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Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

Posted in Bio Instrumentation in Experimental Life Sciences Research, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Curation, Diabetes Mellitus, FDA Regulatory Affairs, Health Economics and Outcomes Research, Healthcare costs and reimbursement, HealthCare IT, Interviews with Scientific Leaders, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Medical Device Therapies for Altzheimer’s Disease, Medical Devices R&D Investment, Personal Health Applications: Tech Innovations serves HealhCare, Translational Effectiveness, tagged #mhealth, #mobilehealth, Cancer - General, cancer patient management, Chemotherapy, compliance issues, Conditions and Diseases, health, Health Information Technology, HIIPA compliance, mobile applications, oncology, oral chemotherapy, patient adherence on June 17, 2014| Leave a Comment »

Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification.

Reporter: Stephen J. Williams, PhD

Article ID #144: Can Mobile Health Apps Improve Oral-Chemotherapy Adherence? The Benefit of Gamification. Published on 6/17/2014

WordCloud Image Produced by Adam Tubman

A report on how gamification mobile applications, like CyberDoctor’s PatientPartner, may improve patient adherence to oral chemotherapy.

(includes interviews with CyberDoctor’s CEO Akhila Satish and various oncologists)

 

Writer/Curator: Stephen J. Williams, Ph.D.

UPDATE 5/15/2019

Please see below for an UPDATE on this post including results from the poll conducted here on the value of a gamification strategy for oral chemotherapy patient adherence as well as a paper describing a well designed development of an application specifically to address this clinical problem.

Studies have pointed to a growing need to monitor and improve medical adherence, especially with outpatient prescription drugs across many diseases, including cancer.

The trend to develop oral chemotherapies, so patients can take their medications in the convenience of their home, has introduced produced a unique problem concerning cancer patient-medication adherence. Traditionally, chemotherapies were administered by a parental (for example intravenous) route by clinic staff, however, as noted by Jennifer M Gangloff in her article Troubling Trend: Medication Adherence:

 

with the trend of cancer patients taking their oral medication at home, the burden of adherence has shifted from clinicians to the patients and their families.

 

A few highlights from Jennifer Gangloff’s article highlight the degree and scope of the problem:

 

1. There is a wide range of adherence for oral chemo– as low as 16% up to 100% adherence rates have been seen in multiple studies
2. High cost in lives and money: estimates in US of 125,000 deaths and $300 billion in healthcare costs due to nonadherence to oral anticancer medications
3. Factors not related to the patient can contribute to nonadherence including lack of information provided by the healthcare system and socioeconomic factors
4. Numerous methods to improve adherence issues (hospital informative seminars, talking pill bottles, reminder phone calls etc.) have met with mixed results.

 

A review by Steve D`Amato of published literature also highlights the extent of problems with highly variable adherence rates including

• 17-27% for hematologic malignancies
• 53-98% for breast cancer
• 97% for ovarian cancer

More strikingly, patient adherence rates can drastically decline over treatment, with one study showing an adherence rate drop from 87% to 50% over 4 years of adjuvant tamoxifen therapy.

 

Tackling The Oral Chemotherapy-Patient Adherence Problem

 

Documented factors leading to non-adherence to oral oncology medications include

1. Patient feels better so stop taking the drug
2. Patient feels worse so stops taking the drug
3. Confusing and complicated dosing regimen
4. Inability to afford medications
5. Poor provider-patient relationships
6. Adverse effects of medication
7. Cognitive impairment (“chemo fog”; mental impairment due to chemotherapy
8. Inadequate education/instruction of discharge

There are many examples of each reason why a patient stopped taking medication. One patient was prescribed capecitabine for her metastatic breast cancer and, upon feeling nausea, started to use antacids, which precipitated toxicities as a result of increased plasma levels of capecitabine.

In a white paper entitled Oral Oncology Treatment Regimens and the Role of Medication Therapy Management on Patient Adherence and Compliance, David Reese, Vice President Oncology at Tx Care Advantage discus how Medication Therapy Management (MTM) programs could intervene to improve medical adherence in both the oncology and non-oncology setting.

This review also documented the difficulties in accurately measuring patient adherence including:

• Inaccuracy of self-reporting
• Lack of applicability of external measurements such as pill counts
• Hawthorne effect: i.e. patient pill documentation reminds them to take next dose

The group suggests that using MTM programs, especially telephony systems involving oncology nurses and pharmacists and utilizing:

• Therapy support (dosing reminders)
• Education
• Side effect management

 

may be a cost-efficient methodology to improve medical adherence.

 

Although nurses are important intermediary educating patients about their oral chemotherapies, it does not appear that solely relying on nurses to monitor patient adherence will be sufficient, as indicated in a survey-based Japanese study.

As reported in May 12, 2014 | Oncology Nursing By Leah Lawrence

 

Systematic Nurse Involvement Key as Oral Chemotherapy Use Grows– at: http://www.cancernetwork.com/oncology-nursing/systematic-nurse-involvement-key-oral-chemotherapy-use-grows

 

Survey results indicated that 90% of nurses reported asking patients on oral chemotherapy about emergency contacts, side effects, and family/friend support. Nurses also provided patients with education materials on their assigned medication.

However, less than one-third of nurses asked if their patients felt confident about managing their oral chemotherapy.

“Nurses were less likely to ask adherence-related questions of patients with refilled prescriptions than of new patients,” the researchers wrote. “Regarding unused doses of anticancer agents, 35.5% of nurses reported that they did not confirm the number of unused doses when patients had refilled prescriptions.”

From the Roswell Park Cancer Institute blog post Making Mobile Health Work

https://www.roswellpark.org/partners-practice/white-papers/making-mobile-health-work

US physicians are recognizing the need for the adoption of mobile in their practice but choice of apps and mobile strategies must be carefully examined before implementation. In addition, most physicians are using mobile communications as a free-complementary service and these physicians are not being reimbursed for their time.

 

Some companies are providing their own oncology-related mobile app services:

CollabRx Announces Oncology-Specific Mobile App with Leading Site for Healthcare Professionals, MedPage Today

(http://www.collabrx.com/collabrx-announces-oncology-specific-mobile-app-with-leading-site-for-healthcare-professionals-medpage-today/)

San Francisco, August 13, 2013 – CollabRx, Inc. (NASDAQ: CLRX), a healthcare information technology company focused on informing clinical decision making in molecular medicine, today announced a multi-year agreement with Everyday Health’s MedPage Today. The forthcoming app, which will target oncologists and pathologists, will focus on the molecular aspects of laboratory testing and therapy development. Over time, the expectation is that this app will serve as a comprehensive point of care resource for physicians and patients to obtain highly credible, expert-vetted and dynamically updated information to guide cancer treatment planning.

The McKesson Foundation’s Mobilizing for Health initiative

has awarded a grant to Partners HealthCare’s Center for Connected Health to develop a mobile health program that uses a smartphone application to help patients with cancer adhere to oral chemotherapy treatments and monitor their symptoms, FierceMobileHealthcare reports.

 

CancerNet announces mobile application (from cancer.net)

http://www.cancer.net/navigating-cancer-care/managing-your-care/mobile-applications

 

However, there is little evidence that the plethora of cancer-based apps is providing any benefit with regard to patient outcome or adherence, as reported in to an article in the Journal of Medical Internet Research, reported at FierceMobileHealthcare (Read more: Cancer smartphone apps for consumers lack effectiveness – FierceMobileHealthcare http://www.fiercemobilehealthcare.com/story/cancer-smartphone-apps-consumers-lack-effectiveness/2013-12-26#ixzz34ucdxVcU )

The report suggests that there are too many apps either offering information, suggesting behavior/lifestyle changes, or measuring compliance data but little evidence to suggest any of these are working the way they intended. The article suggests the plethora of apps may just be adding to the confusion.

Johnson&Johnson’s Wellness & Prevention unit has launched a health-tracking app Track Your Health. Although the company considers it a “gamification“ app, Track Your Health© operates to either feed data from other health tracking apps or allow the user to manually input data.
Read more: J&J launches ‘quantified self’ app to game patients into better behavior – FiercePharmaMarketing http://www.fiercepharmamarketing.com/story/jj-launches-quantified-self-app-game-patients-better-behavior/2014-05-28#ixzz34uhFDJr2

Even ASCO has a list of some oncology-related apps (http://connection.asco.org/commentary/article/id/3123/favorite-hematology-oncology-apps.aspx) and

NIH is offering grants for oncology-related app development (https://www.linkedin.com/groupItem?view=&gid=72923&type=member&item=5870221695683424259&qid=dbf53031-dd21-443c-9152-fad87f85d200&trk=groups_most_popular-0-b-ttl&goback=.gmp_72923)
As reports and clinicians have stated, we need health outcome data and clinical trials to determine the effective of these apps.

MyCyberDoctor™, a True Gamification App, Shows Great Results in Improving Diabetics Medical Adherence and Health Outcome

 

Most of the mobile health apps discussed above, would be classified as tracking apps, because the applications simply record a patient’s actions, whether filling a prescription, interacting with a doctor, nurse, pharmacist, or going to a website to gain information. However, as discussed before, there is no hard evidence this is really impacting health outcomes.

 

Another type of application, termed gamification apps, rely on role-playing by the patient to affect patient learning and ultimately behavior.

An interested twist on this method was designed by Akhila Satish, CEO and developer of CyberDoctor and a complementary application PatientPartner.

 

 

Ms. Akhila Satish, CEO CyberDoctor

 

 

 

 

 

 

 

Please watch video of interview with Akhila Satish, CEO of CyberDoctor at the Health 2.0 conference http://vimeo.com/51695558

 

And a video of the results of the PatientPartner clinical trial here: http://vimeo.com/79537738

 

As reported here, the PatientPartner application was used in the first IRB-approved mhealth clinical-trial to see if the gamification app could improve medical adherence and outcomes in diabetic patients. PatientPartner is a story-driven game in changing health behavior and biomarkers (blood glucose levels in this trial). In the clinical trial, 100 non-adherent patients with diabetes played the PatientPartner game for 15 minutes. Results were amazing, as the trial demonstrated an increase in patient adherence, with only 15 minutes of game playing.

Results from the study

Patients with diabetes who used PatientPartner showed significant improvement in three key areas – medication, diet, and exercise:

• Medication adherence increased by 37%, from 58% to 95% – equivalent to three additional days of medication adherence per week.
• Diet adherence increased by 24% – equivalent to two days of additional adherence a week.
• Exercise adherence increased by 14% – equivalent to one additional day of adherence per week.
• HbA1c (a blood sugar measure) decreased from 10.7% to 9.7%.

As mentioned in the article:

The unique, universal, non-disease specific approach allows PatientPartner to be effective in improving adherence in all patient populations.

PatientPartner is available in the iTunes store and works on the iPhone and iPod Touch. For information on PatientPartner, visit www.mypatientpartner.com.

Ms. Satish, who was named one of the top female CEO’s at the Health Conference, gratuitously offered to answer a few questions for Leaders in Pharmaceutical Business Intelligence (LPBI) on the feasibility of using such a game (role-playing) application to improve medical adherence in the oncology field.

LPBI: The results you had obtained with patient-compliance in the area of diabetes are compelling and the clinical trial well-designed.  In the oncology field, due to the increase in use of oral chemotherapeutics, patient-compliance has become a huge issue. Other than diabetes, are there plans for MyCyberDoctor and PatientPartner to be used in other therapeutic areas to assist with patient-compliance and patient-physician relations?

Ms. Satish: Absolutely! We tested the application in diabetes because we wanted to measure adherence from an objective blood marker (hbA1c). However, the method behind PatientPartner- teaching patients how to make healthy choices- is universal and applicable across therapeutic areas. 

LPBI: Recently, there have been a plethora of apps developed which claim to impact patient-compliance and provide information. Some of these apps have been niche (for example only providing prescription information but tied to pharmacy records and company databases). Your app seems to be the only one with robust clinical data behind it and approaches from a different angle, namely adjusting behavior using a gamefying experience and teaching the patient the importance of compliance. How do you feel this approach geared more toward patient education sets PatientPartner apart from other compliance-based apps?

Ms. Satish: PatientPartner really focuses on the how of patient decision making, rather than the specifics of each decision that is made. It’s a unique approach, and part of the reason PatientPartner works so effectively with such a short initial intervention! We are able to achieve more with less “app” time as a result of this method.  

LPBI: There have been multiple studies attempting to correlate patient adherence, decision-making, and health outcome to socioeconomic status. In some circumstances there is a socioeconomic correlation while other cases such as patient-decision to undergo genetic testing or compliance to breast cancer treatment in rural areas, level of patient education may play a bigger role. Do you have data from your diabetes trial which would suggest any differences in patient adherence, outcome to any socioeconomic status? Do you feel use of PatientPartner would break any socioeconomic barriers to full patient adherence?

Ms. Satish: Within our trial, we had several different clinical sites. This helped us test the product out in a broad, socioeconomically diverse population. It is our hope that with a tool as easy to scale and use as PatientPartner we have the opportunity to see the product used widely, even in populations that are traditionally harder to reach.  

LPBI: There has been a big push for the development of individual, personalized physician networks which use the internet as the primary point of contact between a primary physician and the patient. Individuals may sign up to these networks bypassing the traditional insurance-based networks. How would your application assist in these types of personalized networks?

Ms. Satish: PatientPartner can easily be plugged into any existing framework of communication between patient and provider. We facilitate patient awareness, engagement and accountability- all of which are important regardless of the network structure.

LBPI: Thank you Akhila!

A debate has begun about regulating mobile health applications, and although will be another post, I would just like to summarize a nice article in May, 2014 Oncology Times by Sarah Digiulo “Mobile Health Apps: Should They be Regulated?

In general, in the US there are HIPAA regulations about the dissemination of health related information between a patient and physician. Most of the concerns are related to personal health information made public in an open-access platform such as Twitter or Facebook.

In addition, according to Dr. Don Dizon M.D., Director of the Oncology Sexual Health Clinic at Massachusetts General Hospital, it may be more difficult to design applications directed against a vast, complex disease like cancer with its multiple subtypes than for diabetes.

 

Mobile Health Applications on Rise in Developing World: Worldwide Opportunity

 

According to International Telecommunication Union (ITU) statistics, world-wide mobile phone use has expanded tremendously in the past 5 years, reaching almost 6 billion subscriptions. By the end of this year it is estimated that over 95% of the world’s population will have access to mobile phones/devices, including smartphones.

