Preclinical Therapeutic Efficacy of RAF/MEK/ERK and IGF1R/AKT/mTOR Inhibition in Neuroblastoma.

Activating mutations in the RAS/MAPK pathway are observed in relapsed neuroblastoma. Preclinical studies indicate that these tumors have an increased sensitivity to inhibitors of the RAS/MAPK pathway, such as MEK inhibitors. MEK inhibitors do not induce durable responses as single agents, indicating a need to identify synergistic combinations of targeted agents to provide therapeutic benefit. We previously showed preclinical therapeutic synergy between a MEK inhibitor, trametinib, and a monoclonal antibody specific for IGF1R, ganitumab in RAS-mutated rhabdomyosarcoma. Neuroblastoma cells, like rhabdomyosarcoma cells, are sensitive to the inhibition of the RAS/MAPK and IGF1R/AKT/mTOR pathways. We hypothesized that the combination of trametinib and ganitumab would be effective in RAS-mutated neuroblastoma. In this study, trametinib and ganitumab synergistically suppressed neuroblastoma cell proliferation and induced apoptosis in cell culture. We also observed a delay in tumor initiation and prolongation of survival in heterotopic and orthotopic xenograft models treated with trametinib and ganitumab. However, the growth of both primary and metastatic tumors was observed in animals receiving the combination of trametinib and ganitumab. Therefore, more preclinical work is necessary before testing this combination in patients with relapsed or refractory RAS-mutated neuroblastoma.

Do Specific Ion Effects on Collective Relaxation Arise from Perturbation of Hydrogen-Bonding Network Structure?

The change in the transport properties (i.e., water diffusivity, shear viscosity, etc.) when adding salts to water has been used to classify ions as either being chaotropic or kosmotropic, a terminology based on the presumption that this phenomenon arises from respective breakdown or enhancement of the hydrogen-bonding network structure. Recent quasi-elastic neutron scattering measurements of the collective structural relaxation time, τC, in aqueous salt solutions were interpreted as confirming this proposed origin of ion effects on the dynamics of water. However, we find similar changes in τC in the same salt solutions based on molecular dynamics (MD) simulations using a coarse-grained water model in which no hydrogen bonding exists, challenging this conventional interpretation of mobility change resulting from the addition of salts to water. A thorough understanding of specific ion effects should be useful in diverse material manufacturing and biomedical applications, where these effects are prevalent, but poorly understood.

Stringlet excitation model of the boson peak.

The boson peak (BP), a low-energy excess in the vibrational density of states over the Debye contribution, is often identified as a characteristic of amorphous solid materials. Despite decades of efforts, its microscopic origin still remains a mystery. Recently, it has been proposed, and corroborated with simulations, that the BP might stem from intrinsic localized modes involving one-dimensional (1D) string-like excitations ("stringlets"). We build on a theory originally proposed by Lund that describes the localized modes as 1D vibrating strings, but we specify the stringlet size distribution to be exponential, as observed in simulations. We provide an analytical prediction for the BP frequency ωBP in the temperature regime well below the observed glass transition temperature Tg. The prediction involves no free parameters and accords quantitatively with prior simulation observations in 2D and 3D model glasses based on inverse power law potentials. The comparison of the string model to observations is more uncertain when compared to simulations of an Al-Sm metallic glass material at temperatures well above Tg. Nonetheless, our stringlet model of the BP naturally reproduces the softening of the BP frequency upon heating and offers an analytical explanation for the experimentally observed scaling with the shear modulus in the glass state and changes in this scaling in simulations of glass-forming liquids. Finally, the theoretical analysis highlights the existence of a strong damping for the stringlet modes above Tg, which leads to a large low-frequency contribution to the 3D vibrational density of states, observed in both experiments and simulations.

Influence of swelling on the elasticity of polymer networks cross-linked in the melt state: Test of the localization model of rubber elasticity.

