Preamble and Transition to ACC/AHA Guidelines to Reduce Cardiovascular Risk S50

The goals of the American College of Cardiology (ACC) and the American Heart Association (AHA) are to prevent cardiovascular diseases (CVD); improve the management of people who have these diseases through professional education and research; and develop guidelines, standards, and policies that promote optimal patient care and cardiovascular health. Toward these objectives, the ACC and AHA have collaborated with the National Heart, Lung, and Blood Institute (NHLBI) and stakeholder and professional organizations to develop …

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2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk

Jeffrey L. Anderson, MD, FACC, FAHA, Chair 

Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect 

Nancy M. Albert, PhD, RN, FAHA

Biykem Bozkurt, MD, PhD, FACC, FAHA

Ralph G. Brindis, MD, MPH, MACC

Lesley H. Curtis, PhD, FAHA

David DeMets, PhD[¶¶][1]

Lee A. Fleisher, MD, FACC, FAHA

Samuel

/pdf/2014-acc-aha-guideline-on-perioperative-cardiovascular-3firuin78y.pdf

2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: A report of the American college of cardiology/American heart association task force on practice guidelines

Signalling through the ERBB/HER receptors is intricately involved in human cancer and already serves as a target for several cancer drugs. Because of its inherent complexity, it is useful to envision ERBB signalling as a bow-tie-configured, evolvable network, which shares modularity, redundancy and control circuits with robust biological and engineered systems. Because network fragility is an inevitable trade-off of robustness, systems-level understanding is expected to generate therapeutic opportunities to intercept aberrant network activation.

EGF–ERBB signalling: towards the systems level

The text consists of two sections, one for those studying or practicing diagnostic radiology, nuclear medicine and radiation oncology; the other for those engaged in the study or clinical practice of radiation oncology--a new chapter, on radiologic terrorism, is specifically for those in the radiation sciences who would manage exposed individuals in the event of a terrorist event. The 17 chapters in Section I represent a general introduction to radiation biology and a complete, self-contained course especially for residents in diagnostic radiology and nuclear medicine that follows the Syllabus in Radiation Biology of the RSNA. The 11 chapters in Section II address more in-depth topics in radiation oncology, such as cancer biology, retreatment after radiotherapy, chemotherapeutic agents and hyperthermia.

Radiobiology for the Radiologist

von Hippel-Lindau disease

Cochlear implants have evolved to utilize residual acoustic hearing that combines to electric stimulation, known as electric-acoustic stimulation (EAS). However, there are mixed expectations about the benefits of EAS. A positive perspective expects that contributions from residual hearing provide better access to acoustic cues that is helpful for speech-in-noise perception. An opposing view concerns potentially poorer spectral resolution of EAS electrodes’ stimulation as those electrodes are often inserted close to lateral wall, which may cause poorer speech-in-noise perception. This study aimed to directly compare neural processes of speech-in-noise perception between EAS and standard CI users to provide an answer to the above alternative expectations. We used 64-channel EEG to measure cortical evoked responses to (1) background noise and (2) target word while listeners perform a word-in-noise task. Then, we compared the amplitude ratio of evoked responses to the target word and background noise, referred to as “internal SNR,” which reflects how well target sound is unmasked from the mixture of speech and noise. Based on the comparison of 55 EAS and 22 standard CI users, internal SNR was significantly larger in EAS CI users. This result indicates that EAS provides enhanced neural processes for speech unmasking.

Neural correlates of speech in noise perception differences between combined electric-acoustic stimulation and standard cochlear implants

OBJECTIVE
Vestibular schwannomas (VSs) are benign nerve sheath tumors that result from mutation in the tumor suppressor gene NF2, with functional loss of the protein merlin. The authors have previously shown that c-Jun N-terminal kinase (JNK) is constitutively active in human VS cells and plays a central role in their survival by suppressing accumulation of mitochondrial superoxides, implicating JNK inhibitors as a potential systemic treatment for VS. Thus, the authors hypothesized that the adenosine 5'-triphosphate-competitive JNK inhibitor AS602801 would demonstrate antitumor activity in multiple VS models.


METHODS
Treatment with AS602801 was tested in primary human VS cultures, human VS xenografts, and a genetic mouse model of schwannoma (Postn-Cre;Nf2flox/flox). Primary human VS cell cultures were established from freshly obtained surgical tumor specimens; treatment group media was enriched with AS602801. VS xenograft tumors were established in male athymic nude mice from freshly collected human tumor. Four weeks postimplantation, a pretreatment MRI scan was obtained, followed by 65 days of AS602801 (n = 18) or vehicle control (n = 19) treatment. Posttreatment MRI scans were used to measure final tumor volume. Tumors were then harvested. Finally, Postn-Cre;Nf2flox/flox mice were treated with AS602801 (n = 10) or a vehicle (n = 13) for 65 days. Posttreatment auditory brainstem responses were obtained. Dorsal root ganglia from Postn-Cre;Nf2flox/flox mice were then harvested. In all models, schwannoma identity was confirmed with anti-S100 staining, cell proliferation was measured with the EdU assay, and cell death was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. All protocols were approved by the local institutional review board and Institutional Animal Care and Use Committees.