This presents a tremendous and cost-effective opportunity in developing countries, and especially rural areas, for physicians to reach patients using mHealth platforms.

Drs. Clara Aranda-Jan Neo Mohutsiwa and Svetla Loukanova had conducted a systematic review of the literature on mHealth projects conducted in Africa[1] to assess the reliability of mobile phone and applications to assist in patient-physician relationships and health outcomes. The authors reviewed forty four studies on mHealth projects in Africa, determining their:

• strengths
• weaknesses
• opportunities
• threats

to patient outcomes using these mHealth projects. In general, the authors found that mHealth projects were beneficial for health-related outcomes and their success related to

• accessibility
• acceptance and low-cost
• adaptation to local culture
• government involvement

while threats to such projects could include

• lack of funding
• unreliable infrastructure
• unclear healthcare system responsibilities

Dr.Sreedhar Tirunagari, an oncologist in India, agrees that mHealth, especially gamification applications could greatly foster better patient education and adherencealthough he notes that mHealth applications are not really used in India and may not be of much use for those oncology patients living in rural areas, as  cell phone use is not as prevalent as in the bigger inner cities such as Delhi and Calcutta.

 

Dr. Louis Bretes, an oncologist from Portugal, when asked

1) do you see a use for such apps which either track drug compliance or use gamification systems to teach patients the importance of continuing their full schedule of drug therapy

2) do you feel patient- drug compliance issues in the oncology practice is due to lack of information available to the patient or issues related to drug side effects?

“I think that Apps could help in this setting, we are in
Informatics era but..
The main question is that chronic patients are special ones.
Cancer patients have to deal with prognosis, even in therapies
with curative intent such as aromatase inhibitors are potent
Drugs that can cure; only in the future the patients know.
But meanwhile he or she has to deal with side-effects every day. A PC can help but suffer this symptoms…it. Is a real problem believe me!”

“The main app is his/her doctor”

I would like to invite all oncologists to answer the poll question ABOVE about the use of such gamification apps, like PatientPartner, for improving medical adherence to oral chemotherapy.

UPDATE 5/15/2019

The results of the above poll, although limited, revealed some interesting insights.  Although only five oncologists answered the poll whether they felt gamification applications could help with oral chemotherapy patient adherence, all agreed it would be worthwhile to develop apps based on gamification to assist in the outpatient setting.  In addition, one oncologist felt that the success of mobile patient adherence application would depend on the type of cancer.  None of the oncologist who answered the survey thought that gamification apps would have no positive effect on patient adherence to their chemotherapy.  With this in light, a recent paper by Joel Fishbein of University of Colorado and Joseph Greer from Massachusetts General Hospital, describes the development of a mobile application, in clinical trial, to promote patient adherence to their oral chemotherapy.

 

Mobile Applications to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development

 

Mobile Application to Promote Adherence to Oral Chemotherapy and Symptom Management: A Protocol for Design and Development. Fishbein JN, Nisotel LE, MacDonald JJ, Amoyal Pensak N, Jacobs JM, Flanagan C, Jethwani K Greer JA. JMIR Res Protoc. 2017 Apr 20;6(4):e62. doi: 10.2196/resprot.6198. 

 

Abstract 

BACKGROUND:

Oral chemotherapy is increasingly used in place of traditional intravenous chemotherapy to treat patients with cancer. While oral chemotherapy includes benefits such as ease of administration, convenience, and minimization of invasive infusions, patients receive less oversight, support, and symptom monitoring from clinicians. Additionally, adherence is a well-documented challenge for patients with cancer prescribed oral chemotherapy regimens. With the ever-growing presence of smartphones and potential for efficacious behavioral intervention technology, we created a mobile health intervention for medication and symptom management.

OBJECTIVE:

The objective of this study was to develop and evaluate the usability and acceptability of a smartphone app to support adherence to oral chemotherapy and symptom management in patients with cancer.

METHODS:

We used a 5-step development model to create a comprehensive mobile app with theoretically informed content. The research and technical development team worked together to develop and iteratively test the app. In addition to the research team, key stakeholders including patients and family members, oncology clinicians, health care representatives, and practice administrators contributed to the content refinement of the intervention. Patient and family members also participated in alpha and beta testing of the final prototype to assess usability and acceptability before we began the randomized controlled trial.

RESULTS:

We incorporated app components based on the stakeholder feedback we received in focus groups and alpha and beta testing. App components included medication reminders, self-reporting of medication adherence and symptoms, an education library including nutritional information, Fitbit integration, social networking resources, and individually tailored symptom management feedback. We are conducting a randomized controlled trial to determine the effectiveness of the app in improving adherence to oral chemotherapy, quality of life, and burden of symptoms and side effects. At every stage in this trial, we are engaging stakeholders to solicit feedback on our progress and next steps.

CONCLUSIONS:

To our knowledge, we are the first to describe the development of an app designed for people taking oral chemotherapy. The app addresses many concerns with oral chemotherapy, such as medication adherence and symptom management. Soliciting feedback from stakeholders with broad perspectives and expertise ensured that the app was acceptable and potentially beneficial for patients, caregivers, and clinicians. In our development process, we instantiated 7 of the 8 best practices proposed in a recent review of mobile health app development. Our process demonstrated the importance of effective communication between research groups and technical teams, as well as meticulous planning of technical specifications before development begins. Future efforts should consider incorporating other proven strategies in software, such as gamification, to bolster the impact of mobile health apps. Forthcoming results from our randomized controlled trial will provide key data on the effectiveness of this app in improving medication adherence and symptom management.

TRIAL REGISTRATION:

ClinicalTrials.gov NCT02157519; https://clinicaltrials.gov/ct2/show/NCT02157519 (Archived by WebCite at http://www.webcitation.org/6prj3xfKA).

In this paper, Fishbein et al. describe the  methodology of the developoment of a mobile application to promote oral chemotherapy adherence.   This mobile app intervention was named CORA or ChemOtheRapy Assistant.

Of the approximately 325,000 health related apps on the market (as of 2017), the US Food and Drug Administration (FDA) have only reviewed approximately 20 per year and as of 2016 cleared only about 36 health related apps.

According to industry estimates, 500 million smartphone users worldwide will be using a health care application by 2015, and by 2018, 50 percent of the more than 3.4 billion smartphone and tablet users will have downloaded mobile health applications.  However, there is not much scientific literature providing a framework for design and creation of quality health related mobile applications.

Methods

The investigators separated the app development into two phases: Phase 1 consisted of the mobile application development process and initial results of alpha and beta testing to determine acceptability among the major stakeholders including patients, caregivers, oncologists, nurses, pharmacists, pharmacologists, health payers, and patient advocates.  Phase 1 methodology and results were the main focus of this paper.  Phase 2 consists of an ongoing clinical trial to determine efficacy and reliability of the application in a larger number of patients at different treatment sites and among differing tumor types.

The 5 step development process in phase 1 consisted of identifying features, content, and functionality of a mobile app in an iterative process, including expert collaboration and theoretical framework to guide initial development.

There were two distinct teams: a research team and a technical team. The multidisciplinary research team consisted of the principal investigator, co-investigators (experts in oncology, psychology and psychiatry), a project director, and 3 research assistants.

The technical team consisted of programmers and project managers at Partners HealthCare Connected Health.  Stakeholders served as expert consultants including oncologists, health care representatives, practice administrators, patients, and family members (care givers).  All were given questionaires (HIPAA compliant) and all involved in alpha and beta testing of the product.

There were 5 steps in the development process

1. Implementing a theoretical framework: Patients and their family caregivers now bear the primary responsibility for their medical adherence especially to oral chemotherapy which is now more frequently administered in the home setting not in the clinical setting.  Four factors were identified as the most important barriers to oral chemotherapy adherence: complexity of medication regimes, symptom burden, poor self-management of side effects, and low clinical support.  These four factors were integral in the design of the mobile app and made up a conceptual framework in its design.

1. Conducting Initial Focus Group Interviews with key stakeholders: Stakeholders were taken from within and outside the local community.  In all 32 stakeholders served as study collaborators including 8 patient/families, 8 oncologists/clinicians, 8 cancer practice administrators, and 8 representatives of the health system, community, and overall society.   The goal of these focus groups were to obtain feedback on the proposed study and design included perceived importance of monitoring of adherence to oral chemotherapy, barriers to communication between patients and oncology teams regarding side effects and medication adherence, potential role of mobile apps to address barriers of quality of cancer care, potential feasibility, acceptability, and usage and feedback on the overall study design.

1. Creation of Wireframes (like storyboards or page designs) and Collecting Initial Feedback:  The research and design team, in conjunction with stakeholder input, created content wireframes, or screen blueprints) to provide a visual guide as to what the app would look like.  These wireframes also served as basis for what the patient interviews would look like on the application.  A total of 10 MGH (Massachusetts General Hospital) patients (6 female, 4 male) and most with higher education (BS or higher) participated in the interviews and design of wireframes.  Eight MGH clinicians participated in this phase of wireframe design.

1. Developing, Programming, and Refining the App:  CORA was designed to be supported by PHP/MySQL databases and run on LAMP hosts (Linux, Apache, MySQL, Perl/PHP/Python) and fully HIPAA compliant.  Alpha testing was conducted with various stakeholders and the app refined by the development team (technical team) after feedback.

1. Final beta testing and App prototype for clinical trial: The research team considered the first 5 participants enrolled in the subsequent clinical trial for finalization of the app prototype.

There were 7 updated versions of the app during the initial clinical trial phase and 4 updates addressed technical issues related to smartphone operating system upgrades.

Finally, the investigators list a few limitations in their design and study of this application.  First the patient population was homogenous as all were from an academic hospital setting.   Second most of the patients were of Caucasian ethnic background and most were highly educated, all of which may introduce study bias.  In addition, CORA was available on smartphone and tablet only, so a larger patient population who either have no access to these devices or are not technically savvy may experience issues related to this limitation.

In addition other articles on this site related to Mobile Health applications and Health Outcomes include

Medical Applications and FDA regulation of Sensor-enabled Mobile Devices: Apple and the Digital Health Devices Market

How Social Media, Mobile Are Playing a Bigger Part in Healthcare

E-Medical Records Get A Mobile, Open-Sourced Overhaul By White House Health Design Challenge Winners

Qualcomm Ventures Qprize Regional Competition: MediSafe, an Israeli start-up in the personal health field, is the 2014 Winner of a $100,000 Prize

Friday, April 4 8:30 am- 9:30 am Science Track: Mobile Technology and 3D Printing: Technologies Gaining Traction in Biotech and Pharma – MassBio Annual Meeting 2014, Royal Sonesta Hotel, Cambridge, MA

Information Security and Privacy in Healthcare is part of the 2nd Annual Medical Informatics World, April 28-29, 2014, World Trade Center, Boston, MA

Post Acute Care – Driver of Variation in Healthcare Costs

Kaiser data network aims to improve cancer, heart disease outcomes

 

Additional references

1. Aranda-Jan CB, Mohutsiwa-Dibe N, Loukanova S: Systematic review on what works, what does not work and why of implementation of mobile health (mHealth) projects in Africa. BMC public health 2014, 14:188.

 

 

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Heroes in Medical Research: Developing Models for Cancer Research

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, Health Economics and Outcomes Research, Human Immune System in Health and in Disease, Scientist: Career considerations, Translational Research, tagged animal models of disease, Aviva Lev-Ari, Cancer - General, cancer models, Cell Biology, cloning, Conditions and Diseases, Developmental biology, DNA, gene expression, genetics, history of science, mouse model, National Institutes of Health, Proceedings of the National Academy of Sciences of the United States of America, research, scientific discovery on April 4, 2014| Leave a Comment »

Heroes in Medical Research: Developing Models for Cancer Research

Author, Curator: Stephen J. Williams, Ph.D.

 

The current rapid progress in cancer research would have never come about if not for the dedication of past researchers who had developed many of the scientific tools we use today. In this issue of Heroes in Medical Research I would like to give tribute to the researchers who had developed the some of the in-vivo and in-vitro models which are critical for cancer research.

 

The Animal Modelers in Cancer Research

Helen Dean King, Ph.D. (1869-1955)

Helen Dean King, Ph.D. from www.ExplorePAhistory.com; photo Courtesy of the Wistar Institute Archive Collection, Philadelphia, PA

 

 

The work of Dr. Helen Dean King on rat inbreeding led to development of strains of laboratory animals. Dr. King taught at Bryn Mawr College, then worked at University of Pennsylvania and the Wistar Institute under famed geneticist Thomas Hunt Morgan, researching if inbreeding would produce harmful genetic traits.   At University of Pennsylvania she examined environmental and genetic factors on gender determination.

 

 

 

 

Important papers include [1-6]as well as the following contributions:

“Studies in Inbreeding”, “Life Processes in Gray Norway Rats During Fourteen Years in Captivity”, doctoral thesis on embryologic development in toads (1899)

 

Milestones include:

 

1909    started albino rat breeding and bred 20 female and male from same litter (King colony) to 25

successive generations (inbreeding did not cause harmful traits)

 

1919     started to domesticate the wild Norwegian rats that ran thru Philadelphia (six pairs Norway rats

thru 28 generations)

A good reference for definitions of rat inbreeding versus line generation including a history of Dr. King’s work can be found at the site: Munificent Mischief Rattery and a brief history here.[7] In addition, Dr. King had investigated using rat strains as a possible recipient for tumor cells. The work was an important advent to the use of immunodeficient models for cancer research.

 

As shown below Philadelphia became a hotbed for research into embryology, development, genetics, and animal model development.

 

Beatrice Mintz, Ph.D.

(Beatrice Minz, Ph.D.; photo credit Fox Chase Cancer Center, www.pubweb.fccc.edu)

Dr. Mintz, an embryologist and cancer researcher from Fox Chase Cancer Center in Philadelphia, PA, contributed some of the most seminal discoveries leading to our current understanding of genetics, embryo development, cellular differentiation, and oncogenesis, especially melanoma, while pioneering techniques which allowed the development of genetically modified mice.