The elasticity of polymer networks, formed by cross-linking high molecular mass polymers in the melt state and then swollen by a solvent, involves contributions from both the presence of cross-link network junctions and the interchain interactions associated with the combined effect of excluded volume interactions and topological constraints that become modified when the network is swollen. We test the capacity of the previously developed localization model of rubber elasticity, a mean field "tube model," to describe changes in elasticity observed in classical experimental studies of the mechanical properties of this type of network. In order to obtain a satisfactory comparison to the experiments, it was found to be necessary to account for the independently observed tendency of the network junctions to become localized in the network with appreciable swelling, as well as the interchain interactions emphasized in previous discussions of the localization model.

Closed Traumatic Avulsion of Both Flexor Digitorum Tendons: An Addition to the Leddy and Packer Classification and Review of the Literature.

Objective: We encountered the case of a patient who presented with an avulsion of both flexor digitorum profundus (FDP) and flexor digitorum superficialis (FDS) tendons from their respective insertion in the ring finger. We aim to discuss the novel treatment of this injury pattern in the context of all previously encountered cases in the literature. Materials and Methods: We examined the case of our patient with avulsion of both flexor tendons in the same finger and discuss the novel method of treatment in our case. Additionally, we performed a literature review of all previous reported cases and discuss the treatment modalities and outcomes associated with each. Results: We have shown a novel and successful treatment technique for avulsion of both the FDP and FDS tendons. We identified twelve other cases of this injury pattern and have compared all outcomes documented. Conclusion: Closed tendon avulsion of both flexor tendons in the same finger is rare. We described a case and additionally propose a modification to the flexor tendon avulsion classification to incorporate this injury pattern and aid its management.

Promise and Perils of Precision Oncology for Patients With Pediatric and Young Adult Sarcomas.

The completion of multiple national pediatric precision oncology platform trials and the incorporation of standardized molecular profiling into the diagnostic care of pediatric and young adult patients with sarcomas have proven the feasibility and potential of the approach. In this work, we explore the current state of the art of precision oncology for pediatric and young adults with sarcoma. We highlight important lessons learned and the challenges that should be addressed in the next generation of trials. The chapter outlines current efforts to improve standardization of molecular assays, harmonization of data collection, and novel molecular tools such as cell-free DNA analyses. Finally, we discuss the impacts and psychosocial outcomes experienced by patients and communication strategies for providers.

Mausolates†: Large-Cavity Chelates with Potential as Delivery Vehicles in Nuclear Medicine.

A new type of diborate clathrochelate (cage) ligand featuring nine inwardly pointing nitrogen donors that form a large, rigid cavity, termed a mausolate, is presented. The cavity size and high denticity make this an attractive delivery vehicle for large radionuclides in nuclear medicine. Metal mausolate complexes are stable to air and water (neutral pH) and display extremely high thermal stability (> 400 0C). Lanthanide uptake by the mausolate ligand occurs rapidly in solution at room temperature and once complexed, the lanthanide ions are not displaced by a 250-fold excess of a competitive lanthanide salt over more than one week.

Memory, mood and associated neuroanatomy in individuals with steroid sulphatase deficiency (X-linked ichthyosis).

