NSAIDS Diclofenac and Ibuprofen Associated with Increased Risk of Cardiac Arrest

MedicalResearch.com Interview with:

Kathrine Bach Søndergaard MD, Research Fellow Gentofte University Hospital Department of Cardiology Hellerup

Dr. Søndergaard

Kathrine Bach Søndergaard MD, Research Fellow
Gentofte University Hospital
Department of Cardiology
Hellerup 

MedicalResearch.com: What is the background for this study?

Response: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used and have in previous studies been associated with an increased risk of cardiovascular adverse events, such as myocardial infarction and heart failure. Cardiac arrest is the ultimate adverse event; however, no research exists of the association between cardiac arrest and use of NSAIDs, which we aimed to assess in this study.

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NSAIDS Have Minimal Effect On Back Pain and Risk GI Side Effects

MedicalResearch.com Interview with:

Dr. Gustavo Machado BPhty (Hons) Cert.MDT The George Institute for Global Health Sydney Medical School, University of Sydney Sydney, New South Wales, Australia

Dr. Gustavo Machado

Dr. Gustavo Machado BPhty (Hons) Cert.MDT
The George Institute for Global Health
Sydney Medical School, University of Sydney
Sydney, New South Wales, Australia

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: People with back pain are usually told by their health care practitioners to take analgesic medications to relieve their pain. But our previous research published in the BMJ showed that paracetamol does not have a measurable impact on patient’s symptoms. This resulted in recent changes in guidelines’ recommendations. The 2017 National Institute for Health and Care Excellence (NICE) guidelines/UK no longer recommend paracetamol as a stand-alone intervention for back pain.

So now non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as the analgesic of first choice. However, our results show that compared to placebo, commonly used NSAIDs, such as Ibuprofen (e.g. Nurofen) and Diclofenac (e.g. Voltaren), provide only small benefits for people with back pain while increasing the risk of gastrointestinal adverse effects by 2.5 times.

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Study Reevaluates NSAIDS For PDA in Premature Infants

MedicalResearch.com Interview with:

Jonathan Slaughter, MD, MPH Assistant Professor of Pediatrics Center for Perinatal Research Nationwide Children's Hospital/The Ohio State University Columbus, OH 43205

Dr. Jonathan Slaughter

Jonathan Slaughter, MD, MPH
Assistant Professor of Pediatrics
Center for Perinatal Research
Nationwide Children’s Hospital/The Ohio State University
Columbus, OH 43205

MedicalResearch.com: What are the main findings?

Response: The ductus arteriosus, a fetal blood vessel that limits blood flow through the lungs, normally closes shortly after birth. However, the ductus often remains open in premature infants, leading to patent ductus arteriosus (PDA). Infants with PDA are more likely to die or develop bronchopulmonary dysplasia (BPD), the major chronic lung disease of preterm infants. Nonsteroidal Anti-inflammatory Drug (NSAID) treatment has been shown to close PDAs in preterm infants and NSAID treatment of PDA is common. However, it has never been shown that PDA closure with NSAIDs leads to decreased mortality or improved long-term respiratory outcomes. NSAID closure of PDA has become increasingly controversial in recent years since NSAID treatment has been associated with acute renal injury. Also, these medications are expensive, with the usual three-dose treatment course costing well over $1000 per patient. Due to these controversies, the likelihood of a preterm infant with PDA being treated with NSAIDs varies by clinician and institution and has decreased over time.
Meta-analyses of randomized trials that investigated NSAID (indomethacin and/or ibuprofen) treatment for PDA closure in preterm infants did not show a benefit. However, they were principally designed only to study whether the ductus itself closed following treatment and not to determine if there was an improvement in mortality risk or in respiratory outcomes following NSAID treatment.
Given the difficulty of conducting randomized trials in preterm infants and the urgent need for practicing clinician’s to know whether treatment of PDA in all preterm infants is beneficial, we used a study design that incorporated the naturally occurring practice variation in NSAID treatment for PDA as a mechanism to reduce the risk of biases that are commonly found in non-randomized investigations. This is based on the premise that if NSAID treatment for PDA in preterm infants is truly effective, we should expect to see improved mortality and respiratory outcomes in instances when clinician preference-based NSAID administration rates are higher.