If you get the privilege of hearing her talk, take advantage of it. Dr. Mintz is one of those brilliant scientists who have the ability to look at a clinical problem from the viewpoint of a basic biological question and, at the same time, has the ability to approach the well-thought out questions with equally well thought out experimental design. For example, Dr. Mintz asked if a cell’s developmental fate was affected by location in the embryo. This led to her work by showing teratocarcinoma tumor cells in the developing embryo could revert to a more normal phenotype, essentially proving two important concepts in development and tumor biology:

1. The existence of pluripotent stem cells
2. That tumor cells are affected by their environment (which led to future concepts of the importance of tumor microenvironment on tumor growth

Other seminal discoveries included:

• Development of the first mouse chimeras using novel cell fusion techniques
• With Rudolf Jaenisch in 1974, showed integration of viral DNA from SV40, could be integrated into the DNA of developing mice and persist into adulthood somatic cells, the first transgenesis in mice which led ultimately to:
• Development of the first genetically modified mouse model of human melanoma in 1993

Her current work, seen on the faculty webpage here, is developing mice with predisposition to melanoma to uncover risk factors associated with the early development of melanoma.

In keeping with the Philadelphia tradition another major mouse model which became seminal to cancer drug discovery was co-developed in the same city, same institute and described in the next section.

It is interesting to note that the first cloning of an animal, a frog, had taken place at the Institute for Cancer Research, later becoming Fox Chase Cancer Center, which was performed by Drs. Robert Briggs and Thomas J. King and reported in the 152 PNAS paper Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs.[8]

 

 The Immunodeficient Animal as a Model System for Cancer Research – Dr. Mel Bosma, Ph.D.

 

Melvin J. Bosma, Ph.D.; photo credit Fox Chase Cancer Center

In the summer of 1980 at Fox Chase Cancer Center, Dr. Melvin J. Bosma and his co-researcher wife Gayle discovered mice with deficiencies in common circulating antibodies and since, these mice were littermates, realized they had found a genetic defect which rendered the mice immunodeficient (upon further investigation these mice were unable to produce mature B and T cells). These mice were the first scid (severe combined immunodeficiency) colony. The scid phenotype was later found to be a result of a spontaneous mutation in the enzyme Prkdc {protein kinase, DNA activated, catalytic polypeptide} involved in DNA repair, and ultimately led to a defect in V(D)J recombination of immunoglobulins.

The emergence of this scid mouse was not only crucial for AIDS research but was another turning point in cancer research , as researchers now had a robust in-vivo recipient for human tumor cells. The orthotopic xenograft of human tumor cells now allowed for studies on genetic and microenvironmental factors affecting tumorigenicity, as well as providing a model for chemotherapeutic drug development (see Suggitt for review and references)[9]. A discussion of the pros and cons of the xenograft system for cancer drug discovery would be too voluminous for this post and would warrant a full review by itself. But before the advent of such scid mouse systems researchers relied on spontaneous and syngeneic mouse tumor models such as the B16 mouse melanoma and Lewis lung tumor model.

Other scid systems have been developed such as in the dog, horse, and pig. Please see the following post on this site The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research. The athymic (nude) mouse (nu/nu) also is a popular immunodeficient mouse model used for cancer research

Two other in-vivo tumor models: Patient Derived Xenografts (PDX) and Genetically Engineered Mouse models (GEM) deserve their own separate discussion however the success of these new models can be attributed to the hard work of the aforementioned investigators. Therefore I will post separately and curate PDX and GEM models of cancer and highlight some new models which are having great impact on cancer drug development.

 

References

1.         Loeb L, King HD: Transplantation and Individuality Differential in Strains of Inbred Rats. The American journal of pathology 1927, 3(2):143-167.

2.         Lewis MR, Aptekman PM, King HD: Retarding action of adrenal gland on growth of sarcoma grafts in rats. J Immunol 1949, 61(4):315-319.

3.         Aptekman PM, Lewis MR, King HD: Tumor-immunity induced in rats by subcutaneous injection of tumor extract. J Immunol 1949, 63(4):435-440.

4.         Lewis MR, Aptekman PM, King HD: Inactivation of malignant tissue in tumor-immune rats. J Immunol 1949, 61(4):321-326.

5.         Lewis MR, King HD, et al.: Further studies on oncolysis and tumor immunity in rats. J Immunol 1948, 60(4):517-528.

6.         Aptekman PM, Lewis MR, King HD: A method of producing in inbred albino rats a high percentage of immunity from tumors native in their strain. J Immunol 1946, 52:77-86.

7.         Ogilvie MB: Inbreeding, eugenics, and Helen Dean King (1869-1955). Journal of the history of biology 2007, 40(3):467-507.

8.         Briggs R, King TJ: Transplantation of Living Nuclei From Blastula Cells into Enucleated Frogs’ Eggs. Proceedings of the National Academy of Sciences of the United States of America 1952, 38(5):455-463.

9.         Suggitt M, Bibby MC: 50 years of preclinical anticancer drug screening: empirical to target-driven approaches. Clinical cancer research : an official journal of the American Association for Cancer Research 2005, 11(3):971-981.

 

Other posts on this site about Cancer, Animal Models of Disease, and other articles in this series include:

The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

A Synthesis of the Beauty and Complexity of How We View Cancer

Guidelines for the welfare and use of animals in cancer research

Importance of Funding Replication Studies: NIH on Credibility of Basic Biomedical Studies

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

Report on the Fall Mid-Atlantic Society of Toxicology Meeting “Reproductive Toxicology of Biologics: Challenges and Considerations:

What`s new in pancreatic cancer research and treatment?

Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

Richard Lifton, MD, PhD of Yale University and Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer

 

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The 2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development, 19th March 2014 • New York Academy of Sciences • USA

Posted in CANCER BIOLOGY & Innovations in Cancer Therapy, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, tagged Aileron Therapeutics, Aviva Lev-Ari, Cancer - General, Conditions and Diseases, Facebook, genomics, GlaxoSmithKline, Larry H. Bernstein, Lev-Ari, MDMX, New York Academy of Sciences, Open access, tumor on December 17, 2013| Leave a Comment »

PROGRAM ANNOUNCEMENT

Conference Program is available at

http://www.sachsforum.com/newyork14/

Event’s agenda available at:
http://www.sachsforum.com/newyork14/newyork14-agenda.html

Wednesday, 19th March 2014
Registration and coffee begins – 08.00
Program begins – 08.15
Networking reception will take place at 18.00 – 20.00

Once you arrive at 7 World Trade Center (250 Greenwich St, New York, NY10007, USA).
Please use the D Elevator Bank to the 40th floor where Sachs Team will welcome you at the registration desk.

For urgent issues, please contact:
Tomas@sachsforum.com (cell number +44 77 043 158 71)
Or Mina@sachsforum.com (cell number +44 74 636 695 04) Cells available from 15th March.

Announcement

LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE will cover the event for the Scientific Media

Dr. Lev-Ari will be in attendance on 3/19/2014 at 

The New York Academy of Sciences.

Editorials of event coverage via our 

Open Access Scientific Journal

http://pharmaceuticalintelligence.com

Date             Views to Date      # of articles      “NIH Clicks”  “Nature Clicks”

3/05/2014      338,958                 1,717                 1,830                   965

• 369 Articles on Cancer
• 74 articles on Imaging-based Cancer Patient Management

http://pharmaceuticalintelligence.com/?s=Cancer+

• Cancer e-Book

Series C: e-Books on Cancer & Oncology

Series C Content Consultant: Larry H. Bernstein, MD, FCAP 

VOLUME ONE 

Cancer Biology and Genomics for Disease Diagnosis

2014

Stephen J. Williams, PhD, Senior Editor

sjwilliamspa@comcast.net

Tilda Barliya, PhD, Editor

tildabarliya@gmail.com

Ritu Saxena, PhD, Editor

ritu.uab@gmail.com

http://pharmaceuticalintelligence.com/biomed-e-books/series-c-e-books-on-cancer-oncology/cancer-biology-and-genomics-for-disease-diagnosis/

SIX SOURCES of INVESTMENT for BioMed INVENTIONS

Curator: Aviva Lev-Ari, PhD, RN

Investing and inventing: Is the Tango of Mars and Venus Still on

MEDIA COVERAGE

The Event will be broadcasted via our distributions channels on the Internet and all Search Engines featuring WordPress.com

• Scientific Journal

http://pharmaceuticalintelligence.com

http://pharmaceuticalintelligence.com/2014/03/05/milestone-for-our-venture-we-celebrate-our-top-authors-by-number-of-articles-in-the-journal-to-date-1000-301-58-49-46-43-40-28-20/

 

• Facebook HomePage of LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE

http://www.facebook.com/LeadersInPharmaceuticalBusinessIntelligence

• On Twitter.com  @pharma_BI

http://twitter.com/pharma_BI

• 53 BioMed Groups on LinkedIn.com

http://www.linkedin.com/in/avivalevari

• Dr. Lev-Ari’s BioMed Group launched by and managed by on LinkedIn.com – LEADERS IN PHARMACEUTICAL BUSINESS INTELLIGENCE

http://www.linkedin.com/groups?gid=4346921&trk=hb_side_g

2nd ANNUAL Sachs Cancer Bio Partnering & Investment Forum Promoting Public & Private Sector Collaboration & Investment in Drug Development 19th March 2014 • New York Academy of Sciences • USA

http://www.sachsforum.com/newyork14/

 

The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum is designed to bring together thought leaders from cancer research institutes, patient advocacy groups, pharma and biotech to facilitate partnering and funding/investment. We expect around 200 delegates and there is an online meeting system and meeting facilities to make the event transactional. There will also be a track of about 30 presentations by listed and private biotechnology companies seeking licensing/investment.

The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program:

• Advances in Translational Research
• Strategies for Small Molecule and Biologicals Drug Development
• Deal Making
• Public & Private Partnerships
• Diagnostics
• Immunotherapies and Cancer Vaccines
• Case Study

Confirmed Speakers & Chairs include:
Anne Altmeyer, Executive Director Business Development & Licensing, Novartis Pharmaceuticals
Ariel Jasie, Executive Director of Business Development, Celgene
Beth Jacobs, Managing Partner, Excellentia Global Partners
Boris Peaker, Executive Director, Biotechnology Equity Research, Oppenheimer & Co. Inc.
Carole Nuechterlein, Head Roche Venture Fund, F.Hoffmann-La Roche AG Roche Venture Fund
Dan Snyder, President and COO, MolecularMD
Daryl Mitteldorf, Executive Director, Global Prostate Cancer Alliance
Dennis Purcell, Senior Managing Partner, Aisling Capital
Doug Plessinger, Vice President of Clinical and Medical Affairs, Argos Therapeutics, Inc.
Elizabeth Bachert, Senior Director Worldwide Business Development, Pfizer
Esteban Pombo-Villar, COO, Oxford BioTherapeutics AG
Florian Schodel, CEO, Philimmune LLC
Frederick Cope, President and CSO, Navidea Biopharmaceuticals
Guillaume Vignon, Director of Global BD Oncology, Merck Serono SA
Harren Jhoti, President, Astex Pharmaceuticals Inc.
Harry Glorikan, Managing Director, Precision for Medicine
James Mulé, Executive Vice President and Associate Center Director for Translational Research,
H Lee Moffit Cancer Center
Keith Knutson, Program Director and Principal Investigator of the Cancer Vaccines and immune Therapies Program, Vaccine and Gene Therapy Institute of Florida
Kevin DeGeeter, Analyst, Ladenburg Thalmann & Co, Inc.
Klaus Urbahns, Head, Discovery Technologies, Merck Serono
Kristina Khodova, Project Manager, Oncology, Skolkovo Foundation
Lorenza Castellon, Business Development Consultant, Suda Ltd.
Louis DeGennaro, Executive VP, CMO, The Leukemia and Lymphoma Society
Louise Perkins, Chief Science Officer, Melanoma Research Alliance
Mara Goldstein, Managing Director, Senior Healthcare Analyst, Cantor Fitzgerald
Michael Goldberg, Managing Partner, Montaur Capital
Nathan Tinker, Executive Director, NewYorkBIO
Nicholas Dracopoli, Vice President and Head of Oncology, Janssen Research & Development
Peter Hoang, Managing Director, Office of Innovations, Technology Based Ventures, The University of Texas MD Anderson Cancer Center
Philip Gotwals, Executive Director, Oncology Research Collaborations, Novartis Institutes for BioMedical Research
Robert Petit, CSO, Advaxis Inc.
Stephen Brozak, Managing Partner and President, WBB Securities, LLC
Steven Tregay, CEO, Forma Therapeutics
Steven W. Young, President, Addario lung Cancer Medical Institute
Stuart Barich, Managing Director, Healthcare Investment Banking, Oppenheimer & Company
Tariq Kassum MD, Vice President, Business Development and Strategy, Millennium Pharmaceuticals
TBC, Cardinal Health
TBC, UCSD
Timothy Herpin, Vice President, Head of Transactions (UK), Business Development, AstraZeneca
Vikas Sharma, Director, Business Development, Rexahn Pharmaceuticals, Inc.
Walter Capone, President, The Multiple Myeloma Research Foundation

View the full list of 2013 Forum Speakers & Chairs >>

Presenting Opportunities for Biotech, Pharmaceutical companies  and Patient Advocacy Groups

Presenting at the forum offers excellent opportunities to showcase activities and highlight investment and partnership opportunities. Biotech companies will be able to communicate investment and licensing opportunities. These are for both public and private companies. The audience is comprised of financial and industry investors. These are streamed 15 minute presentations. The patient advocacy presentations are 30 minutes.

Sachs forums are recognised as the leading international stage for those interested in investing in the biotech and life science industry and are highly transactional. They draw together an exciting cross-section of early-stage/pre-IPO, late-stage and public companies with leading investors, analysts, money managers and pharmas. The Boston forum provides the additional interaction with the academic/scientific and patient advocacy communities.

Sponsorship and Exhibition

Sachs Associates has developed an extensive knowledge of the key individuals operating within the European and global biotech industry. This together with a growing reputation for excellence puts Sachs Associates at the forefront of the industry and provides a powerful tool by which to increase the position of your company in this market.

Raise your company’s profile directly with your potential clients. All of our sponsorship packages are tailor made to each client, allowing your organisation to gain the most out of attending our industry driven events.

To learn more about presenting, exhibition or sponsorship opportunities, please contact
Mina Orda + 44 (0)203 463 4890 or by email: Mina Orda.