Steroid sulphatase (STS) cleaves sulphate groups from steroid hormones, and steroid (sulphate) levels correlate with mood and age-related cognitive decline. In animals, STS inhibition or deletion of the associated gene, enhances memory/neuroprotection and alters hippocampal neurochemistry. Little is known about the consequences of constitutive STS deficiency on memory-related processes in humans. We investigated self-reported memory performance (Multifactorial Memory Questionnaire), word-picture recall and recent mood (Kessler Psychological Distress Scale, K10) in adult males with STS deficiency diagnosed with the dermatological condition X-linked ichthyosis (XLI; n = 41) and in adult female carriers of XLI-associated genetic variants (n = 79); we compared results to those obtained from matched control subjects [diagnosed with ichthyosis vulgaris (IV, n = 98) or recruited from the general population (n = 250)]. Using the UK Biobank, we compared mood/memory-related neuroanatomy in carriers of genetic deletions encompassing STS (n = 28) and non-carriers (n = 34,522). We found poorer word-picture recall and lower perceived memory abilities in males with XLI and female carriers compared with control groups. XLI-associated variant carriers and individuals with IV reported more adverse mood symptoms, reduced memory contentment and greater use of memory aids, compared with general population controls. Mood and memory findings appeared largely independent. Neuroanatomical analysis only indicated a nominally-significantly larger molecular layer in the right hippocampal body of deletion carriers relative to non-carriers. In humans, constitutive STS deficiency appears associated with mood-independent impairments in memory but not with large effects on underlying brain structure; the mediating psychobiological mechanisms might be explored further in individuals with XLI and in new mammalian models lacking STS developmentally.

A Laing distal myopathy-associated proline substitution in the ß-myosin rod perturbs myosin cross-bridging activity.

Proline substitutions within the coiled-coil rod region of the ß-myosin gene (MYH7) are the predominant mutations causing Laing distal myopathy (MPD1), an autosomal dominant disorder characterized by progressive weakness of distal/proximal muscles. We report that the MDP1 mutation R1500P, studied in what we believe to be the first mouse model for the disease, adversely affected myosin motor activity despite being in the structural rod domain that directs thick filament assembly. Contractility experiments carried out on isolated mutant muscles, myofibrils, and myofibers identified muscle fatigue and weakness phenotypes, an increased rate of actin-myosin detachment, and a conformational shift of the myosin heads toward the more reactive disordered relaxed (DRX) state, causing hypercontractility and greater ATP consumption. Similarly, molecular analysis of muscle biopsies from patients with MPD1 revealed a significant increase in sarcomeric DRX content, as observed in a subset of myosin motor domain mutations causing hypertrophic cardiomyopathy. Finally, oral administration of MYK-581, a small molecule that decreases the population of heads in the DRX configuration, significantly improved the limited running capacity of the R1500P-transgenic mice and corrected the increased DRX state of the myofibrils from patients. These studies provide evidence of the molecular pathogenesis of proline rod mutations and lay the groundwork for the therapeutic advancement of myosin modulators.

Dielectric Characterization of H2O and CO2 Uptake by Polyethylenimine Films.

The absorption of CO2 by polyethylenimine polymer (PEI) materials is of great interest in connection with proposed carbon capture technologies, and the successful development of this technology requires testing methods quantifying the amount of CO2, H2O, and reaction byproducts under operating conditions. We anticipate that dielectric measurements have the potential for quantifying both the extent of CO2 and H2O absorption within the PEI matrix material as well as insights into subsequent reaction byproducts that can be expected to occur in the presence of moisture. The complexity of the chemistry involved in this reactive binding process clearly points to the need for the use of additional spectroscopic techniques to better resolve the multiple components involved and to validate the model-dependent findings from the dielectric measurements. Here, we employed noncontact resonant microwave cavity instrumentation operating at 7.435 GHz that allows for the precise determination of the complex dielectric permittivity of CO2 films exposed to atmospheres of controlled relative humidity (RH), and N2:CO2 compositions. We find that the addition of CO2 leads to a considerable increase in dielectric loss of the PEI film relative to loss measured in nitrogen (N2) atmosphere across the same RH range. We attribute this effect to a reaction between CO2 and PEI generating a charged dielectrically active species contributing to the dielectric loss in the presence of moisture. Possible reaction mechanisms accounting for these observations are discussed, including the formation of carbamate-ammonium pairs and ammonium cations stabilized by bicarbonate anions that have sufficient local mobility to be dielectrically active in the investigated microwave frequency range. Understanding of these reaction mechanisms and the development of tools to quantify the amount of reactive byproducts are expected to be critical for the design and optimization of carbon capture materials.

