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 …

/pdf/2013-acc-aha-guideline-on-the-assessment-of-cardiovascular-1t8hg65cmz.pdf

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

Boahene et al 1 recently published an article in this journal regarding patients with facial nerve paralysis secondary to occult malignant neoplasms. In their series, they reported 15 patients with isolated progressive facial nerve paralysis, but with normal CT or MRI imaging studies. These patients underwent surgical exploration. Thirteen of them (87%) were found to have malignant involvement of the facial nerve. Only 2 of these 13 patients had a distinct parotid mass identified at surgery. Eleven of the 13 patients received radiation as part of their treatment. With follow-up of 2 to 193 months (mean 3.7 years), 5 patients were alive with no evidence of disease. Of note, 6 patients (46%) developed recurrences at the skull base with intracranial extension of the recurrent disease. The detailed radiation technique and dose were not described in the paper. To reduce skull base recurrences, the radiation field should encompass the skull base to include the whole course of the facial nerve up to its exit from the brain stem. However, it is technically difficult to deliver high doses of radiation to this area because of the proximity of dose-limiting critical structures, including the brain stem, orbit, optic nerve, and optic chiasm. With the development of CT treatment planning, 3D conformal therapy, intensity-modulated radiotherapy (IMRT), and stereotactic guidance radiotherapy, radiation can be delivered more accurately and precisely. These advancements enable better coverage of tumor volume and risk areas as well as sparing of critical structures. This can potentially increase tumor control and reduce severe late side effects. Recently, we treated a patient with optically guided stereotactic radi-

Optically guided stereotactic radiotherapy for facial nerve paralysis secondary to occult malignant neoplasms.

This document discusses, among other things, systems and methods for device-assisted manipulation of an implant's position in a patient, such as for delivering and positioning a cochlear implant. An exemplary modular system includes an implant position manipulator (IPM) unit reversibly engaging an elongate member of an implant, and a user control device for applying driving force to the IPM unit to regulate the motion of the implant. The system may include sensors providing feedback on the position or the motion of the implant, or the force or friction applied to the implant during the implantation procedure.

Modular implant position manipulator system

Objectives:(1) Identify intracellular signaling pathways required for translating biophysical cues into directed neurite growth. (2) Describe the role of TRPVI channels as mediators of cell response to microtopographical features.Methods:Microscopic parallel grooves were generated on methacrylate polymers using photopolymerization. Spiral ganglion neurites (SGNs) were cultured on the polymers, and alignment to grooves was quantified using a ratio of aligned length to total neurite length. Control alignment was compared with that of SGNs treated with RhoA activator, RhoA inhibitor, ROCK inhibitors, cAMP and cGMP analogs, and TRPV channel inhibitors. RNA interference was used to reduce expression of ROCK and TRPVI to confirm that activity of each was required for alignment. Alignment of NIH3T3 fibroblasts was compared to fibroblasts transfected with TRPVI.Results:Neurites aligned preferentially to micropattern grooves. RhoA activator and cGMP analogs increased alignment, while RhoA inhibitor and cAMP analog...

Microtopographical Features Recruit RhoA/ROCK through TRPV1 Channels to Direct Cell and Neurite Growth:

INTRODUCTION: Meningiomas are the most common primary CNS tumor. Yet when surgical and radiation fail, no further treatments exist. Metabolomics is the study of metabolic networks and has been used to discover new treatments in cancers; however, few attempts have been made to apply metabolomics to meningiomas. METHODS: Primary tumors were obtained from surgeries at the University of Iowa. Primary tumor specimens were immediately flash-frozen in liquid nitrogen, while tissue for culture was placed on ice and immediately transferred for cell culturing. Upon reaching >90% confluence, cultures were treated with 0gy, 3gy, 10gy, or 20gy gamma radiation. Six or 72 hours after radiation the cultures were washed then flash frozen in liquid nitrogen. Metabolomic profiles were obtained with a ThermoISQ gas chromatography-mass spectrometer. Data was analyzed using MetaboAnalyst 5.0. RESULTS: Forty WHO grade 1 and fourteen WHO grade 2/3 tumors were included. Eleven tumors were also successfully cultured. Partial least squares-discriminant analysis (PLS-DA) demonstrated expected clustering of primary tumors according to pathologic grade. Among the primary tumors, 12 metabolites were found to be significantly elevated in WHO grade 2/3 tumors.In parallel, primary cell cultures were developed to test the effect of radiation on the tumors, but unsupervised clustering found that inter-tumor heterogeneity was greater than the treatment effect from radiation. CONCLUSIONS: High-grade meningiomas display distinct metabolite levels compared to benign meningiomas, suggestive of altered metabolic pathway utilization. Standard cell cultures did not reveal significant metabolic changes following radiation, but it is unclear whether this was due to technique or a true finding. Further experiments are needed to elucidate the functional implications of these findings.