 

	Register Now Register To Exhibit Register To Present OVERVIEW Speakers Presenting Companies Attendees Program Sponsors / Supporters Venue Accommodation
	Companies Who Presented at the 2013 Forum Included: Aileron Therapeutics, Inc. AnaptysBio, Inc Argos Therpeutics, Inc Atossa Genetics BioCancell Ltd. BioLineRx Ltd. Cellectis CENTROSE Churchill Pharmaceuticals Constellation Pharmaceuticals CureVac GmbH Dicerna Pharmaceuticals Etubics Corporation Genisphere immatics biotechnologies GmbH ImmunoGen, Inc Life Science Nation MacroGenics, Inc Melanovus Oncology MiNA Therapeutics MolecularMD Oncolix, Inc. OncoSec Medical Incorporated Oxford BioTherapeutics RAMOT at Tel Aviv University Rescue Therapeutics, Inc. Sialix, Inc. Sorrento Therapeutics to-BBB technologies BV TVAX Biomedical, Inc. The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum is designed to bring together thought leaders from cancer research institutes, patient advocacy groups, pharma and biotech to facilitate partnering and funding/investment. We expect around 200 delegates and there is an online meeting system and meeting facilities to make the event transactional. There will also be a track of about 30 presentations by listed and private biotechnology companies seeking licensing/investment.The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program: Advances in Translational Research Strategies for Small Molecule and Biologicals Drug Development Deal Making Public & Private Partnerships Confirmed Speakers & Chairs include: The 2nd Annual Sachs Cancer Bio Partnering & Investment Forum will cover the following topics in the program: Advances in Translational Research Strategies for Small Molecule and Biologicals Drug Development Deal Making Public & Private Partnerships Diagnostics Immunotherapies and Cancer Vaccines Confirmed Speakers & Chairs include: Anne Altmeyer, Executive Director Business Development & Licensing, Novartis Pharmaceuticals Ariel Jasie, Executive Director of Business Development, Celgene Beth Jacobs, Managing Partner, Excellentia Global Partners Boris Peaker, Executive Director, Biotechnology Equity Research, Oppenheimer & Co. Inc. Carole Nuechterlein, Head Roche Venture Fund, F.Hoffmann-La Roche AG Roche Venture Fund Daryl Mitteldorf, Executive Director, Global Prostate Cancer Alliance Dennis Purcell, Senior Managing Partner, Aisling Capital Doug Plessinger, Vice President of Clinical and Medical Affairs, Argos Therapeutics, Inc. Elizabeth Bachert, Senior Director Worldwide Business Development, Pfizer Esteban Pombo-Villar, COO, Oxford BioTherapeutics AG Florian Schodel, CEO, Philimmune LLC Guillaume Vignon, Director of Global BD Oncology, Merck Serono SA Harren Jhoti, President, Astex Pharmaceuticals Inc. Harry Glorikan, Managing Director, Precision for Medicine James Mulé, Executive Vice President and Associate Center Director for Translational Research, H Lee Moffit Cancer Center Keith Knutson, Program Director and Principal Investigator of the Cancer Vaccines and immune Therapies Program, Vaccine and Gene Therapy Institute of Florida Klaus Urbahns, Head, Discovery Technologies, Merck Serono Kristina Khodova, Project Manager, Oncology, Skolkovo Foundation Lorenza Castellon, Business Development Consultant, Suda Ltd. Louis DeGennaro, Executive VP, CMO, The Leukemia and Lymphoma Society Louise Perkins, Chief Science Officer, Melanoma Research Alliance Mara Goldstein, Managing Director, Senior Healthcare Analyst, Cantor Fitzgerald Nathan Tinker, Executive Director, NewYorkBIO Nicholas Dracopoli, Vice President and Head of Oncology, Janssen Research & Development Peter Hoang, Managing Director, Office of Innovations, Technology Based Ventures, The University of Texas MD Anderson Cancer Center Philip Gotwals, Executive Director, Oncology Research Collaborations, Novartis Institutes for BioMedical Research Robert Petit, CSO, Advaxis Inc. Steven Tregay, CEO, Forma Therapeutics Steven W. Young, President, Addario lung Cancer Medical Institute Stuart Barich, Managing Director, Healthcare Investment Banking, Oppenheimer & Company Tariq Kassum MD, Vice President, Business Development and Strategy, Millennium Pharmaceuticals Timothy Herpin, Vice President, Head of Transactions (UK), Business Development, AstraZeneca Walter Capone, President, The Multiple Myeloma Research Foundation _______ View the full list of 2013 Forum Speakers & Chairs >> Presenting Opportunities for Biotech, Pharmaceutical companies  and Patient Advocacy Groups Presenting at the forum offers excellent opportunities to showcase activities and highlight investment and partnership opportunities. Biotech companies will be able to communicate investment and licensing opportunities. These are for both public and private companies. The audience is comprised of financial and industry investors. These are streamed 15 minute presentations. The patient advocacy presentations are 30 minutes. Sachs forums are recognised as the leading international stage for those interested in investing in the biotech and life science industry and are highly transactional. They draw together an exciting cross-section of early-stage/pre-IPO, late-stage and public companies with leading investors, analysts, money managers and pharmas. The Boston forum provides the additional interaction with the academic/scientific and patient advocacy communities. Sponsorship and Exhibition Sachs Associates has developed an extensive knowledge of the key individuals operating within the European and global biotech industry. This together with a growing reputation for excellence puts Sachs Associates at the forefront of the industry and provides a powerful tool by which to increase the position of your company in this market. Raise your company’s profile directly with your potential clients. All of our sponsorship packages are tailor made to each client, allowing your organisation to gain the most out of attending our industry driven events. To learn more about presenting, exhibition or sponsorship opportunities, please contact Mina Orda + 44 (0)203 463 4890 or by email: Mina Orda. SOURCE http://www.sachsforum.com/newyork14/index.html From: Mina@sachsforum.com To: AvivaLev-Ari@alum.berkeley.edu Sent: Mon Dec 16 12:01:21 UTC 2013 From: Tomas Andrulionis <Tomas@sachsforum.com> Date: Tue, 10 Dec 2013 16:13:53 +0000 To: “avivalev-ari@alum.berkeley.edu” <avivalev-ari@alum.berkeley.edu> Conversation: Complimentary Invitation for the 2nd Annual Sachs Cancer Bio Partnering & Investment Forum, 19th March 2014, New York Academy of Sciences

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Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Posted in Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Biology and its relations to Metabolic Disease, Health Economics and Outcomes Research, Human Sensation and Cellular Transduction: Physiology and Therapeutics, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Scientist: Career considerations, tagged ASPET, calcium signaling, Cardiovascular disease, Conditions and Diseases, health, neuropharmacology, pharmacology, pioneers in medicine, regulation of calcium homeostasis, research, toxicology on October 29, 2013| Leave a Comment »

Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor

Writer/Curator: Stephen J. Williams, Ph.D.

Article ID #83: Heroes in Medical Research: Dr. Carmine Paul Bianchi Pharmacologist, Leader, and Mentor. Published on 10/29/2013

WordCloud Image Produced by Adam Tubman

Past articles in this Heroes in Medical Research series had focused on those seemingly small discoveries, sometimes gained serendipitously and through careful observation and experimentation, which led to some of our most important breakthroughs of our time.  I have tried to make the posts more about the people and less about the discoveries

However, though seminal discoveries are so important to the future of science (and should be celebrated), equally if not MORE IMPORTANT is the MENTORING of future scientists and the PROMOTION of fields of study.  One person who exemplified these values was Dr. Carmine Paul Bianchi, who had recently just passed away this August, and will be sorely missed in the field of pharmacology and toxicology.

For those who were not familiar with Dr. Bianchi I have curated some pertinent information about his work as a scientist, professor and Chairman in pharmacology, and leader and spokesperson for the field of pharmacology.  He was one of the founders of the Mid-Atlantic Pharmacology Society and was an advocate and influential in the careers of many pharmacologists and toxicologists.

Comments from fellow colleagues are very welcome (in comment section at end of post)

The following is separated in 3 sections:

• An obituary from the Philadelphia Inquirer
•  A section of the history of the Pharmacology Department at Thomas Jefferson University where Dr. Bianchi was Chairman
• A few important textbooks and scientific articles he had authored

 

Carmine Paul Bianchi, 86, pharmacology professor

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Carmine Paul Bianchi

By Bonnie L. Cook, Inquirer Staff Writer

Posted: August 20, 2013

Carmine Paul Bianchi, 86, of Boothwyn, a professor of pharmacology in Philadelphia for many years, died Tuesday, Aug. 13, of a digestive ailment at Taylor Hospice House in Ridley Park.

Born in Newark, N.J., and raised in Maplewood, Dr. Bianchi served as an Army surgical technician in Tilton General Hospital at Fort Dix from 1945 to 1947.

He earned a bachelor’s degree in chemistry from Columbia University in 1950, a master’s in physiology and biochemistry from Rutgers University in 1953, and a doctorate in physiology and physical chemistry in 1956 from Rutgers.

In the 1950s, he did research at Rutgers and was a public health fellow and visiting scientist at the National Institutes of Health in Maryland.

From 1961 to 1976, he held a number of jobs in the department of pharmacology in the University of Pennsylvania School of Medicine. That culminated in his being named professor of pharmacology.

Dr. Bianchi left in 1976 for Jefferson Medical College of Thomas Jefferson University, where he became pharmacology professor and chairman of the pharmacology department from 1976 to 1987. In 1987, he stepped down from the chairmanship but remained professor of pharmacology. He retired in 1997 as professor emeritus.

Dr. Bianchi was a member of many professional groups, including the New York Academy of Sciences and the American Association for the Advancement of Science.

He was a leader and author in pharmacology, helping edit an industry journal and making himself available for consultation to medical examiners and experts in toxicology.

He wrote or contributed to three books and 200 scientific papers and lectured widely. He enjoyed mentoring medical and graduate students.

His family called Dr. Bianchi “a true renaissance man” who was as comfortable discussing English, history, and politics as he was the sciences.

 

 

 

The following was taken from a history of  Department of Pharmacology  at Thomas Jefferson University  and can be viewed at: http://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1008&context=wagner2

 

 

Carmine Paul Bianchi, Ph.D;

Third Chairman (1976-1986)

The new Chairman of the Department, effective

July 1, 1976, was Carmine Paul Bianchi, Ph.D.

(Figure 8-3) from the University of Pennsylvania

School of Medicine, where he had been Professor

of Pharmacology since [969 and a member of the

faculty of that Department since 1961.

Dr. Bianchi was born on April 9, [927, in

Newark, New Jersey. After receiving his diploma

at Columbia High School in 1945, he spent two

years in the Army Medical Corps as Technical Sgt.

Fourth Grade. He then attended Columbia

University, where he majored in chemistry and

obtained the B.A. degree in 1950. Like Dr.

Gruber, the first Chairman of the Pharmacology

Department at Jefferson, Bianchi earned his Ph.D.

in physiology. He pursued his graduate studies at

Rutgers University, supplementing his physiology

major with a biochemistry minor for the M.S.

degree in [953 and with a physical chemistry minor

for the Ph.D. degree in 1956. Dr. Bianchi then

spent several years at the National Institutes of

Health-two years as a Public Health Fellow and

one as a Visiting Scientist. Following that he was

Assistant Member of the Institute for Muscle

Disease in New York for one year. In 1961 Dr.

Bianchi became classified professionally as a

pharmacologist by becoming an Associate in the

Department of Pharmacology at the University of

Pennsylvania School of Medicine. There he

advanced to Professorship in 1969 and remained

until he came to Jefferson. The evolution of Dr.

Bianchi’s career from physiology to pharmacology

was the logical result of his investigations of the

effect of various drugs on the metabolism and

distribution of some of the important elements of

the body, notably calcium. His major field of

interest became classified and remained in

electrolyte pharmacology.

Throughout his career Dr. Bianchi has been

very active in the affairs of outside professional

organizations. He is a member of the American

Society for Pharmacology and Experimental

Therapeutics, the American Physiological Society,

the American Chemical Society, and the

International Society of Toxicology, to name

only a few. He served as President of both the

Philadelphia Physiological Society and the John

Morgan Society in the same year (1973-1974), and

of the Philadelphia Chapter of the Society for

Neuroscience (1979-1980). He gave much time

and valuable services as Field Editor for the

Journal of Pharmacology and Experimental

Therapeutics ([970-1979) and as a member of the

Pharmacology Section of the National Board of

Medical Examiners (1981-1985).

After Dr. Bianchi became Chairman no

immediate changes in the general structure and

activities of the Department took place. He

enlarged the Department and filled vacancies

occasioned by the retirement of some faculty

members. The didactic schedules and subject

matter offered to the medical and graduate

students underwent only minor annual changes.

Research activities were augmented by the

addition of Dr. Bianchi’s specialty in electrolyte

pharmacology and the appointments of new staff

members for investigations in that and related

flelds. Through the following decade there was a

marked change in the faculty structure of the

Department. The [975 Jefferson catalogue, for

example, listed 15 faculty appointments in

Pharmacology, of which eight were on a primary

full-time basis with offices and laboratories in the

Department. In 1985 there were 36 faculty

appointments of which eight were on a primary

full-time basis. The large increase in the total

number of faculty resulted from adjunct

appointments from outside organizations and from

secondary appointments of faculty members of the

Clinical Departments at Jefferson. This expansion

reflected a broadening of interests and interactions

on both the scientific and clinical fronts in clinical

pharmacology and clinical toxicology.

A notable addition to the faculty of the

Department in 1978 was Dr. Hyman Menduke

as Professor of Pharmacology

(Biostatistics). After receiving his Ph.D. in

Economic Statistics at the University of

Pennsylvania, Menduke came to Jefferson in 1953

as Assistant Professor of Biostatistics with no

official Departmental affiliation until 1963, when

he was appointed Professor of Preventive

Medicine (Biostatistics). When Dr. Menduke first

came to Jefferson he gave a ten-hour course in

biostatistics to the second-year medical students in

time provided during their pharmacology course.

Through the years his offerings expanded to a

12-hour course for freshman medical students and

introductory and advanced courses for graduate

students. An early and valuable contribution was a

series of individual conferences with graduate

students on the statistical planning of their

research problems and the later analysis of their

data.

 

The interests and activities of the Department in

research in toxicology have been emphasized.