Identifying human pre-mRNA cleavage and polyadenylation factors by genome-wide CRISPR screens using a dual fluorescence readthrough reporter.

Messenger RNA precursors (pre-mRNA) generally undergo 3' end processing by cleavage and polyadenylation (CPA), which is specified by a polyadenylation site (PAS) and adjacent RNA sequences and regulated by a large variety of core and auxiliary CPA factors. To date, most of the human CPA factors have been discovered through biochemical and proteomic studies. However, genetic identification of the human CPA factors has been hampered by the lack of a reliable genome-wide screening method. We describe here a dual fluorescence readthrough reporter system with a PAS inserted between two fluorescent reporters. This system enables measurement of the efficiency of 3' end processing in living cells. Using this system in combination with a human genome-wide CRISPR/Cas9 library, we conducted a screen for CPA factors. The screens identified most components of the known core CPA complexes and other known CPA factors. The screens also identified CCNK/CDK12 as a potential core CPA factor, and RPRD1B as a CPA factor that binds RNA and regulates the release of RNA polymerase II at the 3' ends of genes. Thus, this dual fluorescence reporter coupled with CRISPR/Cas9 screens reliably identifies bona fide CPA factors and provides a platform for investigating the requirements for CPA in various contexts.

Glastonbury Festival: Medical Care at the World's Largest Greenfield Music Festival.

INTRODUCTION: Music festivals have become an increasingly popular form of mass-gathering event, drawing an increasing number of attendees across the world each year. While festivals exist to provide guests with an enjoyable experience, there have been instances of serious illness, injury, and in some cases death. Large crowds, prolonged exposure to loud music, and high rates of drug and alcohol consumption can pose a dangerous environment for guests as well as those looking after them. METHODS: A retrospective review of electronic patient records (EPRs) at the 2022 Glastonbury Festival was undertaken. All patients who attended medical services on-site during the festival and immediately after were included. Patient demographics, diagnosis, treatment received, and discharge destination were obtained and analyzed. RESULTS: A total of 2,828 patients received on-site medical care. The patient presentation rate (PPR) was 13.47 and the transport-to-hospital rate (TTHR) was 0.30 per 1,000 guests. The most common diagnoses were joint injuries, gastrointestinal conditions, and blisters. Only 164 patients (5.48%) were diagnosed as being intoxicated. Overall, 552 patients (19.52%) were prescribed a medication to take away and 268 (9.48%) had a dressing for a minor wound. One patient (0.04%) underwent a general anesthetic and no patients required cardiopulmonary resuscitation. Most patients were discharged back to the festival site (2,563; 90.66%). DISCUSSION: Minor conditions were responsible for many presentations and most patients only required mild or non-invasive interventions, after which they could be safely discharged back to the festival. Older adults were diagnosed with a different frequency of conditions compared to the overall study population, something not reported previously. Intoxicated patients only accounted for a very small amount of the medical workload.

Midlife cumulative deficit frailty predicts Alzheimer's disease-related plasma biomarkers in older adults.