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NSAIDS May Increase Mortality From Endometrial Cancer

MedicalResearch.com Interview with:

Theodore Brasky, PhD Research Assistant Professor Center of Excellence in Regulatory Tobacco Science Epidemiology College of Public Health The Ohio State University

Dr. Theodore Brasky

Theodore Brasky, PhD
The Ohio State University
Comprehensive Cancer Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There is a significant amount of data to suggest that long-term, regular use of nonsteroidal anti-inflammatory drugs (NSAIDS; examples include aspirin and ibuprofen) are associated with reduced risks of several cancers. Although the data across studies are inconsistent, one such candidate is endometrial cancer, which is the most common gynecologic cancer. There is good evidence that the use of these medications is associated with improved prognosis among patients diagnosed with colon cancer. Despite the importance of inflammation in endometrial cancer progression, very few have examined whether use of NSAIDs is associated with risk of death or recurrence from the disease. The study we published is the first of its kind to examine NSAID use comprehensively and in a study of over 4,000 patients.

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New Ibuprofen Formulation May Avoid Cardiac Side Effects

MedicalResearch.com Interview with:

Dr Nicholas Kirkby BHF Intermediate Fellow | Vascular Biology National Heart & Lung Institute | Imperial College London London

Dr Nicholas Kirkby

Dr Nicholas Kirkby
BHF Intermediate Fellow | Vascular Biology
National Heart & Lung Institute | Imperial College London
London

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We know drugs like ibuprofen, called ‘non-steroidal anti-inflammatory drugs’ cause an increase in the risk of heart attacks. These side effects cause very real concerns for the many millions of people who rely on them. They are also the reason why there are no new drugs in this class and why they have been withdrawn (2011) for use as a preventative treatment for colon cancer. Previous research from our group suggests that L-arginine supplements may prevent the cardiovascular side effects caused by these drugs. Our findings here suggest that a particular formulations of ibuprofen, called ibuprofen arginate, which is already available in many parts of the world, can act like an L-arginine supplement and that this could potentially protect the cardiovascular system.

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Can NSAIDs Prevent Some Basal Cell Skin Cancers?

Nirmala Pandeya, PhD Post Doctoral Research Fellow Faculty of Medicine and Biomedical Sciences, School of Public Health Herston campus The University of QueenslandMedicalResearch.com Interview with:
Nirmala Pandeya, PhD

Post Doctoral Research Fellow
Faculty of Medicine and Biomedical Sciences, School of Public Health
Herston campus The University of Queensland

Medical Research: What is the background for this study?

Dr. Pandeya: Basal cell carcinoma (BCC) is the most common cancer. Although BCC is curable and has low mortality, its high occurrence in the population causes significant healthcare and financial burdens to the community. Hence exploring preventive strategies for this cancer is important in reducing the burden. To date few chemopreventives for BCC have been identified.

In many cancer cells, inflammatory biomarkers such as cyclooxygenase-2 (COX-2) and its product prostaglandin E2 are increased and basal cell carcinoma is no exception. Anti-inflammatory drugs, suppressing COX-2 activity, have been shown to reduce the risk of various cancers including squamous cell carcinoma of the skin, so they also have a potential to prevent BCC. But to date research evidence on the benefit of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) on basal cell carcinoma has been inconsistent. So we reviewed and synthesized all published epidemiological studies on NSAIDs and BCC to combine results and estimate the overall pooled effect.

Medical Research: What are the main findings?

Dr. Pandeya: After thorough evaluation, we identified eleven studies that were relevant and pooling showed a 10% reduction in risk of BCC among those using any kind of NSAIDs. Aspirin and non-aspirin NSAIDs analysed separately suggested a reduced risk of basal cell carcinoma, but were not statistically significant likely due to lack of power. Our research found strongest risk reduction of BCC by the use of NSAIDs among those with either a history of skin cancers or high prevalence of actinic keratosis.

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NSAIDS Work For Menses Pain But Carry Risk of Side Effects

MedicalResearch.com Interview with:
Jane Marjoribanks
Obstetrics and Gynaecology
University of Auckland, National Women’s Hospital,
Auckland, New Zealand

MedicalResearch: What is the background for this study?