Toxicology continued as an important part of the

research program after Dr. Bianchi became

Chairman in 1976, although under his direction

the major emphasis in research became redirected

toward the general areas of cell pharmacology and

neuropharmacology.

In accord with its continuing research and

teaching activities in toxicology, the Department

starting in 1977 organized a series of annual

workshops on Industrial Toxicology sponsored by

the College of Graduate Studies. These were

four-day symposia on important toxicologic

problems in industry and the general environment,

presented by toxicologically involved Jefferson

faculty and by invited experts from other

universities, industry, and government.

In 1979 the Department was awarded a training

grant in Industrial and Environmental Toxicology

by the National Institute of Environmental Health

Sciences. The purpose of this award was to

provide postdoctoral training in toxicology for

individuals who had previously received their

Ph.D. degrees in other sciences. Ten M.S. degrees

were subsequently awarded in this program

through the years from 1981 to 1986.

On December 14, 1978, a full day’s workshop

with outside invited experts was held to discuss

the formation of a Toxicology Center and the

establishment of a Chair in Toxicology-Pathology

to broaden the base of research and training in

toxicology at Jefferson. It was envisioned that the

Center would be an administrative Division within

the Department of Pharmacology, with research

participation from other basic science departments

and the Department of Medicine. Although funds

accumulated in support of a Toxicology Center,

disagreements developed relating to the

administrative base of the Center.

 

A few articles from Dr. Bianchi showing the diversity of his research interests including calcium mobilization, neurotoxicology, and cellular metabolism and physiology.

Muscle fatigue and the role of transverse tubules.

Bianchi CP, Narayan S.

Science. 1982 Jan 15;215(4530):295-6. No abstract available.

 

Effect of adenosine on oxygen uptake and electrolyte content of frog sartorius muscle.

Prosdocimi M, Bianchi CP.

J Pharmacol Exp Ther. 1981 Jul;218(1):92-6.

 

The effect of diazepam on tension and electrolyte distribution in frog muscle.

Degroof RC, Bianchi CP, Narayan S.

Eur J Pharmacol. 1980 Aug 29;66(2-3):193-9.

 

Steady state maintenance of electrolytes in the spinal cord of the frog.

Bianchi CP, Erulkar SD.

J Neurochem. 1979 Jun;32(6):1671-7. No abstract available.

An in-vitro model of anesthetic hypertonic hyperpyrexia, halothane–caffeine-induced muscle contractures: prevention of contracture by procainamide.

Strobel GE, Bianchi CP.

Anesthesiology. 1971 Nov;35(5):465-73. No abstract available.

 

The effects of psychoactive agents on calcium uptake by preparations of rat brain mitochondria.

Tjioe S, Haugaard N, Bianchi CP.

J Neurochem. 1971 Nov;18(11):2171-8. No abstract available.

 

The effect of veratridine on sodium-sensitive radiocalcium uptake in frog sartorius muscle.

Johnson P, Bianchi CP.

Eur J Pharmacol. 1971 Sep;16(1):90-9. No abstract available.

 

The function of ATP in Ca2+ uptake by rat brain mitochondria.

Tjioe S, Bianchi CP, Haugaard N.

Biochim Biophys Acta. 1970 Sep 1;216(2):270-3. No abstract availabl

 

The effects of pH gradients on the uptake and distribution of C14-procaine and lidocaine in intact and desheathed sciatic nerve trunks.

Strobel GE, Bianchi CP.

J Pharmacol Exp Ther. 1970 Mar;172(1):18-32. No abstract available

 

 

More articles by CP Bianchi  can be found at: http://www.ncbi.nlm.nih.gov/pubmed/?term=Bianchi%20CP[auth]

The following is one of the seminal books Dr. Bianchi authored:

 

Role of Calcium Channels of the Sarcolemma and the Sarcoplasmic Reticulum in Skeletal Muscle Functions

http://link.springer.com/article/10.1007%2F978-1-4615-3362-7_17/lookinside/000.png

AND

Advances in General and Cellular Pharmacology (1976)

Toshio Narahashi; Carmine Paul Bianchi

The author of the Advances in General and Cellular Pharmacology is Toshio Narahashi; Carmine Paul Bianchi – very good writer. You can download this e-book absolutely for free. This ebook’s ISBN number is 9781461582007. if you were searching for for free download of kindle books, google books, free pdf books, pdf ebooks, e-books, pdf files or pdf ebooks just stay here for a while, download what you wanted for free and enjoy!

Advances in General and Cellular Pharmacology – Toshio Narahashi; Carmine Paul Bianchi – PDF Free Download Ebook also for Kindle

 

Other articles in this series published on this site include:

Heroes in Medical Research: Dr. Robert Ting, Ph.D. and Retrovirus in AIDS and Cancer

Heroes in Medical Research: Barnett Rosenberg and the Discovery of Cisplatin

Volume Two: Interviews with Scientific Leaders

 

 

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The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomedical Measurement Science, CANCER BIOLOGY & Innovations in Cancer Therapy, FDA Regulatory Affairs, Health Economics and Outcomes Research, Interviews with Scientific Leaders, tagged animal models of disease, Aviva Lev-Ari, Biology, Cancer - General, Cancer research, Conditions and Diseases, Davinci, Food and Drug Administration, porcine models, preclinical testing, SCID, severe combined immunodeficiency, toxicity testing, toxicology on October 10, 2013| Leave a Comment »

 

The SCID Pig:  How Pigs are becoming a Great Alternate Model for Cancer Research[1]

Author/Writer: Stephen J. Williams, Phd

Article ID #80: The SCID Pig: How Pigs are becoming a Great Alternate Model for Cancer Research. Published on 10/10/2013

WordCloud Image Produced by Adam Tubman

UPDATED 3/14/2020

The need for alternate models of human cancer

Many worldwide regulatory bodies are in agreement that proper choice of animal model is necessary for adequate extrapolation of toxicity and efficacy data from animal to human, considering the varied classes of therapeutics now being developed for oncology.  The inability of screens, reliant on human xenografts grown in immunocompromised mice to evaluate host-immune and species-dependent effects, has made development of alternative animal-models a priority.   This is evident in the fact that ninety percent of new anticancer drugs which showed anti-tumor efficacy in mouse preclinical models failed in human clinical studies. A recently developed “humanized” mouse model may assist in testing the metabolism of cancer drugs but still relies on older “immunosuppression” mouse models (http://stehlin.org/mouse-model-development/). This inadequacy of older, accepted models is clearly evident when evaluating safety and efficacy of adenoviral based gene therapies such as oncolytic conditionally-replicative adenovirus (CRAd).  Although new-generation CRAds present with a relative safe profile[2, 3], adenoviral particles, especially the Ad5 based virus used for most CRAds, have the tendency to replicate in non-tumor tissue, such as liver and lung, resulting in tissue-specific toxicities[4-7].  The manifestation of these toxicities is only evident in species permissive for viral replication, such as the pig. Indeed, one of the first clinical trials with older adenovirus gene therapy, resulting in severe hepatic toxicity and fatality, may have been prevented if more appropriate preclinical screens were conducted.  Thereafter, strict regulatory guidelines for adenoviral-based clinical trials have been issued, with particular emphasis on vector dosage, safety and toxicity[8]. Indeed, at Schering-Plough, a toxicology program was initiated to evaluate SCH 58500, and adenoviral gene therapy directed against p53, which involved use of non-immunogenic rats compared with testing in Yorkshire pigs made immunoreactive to the vector[9, 10].  In fact, data from the pig study revealed a faster clearance of virus as well as toxicities not seen in non-immunogenic, non-permissive hosts such as rat and mouse.

Therefore, development of a porcine model of cancer would permit both testing of both the efficacy and safety of these therapies in the same animal.

Development of large animal models of cancer

To date, large animal tumor models have been used for studying spontaneously formed tumors in dogs and cats [11](Vail, 2000, Cancer Invest), the most common being canine [12] and feline non-Hodgkin’s lymphoma [13]. The advantages of these companion models are the outbred nature of the animals, comparable size and kinetics to human tumors [14-18], and high incidence rates. Allografts of the outbred-canine transplanted venereal tumor have been used to test the ability to detect tumors using X-ray computed tomography and MRI with the ultimate goal of imaging-guided intervention. Researchers have recently utilized the spontaneously arising canine and feline soft tissue sarcomas to study effects of hyperthermia on chemotherapy pharmocokinetics, development of hypoxic cell markers, and cancer imaging techniques [15, 19-26]

Although it appears that, for a select number of tumor types, spontaneously arising tumors in large outbred animals can be useful to model the human disease, it is disappointing these spontaneous arising tumors are limited to discrete tumor types. However, due to recent advances in sequencing of several domestic animal genomes and the development of new cloning strategies, it is now very feasible to utilize other animal models more relevant to human disease, notably the miniature pig.

The Gottingen mini-pig

Large animals in medical research: Advantages of the minipig

Due to recent advances in sequencing of several domestic animal genomes [27, 28] and the development of new organism cloning technologies [29-31], it is now very feasible to utilize other species to model human disease, notably the pig. The development of porcine models of human disease has gained much interest lately. Advantages include the resemblance in anatomy, physiology, and genetic makeup with the human, as well as new methods to manipulate the pig genome [32, 33]. To date, porcine models of human metabolic syndrome [34] and diabetes [35], aortic aneurism [36], infectious disease resistance [32, 37], seizure [38], neurologic syndromes [33], and pancreatitis [39] have been developed. Recently, a genetically-engineered porcine model of cystic fibrosis was produced in collaboration with investigators at University of Iowa and Exemplar Genetics [40-42]. Additionally, Cho et al. successfully transplanted spontaneously transformed leukemic and lymphatic tumor cells in a major histocompatibility complex (MHC)-defined inbred miniature swine model [43], suggesting feasibility of an ex vivo strategy to develop a porcine tumor model. Porcine models have, also, been used to develop, test and refine surgical [44, 45] and laparoscopic techniques [46, 47], radio- and cryoablation protocols of tissues [48-52] and robotic surgery using the da Vinci Surgical SystemÒ [53, 54].  In addition, because of the size of porcine organs and their resemblance to the human (in genetics) the minipig is very useful and abundant of a source to isolate specific cell types for in vitro studies.  Below is a figure showing the comparable size of human and porcine ovaries to the mouse and  ability to purify  porcine ovarian epithelial cells and their similarity to human and mouse ovarian epithelial cells.

Figure 1.  The human and pig ovary have similar size and can yield a greater number of isolated cells than one can get from a mouse ovary.

Figure 2.  Isolation and morphology of ovarian epithelial cells from three sources:

A) Devonshire/Yorkshire pig

B) normal human ovary

c) SV129/BL6  mouse

note cobblestone epithelial morphology from all three sources©

To date, there has been no allograft or xenograft model of cancer in pigs. The consensus amongst many surgeons suggests development of a minipig tumor model would be an invaluable tool for developing surgical skills. 

A recent advancement in porcine tumor modeling was made by collaboration between researchers from the laboratories of Dr. Stefan Bossmann and Deryl Troyer at Kansas State and Iowa State, respectively[1].  The joint collaboration resulted in the development of the first severe combined immunodeficient pig line (SCID pig) which was shown to be able to accept human tumor xenografts.  The line of immunodeficient pig was discovered when Yorkshire pigs were bred for increased feed efficiency and a line of pigs exhibited SCID-like symptoms including:

• Decreased levels of circulating lymphocytes
• Atrophied thymus and lymph nodes

The SCID phenotype in mice have been ascribed to defects in a DNA-dependent protein kinase gene which prevents variable-diversity-joining [V(D)J] gene region recombination[55].  There have been multiple genetic defects found in humans resulting in SCID, including defects in adenylate kinase2, Janus kinase 3, the IL2 receptor, and the IL-7 receptor[56]. The SCID phenotype in this pig line has a simple autosomal recessive inheritance pattern which, as described below in an interview with the authors, allows for the propagation of this porcine line.

An important feature of SCID models is the ability of these animals to act as a recipient of human tumorigenic cell lines.  In fact, growth of cell lines in SCID mice is a common test for tumorigenicity.  Therefore, to test if these pigs could act as recipients for human cancer cell lines, the authors inoculated the SCID Yorkshire pigs with 4 million A3755M human melanoma cells or PANC1 human pancreatic carcinoma cells subcutaneously in the left and right ears respectively of three pigs.  Some features of the results include:

• All injection sites showed evidence (either histologic or palpable) of tumor growth
• Tumors showed characteristic histologic features of malignant neoplasm including

1. Bizarre and atypical mitotic figures
2. Anisocytosis (different cell sizes and shapes; feature of malignancy)
3. Anisokaryosis (different size and shape of nucleus)

• tumors stained with anti-human mitochondrial antibody (a marker of epithelial cancer cells) showed strong cytoplasmic staining of neoplastic cells
• interestingly no necrotic regions in the tumor

 

Figure 3. Visual evidence of human tumor cells growing in SCID pig ear (day 20). B) Same picture as A) but circle outlines growth.  From reference 1. Basel et al., used with permission from Mary Liebert.

It is interesting to note that these tumors only grew roughly 10 x 5.5 mm, which is genrally large enough to do preclinical studies but may be too expensive to be of use for xenograft studies.  However it would be very feasible to conduct allograft studies in these SCID pigs.

Dr. Jack Dekkers, C.F. Curtiss Distinguished Professor and Section Leader of Animal Breeding and Genetics at Iowa State University, was kind to answer a few questions about the SCID pig model.

Question: You had mentioned this line was identified after breeding Yorkshire pigs for increased feed efficiency.  Have you identified or hypothesize which altered pathway or molecular defect which results in a SCID phenotype?  Is this SCID phenotype a result of a metabolic syndrome these pigs could have?

Dr. Dekkers: We indeed identified the SCID phenotype in a line of pigs that we had selected for increased feed efficiency. However, I don’t think this phenotype has anything to do with the selection we practiced; it was either already present in the founders of the line or it was a random mutation that occurred in the line, independent of the selection for feed efficiency. We have narrowed the mutation that causes the SCID in our pigs down to a chromosomal region and have a very strong candidate gene in that region that we are currently pursuing.

Question: In your opinion, is it possible to produce a highly inbred immunocompromised strain of pig such as a Gottingen minipig?