BACKGROUND: The study explores whether frailty at midlife predicts mortality and levels of biomarkers associated with Alzheimer's disease and related dementias (ADRD) and neurodegeneration by early old age. We also examine the heritability of frailty across this age period. METHODS: Participants were 1,286 community-dwelling men from the Vietnam Era Twin Study of Aging at average ages 56, 62 and 68, all without ADRD at baseline. The cumulative deficit frailty index (FI) comprised 37 items assessing multiple physiological systems. Plasma biomarkers at age 68 included beta-amyloid (Aß40, Aß42), total tau (t-tau) and neurofilament light chain (NfL). RESULTS: Being frail doubled the risk of all-cause mortality by age 68 (OR = 2.44). Age 56 FI significantly predicted age 68 NfL (P = 0.014), Aß40 (P = 0.001) and Aß42 (P = 0.023), but not t-tau. Age 62 FI predicted all biomarkers at age 68: NfL (P = 0.023), Aß40 (P = 0.002), Aß42 (P = 0.001) and t-tau (P = 0.001). Age 68 FI scores were associated with age 68 levels of NfL (P = 0.027), Aß40 (P < 0.001), Aß42 (P = 0.001) and t-tau (P = 0.003). Genetic influences accounted for 45-48% of the variance in frailty and significantly contributed to its stability across 11 years. CONCLUSIONS: Frailty during one's 50s doubled the risk of mortality by age 68. A mechanism linking frailty and ADRD may be through its associations with biomarkers related to neurodegeneration. Cumulative deficit frailty increases with age but remains moderately heritable across the age range studied. With environmental factors accounting for about half of its variance, early interventions aimed at reducing frailty may help to reduce risk for ADRD.

Self-Cross-Linking of MXene-Intercalated Graphene Oxide Membranes with Antiswelling Properties for Dye and Salt Rejection.

Membrane-based water purification is poised to play an important role in tackling the potable water crisis for safe and clean water access for the general population. Several studies have focused on near two-dimensional membranes for this purpose, which is based on an ion rejection technique. However, membrane swelling in these materials has emerged as a significant challenge because it leads to the loss of function. Herein, we report a self-cross-linked MXene-intercalated graphene oxide (GO) membrane that retains ion and dye rejection properties because the physical cross-linking interaction between Ti-O-Ti and neighboring nanosheets effectively suppresses the swelling of the membrane. In addition to the associative Ti-O-Ti bonds, C-O-C, O=C-O, and C-OH bonds are also formed, which are important for inhibiting the swelling of the membrane. To ensure the longevity of these membranes in a service context, they were subjected to heat pressurization and subsequent thermal annealing. The membrane subjected to this novel processing history exhibits minimal swelling upon immersion in solutions and retains function, rejecting salt and dyes over a wide range of salt and dye concentrations. Furthermore, these membranes successfully rejected dye and salt over a period of 72 h without a degradation of function, suggesting that these membranes have the requisite durability for water filtration applications.

A closer examination of the nature of atomic motion in the interfacial region of crystals upon approaching melting.

Although crystalline materials are often conceptualized as involving a static lattice configuration of particles, it has recently become appreciated that string-like collective particle exchange motion is a ubiquitous and physically important phenomenon in both the melting and interfacial dynamics of crystals. This type of collective motion has been evidenced in melting since early simulations of hard disc melting by Alder et al. [Phys. Rev. Lett. 11(6), 241-243 (1963)], but a general understanding of its origin, along with its impact on melting and the dynamics of crystalline materials, has been rather slow to develop. We explore this phenomenon further by focusing on the interfacial dynamics of a model crystalline Cu material using molecular dynamics simulations where we emphasize the geometrical nature and spatial extent of the atomic trajectories over the timescale that they are caged, and we also quantify string-like collective motion on the timescale of the fast ß-relaxation time, τf, i.e., "stringlets." Direct visualization of the atomic trajectories in their cages over the timescale over which the cage persists indicates that they become progressively more anisotropic upon approaching the melting temperature Tm. The stringlets, dominating the large amplitude atomic motion in the fast dynamics regime, are largely localized to the crystal interfacial region and correspond to "excess" modes in the density of states that give rise to a "boson peak." Moreover, interstitial point defects occur in direct association with the stringlets, demonstrating a link between classical defect models of melting and more recent studies of melting emphasizing the role of this kind of collective motion.

Recognition and management of left atrial dissection during mitral repair.