522 Metabolomic Analysis of 54 Meningiomas Reveals Distinct Metabolite Profiles in WHO 1 and WHO 2/3 Tumors


 Introduction: Avasopasem manganese (GC4419) is a selective superoxide dismutase mimetic which has recently completed a Phase 3 clinical trial (NCT03689712) demonstrating a significant reduction in the severity of oral mucositis in patients receiving standard cisplatin and radiotherapy for head and neck squamous cell carcinoma (HNSCC). Up to 66% of HNSCC patients experience ototoxicity from platinum-based chemotherapy, resulting in tinnitus and hearing loss. The analysis of clinical trial data also revealed that patients treated with GC4419 in addition to cisplatin (cis) and radiotherapy reported less tinnitus than those treated with standard therapy alone. The generation of reactive oxygen species has long been recognized as an important contributor to cis-induced hearing loss; therefore, we hypothesize that administration of GC4419 with cisplatin can prevent ototoxicity by scavenging superoxide.
 Results: Organotypic cultures using postnatal day 2 or 3 mouse cochlea were treated with cis 4 µM and 0.5, 2, or 4 µM GC4419 for 24 hours. The explants were then stained for anti-myosin-VIIa. Hair cells were counted, and it was determined that 4 µM cis was sufficient to cause a decrease in hair cell numbers and GC4419 dose as low as 2 µM protected against this biological endpoint. To assess the effects of GC4419 on hearing loss in vivo, CBA/CaJ mice were treated as follows: 5 mice (1 female, 4 males) received 3 mg/kg cis IP, 4 mice (2 males and 2 females) received vehicle, 3 mice (2 females, 1 males) received 10 mg/kg IP GC4419, and 5 mice (2 females, 3 males) were treated with GC4419 10 minutes prior to cisplatin injection. Cis and GC4419 were administered for four consecutive days followed by two days of GC4419. The animals were allowed 8 recovery days, with Normosol SQ and high calorie food administered, prior to a second repetition of the treatment cycle. This protocol for cis dosing was found to be lethal in three mice in the cisplatin only group. Auditory brainstem response testing was performed before and after treatment, revealing elevated hearing thresholds in cis treated mice but not in mice treated with GC4419 and cis. Additionally, the cis treatment group experienced greater weight loss than the mice treated with GC4419 and cis Separately, in an H1299 tumor xenograft model in nu/nu mice, GC4419 5 mg/kg IP BID over 14 days was shown not to interfere with, and in fact somewhat increased, the tumor growth delay with cis 5 mg/kg IP QW x 3.
 Conclusion: These results support the hypothesis that treatment with the SOD mimetic GC4419 can reduce cis induced ototoxicity by scavenging superoxide and justify further studies to determine if this mechanism based approach can be implemented in cancer therapy. (Supported by a sponsored research agreement between the University of Iowa and Galera Therapeutics, Inc.)
 Citation Format: Keegan A. Christensen, Osama Tarabichi, Sei Sho, Hidaly Hernández, Bryce Hunger, Melissa A. Fath, Jeffery Keene, Robert Beardsley, Marlan Hansen, Douglas R. Spitz. Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5062.

Marlan R. Hansen

Papers

Optically guided stereotactic radiotherapy for facial nerve paralysis secondary to occult malignant neoplasms.

Modular implant position manipulator system

Microtopographical Features Recruit RhoA/ROCK through TRPV1 Channels to Direct Cell and Neurite Growth:

522 Metabolomic Analysis of 54 Meningiomas Reveals Distinct Metabolite Profiles in WHO 1 and WHO 2/3 Tumors

Abstract 5062: Small molecule superoxide dismutase mimetic avasopasem manganese for the mitigation of cisplatin induced ototoxicity