamental material properties of high energy density conditions. X-ray diffraction (XRD) is a key atomic scale probe since it provides direct observation of the compression and strain of the crystal lattice and is used to detect, identify, and quantify phase transitions. Because of the destructive nature of Z-Dynamic Material Property (DMP) experiments and low signal vs background emission levels of XRD, it is very challenging to detect a diffraction signal close to the Z-DMP load and to recover the data. We have developed a new Spherical Crystal Diffraction Imager (SCDI) diagnostic to relay and image the diffracted x-ray pattern away from the load debris field. The SCDI diagnostic utilizes the Z-Beamlet laser to generate 6.2-keV Mn-Heα x rays to probe a shock-compressed material on the Z-DMP load. A spherically bent crystal composed of highly oriented pyrolytic graphite is used to collect and focus the diffracted x rays into a 1-in. thick tungsten housing, where an image plate is used to record the data.

Unfused tetanic contractions evoked in fast motor units exhibit extra-efficient force production at the onset of contraction, an effect called “boost”. Boost is diminished in subsequent contractions if there is a short rest period between contractions, but can be re-established with a longer period of rest. We tested the hypothesis that contractile activity and rest could enhance boost-related metrics. Two sets of 3 unfused tetani were evoked 3 min apart in fast fatigable (FF) and fast fatigue-resistant (FR) motor units of the rat medial gastrocnemius. The greatest changes occurred in the first unfused tetanic contractions. Relative to the first contraction in the first set, the first contraction in the second set exhibited higher peak force during boost in a subset of motor units (76% of FF and 48% of FR). Enhanced force during boost was influenced by interaction of slowing of twitch contraction time (up to 20% and 25%, for FF and FR motor units, respectively), half-relaxation time (up to 37% and 49% for FF and FR motor units, respectively), and potentiation of the first twitch (up to 13% and 5% for FF and FR motor units, respectively). Examination of twitches evoked between sets suggested opportunity for greater enhancement of boost with shorter intervening rest periods. The phenomenon of enhanced boost following motor unit activity may interest sports scientists.

We present an overview of the magneto-inertial fusion (MIF) concept Magnetized Liner Inertial Fusion (MagLIF) pursued at Sandia National Laboratories and review some of the most prominent results since the initial experiments in 2013. In MagLIF, a centimeter-scale beryllium tube or ‘liner’ is filled with a fusion fuel, axially pre-magnetized, laser pre-heated, and finally imploded using up to 20 MA from the Z machine. All of these elements are necessary to generate a thermonuclear plasma: laser preheating raises the initial temperature of the fuel, the electrical current implodes the liner and quasi-adiabatically compresses the fuel via the Lorentz force, and the axial magnetic field limits thermal conduction from the hot plasma to the cold liner walls during the implosion. MagLIF is the first MIF concept to demonstrate fusion relevant temperatures, significant fusion production (>1013 primary DD neutron yield), and magnetic trapping of charged fusion particles. On a 60 MA next-generation pulsed-power machine, two-dimensional simulations suggest that MagLIF has the potential to generate multi-MJ yields with significant self-heating, a long-term goal of the US Stockpile Stewardship Program. At currents exceeding 65 MA, the high gains required for fusion energy could be achievable.