BACKGROUND: Left atrial dissection (LAtD) is a rare but potentially life-threatening complication of mitral valve surgery. Its management is not well stablished in the literature. However, early recognition through intraoperative TEE and attention to changes in the left atrial free wall during saline leak testing can lead to avoidance of severe complications. CASE PRESENTATION: We report a case of LAtD detected by intraoperative transesophageal echocardiogram (TEE) following mitral valve repair for primary mitral valve regurgitation secondary to degenerative mitral valve disease with MAZE IV procedure for atrial fibrillation. LAtD was noted on TEE as an expanding double density along the wall of the left atrium with a jet originating at the posterior annulus flowing into the LAtD which was repaired. Separation from bypass following LAtD repair was complicated by severe biventricular dysfunction requiring significant inotropic support and placement of an intra-aortic balloon pump (IABP). Patient's post-operative course was further complicated by right sided heart failure requiring placement of a right sided impella which was subsequently removed on POD 4. Patient was discharged home on POD 17. Transthoracic echo at 1 month, 3 months demonstrated resolution of the LAtD. A follow up echo at 4 years showed complete resolution of the LAtD with an intact mitral repair, trace mitral regurgitation, and a mean gradient across the repair of 3 mm Hg. CONCLUSIONS: Left atrial dissection is a rare but serious complication of mitral valve surgery. We provide a review of the current literature regarding LAtD, emphasizing the need to consider this complication early during mitral surgery to allow for uncomplicated repair.

Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Importance: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma. Objective: To assess whether CPVs are associated with outcome among children with rhabdomyosarcoma. Design, Setting, and Participants: In this cohort study, data were obtained for individuals, aged 0.01-23.23 years, newly diagnosed with rhabdomyosarcoma who were treated across 171 Children's Oncology Group sites from March 15, 1999, to December 8, 2017. Data analysis was performed from June 16, 2021, to May 15, 2023. Exposure: The presence of a CPV in 24 rhabdomyosarcoma-associated cancer-predisposition genes (CPGs) or an expanded set of 63 autosomal-dominant CPGs. Main Outcomes and Measures: Overall survival (OS) and event-free survival (EFS) were the main outcomes, using the Kaplan-Meier estimator to assess survival probabilities and the Cox proportional hazards regression model to adjust for clinical covariates. Analyses were stratified by tumor histology and the fusion status of PAX3 or PAX7 to the FOXO1 gene. Results: In this study of 580 individuals with rhabdomyosarcoma, the median patient age was 5.9 years (range, 0.01-23.23 years), and the male-to-female ratio was 1.5 to 1 (351 [60.5%] male). For patients with CPVs in rhabdomyosarcoma-associated CPGs, EFS was 48.4% compared with 57.8% for patients without a CPV (P = .10), and OS was 53.7% compared with 65.3% for patients without a CPV (P = .06). After adjustment, patients with CPVs had significantly worse OS (adjusted hazard ratio [AHR], 2.49 [95% CI, 1.39-4.45]; P = .002), and the outcomes were not better among patients with embryonal histology (EFS: AHR, 2.25 [95% CI, 1.25-4.06]; P = .007]; OS: AHR, 2.83 [95% CI, 1.47-5.43]; P = .002]). These associations were not due to the development of a second malignant neoplasm, and importantly, patients with fusion-negative rhabdomyosarcoma who harbored a CPV had similarly inferior outcomes as patients with fusion-positive rhabdomyosarcoma without CPVs (EFS: AHR, 1.35 [95% CI, 0.71-2.59]; P = .37; OS: AHR, 1.71 [95% CI, 0.84-3.47]; P = .14). There were no significant differences in outcome by CPV status of the 63 CPG set. Conclusions and Relevance: This cohort study identified a group of patients with embryonal rhabdomyosarcoma who had a particularly poor outcome. Other important clinical findings included that individuals with TP53 had poor outcomes independent of second malignant neoplasms and that patients with fusion-negative rhabdomyosarcoma who harbored a CPV had outcomes comparable to patients with fusion-positive rhabdomyosarcoma. These findings suggest that germline CPV testing may aid in clinical prognosis and should be considered in prospective risk-based clinical trials.