Response: This study is a systematic review of all randomised evidence published up to January 2015 on the effectiveness and safety of non-steroidal inflamatory drugs (NSAIDs) used to treat primary dysmenorrhoea (period pain). It includes 80 randomised controlled trials (total 5820 participants), which compare 20 different NSAIDs versus placebo, other NSAIDs or paracetamol.

The review was prepared by researchers from the Cochrane Collaboration, which is a global independent network of contributors (37,000 from more than 130 countries) who gather and summarize the best evidence from research to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest.

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Antidepressants Plus NSAIDS May Increase Risk of Bleeding in Brain

MedicalResearch.com Interview with:
Byung-Joo Park, MD, MPH, PhD
Professor
Department of Preventive Medicine
Seoul National University College of Medicine

Medical Research: What is the background for this study? What are the main findings?

Response: Antidepressants and NSAIDs are each thought to increase the risk of abnormal bleeding.  However, previous studies found neither antidepressants nor NSAIDs alone to be associated with an increased risk of intracranial haemorrhage.  Our research found that combined use of NSADIs in antidepressant users showed the increased relative risk of intracranial haemorrhage risk within the initial 30-days of combined use.

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NSAIDS May Be Helpful In Bladder Cancer Prevention

James Scheiman, M.D. Professor of Gastroenterology University of Michigan Medical SchoolMedicalResearch.com Interview with:
James Scheiman, M.D.
Professor of Gastroenterology
University of Michigan Medical School

Medical Research: What is the background for this study? What are the main findings?

Dr. Scheiman: Using aspirin or other nsaids to reduce the risk of many cancers has been an active area of investigation. This study demonstrates in an animal model that a commonly used nsaid (naproxen) reduces bladder tumor development, while the concomitant use of an acid blocking drug– which has been shown in many clinical studies to reduce the ulcers and bleeding associated with nsaids in humans – is also effective. Naproxen has been shown to reduce colon polyps and skin cancers in animal models as well, so this broad effect demonstrates a novel strategy to test in clinical trials.

Medical Research: What should clinicians and patients take away from your report?

Dr. Scheiman: The study shows that using two commonly used classes of drugs together (one which, the proton pump inhibitor, can mitigate the adverse GI side effects of the other without affecting the cancer-reducing effect) may have value to reduce the risk of a number of common cancers. This idea needs to be studied in a clinical trial.

Citation:

Ronald A. Lubet, James M. Scheiman, Ann Bode, Jonathan White, Lori Minasian, M. Margaret Juliana, Daniel L. Boring, Vernon E. Steele, and Clinton J. Grubbs. Prevention of Chemically Induced Urinary Bladder Cancers by Naproxen: Protocols to Reduce Gastric Toxicity in Humans Do Not Alter Preventive Efficacy. Cancer Prevention Research, March 2015 DOI: 10.1158/1940-6207.CAPR-14-0347

MedicalResearch.com Interview with: James Scheiman, M.D. (2015). NSAIDS May Be Helpful In Bladder Cancer Prevention 

NSAIDS After Heart Attack Increase Risk of Bleeding and Further Heart Attacks

MedicalResearch.com Interview with:
Anne-Marie Schjerning Olsen, MD, PhD Department of Cardiology Gentofte Hospital, University of Copenhagen DenmarkAnne-Marie Schjerning Olsen, MD, PhD
Department of Cardiology
Gentofte Hospital, University of Copenhagen
Denmark

MedicalResearch.com: What is the background for this study?

Dr. Olsen: The question addressed in the study was: Do people who have had a myocardial infarction (heart attack) and are who taking drugs (known as antithrombotics) to reduce their risk of further heart attacks have an increased risk of serious bleeding, especially gastrointestinal bleeding, and of further heart attacks if they also take painkillers known as non-steroidal anti-inflammatory drugs (NSAIDs)?

We found that taking NSAIDs, even for periods of under one week (3-4 days for bleeding), was associated with increased risks of both bleeding and of further heart attacks.

Background: People who have suffered a heart attack are prescribed medicines afterwards to reduce their risk of another one. The medicines usually include two ’antithrombotic drugs’ which make platelets in the blood less sticky – the two most commonly used drugs are aspirin and clopidogrel. A side effect of antithrombotic treatment is that the drugs increase bleeding risk.

Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation. They are very effective and are among the most widely used drugs in the world. Some NSAIDs can be bought across the counter without a prescription, for example, ibuprofen. NSAIDs have side effects too. All of them increase the risk of bleeding, especially gastro-intestinal bleeding arising from damage (ulcers) caused to the gut lining. Some NSAIDs, for example diclofenac, are also associated with a small increase in the risk of heart attack – this risk matters most for people already at risk of a heart attack. The medical advice is for these patients to avoid NSAIDs and for their doctors to avoid prescribing them if possible.

But pain is a common problem and very distressing for people – so in practice, NSAIDs are used quite often by patients who have had a heart attack. If NSAIDs are to be taken by heart attack patients, then it is important that both they and their doctors know the risks so that they can weigh up the benefits and downsides and make an informed decision.

What this study did: This was a cohort study that included everyone in Denmark aged 30 years or older who had had a first heart attack and who was taking antithrombotic medicines. Using hospital and dispensing registries, we examined patients who had suffered serious bleeding (causing admission to hospital and/or death) or who had another heart attack or cardiac event to see if they had been prescribed NSAIDs or not.

Dr. Olsen: The study findings: In this study of over 60,000 patients in Denmark taking antithrombotic medicines, one third of them had at least one prescription for NSAIDs, commonly ibuprofen or diclofenac, dispensed over a median study time of 3.5 years. In the same period, 8.5% (5,288 patients or 1 in 12 of the study group) had a gastrointestinal bleed (of whom 799 or 15% died) and 30% (18,568; 1 in 3) had a new cardiac event, mostly heart attack. While these events happened to patients who were prescribed NSAIDs and also to patients were not prescribed NSAIDs, we found that the risk of bleeding was doubled when patients were taking NSAIDs compared with not taking them. The risk occurred within 3 days of starting a NSAID. The risk of a cardiac event (mainly heart attack) was increased by 40% when taking NSAIDs compared with not taking them and also occurred within days of starting a NSAID.

In other words, the NSAIDs appeared 1) to increase the bleeding risk already existing with antithrombotics and 2) to diminish the cardiac protection that antithrombotics provided.

Limitations: This is just one study, although it is a big one. It was a ’real-life’ observational study not a randomised controlled clinical trial. More studies are needed to confirm what we have found.

MedicalResearch:  Why is this important information for patients and doctors to know?

Dr. Olsen: NSAIDs were used a lot by the patients in this study – pain is a common problem and can cause great suffering. There has been a tendency to think that short-term use of NSAIDs is safe – our study suggests this in not the case and that even a few days of use is associated with increased risks of both bleeding and cardiac events, mainly heart attacks. People may be happy to take these risks to have relief from pain but it is very important that they aware of the risks and can make an informed decision about taking NSAIDs for pain relief.

Citation:

Schjerning Olsen A, Gislason GH, McGettigan P, et al. Association of NSAID Use With Risk of Bleeding and Cardiovascular Events in Patients Receiving Antithrombotic Therapy After Myocardial Infarction. JAMA. 2015;313(8):805-814. doi:10.1001/jama.2015.0809.

Anne-Marie Schjerning Olsen, MD, PhD Department of Cardiology (2015). NSAIDS After Heart Attack Increase Risk of Bleeding and Further Heart Attacks 

NSAIDS May Prevent Some Squamous Cell Skin Cancers

Dr Catherine Olsen  |  Senior Research Officer QIMR Berghofer Medical Research Institute Royal Brisbane Hospital, QLD 4029MedicalResearch.com Interview with:
Dr Catherine Olsen  |  Senior Research Officer
QIMR Berghofer Medical Research Institute
Royal Brisbane Hospital, QLD 4029

Medical Research: What is the background for this study? What are the main findings?

Response: Squamous cell carcinomas (SCCs)are the second most common skin cancer occurring in white skinned populations. They cause significant morbidity as they can invade local structures (often the nose or ears) and they also have the potential to metastasize although most are successfully treated before any spread occurs. They are also very expensive cancers to treat because they are so common, posing a significant burden on health care budgets. NSAIDS have been shown to be protective for other cancers (e.g. colorectal and oesophageal cancer). This prompted use to evaluate all of the available evidence on NSAIDs use and SCC by conducting a systematic review and meta-analysis of the association.
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Supplement May Reduce Cardiovascular Risks Linked to NSAIDS

MedicalResearch.com Interview with:
Dr. Jane A. Mitchell
National Heart and Lung Institute
Imperial College, London, UK

Medical Research: What is the background for this study? What are the main findings?