Background: Based on results from the ATAC and IMPACT trials, Dowsett et al.1 hypothesized that “short-term changes in proliferation in the neoadjuvant setting may be able to predict outcome during adjuvant use of the same treatments.” Recent neoadjuvant studies2,3,4 of novel agents for HR+ breast cancer used Ki67, a biomarker for cell proliferation, as an endpoint for evaluating biological activity. However, the potential of this endpoint for predicting the adjuvant efficacy of therapeutic agents remains highly uncertain, motivating continued study based on clinical data. After curating relevant data from multiple trials (in both the neoadjuvant and adjuvant settings), a statistical model was constructed to evaluate the current evidence regarding this hypothesis. Methods: Data were collated from randomized trials of systemic therapies in post-menopausal women with HR+ breast cancer reporting Ki67 reduction in the neoadjuvant setting (7 studies) or disease-free survival (DFS) in the adjuvant setting (5 studies). A Bayesian hierarchical joint network meta-analysis model was constructed and fit to the data to evaluate: (1) if there is an association between study-level neoadjuvant Ki67 reduction for a given regimen and corresponding adjuvant DFS hazard ratio, and (2) if the relationship does exist, what DFS effect does it predict for various regimens for which only neoadjuvant data are currently available. Results: The results of the statistical model indicate that effect-size based on neoadjuvant Ki67 correlates with adjuvant (DFS) hazard ratio. Using neoadjuvant Ki67 data for several therapies for which adjuvant data are presently unavailable, we demonstrated how forecasts (and associated confidence intervals) of adjuvant effect-size may be produced using the model. Conclusions: While randomized trials yielding paired data from both clinical settings are sparse, this assessment using a statistically rigorous approach sheds additional light on the hypothesis of a correlation between neoadjuvant Ki67 changes and adjuvant DFS improvements. This analysis suggests the potential utility of Ki67 as a surrogate endpoint to screen/prioritize experimental regimens for development in the adjuvant setting. References: 1. Dowsett, M. et al., Clin Cancer Res, 2005. 11(2): p951s-958s. 2. Baselga, J., et al., J of Clin Oncol, 2009. 27(16): p. 2630-2637. 3. Kuter, I., et al., Breast Cancer Res Treat, 2012. 133(1): p. 237-246. 4. Hurvitz, S., et al., Cancer Res, 2017. 77(4 Supplement): p. S4-06-S4-06. Citation Format: Johnston SRD, Frenzel MJ, Thomas ZM, Hu T, Barriga S, Smith IC, Hurvitz S. A multi-study correlative analysis of change in Ki67 in the neoadjuvant setting and disease free survival improvement in the adjuvant setting [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-09-01.

At the Z Facility at Sandia National Laboratories, the magnetized liner inertial fusion (MagLIF) program aims to study the inertial confinement fusion in deuterium-filled gas cells by implementing a three-step process on the fuel: premagnetization, laser preheat, and Z-pinch compression. In the laser preheat stage, the Z-Beamlet laser focuses through a thin polyimide window to enter the gas cell and heat the fusion fuel. However, it is known that the presence of the few μm thick window reduces the amount of laser energy that enters the gas and causes window material to mix into the fuel. These effects are detrimental to achieving fusion; therefore, a windowless target is desired. The Lasergate concept is designed to accomplish this by “cutting” the window and allowing the interior gas pressure to push the window material out of the beam path just before the heating laser arrives. In this work, we present the proof-of-principle experiments to evaluate a laser-cutting approach to Lasergate and explore the subsequent window and gas dynamics. Further, an experimental comparison of gas preheat with and without Lasergate gives clear indications of an energy deposition advantage using the Lasergate concept, as well as other observed and hypothesized benefits. While Lasergate was conceived with MagLIF in mind, the method is applicable to any laser or diagnostic application requiring direct line of sight to the interior of gas cell targets.

Purpose Abemaciclib, a cyclin-dependent kinase 4 and 6 inhibitor, demonstrated efficacy as monotherapy and in combination with fulvestrant in women with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced breast cancer previously treated with endocrine therapy. Methods MONARCH 3 is a double-blind, randomized phase III study of abemaciclib or placebo plus a nonsteroidal aromatase inhibitor in 493 postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had no prior systemic therapy in the advanced setting. Patients received abemaciclib or placebo (150 mg twice daily continuous schedule) plus either 1 mg anastrozole or 2.5 mg letrozole, daily. The primary objective was investigator-assessed progression-free survival. Secondary objectives included response evaluation and safety. A planned interim analysis occurred after 189 events. Results Median progression-free survival was significantly prolonged in the abemaciclib arm (hazard ratio, 0.54; 95% CI, 0.41 to 0.72; P = .000021; median: not reached in the abemaciclib arm, 14.7 months in the placebo arm). In patients with measurable disease, the objective response rate was 59% in the abemaciclib arm and 44% in the placebo arm ( P = .004). In the abemaciclib arm, diarrhea was the most frequent adverse effect (81.3%) but was mainly grade 1 (44.6%). Comparing abemaciclib and placebo, the most frequent grade 3 or 4 adverse events were neutropenia (21.1% v 1.2%), diarrhea (9.5% v 1.2%), and leukopenia (7.6% v 0.6%). Conclusion Abemaciclib plus a nonsteroidal aromatase inhibitor was effective as initial therapy, significantly improving progression-free survival and objective response rate and demonstrating a tolerable safety profile in women with HR-positive, HER2-negative advanced breast cancer.

