Hadamard States and Adiabatic Vacua

Reversing a slight detrimental effect of the mailer related to TeXabilityComment: 10pages, LaTeX (RevTeX-preprint style

Stapled EGFR peptide reduces inflammatory breast cancer and inhibits additional HER-driven models of cancer

Background: The human epidermal growth factor receptor (HER) family of transmembrane tyrosine kinases is overexpressed and correlates with poor prognosis and decreased survival in many cancers. The receptor family has been therapeutically targeted, yet tyrosine kinase inhibitors (TKIs) do not inhibit kinase-independent functions and antibody-based targeting does not affect internalized receptors. We have previously demonstrated that a peptide mimicking the internal juxtamembrane domain of HER1 (EGFR; EJ1) promotes the formation of non-functional HER dimers that inhibit kinase-dependent and kinase-independent functions of HER1 (ERBB1/EGFR), HER2 (ERBB2) and HER3 (ERBB3). Despite inducing rapid HER-dependent cell death in vitro, EJ1 peptides are rapidly cleared in vivo, limiting their efficacy. Method: To stabilize EJ1 activity, hydrocarbon staples (SAH) were added to the active peptide (SAH-EJ1), resulting in a 7.2-fold increase in efficacy and decreased in vivo clearance. Viability assays were performed across HER1 and HER2 expressing cell lines, therapeutic-resistant breast cancer cells, clinically relevant HER1-mutated lung cancer cells, and patient-derived glioblastoma cells, in all cases demonstrating improved efficacy over standard of care pan-HER therapeutics. Tumor burden studies were also performed in lung, glioblastoma, and inflammatory breast cancer mouse models, evaluating tumor growth and overall survival. Results: When injected into mouse models of basal-like and inflammatory breast cancers, EGFRvIII-driven glioblastoma, and lung adenocarcinoma with Erlotinib resistance, tumor growth is inhibited and overall survival is extended. Studies evaluating the toxicity of SAH-EJ1 also demonstrate a broad therapeutic window. Conclusions: Taken together, these data indicate that SAH-EJ1 may be an effective therapeutic for HER-driven cancers with the potential to eliminate triple negative inflammatory breast cancer.Arizona Cancer Therapeutics; Ginny L Clements Breast Cancer Research Fund; NIH [NIH 1R41CA203353]; NCI [P30 CA023074]Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Supersymmetry Breaking in the Early Universe

Supersymmetry breaking in the early universe induces scalar soft potentials with curvature of order the Hubble constant. This has a dramatic effect on the coherent production of scalar fields along flat directions. For the moduli problem it generically gives a concrete realization of the problem by determining the field value subsequent to inflation. However it might suggest a solution if the minimum of the induced potential coincides with the true minimum. The induced Hubble scale mass also has important implications for the Affleck-Dine mechanism of baryogenesis. This mechanism requires large squark or slepton expectation values to develop along flat directions in the early universe. This is generally not the case if the induced mass squared is positive, but does occur if it is negative. The resulting baryon to entropy ratio depends mainly on the dimension of the nonrenormalizable operator in the superpotential which stabilizes the flat direction, and the reheat temperature after inflation. Unlike the original scenario, it is possible to obtain an acceptable baryon asymmetry without subsequent entropy releases.Comment: 11 pages, requires phyzz

A comment on multiple vacua, particle production and the time dependent AdS/CFT correspondence

We give an explicit formulation of the time dependent AdS/CFT correspondence when there are multiple vacua present in Lorentzian signature. By computing sample two point functions we show how different amplitudes are related by cosmological particle production. We illustrate our methods in two example spacetimes: (a) a ``bubble of nothing'' in AdS space, and (b) an asymptotically locally AdS spacetime with a bubble of nothing on the boundary. In both cases the alpha vacua of de Sitter space make an interesting appearance.Comment: 9 page

Melting and differentiation of early-formed asteroids: The perspective from high precision oxygen isotope studies

A number of distinct methodologies are available for determining the oxygen isotope composition of minerals and rocks, these include laser-assisted fluorination, secondary ion mass spectrometry (SIMS)and UV laser ablation. In this review we focus on laser-assisted fluorination, which currently achieves the highest levels of precision available for oxygen isotope analysis. In particular, we examine how results using this method have furthered our understanding of early-formed differentiated meteorites. Due to its rapid reaction times and low blank levels, laser-assisted fluorination has now largely superseded the conventional externally-heated Ni “bomb” technique for bulk analysis. Unlike UV laser ablation and SIMS analysis, laser-assisted fluorination is not capable of focused spot analysis. While laser fluorination is now a mature technology, further analytical improvements are possible via refinements to the construction of sample chambers, clean-up lines and the use of ultra-high resolution mass spectrometers. High-precision oxygen isotope analysis has proved to be a particularly powerful technique for investigating the formation and evolution of early-formed differentiated asteroids and has provided unique insights into the interrelationships between various groups of achondrites. A clear example of this is seenin samples that lie close to the terrestrial fractionation line (TFL). Based on the data from conventional oxygen isotope analysis, it was suggested that the main-group pallasites, the howardite eucrite diogenite suite (HEDs) and mesosiderites could all be derived from a single common parent body. However,high precision analysis demonstrates that main-group pallasites have a Δ17O composition that is fully resolvable from that of the HEDs and mesosiderites, indicating the involvement of at least two parent bodies. The range of Δ17O values exhibited by an achondrite group provides a useful means of assessing the extent to which their parent body underwent melting and isotopic homogenization. Oxygen isotope analysis can also highlight relationships between ungrouped achondrites and the more well-populated groups. A clear example of this is the proposed link between the evolved GRA 06128/9 meteorites and the brachinites. The evidence from oxygen isotopes, in conjunction with that from other techniques, indicates that we have samples from approximately 110 asteroidal parent bodies (∼60 irons, ∼35 achondrites and stony-iron, and ∼15 chondrites) in our global meteorite collection. However, compared to the likely size of the original protoplanetary asteroid population, this is an extremely low value. In addition, almost all of the differentiated samples (achondrites, stony-iron and irons) are derived from parent bodies that were highly disrupted early in their evolution. High-precision oxygen isotope analysis of achondrites provides some important insights into the origin of mass-independent variation in the early Solar System. In particular, the evidence from various primitive achondrite groups indicates that both the slope 1 (Y&R) and CCAM lines are of primordial significance. Δ17O differences between water ice and silicate-rich solids were probably the initial source of the slope 1 anomaly. These phases most likely acquired their isotopic composition as a result of UV photo-dissociation of CO that took place either in the early solar nebula or precursor giant molecular cloud. Such small-scale isotopic heterogeneities were propagated into larger-sized bodies, such as asteroids and planets, as a result of early Solar System processes, including dehydration, aqueous alteration,melting and collisional interactions