Dr. Mitchell: Anti-inflammatory drugs (NSAIDs) work by inhibiting the enzyme COX-2. COX-2 selective anti-inflammatory drugs, like Vioxx, were introduced to reduce gastrointestinal side effects associated with these drugs. However, COX-2 inhibitors as well as most older NSAIDs are associated with increased risk of heart attacks although the precise mechanisms underlying these side effects are not completely understood.

The main findings of this study are:

1) COX-2 is highly expressed in the kidney where its genetic deletion leads to changes in more than 1000 genes.

2) Analysis of these genes revealed changes in 2-3 specific genes that regulate levels of ADMA, an endogenous inhibitor of the nitric oxide released by vessels, that can be reversed by giving more of the substrate for NO, L-arginine.

3) Further studies showed that ADMA was indeed increased in the plasma of mice where COX-2 gene was knocked out or in normal mice given a COX-2 inhibitor.

4) In mice where COX-2 was knocked out the release of nitric oxide from vessels was reduced and this could be reversed by supply L-arginine.

5) ADMA was also increased in human volunteers taking a COX-2 inhibitor

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NSAIDS May Increase Risk of Venous Thromboembolism

Patompong Ungprasert, MD Division of Rheumatology Mayo Clinic, MN
MedicalResearch.com Interview with:

Patompong Ungprasert, MD
Division of Rheumatology
Mayo Clinic, MN

Medical Research: What are the main findings of the study?

Dr. Ungprasert: We find a statistically significant association between NSAIDs (non-steroidal anti-inflammatory drugs) use and VTE (venous thromboembolism).
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Regular Use of Some NSAIDs May Increase Adverse Cardiovascular Events.

Anthony Bavry, MD MPH Interventional Cardiology, North Florida/South Georgia Veterans Health System Associate Professor of Medicine, University of Florida Gainesville, FL 32610MedicalResearch.com Interview with:
Anthony Bavry, MD MPH
Interventional Cardiology, North Florida/South Georgia Veterans Health System
Associate Professor of Medicine, University of Florida
Gainesville, FL 32610

Medical Research: What are the main findings of the study?
Dr. Bavry:
1) Among post-menopausal women, the regular use of NSAIDs was associated with an increased risk of cardiovascular death, myocardial infarction, or stroke.
2) Cardiovascular risk was observed among users of celecoxib, naproxen, but not ibuprofen.
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NSAIDS Associated with Atrial Fibrillation

 Bruno Stricker, MB PhD Professor of Pharmaco-epidemiology Professor of Pharmacoepidemiology Erasmus MCMedicalResearch.com Interview with:
Bruno Stricker, MB PhD
Professor of Pharmaco-epidemiology
Professor of Pharmacoepidemiology
Erasmus MC


MedicalResearch.com: What are the main findings of the study?

Dr. Stricker: NSAIDs/painkillers may cause atrial fibrillation.

MedicalResearch.com: What should patients and provider take away from this study?

Dr. Stricker:

  1. Atrial fibrillation is the main risk factor of stroke.
  2. Patients with cardiovascular disease should be careful with NSAIDs

Citation:

 

NSAIDS and Risk of Miscarriage

MedicalResearch.com Interview with:
Dr. Sharon Daniel MD, MPH
Physician, Intern in pediatrics at Soroka Medical Center, Beer-Sheva, Israel
PhD Candidate
and
Prof. Amalia Levy (MPH, PhD
Epidemiologist, Head of the Department of Public Health
Principle Investigator.
Ben-Gurion University of the Negev in Beer-Sheva, Israel,

MedicalResearch.com: What are the main findings of the study?