Objective: Abemaciclib is an oral, selective inhibitor of CDK4 & 6 that exhibited single agent activity in the MONARCH 1 clinical trial1. The relationship between abemaciclib exposure as monotherapy and response for efficacy and adverse events was evaluated in patients with metastatic breast cancer. Methods: Abemaciclib (200 mg) was administered orally on a continuous schedule every 12 hours in 28 day cycles until disease progression. Sparse pharmacokinetic samples (PK) were collected, cycle (C) 1 day (D) 1 pre dose, C1D15 4 and 7 hours post dose, C2D1 pre and 3 hours post dose, and pre dose on C3D1. Exposure metrics were predicted from a population PK model and included the minimum concentration after a single dose on D1(Cmin,d1), maximum concentration at steady state (Cmax,ss), and minimum concentration at steady state (Cmin,ss ). Exposure to abemaciclib, active metabolites LSN2839567 (M2) and LSN3106726 (M20), and total active species (abemaciclib + M2 + M20) were tested. Response endpoints including efficacy and adverse events were evaluated 12 months after the last patient entered treatment. The relationship between exposure and objective response rate (ORR) was evaluated by quartile analysis and logistic regression. The relationship between exposure and progression free survival (PFS) was evaluated by Kaplan Meier analysis of exposure quartiles and a Cox Proportional Hazard model with PFS as the response and exposure as a covariate. The relationship between exposure and neutropenia, diarrhea, fatigue, nausea, vomiting, and any treatment emergent adverse event (TEAE) was evaluated by logistic regression on the incidence of any grade, grade≥ 2, and grade ≥ 3 events. No adjustments for multiplicity were performed. Results: Analyses included 132 patients. A summary of the exposures in MONARCH 1 are presented in Table 1. The confirmed ORR was 19.7%, and median PFS was 5.95 months (95%CI: 4.2, 7.5). There was no statistically significant relationship between Cmin,d1, Cmin,ss, Cmax,ss for abemaciclib, M2, M20, or total analyte and ORR or PFS. There were no statistically significant and clinically relevant relationships between abemaciclib exposure and TEAEs. Conclusion: The results of the exposure-response analysis support the abemaciclib single agent starting dose of 200 mg twice daily and dose reductions in 50 mg decrements as needed for adverse events. Further studies to refine the PK model and evaluate relationships between exposure and response are warranted. Table 1 Abemaciclib exposures in MONARCH 1 Geometric Mean (µm) (CV%)AnalyteCmax,ss (µm)Cmin,d1 (µm)Cmin,ss (µm)Abemaciclib0.509 (42.6)0.136 (54.2)0.356 (59.9)M20.247 (62.4)0.0511 (51.4)0.187 (83.8)M200.395 (61)0.0687 (56.7)0.312 (79.9)Total Active Species1.19 (43.2)0.262 (47.6)0.888 (60.7)References: 1. Dickler, M. et al. American Society of Clinical Oncology (ASCO), abstract #510 (2016). Citation Format: O'Shaughnessy J, Chigutsa E, Kambhampati SRP, Sykes A, Frenzel M, Nanda S, Koustenis A, Smith I, Turner PK. Abemaciclib exposure-response relationship in patients with metastatic breast cancer in MONARCH 1 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-11-11.