Dr. Dekkers: We are working on breeding the SCID mutation into mini pigs. But in the meantime, we have used bone marrow transfer to create a male that is homozygous SCID (it’s an autosomal recessive) and reproducing. This allows us to produce litters that are 50% SCID and 50% normal (carriers) by mating him to carrier females.

REFERENCES

1.         Basel MT, Balivada S, Beck AP, Kerrigan MA, Pyle MM, Dekkers JC, Wyatt CR, Rowland RR, Anderson DE, Bossmann SH et al: Human xenografts are not rejected in a naturally occurring immunodeficient porcine line: a human tumor model in pigs. BioResearch open access 2012, 1(2):63-68.

2.         Dobbelstein M: Replicating adenoviruses in cancer therapy. Curr Top Microbiol Immunol 2004, 273:291-334.

3.         Lichtenstein DL, Wold WS: Experimental infections of humans with wild-type adenoviruses and with replication-competent adenovirus vectors: replication, safety, and transmission. Cancer Gene Ther 2004, 11(12):819-829.

4.         Volpers C, Kochanek S: Adenoviral vectors for gene transfer and therapy. J Gene Med 2004, 6 Suppl 1:S164-171.

5.         Brand K, Arnold W, Bartels T, Lieber A, Kay MA, Strauss M, Dorken B: Liver-associated toxicity of the HSV-tk/GCV approach and adenoviral vectors. Cancer Gene Ther 1997, 4(1):9-16.

6.         Lieber A, He CY, Meuse L, Schowalter D, Kirillova I, Winther B, Kay MA: The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol 1997, 71(11):8798-8807.

7.         Keedy V, Wang W, Schiller J, Chada S, Slovis B, Coffee K, Worrell J, Thet LA, Johnson DH, Carbone DP: Phase I study of adenovirus p53 administered by bronchoalveolar lavage in patients with bronchioloalveolar cell lung carcinoma: ECOG 6597. J Clin Oncol 2008, 26(25):4166-4171.

8.         Assessment of adenoviral vector safety and toxicity: report of the National Institutes of Health Recombinant DNA Advisory Committee. Hum Gene Ther 2002, 13(1):3-13.

9.         Morrissey RE, Horvath C, Snyder EA, Patrick J, Collins N, Evans E, MacDonald JS: Porcine toxicology studies of SCH 58500, an adenoviral vector for the p53 gene. Toxicol Sci 2002, 65(2):256-265.

10.       Morrissey RE, Horvath C, Snyder EA, Patrick J, MacDonald JS: Rodent nonclinical safety evaluation studies of SCH 58500, an adenoviral vector for the p53 gene. Toxicol Sci 2002, 65(2):266-275.

11.       Vail DM, MacEwen EG: Spontaneously occurring tumors of companion animals as models for human cancer. Cancer Invest 2000, 18(8):781-792.

12.       Leifer CE, Matus RE: Canine lymphoma: clinical considerations. Semin Vet Med Surg (Small Anim) 1986, 1(1):43-50.

13.       MacEwen EG: Spontaneous tumors in dogs and cats: models for the study of cancer biology and treatment. Cancer Metastasis Rev 1990, 9(2):125-136.

14.       Schwyn U, Crompton NE, Blattmann H, Hauser B, Klink B, Parvis A, Ruslander D, Kaser-Hotz B: Potential tumour doubling time: determination of Tpot for various canine and feline tumours. Vet Res Commun 1998, 22(4):233-247.

15.       Zeman EM, Calkins DP, Cline JM, Thrall DE, Raleigh JA: The relationship between proliferative and oxygenation status in spontaneous canine tumors. Int J Radiat Oncol Biol Phys 1993, 27(4):891-898.

16.       LaRue SM, Fox MH, Withrow SJ, Powers BE, Straw RC, Cote IM, Gillette EL: Impact of heterogeneity in the predictive value of kinetic parameters in canine osteosarcoma. Cancer Res 1994, 54(14):3916-3921.

17.       Vail DM, Kisseberth WC, Obradovich JE, Moore FM, London CA, MacEwen EG, Ritter MA: Assessment of potential doubling time (Tpot), argyrophilic nucleolar organizer regions (AgNOR), and proliferating cell nuclear antigen (PCNA) as predictors of therapy response in canine non-Hodgkin’s lymphoma. Exp Hematol 1996, 24(7):807-815.

18.       Guglielmino R, Canese MG, Miniscalco B, Geuna M: Comparison of clinical, morphological, immunophenotypical and cytochemical characteristics of LGL leukemia/lymphoma in dog, cat and human. Eur J Histochem 1997, 41 Suppl 2:23-24.

19.       Cline JM, Thrall DE, Rosner GL, Raleigh JA: Distribution of the hypoxia marker CCI-103F in canine tumors. Int J Radiat Oncol Biol Phys 1994, 28(4):921-933.

20.       Thrall DE, McEntee MC, Cline JM, Raleigh JA: ELISA quantification of CCI-103F binding in canine tumors prior to and during irradiation. Int J Radiat Oncol Biol Phys 1994, 28(3):649-659.

21.       Raleigh JA, La Dine JK, Cline JM, Thrall DE: An enzyme-linked immunosorbent assay for hypoxia marker binding in tumours. Br J Cancer 1994, 69(1):66-71.

22.       Thrall DE, Larue SM, Pruitt AF, Case B, Dewhirst MW: Changes in tumour oxygenation during fractionated hyperthermia and radiation therapy in spontaneous canine sarcomas. Int J Hyperthermia 2006, 22(5):365-373.

23.       Siddiqui F, Li CY, Larue SM, Poulson JM, Avery PR, Pruitt AF, Zhang X, Ullrich RL, Thrall DE, Dewhirst MW et al: A phase I trial of hyperthermia-induced interleukin-12 gene therapy in spontaneously arising feline soft tissue sarcomas. Mol Cancer Ther 2007, 6(1):380-389.

24.       Sostman HD, Prescott DM, Dewhirst MW, Dodge RK, Thrall DE, Page RL, Tucker JA, Harrelson JM, Reece G, Leopold KA et al: MR imaging and spectroscopy for prognostic evaluation in soft-tissue sarcomas. Radiology 1994, 190(1):269-275.

25.       Dennis R: Imaging features of orbital myxosarcoma in dogs. Vet Radiol Ultrasound 2008, 49(3):256-263.

26.       Mueller F, Fuchs B, Kaser-Hotz B: Comparative biology of human and canine osteosarcoma. Anticancer Res 2007, 27(1A):155-164.

27.       Cockett NE: Current status of the ovine genome map. Cytogenet Genome Res 2003, 102(1-4):76-78.

28.       Schook LB, Beever JE, Rogers J, Humphray S, Archibald A, Chardon P, Milan D, Rohrer G, Eversole K: Swine Genome Sequencing Consortium (SGSC): A Strategic Roadmap for Sequencing The Pig Genome. Comp Funct Genomics 2005, 6(4):251-255.

29.       Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH: Viable offspring derived from fetal and adult mammalian cells. Nature 1997, 385(6619):810-813.

30.       Cibelli JB, Stice SL, Golueke PJ, Kane JJ, Jerry J, Blackwell C, Ponce de Leon FA, Robl JM: Cloned transgenic calves produced from nonquiescent fetal fibroblasts. Science 1998, 280(5367):1256-1258.

31.       Polejaeva IA, Chen SH, Vaught TD, Page RL, Mullins J, Ball S, Dai Y, Boone J, Walker S, Ayares DL et al: Cloned pigs produced by nuclear transfer from adult somatic cells. Nature 2000, 407(6800):86-90.

32.       Lunney JK: Advances in swine biomedical model genomics. Int J Biol Sci 2007, 3(3):179-184.

33.       Schook LB, Kuzmuk K, Adam S, Rund L, Chen K, Rogatcheva M, Mazur M, Pollock C, Counter C: DNA-based animal models of human disease: from genotype to phenotype. Dev Biol (Basel) 2008, 132:15-25.

34.       Spurlock ME, Gabler NK: The development of porcine models of obesity and the metabolic syndrome. J Nutr 2008, 138(2):397-402.

35.       Palin MF, Labrecque B, Beaudry D, Mayhue M, Bordignon V, Murphy BD: Visfatin expression is not associated with adipose tissue abundance in the porcine model. Domest Anim Endocrinol 2008, 35(1):58-73.

36.       Sadek M, Hynecek RL, Goldenberg S, Kent KC, Marin ML, Faries PL: Gene expression analysis of a porcine native abdominal aortic aneurysm model. Surgery 2008, 144(2):252-258.

37.       Saetre T, Hoiby EA, Aspelin T, Lermark G, Lyberg T: Acute serogroup A streptococcal shock: A porcine model. J Infect Dis 2000, 182(1):133-141.

38.       Marchi N, Angelov L, Masaryk T, Fazio V, Granata T, Hernandez N, Hallene K, Diglaw T, Franic L, Najm I et al: Seizure-promoting effect of blood-brain barrier disruption. Epilepsia 2007, 48(4):732-742.

39.       Tao J, Gong D, Ji D, Xu B, Liu Z, Li L: Improvement of monocyte secretion function in a porcine pancreatitis model by continuous dose dependent veno-venous hemofiltration. Int J Artif Organs 2008, 31(8):716-721.

40.       Rogers CS, Abraham WM, Brogden KA, Engelhardt JF, Fisher JT, McCray PB, Jr., McLennan G, Meyerholz DK, Namati E, Ostedgaard LS et al: The porcine lung as a potential model for cystic fibrosis. Am J Physiol Lung Cell Mol Physiol 2008, 295(2):L240-263.

41.       Rogers CS, Stoltz DA, Meyerholz DK, Ostedgaard LS, Rokhlina T, Taft PJ, Rogan MP, Pezzulo AA, Karp PH, Itani OA et al: Disruption of the CFTR gene produces a model of cystic fibrosis in newborn pigs. Science 2008, 321(5897):1837-1841.

42.       Rogers CS, Hao Y, Rokhlina T, Samuel M, Stoltz DA, Li Y, Petroff E, Vermeer DW, Kabel AC, Yan Z et al: Production of CFTR-null and CFTR-DeltaF508 heterozygous pigs by adeno-associated virus-mediated gene targeting and somatic cell nuclear transfer. J Clin Invest 2008, 118(4):1571-1577.

43.       Cho PS, Lo DP, Wikiel KJ, Rowland HC, Coburn RC, McMorrow IM, Goodrich JG, Arn JS, Billiter RA, Houser SL et al: Establishment of transplantable porcine tumor cell lines derived from MHC-inbred miniature swine. Blood 2007, 110(12):3996-4004.

44.       Hammond I, Taylor J, Obermair A, McMenamin P: The anatomy of complications workshop: an educational strategy to improve the training and performance of fellows in gynecologic oncology. Gynecol Oncol 2004, 94(3):769-773.

45.       Schneider C, Jung A, Reymond MA, Tannapfel A, Balli J, Franklin ME, Hohenberger W, Kockerling F: Efficacy of surgical measures in preventing port-site recurrences in a porcine model. Surg Endosc 2001, 15(2):121-125.

46.       Rassweiler JJ, Henkel TO, Potempa DM, Frede T, Stock C, Gunther M, Alken P: [Laparoscopic training in urology. An essential principle of laparoscopic interventions in the retroperitoneum]. Urologe A 1993, 32(5):393-402.

47.       Orvieto MA, Zorn KC, Lyon MB, Tolhurst SR, Rapp DE, Seip R, Sanghvi N, Shalhav A: High intensity focused ultrasound renal tissue ablation: a laparoscopic porcine model. J Urol 2009, 181(2):861-866.

48.       Ng KK, Lam CM, Poon RT, Shek TW, To JY, Wo YH, Ho DW, Fan ST: Comparison of systemic responses of radiofrequency ablation, cryotherapy, and surgical resection in a porcine liver model. Ann Surg Oncol 2004, 11(7):650-657.

49.       Alemany R, Balague C, Curiel DT: Replicative adenoviruses for cancer therapy. Nat Biotechnol 2000, 18(7):723-727.

50.       Kahlenberg MS, Volpe C, Klippenstein DL, Penetrante RB, Petrelli NJ, Rodriguez-Bigas MA: Clinicopathologic effects of cryotherapy on hepatic vessels and bile ducts in a porcine model. Ann Surg Oncol 1998, 5(8):713-718.

51.       Long JP, Faller GT: Percutaneous cryoablation of the kidney in a porcine model. Cryobiology 1999, 38(1):89-93.

52.       Scott DM, Young WN, Watumull LM, Lindberg G, Fleming JB, Rege RV, Brown RJ, Jones DB: Development of an in vivo tumor-mimic model for learning radiofrequency ablation. J Gastrointest Surg 2000, 4(6):620-625.

53.       Molpus KL, Wedergren JS, Carlson MA: Robotically assisted endoscopic ovarian transposition. Jsls 2003, 7(1):59-62.

54.       Hanly EJ, Marohn MR, Bachman SL, Talamini MA, Hacker SO, Howard RS, Schenkman NS: Multiservice laparoscopic surgical training using the daVinci surgical system. Am J Surg 2004, 187(2):309-315.

55.       Finnie NJ, Gottlieb TM, Blunt T, Jeggo PA, Jackson SP: DNA-dependent protein kinase defects are linked to deficiencies in DNA repair and V(D)J recombination. Philosophical transactions of the Royal Society of London Series B, Biological sciences 1996, 351(1336):173-179.

56.       Notarangelo LD: Primary immunodeficiencies. The Journal of allergy and clinical immunology 2010, 125(2 Suppl 2):S182-194.

UPDATED 3/14/2020

A recent Research Article and Research Article Summary in Science discusses, by the primary author of her study that describes the utility of the pig as an excellent surrogate model of the human brain and human brain function.  The study, by Dr. Evelina Sjostdedt et al., was an integrative analysis of porcine, mouse, and human transcriptomic, genomic, and proteomic data from discrete anatomical regions of the brain.  The global analysis suggested that there is similar regional organization and expression patterns among the three mammalian species.  The authors found interspecies variability with respect for many neurotransmitter receptors.

However, for some regions of the brain, such as the cerebellum and hypothalamus, the human global expression profile is closer to that of the pig than of the mouse, suggesting that the pig might be considered a preferred animal model to study many brain processes.

In addition, interestingly, the authors found that many signature genes canonically thought to only be expressed in certain brain cells (astrocytes, microglia, oligodendrocytes) are expressed in higher levels in peripheral organs as well as immune cells.