RESULTS
Treatment with AS602801 decreased cell proliferation and increased apoptosis in primary human VS cultures. The systemic administration of AS602801 in mice with human VS xenografts reduced tumor volume and cell proliferation. Last, the AS602801-treated Postn-Cre;Nf2flox/flox mice demonstrated decreased cell proliferation in glial cells in the dorsal root ganglia. However, AS602801 did not significantly delay hearing loss in Postn-Cre;Nf2flox/flox mice up to 3 months posttreatment.


CONCLUSIONS
The data suggest that JNK inhibition with AS602801 suppresses growth of sporadic and neurofibromatosis type 2-associated VSs. As such, AS602801 is a potential systemic therapy for VS and warrants further investigation.

Reduction of sporadic and neurofibromatosis type 2-associated vestibular schwannoma growth in vitro and in vivo after treatment with the c-Jun N-terminal kinase inhibitor AS602801.


 
 
 Meningiomas and schwannomas account for 45% of primary CNS tumors. Yet when surgery and radiation fail, no further treatments exist. Metabolomics has been used to discover new cancer therapies; however, to date few have used metabolomics to study meningiomas and schwannomas. Here we present initial results and lessons learned from this novel endeavor.
 
 
 
 Primary tumors were obtained from patients during surgery and immediately taken for culturing or xenograft implantation. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation, then flash frozen 6 or 72 hours post-treatment. Xenograft tumors were implanted in nude mice. MRI 4 weeks post-implantation confirmed tumor viability. Mice were then given 10gy, 20gy, or sham radiation treatment. Xenografts were harvested 72 hours post-treatment. Metabolites were measured with a ThermoISQ gas chromatography-mass spectrometer.
 
 
 
 Eleven meningiomas and nine schwannomas were successfully cultured. Unsupervised hierarchical clustering of cultures demonstrated greater influence from tumor of origin than from radiation. Univariate analysis of schwannoma xenografts demonstrated elevated ornithine following radiation (fold change 1.62; P = 0.008). However, principal component analysis did not show significant between-group differentiation. Orthotopic meningioma xenografts did not produce sufficient tissue for metabolomics; however, subsequent subcutaneous implants have been successful (data forthcoming).
 
 
 
 Standard cell cultures did not reveal significant metabolic changes following radiation; it is unclear whether this was due to culture technique or inter-tumor heterogeneity. In radiated schwannoma xenografts, elevated ornithine may implicate related pathways such as ornithine decarboxylase-mediated polyamide synthesis for DNA double-strand break repair. Compared to other ‘-omics’ studies, metabolomics requires more tissue per sample ( >10mg) and is more sensitive to environmental conditions. Thus, large sample sizes are needed to detect significant changes, and xenografts are likely superior to cell culture. Future plans include increased xenograft sample size and stable isotope tracing for pathway analysis.


/pdf/tmet-34-radiation-metabolomics-in-primary-human-meningioma-14jthdul.pdf

Tmet-34. radiation metabolomics in primary human meningioma and schwannoma: early experience and initial results

Introduction: Schwannomas account for 8% of primary CNS tumors. Surgery and radiation can be curative, but when they fail few treatment options remain. Metabolomics is the study of metabolic networks and has helped identify novel cancer therapies; however, the schwannoma metabolome has yet to be described. Furthermore, because there is no anatomical location with large numbers (>10 mg) of pure Schwann cells, there is no direct control tissue for Schwannomas. Thus, we aimed to characterize the metabolic profile of primary human schwannomas, explore patient-derived xenografts as a model for schwannoma metabolism, and use these xenografts to describe radiation-induced metabolic changes in schwannomas. 

Metabolomic Analysis of Primary and Xenograft Schwannomas Reveals Altered Amino Acid Metabolism Following Radiation

Background: Maximum performance and long-term stability of bilateral cochlear implants has become an important topic because there has been increasing numbers of recipients of bilateral cochlear implants. Purpose: To determine the performance over time (up to 6yr) of subjects with simultaneous bilateral cochlear implants (CI1CI) on word recognition and localization.

Marlan R. Hansen

Papers

Neural correlates of speech in noise perception differences between combined electric-acoustic stimulation and standard cochlear implants

Reduction of sporadic and neurofibromatosis type 2-associated vestibular schwannoma growth in vitro and in vivo after treatment with the c-Jun N-terminal kinase inhibitor AS602801.

Tmet-34. radiation metabolomics in primary human meningioma and schwannoma: early experience and initial results

Metabolomic Analysis of Primary and Xenograft Schwannomas Reveals Altered Amino Acid Metabolism Following Radiation

Performance over Time on Adults with Simultaneous