Dichroic coatings have been developed for high transmission at 527 nm and high reflection at 1054 nm for laser operations in the nanosecond pulse regime. The coatings consist of HfO2 and SiO2 layers deposited with e-beam evaporation, and laser-induced damage thresholds as high as 12.5 J/cm2 were measured at 532 nm with 3.5 ns pulses (22.5 degrees angle of incidence, in S-polarization). However, laser damage measurements at the single wavelength of 532 nm do not adequately characterize the laser damage resistance of these coatings, since they were designed to operate at dual wavelengths simultaneously. This became apparent after one of the coatings damaged prematurely at a lower fluence in the beam train, which inspired further investigations. To gain a more complete understanding of the laser damage resistance, results of a dual-wavelength laser damage test performed at both 532 nm and 1064 nm are presented.

The amount of calcium released from the sarcoplasmic reticulum in skeletal muscle rapidly declines during repeated twitch contractions. In this study, we test the hypothesis that caffeine can mitigate these contraction-induced declines in calcium release. Lumbrical muscles were isolated from male C57BL/6 mice and loaded with the calcium-sensitive indicator, AM-furaptra. Muscles were then stimulated at 8 Hz for 2.0 s in the presence or absence of 0.5 mM caffeine, at either 30 °C or 37 °C. The amplitude and area of the furaptra-based intracellular calcium transients and force produced during twitch contractions were calculated. For each of these measures, the values for twitch 16 relative to twitch 1 were higher in the presence of caffeine than in the absence of caffeine at both temperatures. We conclude that caffeine can attenuate contraction-induced diminutions of calcium release during repeated twitch contractions, thereby contributing to the inotropic effects of caffeine.

Experiments on the Sandia Z pulsed-power accelerator have demonstrated the ability to produce warm dense matter (WDM) states with unprecedented uniformity, duration, and size, which are ideal for investigations of fundamental WDM properties. For the first time, space-resolved x-ray Thomson scattering (XRTS) spectra from shocked carbon foams were recorded on Z. The large (>20 MA) electrical current produced by Z was used to launch Al flyer plates up to 25 km/s. The impact of the flyer plate on a CH2 foam target produced a shocked state with an estimated pressure of 0.75 Mbar, density of 0.52 g/cm3, and temperature of 4.3 eV. Both unshocked and shocked portions of the foam target were probed with 6.2 keV x-rays produced by focusing the Z-Beamlet laser onto a nearby Mn foil. The data are composed of three spatially distinct spectra that were simultaneously captured with a single spectrometer with high spectral (4.8 eV) and spatial (190 µm) resolutions. Detailed spectral information from three target locations is provided simultaneously: the incident x-ray source, the scattered signal from unshocked foam, and the scattered signal from shocked foam.

In this paper, we introduce a novel experimental platform for the study of the Richtmyer–Meshkov instability in a cylindrically converging geometry using a magnetically driven cylindrical piston. Magnetically driven solid liner implosions are used to launch a shock into a liquid deuterium working fluid and, ultimately, into an on-axis rod with a pre-imposed perturbation. The shock front trajectory is tracked through the working fluid and up to the point of impacting the rod through the use of on axis photonic Doppler velocimetry. This configuration allows for precise characterization of the shock state as it impacts the perturbed rod interface. Monochromatic x-ray radiography is used to measure the post-shock interface evolution and rod density profile. The ALEGRA MHD model is used to simulate the dynamics of the experiment in one dimension. We show that late in time the perturbation growth becomes non-linear as evidenced by the observation of high-order harmonics, up to n = 5. Two dimensional simulations performed using a combination of the GORGON MHD code and the xRAGE radiation hydrodynamics code suggest that the late time non-linear growth is modified by convergence effects as the bubbles and spikes experience differences in the pressure of the background flow.

Pulsed power accelerators compress electrical energy in space and time to provide versatile experimental platforms for high energy density and inertial confinement fusion science. The 80-TW “Z” pulsed power facility at Sandia National Laboratories is the largest pulsed power device in the world today. Z discharges up to 22 MJ of energy stored in its capacitor banks into a current pulse that rises in 100 ns and peaks at a current as high as 30 MA in low-inductance cylindrical targets. Considerable progress has been made over the past 15 years in the use of pulsed power as a precision scientific tool. This paper reviews developments at Sandia in inertial confinement fusion, dynamic materials science, x-ray radiation science, and pulsed power engineering, with an emphasis on progress since a previous review of research on Z in Physics of Plasmas in 2005.