Please go to the full article in Science,

An atlas of the protein-coding genes in the human, pig, and mouse brain, 

Science  06 Mar 2020:
Vol. 367, Issue 6482, eaay5947
DOI: 10.1126/science.aay5947

to access the data used in this study, which includes high resolution images and metadata have also been made publicly available in the open-access Human Protein Atlas (HPA) Brain Atlas. at www.proteinatlas.org.

Other articles on this site pertaining to Alternate Animal Models and Cancer and Disease include:

Guidelines for the welfare and use of animals in cancer research

Demythologizing sharks, cancer, and shark fins

Predicting Drug Toxicity for Acute Cardiac Events

FDA Guidelines For Developmental and Reproductive Toxicology (DART) Studies for Small Molecules

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Carotid Ultrasound more sensitive for Detecting Subclinical Atherosclerosis in patients with rheumatoid arthritis (RA) than CT with calculation of Coronary Artery Calcification Scores

Posted in Atherogenic Processes & Pathology, Frontiers in Cardiology and Cardiovascular Disorders, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Origins of Cardiovascular Disease, Peripheral Arterial Disease & Peripheral Vascular Surgery, tagged Atherosclerosis, Cardiovascular disease, Cardiovascular Disorders, Conditions and Diseases, European League Against Rheumatism, rheumatoid arthritis on October 9, 2013| Leave a Comment »

Carotid Ultrasound more sensitive for Detecting Subclinical Atherosclerosis in patients with rheumatoid arthritis (RA) than CT with calculation of Coronary Artery Calcification Scores

Reporter: Aviva Lev-Ari, PhD, RN

Ultrasound Predicts CVD Risk in Arthritis

Published: Oct 8, 2013 | Updated: Oct 8, 2013

By Nancy Walsh, Staff Writer, MedPage Today

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

 

Carotid ultrasound was more sensitive for detecting subclinical atherosclerosis in patients with rheumatoid arthritis (RA) than CT with calculation of coronary artery calcification scores, Spanish researchers found.

Among a group of 60 patients classified as being at moderate cardiovascular risk on a conventional scoring system, the presence of severe abnormalities on ultrasound reclassified 51 as being at high or very high risk, according to Miguel A. Gonzalez-Gay, MD, of Universitario Marques de Valdecilla in Santander, and colleagues.

And of those 51 reclassified patients, only 12 would have been reclassified as being at high or very high cardiovascular risk using a coronary artery calcification score,the researchers reported in the NovemberAnnals of the Rheumatic Diseases.

Patients with RA are at markedly increased risk for cardiovascular disease (CVD), both from conventional risk factors and the ongoing systemic inflammation associated with RA.

Comprehensive management of these patients therefore should include risk assessment and appropriate interventions, but “adequate stratification of the CV risk in patients with RA is still far from being completely established,” Gonzalez-Gay and colleagues noted.

The insensitivity of conventional risk assessments such as the Systematic Coronary Risk Evaluation (SCORE), even when modified by the European League Against Rheumatism(mSCORE) to account for the increased background risk in RA, has been confirmed byreports of ischemic heart disease among patients not considered to be at elevated risk on these measures.

These researchers previously suggested that carotid ultrasonography be added to the overall risk assessment of RA patients, particularly those with moderate SCORE risk, but whether other noninvasive approaches such as coronary artery calcification also could be useful has been uncertain.

Therefore, they enrolled 95 rheumatoid arthritis patients with no history of cardiovascular events and no diabetes or chronic renal disease.

Most were women, mean age was 59, and mean disease duration was 11 years.

Rheumatoid factor and/or anticyclic citrullinated peptide was present in 72%, and extra-articular manifestations in 16%.

All patients had carotid ultrasonography to assess for plaque and multi-detector CT scanning to detect coronary artery calcification.

Carotid intima-media thickness of 0.90 or the presence of plaque was considered predictive of CVD on ultrasound.

A coronary artery calcification score of zero was considered normal, and a score over 100 indicated a high likelihood of coronary artery disease.

Patients also were given conventional SCORE ratings, based on factors such as age, sex, smoking, blood pressure, and atherogenic index, as well as mSCORE ratings, to estimate the 10-year risk for a fatal cardiovascular event.

The mean SCORE was 2.30, and the mean mSCORE was 2.78.

Cardiovascular risk according to mSCORE was low in 21, moderate in 60, and high or very high in 14.

Most patients with low mSCOREs also had scores of zero for coronary artery calcification, and none of the low mSCORE patients had calcification scores above 100.

But 57% of patients with calcification scores of zero had carotid plaques identified on ultrasound, as did 76.3% of patients with calcification scores between 1 and 100.

While calcification scores above 100 weren’t much more sensitive than mSCOREs for detection of high risk (23.6% versus 19.4%), almost all (70 of 72) patients with high or very high risk were identified with carotid ultrasound, for a sensitivity of 97.2% (95% CI 90.3-99.7).

And when the ultrasound model of intima-media thickness above 0.9 mm and/or carotid plaque also included mSCOREs above 5%, all 72 were correctly identified, for a sensitivity of 100% (95% CI 95-100).

This lack of sensitivity for calcification scores likely reflects the finding that arterial calcification is a later vascular development, and its absence doesn’t rule out the presence of the more vulnerable noncalcified plaques, the researchers explained.

“These results support the use of carotid ultrasonography as the imaging technique of choice for detection of high/very high CV risk in RA patients with moderate mSCORE,” they said.

In an editorial accompanying the study, Patrick H. Dessein, MD, of the University of Witwatersrand in Johannesburg, South Africa, and Anne G. Semb, MD, of Diakonhjemmet Hospital in Oslo, Norway, noted that the use of ultrasound more than tripled the number of patients considered to be at high risk.

If only mSCORE was used for risk stratification, they pointed out, many patients “in routine clinical settings” would be unlikely to receive preventive treatments, “with the serious consequences this has.”

Dessein and Semb also noted that there were certain limitations to this study, including its cross-sectional design and inclusion of patients with long disease duration.

“It remains to be clarified whether carotid ultrasound is as helpful among patients with early disease versus those with longstanding disease in enhancing CVD risk stratification,” the editorialists wrote.

The authors reported no conflicting interests.

From the American Heart Association:

• 2011 ASA/ACCF/AHA/AANN/AANS/ACR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease

http://www.medpagetoday.com/Rheumatology/Arthritis/42138?xid=nl_mpt_DHE_2013-10-09&utm_content=&utm_medium=email&utm_campaign=DailyHeadlines&utm_source=WC&eun=g99985d0r&userid=99985&email=avivalev-ari@alum.berkeley.edu&mu_id=5099207

 

 

 

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Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, CANCER BIOLOGY & Innovations in Cancer Therapy, Cancer Prevention: Research & Programs, Cell Biology, Signaling & Cell Circuits, Computational Biology/Systems and Bioinformatics, Genome Biology, Health Economics and Outcomes Research, Interviews with Scientific Leaders, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, tagged Aviva Lev-Ari, breast cancer, Cancer - General, colon cancer, Conditions and Diseases, DNA, DNA Sequencing, gene expression, genetics, intratumoral heterogeneity, microarray, National Institutes of Health, Personalized medicine, Proceedings of the National Academy of Sciences of the United States of America, Proteomics, Whole genome sequencing on September 4, 2013| Leave a Comment »

Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn

Curator and Writer: Stephen J. Williams, Ph.D.

Article ID #77: Issues in Personalized Medicine: Discussions of Intratumor Heterogeneity from the Oncology Pharma forum on LinkedIn. Published on 9/4/2013

WordCloud Image Produced by Adam Tubman

In an earlier post entitled “Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing” the heterogenic nature of solid tumors was discussed.  There resulted an excellent discussion in the Oncology Pharma forum on LinkedIn so I curated the comments (below article) to foster further discussion. To summarize the original post, this was a discussion of Dr. Charles Swanton’s paper[1] in which he and colleagues had noticed that individual biopsies from primary renal tumors displayed a variety of mutations of the same and different tumor suppressor genes (TSG), thereby not only revealing the heterogeneity of individual tumors but also how tumors can evolve.  Thus it was suggested that individual cells of a primary tumor can represent individual clones, each evolving on a distinct pathway to tumorigenicity and metastasis as each clone would have accumulated different passenger mutations.  It is these passenger mutations which have been posited to be responsible for a tumor’s continued growth (as discussed in the following post Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers).  Indeed, as Dr. Swanton mentioned in the posting that it is very likely a solid tumor contains discrete clones with different driver and passenger mutations and possibly different mutated TSG but also this intra-tumor heterogeneity would have great implications for personalized chemotherapeutic strategies, not only against the primary tumor but against resistant outgrowth clones, and to the metastatic disease, as Swanton and colleagues had found that the metastatic disease displayed tremendously increased genomic instability than the underlying primary disease.

Therefore it may behoove the clinical oncologist to view solid tumors as a collection of multiple clones, each having their own mutagenic spectrum and tumorigenic phenotype.  Each of these clones may acquire further mutations which provide growth advantage over other clones in the early primary tumor.  In addition, branched evolution of a clone most likely depends more on genomic instability and epigenetic factors than on solely somatic mutation.

This is echoed in a  report in Carcinogenesis back in 2005[3] Lorena Losi, Benedicte Baisse, Hanifa Bouzourene and Jean Benhatter had shown some similar results in colorectal cancer as their abstract described:

“In primary colorectal cancers (CRCs), intratumoral genetic heterogeneity was more often observed in early than in advanced stages, at 90 and 67%, respectively. All but one of the advanced CRCs were composed of one predominant clone and other minor clones, whereas no predominant clone has been identified in half of the early cancers. A reduction of the intratumoral genetic heterogeneity for point mutations and a relative stability of the heterogeneity for allelic losses indicate that, during the progression of CRC, clonal selection and chromosome instability continue, while an increase cannot be proven.”

Therefore if a tumor had evolved in time closer to the initial driver mutation multiple therapies may be warranted while tumors which had not yet evolved much from their driver mutation may be tackled with an agent directed against that driver, hence the branched evolution as shown in the following diagram:

Cancer Sequencing Unravels clonal evolution. From Carlos Caldas. (2012). Nature Biotechnology V.30 pp 405-410.[2] used with permission.

 

 

 

 

 

 

An article written by Drs. Andrei Krivtsov and Scott Armstron entitled “Can One Cell Influence Cancer Heterogeneity”[4] commented on a study by Friedman-Morvinski[5] in Inder Verma’s laboratory discussed how genetic lesions can revert differentiated neorons and glial cells to an undifferentiated state [an important phenotype in development of glioblastoma multiforme].

In particular it is discussed that epigenetic state of the transformed cell may contribute to the heterogeneity of the resultant tumor.  Indeed many investigators (initially discovered and proposed by Dr. Beatrice Mintz of the Institute for Cancer Research, later to be named the Fox Chase Cancer Center) show the cellular microenvironment influences transformation and tumor development[6-8].

Briefly the Friedman-Morvinski study used intra-cerebral ventricular (ICV) injection of lentivirus to introduce oncogenes within the CNS and produced tumors of multiple cell origins including neuronal and glial cell origin (neuroblastoma and glioma).  The important takeaway was differentiated somatic cells which acquire genetic lesions can transform to form multiple tumor types.  As the authors state, “cellular differentiation and specialization are accompanied by gradual changes in epigenetic programs” and that “the cell of origin may influence the epigenetic state of the tumor”.   In essence this means that the success of therapy may depend on the cellular state (whether stem cell, progenitor cell, or differentiated specialized cell) at time of transformation.  In other words tumors arising from cells with an epigenetic state seen in stem cells would be more resistant to therapy unless given an epigenetic therapy, such as azacytididne, retinoic acid or HDAC inhibitors.

 

So as the Oncology Pharma forum on LinkedIn was such an excellent discussion I would like to post the comments for curation purposes and foster further discussion.  I would like to thank everyone’s great comments below.  I would especially like to thank Dr. Emanuel Petricoin from George Mason and Dr. David Anderson for supplying extra papers which will be the subject of a future post. I had curated each comment with inserted LIVE LINKS to make it easier to refer to a paper and/or company mentioned in the comment.

The comments seemed to center on three main themes:

1. 1.      Clinicians pondering the benefit to mutational spectrum analysis to determine personalized therapy and develop biomarkers of early disease
2. 2.      A shift in the clinicians paradigm of cancer development, diagnoses, and treatment from strictly histologic evaluation to a genetic and altered cellular pathway view
3. 3.      Use of proteomics, microarray and epigenetics as an alternative to mutational analysis to determine aberrant cellular networks in various stages of tumor development

 

Victor Levenson • Thanks for posting this! To be honest, I am puzzled by the insistence on sequencing as a tool for tumor analysis – we know that expression patterns rather than mutations in a limited number of genes determine tumor physiology (or, even more, physiology of any tissue). Since the AACR-2012 we know that different tumors have similar or even identical mutations, so >functional< rather than >structural< differences are important. Frankly, I’d be much more excited learning about expression pattern heterogeneity in tumors.Granted that is much more challenging than NGS sequencing, but the value of the data would be incomparable, especially in its application to biomarker development.

Stephen J. Williams, Ph.D. • Dear Dr. Levenson, thanks for your comments. I agree with you and in no way am insisting on the releiance of sequencing mutations in cancer as the sole means for determining therapy. It is extremely true that tumors will show tremendous heterogeneity of mRNA expression. There are a number of studies (one which I will post on pharmaceuticalintelligence.com) that individual tumor cells will have differing expression patterns based on the levels of regional hypoxia within the tumor as well as other microenvironmental factors. I do have two posts on pharmaceuticalintelligence.com on this matter, curating various programs around the world which are using microarray expression analysis of tumors to determine personalized strategies. I believe the reliance on mutational analysis is based on the drugs that have been developed (such as Gleevec and crizotinib) which are based on mutant forms of BCR-Abl and ALK, respectively. However (as per two posts I did based on Mike Martin on our site “Mathematical Models of Driver and Passenger mutations) where he discusses how certain driver mutations will get the senescent cell over the hump to get to fully transformed and contribute to a certain level of growth while subsequent passengers are responsible for the sustained survival and expansion of the tumor.