Pathologic fracture and hardware failure in Streptococcus anginosus femoral osteomyelitis: Case report

Introduction: Pathologic fracture of the femur due to Streptococcus anginosus osteomyelitis has rarely been described. With limited evidence for treating S. anginosus osteomyelitis, the orthopaedic surgeon is presented with a difficult treatment decision at index presentation. Presented here is a case of failed conservative management, diagnostic dilemma, failed hardware stabilization, and definitive surgical treatment resulting in good clinical outcome. Case presentation: A 69-year-old male experienced acute right thigh pain, edema, and erythema after dental treatment 17 days prior. He was diagnosed with right femoral diaphyseal osteomyelitis and Brodie's abscess. Blood cultures grew S. anginosus, but all site-specific tissue cultures resulted negative. Initial management consisted of intravenous antibiotic therapy and percutaneous abscess drainage. Months later, the patient sustained a displaced pathologic fracture of the diaphyseal femur and there was concern for neoplasm, but biopsies were negative. Stabilization was attempted with a lateral plate and screws. This hardware catastrophically failed in the setting of an oligotrophic femoral nonunion. Ultimately, the patient was successfully treated with an intramedullary nail coated with antibiotic-impregnated cement. Twelve months later, the patient achieved clinical and radiographic healing with no evidence of relapse of his osteomyelitis. Clinical discussion: Conservative management of S. anginosus femoral osteomyelitis was inadequate and corroborates the existing literature. S. anginosus osteomyelitis and pyomyositis may be most optimally treated aggressively with early surgical intervention. Conclusion: Early surgical debridement and stabilization of the compromised bone with an antibiotic coated intramedullary nail following medullary reaming may prevent pathologic fracture, eradicate infection, and achieve predictable outcomes

International Veterinary Epilepsy Task Force consensus proposal: Medical treatment of canine epilepsy in Europe

In Europe, the number of antiepileptic drugs (AEDs) licensed for dogs has grown considerably over the last years. Nevertheless, the same questions remain, which include, 1) when to start treatment, 2) which drug is best used initially, 3) which adjunctive AED can be advised if treatment with the initial drug is unsatisfactory, and 4) when treatment changes should be considered. In this consensus proposal, an overview is given on the aim of AED treatment, when to start long-term treatment in canine epilepsy and which veterinary AEDs are currently in use for dogs. The consensus proposal for drug treatment protocols, 1) is based on current published evidence-based literature, 2) considers the current legal framework of the cascade regulation for the prescription of veterinary drugs in Europe, and 3) reflects the authors’ experience. With this paper it is aimed to provide a consensus for the management of canine idiopathic epilepsy. Furthermore, for the management of structural epilepsy AEDs are inevitable in addition to treating the underlying cause, if possible

CPR in medical schools: learning by teaching BLS to sudden cardiac death survivors – a promising strategy for medical students?

BACKGROUND: Cardiopulmonary resuscitation (CPR) training is gaining more importance for medical students. There were many attempts to improve the basic life support (BLS) skills in medical students, some being rather successful, some less. We developed a new problem based learning curriculum, where students had to teach CPR to cardiac arrest survivors in order to improve the knowledge about life support skills of trainers and trainees. METHODS: Medical students who enrolled in our curriculum had to pass a 2 semester problem based learning session about the principles of cardiac arrest, CPR, BLS and defibrillation (CPR-D). Then the students taught cardiac arrest survivors who were randomly chosen out of a cardiac arrest database of our emergency department. Both, the student and the Sudden Cardiac Death (SCD) survivor were asked about their skills and knowledge via questionnaires immediately after the course. The questionnaires were then used to evaluate if this new teaching strategy is useful for learning CPR via a problem-based-learning course. The survey was grouped into three categories, namely "Use of AED", "CPR-D" and "Training". In addition, there was space for free answers where the participants could state their opinion in their own words, which provided some useful hints for upcoming programs. RESULTS: This new learning-by-teaching strategy was highly accepted by all participants, the students and the SCD survivors. Most SCD survivors would use their skills in case one of their relatives goes into cardiac arrest (96%). Furthermore, 86% of the trainees were able to deal with failures and/or disturbances by themselves. On the trainer's side, 96% of the students felt to be well prepared for the course and were considered to be competent by 96% of their trainees. CONCLUSION: We could prove that learning by teaching CPR is possible and is highly accepted by the students. By offering a compelling appreciation of what CPR can achieve in using survivors from SCD as trainees made them go deeper into the subject of resuscitation, what also might result in a longer lasting benefit than regular lecture courses in CPR