Amplification of the transverse scattered component of stimulated Brillouin scattering (SBS) can contribute to optical damage in the large aperture optics of multi-kJ lasers. Because increased laser bandwidth from optical phase modulation (PM) can suppress SBS, high energy laser amplifiers are injected with PM light. Phase modulation distributes the single-frequency spectrum of a master oscillator laser among individual PM sidebands, so a sufficiently high modulation index β can maintain the fluence for all spectral components below the SBS threshold. To avoid injection of single frequency light in the event of a PM failure, a high-speed PM failsafe system (PMFS) must be employed. Because PM is easily converted to AM, essentially all PM failsafes detect AM, with the one described here employing a novel configuration where optical heterodyne detection converts PM to AM, followed by passive AM power detection. Although the PMFS is currently configured for continuous monitoring, it can also detect PM for pulse durations ≥2 ns and could be modified to accommodate shorter pulses. This PMFS was deployed on the Z-Beamlet Laser (ZBL) at Sandia National Laboratories, as required by an energy upgrade to support programs at Sandia's Z Facility such as magnetized liner inertial fusion. Depending on the origin of a PM failure, the PMFS responds in as little as 7 ns. In the event of an instantaneous failure during initiation of a laser shot, this response time translates to a 30-50 ns margin of safety by blocking a pulse from leaving ZBL's regenerative amplifier, which prevents injection of single frequency light into the main amplification chain. The performance of the PMFS, without the need for operator interaction, conforms to the principles of engineered safety.

CDK4 & 6 inhibitors have enhanced the effectiveness of endocrine therapy (ET) in patients with advanced breast cancer (ABC). This paper presents exploratory analyses examining patient and disease characteristics that may inform in whom and when abemaciclib should be initiated. MONARCH 2 and 3 enrolled women with HR+, HER2- ABC. In MONARCH 2, patients whose disease had progressed while receiving ET were administered fulvestrant+abemaciclib/placebo. In MONARCH 3, patients received a nonsteroidal aromatase inhibitor+abemaciclib/placebo as initial therapy for advanced disease. A combined analysis of the two studies was performed to determine significant prognostic factors. Efficacy results (PFS and ORR in patients with measurable disease) were examined for patient subgroups corresponding to each significant prognostic factor. Analysis of clinical factors confirmed the following to have prognostic value: bone-only disease, liver metastases, tumor grade, progesterone receptor status, performance status, treatment-free interval (TFI) from the end of adjuvant ET, and time from diagnosis to recurrence. Prognosis was poorer in patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or short TFI (20 months. These analyses identified prognostic factors and demonstrated that patients with poor prognostic factors derived the largest benefit from the addition of abemaciclib., Biomarkers: Prognostic factors indicate likely beneficiaries of cell cycle–blocking therapy A series of clinical factors may help identify those patients with hormone receptor-positive breast cancer who are most likely to benefit from a newly approved cell cycle–blocking drug. Angelo Di Leo from the Hospital of Prato, Italy, and colleagues retrospectively analyzed data from two phase III trials that evaluated the CDK4 & 6 inhibitor abemaciclib against a placebo administered in combination with either fulvestrant endocrine therapy or an aromatase inhibitor. Pooling the results, the researchers found that patients with certain indicators of poor prognosis—including liver metastases, progesterone receptor negativity, high-grade tumors, or short treatment-free intervals following the completion of adjuvant endocrine therapy—benefited most from abemaciclib, as measured by progression-free survival. The findings, if confirmed in prospective trials, could help inform personalized drug choices for patients.