Answer: We tested the risk for miscarriage following the use of NSAIDs (ibuprofen, diclofenac, naproxen, indomethacin, etodolac) on the first trimester of pregnancy. We did not find increased risk among women who took those drugs during the first trimester of pregnancy, although we did find increased risk after the use of indomethacin. We found higher risk after the use of specific NSAIDs (Celecoxib, Rofecoxib, Etoricoxib) which are usually used to treat inflammatory diseases, only the exposure group was very small.
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Report: NSAIDS reduce the severity of postpartum breast cancers in animal models

Published online on Aug. 7, 2011, the journal Nature Medicine reports that non-steroidal anti-inflammatory drugs including ibuprofen reduce the severity of postpartum breast cancers in animal models. “We caution patients and providers that because a mother’s body is undergoing radical changes during this time, we can’t yet speak to the safety of these drugs for women diagnosed with or at risk for postpartum breast cancer, and thus can’t yet recommend NSAIDs as a preventative therapy or cancer treatment,” says Pepper Schedin, PhD, investigator at the University of Colorado Cancer Center and professor in the division of medical oncology at the University of Colorado School of Medicine, who teamed up on this study with Virginia Borges, MD, an expert in young women’s breast cancer who is also at the Cancer Center. First authors of this important paper are University of Colorado trainees, Drs. Traci Lyons and Jenean O’Brien.

The story starts with breast involution – the process by which milk-producing cells that are no longer needed are killed and replaced with fat cells. During this time of change, the breast is especially susceptible to the development of cancer. In fact, recent studies show that women who have children before age 30 increase their risk of pre-menopausal breast cancer by 10% and women who wait to have children until after age 35 increase their risk by 30%. Not only is breast cancer more prevalent in young mothers than women who have not had a child, but cancers diagnosed in the early years postpartum tend to be more aggressive, with increased risk of spreading to other organs.  For example, one study reported that women diagnosed with cancer within two years of giving birth had a 40% five-year survival rate, as opposed to a 70% five-year survival rate for women diagnosed outside the postpartum window.

What this University of Colorado research team discovered is that breast involution shares similarities with wounds, and wounds can cause cells to become cancerous in addition to promoting metastasis of otherwise localized tumor cells. Two wound-like changes that occur in the postpartum breast are an increase in fibrous collagen (the protein that gives our flesh structure) and increase of an enzyme called COX-2.

In addition to causing inflammation and pain, COX-2 aids the formation of fibrous collagen, which in the process of wound healing serves as a highway along which healthy skin cells travel in order to close the wound. However, this collagen also forms a rich architecture for the growth and spread of cancers. In short, breast involution leads to COX-2, which leads to fibrous collagen, which promotes the release of more COX-2, and this positive feedback loop can help a tumor grow and push into other tissues.

It’s a vicious chain, but one with a weak link: many drugs exist that inhibit COX-2. These include the non-steroidal anti-inflammatories (NSAIDs), such as ibuprofen, or celecoxib, which is a more targeted COX-2 inhibitor used in other inflammatory diseases like arthritis. “Inhibition of COX-2 slows the formation of fibrillar collagen and thus both tumor growth and the tumor’s travel into the lung,” write Schedin and collaborators. Sure enough, Schedin and the research team found that in postpartum mice, ibuprofen and celecoxib treatment reduced mammary tumor size, collagen architecture, COX-2 expression, and breast tumor cell spreading into the lung.

However, recommending ibuprofen for women undergoing breast involution is premature.  Schedin and Borges point out that early studies of vitamin A in lung cancer and vitamin E in prostate cancer at first found the vitamins to be cancer-fighting but eventually showed them to be cancer-promoting. “It becomes a numbers game,” says Borges, “with the benefit of the drug weighed against its dangers. It seems as if the safety of these drugs is self-evident, but it’s only because we don’t fully understand the effects of NSAIDs during this unique period of a woman’s life, when her body is undergoing dramatic changes. So it becomes very important to study the effects of NSAID treatment in this particular group of women before we can make any prevention recommendations.”

This is about the fifth step down an extremely promising path toward identifying a simple, inexpensive, effective treatment of postpartum breast cancers. But there are many steps still to go.

 —

Supported by Department of Defense Synergistic Idea Award #BC060531, Komen Foundation #KG090629, Mary Kay Ash Foundation #078-08 and University of Colorado Cancer Center grants to PS and VB, Department of Defense Award #BC074970 to PJK, American Cancer Society New England Division Postdoctoral Fellowship Spin Odyssey #PF-08-257-01-CSM to TRL, Department of Defense Postdoctoral grant BC087579 to AM, and Department of Defense Predoctoral Grant #BC073482 to JO.