Centronuclear myopathy (CNM) is a congenital myopathy that is histopathologically characterized by centrally located nuclei, central aggregation of oxidative activity, and type I fiber predominance and hypotrophy. Here, we obtained commercially available mice overexpressing phospholamban (PlnOE), a well-known inhibitor of sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs), in their slow-twitch type I skeletal muscle fibers to determine the effects on SERCA function. As expected with a 6- to 7-fold overexpression of phospholamban, SERCA dysfunction was evident in PlnOE muscles, with marked reductions in rates of Ca2+ uptake, maximal ATPase activity and the apparent affinity of SERCA for Ca2+. However, our most significant discovery was that the soleus and gluteus minimus muscles from the PlnOE mice displayed overt signs of myopathy: they histopathologically resembled human CNM, with centrally located nuclei, central aggregation of oxidative activity, type I fiber predominance and hypotrophy, progressive fibrosis and muscle weakness. This phenotype is associated with significant upregulation of muscle sarcolipin and dynamin 2, increased Ca2+-activated proteolysis, oxidative stress and protein nitrosylation. Moreover, in our assessment of muscle biopsies from three human CNM patients, we found a significant 53% reduction in SERCA activity and increases in both total and monomeric PLN content compared with five healthy subjects, thereby justifying future studies with more CNM patients. Altogether, our results suggest that the commercially available PlnOE mouse phenotypically resembles human CNM and could be used as a model to test potential mechanisms and therapeutic strategies. To date, there is no cure for CNM and our results suggest that targeting SERCA function, which has already been shown to be an effective therapeutic target for murine muscular dystrophy and human cardiomyopathy, might represent a novel therapeutic strategy to combat CNM., Summary: Phospholamban overexpression in mouse slow-twitch muscle impairs SERCA function and causes histopathological features associated with human centronuclear myopathy.

Apoptotic signaling plays an important role in the development and maintenance of healthy skeletal muscle. However, dysregulation of apoptotic signals in skeletal muscle is associated with atrophy and loss of function. Apoptosis repressor with caspase recruitment domain (ARC) is a potent anti-apoptotic protein that is highly expressed in skeletal muscle; however, its role in this tissue has yet to be elucidated. To investigate whether ARC deficiency has morphological, functional, and apoptotic consequences, skeletal muscle from 18 week-old wild-type and ARC knockout (KO) mice was studied. In red muscle (soleus), we found lower maximum tetanic force, as well as a shift towards a greater proportion of type II fibers in ARC KO mice. Furthermore, the soleus of ARC KO mice exhibited lower total, as well as fiber type-specific cross sectional area in type I and IIA fibers. Interestingly, these changes in ARC KO mice corresponded with increased DNA fragmentation, albeit independent of caspase or calpain activation. However, cytosolic fractions of red muscle from ARC KO mice had higher apoptosis inducing factor content, suggesting increased mitochondrial-mediated, caspase-independent apoptotic signaling. This was confirmed in isolated mitochondrial preparations, as mitochondria from skeletal muscle of ARC KO mice were more susceptible to calcium stress. Interestingly, white muscle from ARC KO mice showed no signs of altered apoptotic signaling or detrimental morphological differences. Results from this study suggest that even under basal conditions ARC influences muscle apoptotic signaling, phenotype, and function, particularly in slow and/or oxidative muscle.

PURPOSE: We examined how muscle length and time between stimuli (inter-pulse interval, IPI) influence declines in force (sag) seen during unfused tetani in the human adductor pollicis muscle. METHODS: A series of 16-pulse contractions were evoked with IPIs between 1 × and 5 × the twitch time to peak tension (TPT) at large (long muscle length) and small (short muscle length) thumb adduction angles. Unfused tetani were mathematically deconstructed into a series of overlapping twitch contractions to examine why sag exhibits length- and IPI-dependencies. RESULTS: Across all IPIs tested, sag was 62% greater at short than long muscle length, and sag increased as IPI was increased at both muscle lengths. Force attributable to the second stimulus increased as IPI was decreased. Twitch force declined from maximal values across all IPI tested, with the greatest reductions seen at short muscle length and long IPI. At IPI below 2 × TPT, the twitch with highest force occurred earlier than the peak force of the corresponding unfused tetani. Contraction-induced declines in twitch duration (TPT + half relaxation time) were only observed at IPI longer than 1.75 × TPT, and were unaffected by muscle length. CONCLUSIONS: Sag is an intrinsic feature of healthy human adductor pollicis muscle. The length-dependence of sag is related to greater diminution of twitch force at short relative to long muscle length. The dependence of sag on IPI is related to IPI-dependent changes in twitch duration and twitch force, and the timing of peak twitch force relative to the peak force of the associated unfused tetanus.