Victor Levenson • Dr. Williams, thanks for the comments. Driving a senescent cell into proliferative stage is a tremendous change, which >may< begin with a mutation, but involves dramatic restructuring of transcription patterns that will drive the process. Hypoxia will definitely contribute to variations in the patterns, although will probably not be the main driver of the process. As to whether a mutation or a change in transcription pattern initiate the process, I am not sure we will ever be able to determine <grin>.

Vanisree Staniforth • Thanks for posting! Certainly a thought provoking article with regard to the future of personalized cancer therapies.

 

Dr. Raj Batra • If we follow Dr Levenson’s proposed conceptual approach (which we also published in 2009 and 2010), we are MUCH more likely to significantly impact tumor morbidity and mortality.

Stephen J. Williams, Ph.D. • Thanks Vanisiree and Dr. Batra for your comments. Hopefully we will see, from the future cancer statistics, how personlized therapy have improved outcomes for the solid tumors, like the hematologic cancers. 26 days ago

Emanuel Petricoin • The issue about intra and inter tumor heterogeneity is very important however since it is unknown which mutations are true drivers, an explanation of the results found in these studies simply could be the variances are all in the inconsequential mutations and the commonality is the driver mutations. Moreover, at the end of the day, its not the mRNA expression that we really care about but the functional protein signaling -phosphoprotein driven signaling architecture, that we care about since these are the drug targets directly.

Mohammad Azhar Aziz,PhD • This article addresses the potential complexity of dealing with cancer which is apparently increasing proportionally with the amount of data generated. Intratumor heterogeneity will remain there and even multiple biopsies that are randomly chosen will offer no conclusive solution.Mutations,expression profiles and functional protein signaling (as discussed above) alone can not provide any breakthrough. It will be a composite picture of all these and many other components (e.g. microenvironment, alternative splicing, epigenetics,non-coding RNAs etc.) that will hold the promises in the future. We have made phenomenal advances in understanding each of these aspects separately but definitely lack the tools to integrate all these. Developing tools to integrate all these data may provide some breakthrough in understanding and thus treating cancer.

Emanuel Petricoin • I agree Mohammad in a systems biology approach however the current compendium of drugs largely are kinase inhibitors or enzymatic inhibitors. Since most studies have shown little correlation between gene mutation and protein levels and phosphoprotein levels, for example, it is no wonder why the recent spate of failed trials (e.g. stratification by PIK3CA mutation or PTEN mutation for AKT-mTOR inhibitors) should come as any shock. We will be publishing work using protein pathway activation mapping coupled to laser dissection of a number of intra and inter tumoral analysis that indicates that the signaling architecture appears much more stable.

Stephen J. Williams, Ph.D. • Thank you Dr. Pettricoin for your comments. I eagerly await the publication of your results concerning proteomic evaluation of multiple biopsies of a tumor. I am very interested that you found limited intratuoral heterogeneity of signaling pathways given the diversity of intratumoral microenvironmental stresses (changes in regional hypoxia, blood flow, and populations of cancer stem cells). I agree with you and Mohammed that proteomic profiling will be imperative in determining personalized approaches for targeted therapy. Dr. Swanton had informed me that they had used IHC to determine if mTOR signaling had correlated with the mutational spectrum they had seen. In addition he had mentioned that there was enhanced genomic instability in the metastatic disease relative to the primary tumor and it would be very interesting to see how signaling pathways change in cohorts of matched metastatic and primary tumors. A few years ago we were looking at genes which were completely lost upon transformation of ovarian epithelial cells and worked up one of those genes (CRBP1) in cohorts of human ovarian cancer samples, using expression analysis in conjunction with laser capture microdissection and backed up by IHC analysis, and found that the expression pattern of CRBP1 was uniform in a tumor, either there was a complete loss in all cells in a tumor of CRBP1 or all the cells expressed the protein. Therefore I am curious if intratumor heterogeneity is dependent on the cell lineage and evolution of the transformed cell into a full tumor or a function of a discrete population of stem cells with varied genomic instability. Your results might suggest a more clonal evolution rather than a branched evolution which was found in this paper.
It is interesting that you mention the tough trials with the PTEN/PI3K/AKT axis of inhibitors. In high grade serous ovarian cancer we were never able to find any PI3K, PTEN, nor AKT mutations yet PI3K activity is usually overactive. If feel both your and Mohammed’s assessment that a systems biology approach instead of just relying on DNA mutational analysis will be more important in the future. In addition, there is nice work from Dr. Jefferey Peterson at Fox Chase and the development of a database of kinase inhibitors and activity effects on the kinome, showing the vast amount of crosstalk between once thought linear enzyme systems. If TKI’s will be the brunt of pharma’s development I feel they need to quickly develop as many TKI’s as they can now before we get to a clinical problem (resistance and lack of available therapeutics).

Emanuel Petricoin • Thanks Steven- yes, we are working with Charlie Swanton and Marco on the renal sets- our other studies are from breast and colon cancers. I think one of the things we do that really no one else is doing, unfortunately, is to laser capture microdissect the tumor cells from these specimens so that we have a more pure and accurate view of the signaling architecture. One confounder from the proteomic stand-point is the fact that pre-analytical variables such as post-excision delay times where the tissue is a hypoxic wound and signaling changes fluctuating as the tissue reacts to the ex-vivo condition can really effect things. When we look at tissue sets where the tissue is biopsied and immediately frozen we really dont see big differences in the signaling – the within tumor architecture is much more similar then between. We use the reverse phase array technology we invented to provide quantitative analysis on hundreds of phosphoproteins at once – so a nice view of the functional protein activation network. Your results of CRBP1 in ovarian tumors and the IHC data are very interesting. We will see how this all plays out. Of course once other confounder with the mutational data is that we really dont know what are the drivers and what are the passengers…
Yes I know Jeff Peterson’s work- its fantastic. In the end the hope I think- and in my personal opinion- will be rationally combined therapeutics based on the signaling architecture of each individual patient.

Incidentally, we just published a paper that you may be interested in from a “systems biology” standpoint-

SYSTEMS ANALYSIS OF THE NCI-60 CANCER CELL LINES BY ALIGNMENT OF PROTEIN PATHWAY ACTIVATION MODULES WITH “-OMIC” DATA FIELDS AND THERAPEUTIC RESPONSE SIGNATURES.

Federici G, Gao X, Slawek J, Arodz T, Shitaye A, Wulfkuhle JD, De Maria R, Liotta LA, Petricoin EF 3rd. Mol Cancer Res. 2013 May

also- we published a paper that speaks directly to your point where we compared the signaling network activation of patient-matched primary colorectal cancers and synchronous liver mets. indeed there is huge systemic differences in the liver metastasis compared to the primary. there is no doubt in my mind that we will need to biopsy the metastasis to know how to treat. Looking at the primary tumor as a guide for therapy is a fools errand. here is the paper reference:

Protein pathway activation mapping of colorectal metastatic progression reveals metastasis-specific network alterations.

Silvestri A, Calvert V, Belluco C, Lipsky M, De Maria R, Deng J, Colombatti A, De Marchi F, Nitti D, Mammano E, Liotta L, Petricoin E, Pierobon M.

Clin Exp Metastasis. 2013 Mar;30(3):309-16. doi: 10.1007/s10585-012-9538-5. Epub 2012 Sep 29.

Center for Applied Proteomics and Molecular Medicine, George Mason University, 10900 University Blvd., Manassas, VA, 20110, USA.

Abstract

The mechanism by which tissue microecology influences invasion and metastasis is largely unknown. Recent studies have indicated differences in the molecular architecture of the metastatic lesion compared to the primary tumor, however, systemic analysis of the alterations within the activated protein signaling network has not been described. Using laser capture microdissection, protein microarray technology, and a unique specimen collection of 34 matched primary colorectal cancers (CRC) and synchronous hepatic metastasis, the quantitative measurement of the total and activated/phosphorylated levels of 86 key signaling proteins was performed. Activation of the EGFR-PDGFR-cKIT network, in addition to PI3K/AKT pathway, was found uniquely activated in the hepatic metastatic lesions compared to the matched primary tumors. If validated in larger study sets, these findings may have potential clinical relevance since many of these activated signaling proteins are current targets for molecularly targeted therapeutics. Thus, these findings could lead to liver metastasis specific molecular therapies for CRC.

Adrian Anghel • I think both patterns (protein phosphorylation and mRNA) should be important in this complicated equation of heterogeneity. Let’s not forget the so-called functional miRNA-mRNA regulatory modules (FMRMs). Also I think we have different patterns of this heterogeneity for different evolutive stages of the tumour.

 

Alvin L. Beers, Jr., M.D. • This is a great study, but bad news for attempting to tailor treatment based on molecular markers. Dr. Swanton’s comment: “herterogeneity is likely to complicate matters” is an understatement. Intratumoral heterogeneity, branched, instead of linear, evolution of mutational events portends a nightmare in trying to predict location and volume of biopsies. I am reminded of a series of articles in Nature 491 (22 November 2012) “Physical Scientists take on Cancer”. There is a great comment by Jennie Dusheck: “Cancer researchers now recognize that taming wild cancer cells – populations of cells that evolve, cooperate, and roam freely through the body-demand a wider-angle view than molecular biology has been able to offer. Cross-disciplinary collaborations can approach cancer a greater spatial and temporal scales, using mathematical methods more typical of engineering, physics, ecology and evolutionary biology. The sense of failure so evident five years ago is giving way to the excitement of a productive intellectual partnership.” I’m not certain how well the “productive partnership” is going, but this Swanton study confirms the limitations of molecular biology.

Stephen J. Williams, Ph.D. • Thanks Dr. Beers for adding in your comment and adding in Jennie’s comment. Certainly it is something to be aware of if a cancer center’s strategy is to rely solely on gene arrays to genotype tumors. I think Dr. Pettricoin’s work on using proteomics might give some resolution to the matter however, in communicating with Dr. Swanton, I did not get the feeling of an “all hope is lost” but just that, in the case of solid tumors like renal, that careful monitoring of tumors after treatment may be warranted and, more interestingly, from a scientific standpoint, is the genetic complexity surrounding the origin of the disease, and not simple mutational spectrum of a single clone.

Burke Lillian • This is clinically a very important issue. Right now, sequencing or massive approaches such as pan-phosphorylation studies are helpful because, although we know many of the drivers, these studies are actually identifying new genes or new pathways that are activated. After a few (or several years), we truly will know which genes are typically activated and there will be panels to look for these.

Emanuel Petricoin • yes, I agree. In fact, the company that I co-founded, Theranostics Health, Inc– is launching a CLIA based protein pathway activation mapping test at ASCO that measures actionable drug targets (e.g. phospho HER2, EGFR, HER3, AKT, ERK, JAK, STAT, p70S6) and total HER2, EGFR, HER3 and PTEN. So these tests are coming even now.

 

Alvin L. Beers, Jr., M.D. • I do not think that “all hope is lost” nor did I have the impression that Dr. Swanton feels that way with regards to molecular profiling of cancer. I certainly applaud further research into the molecular aspects of cancer biology. But I do not believe that this will be sufficient. Integrating physicial sciences into cancer biology makes perfect sense toward better understanding of this complex disease.

Eleni Papadopoulos-Bergquist • I have enjoyed reading these comments and different ideas regarding genetic testing and profiling. As a nurse and researcher at heart, this is information that will make a huge impact on drug protocols, therefore allowing the best and most specific treatment to each individual rather than having a standard treatment protocol. Even with the scientific complexity of specifying genotypes of particular cancers, there is still the question of each individuals body responding to treatment. I’d love to have some dialogue regarding immune response.

Bradford Graves • I too have enjoyed reading this discussion. I am not a clinician but as a drug discovery researcher I have been struck by some parallels to the concept of virus fitness in virology – particularly as applied to HIV. Drug discovery cannot wait for the final answers to the many important questions being addressed in the discussion initiated by Dr. Williams. The best we can do is to pursue a broad range of therapeutics that will give the clinicians the armament they will need to either cure a given cancer or to at least turn it into a chronic as opposed to an acute disease. There has been a measure of success in the HIV field and it seems like it will be achievable for cancer. Obviously, to the extent that the labels of driver and passenger mutations can be correctly applied will help to prioritize the targets we address.

David W. Anderson • I would suggest that you look at the following publications:

Horn and Pao, (2009) JCO 26: 4232-4234.

Bunn and Doebele (2011) JCO:29:1-3

Boguski et al. (2009) Customized care 2020: how medical sequencing and network biology will enable personalized medicine. F1000 Bio Report 1:7.

Jones, S et al. (2010). Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biology. 11:R82. Marco Marra’s group in Toronto.

Also look at how companies and organizations like Foundation Medicine, Caris, Clarient, and CollabRx who are using genomics and sequencing on a large scale to address cancer from a personalized/individual approach.

Cancer is/will be a chronic disease requiring individualized/combinatorial therapies in many cases.

Alvin L. Beers, Jr., M.D. • David. These are excellent articles by Paul Bunn and Mark Boguski regarding integrating molecular markers into diagnostic evaluation, and I’ve seen other papers of similiar elk, and likely there will be more to come. Particularly in NSC lung cancer, the SOC is to use these markers up front. Diagnosis based on histology alone can no longer be recommended. The challenge for the future is how to integrate other aspects of cell biology with these markers. It remains daunting that not only do we see heterogeneity in molecular within tumors at a particularly point in time, but that there is often an evolution of markers over time, ie, a “plasticity” of markers, whether treatment is given or not. We know that targeted agents, TKI’s, enzyme inhibitors are not curative, but do give an improvement in PFS. A great deal of this resistance has to do with this “moving target” aspect of cancer cell biology..

 

References:

1.         Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P et al: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. The New England journal of medicine 2012, 366(10):883-892.

2.         Caldas C: Cancer sequencing unravels clonal evolution. Nature biotechnology 2012, 30(5):408-410.

3.         Losi L, Baisse B, Bouzourene H, Benhattar J: Evolution of intratumoral genetic heterogeneity during colorectal cancer progression. Carcinogenesis 2005, 26(5):916-922.

4.         Krivtsov AV, Armstrong SA: Cancer. Can one cell influence cancer heterogeneity? Science 2012, 338(6110):1035-1036.

5.         Friedmann-Morvinski D, Bushong EA, Ke E, Soda Y, Marumoto T, Singer O, Ellisman MH, Verma IM: Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice. Science 2012, 338(6110):1080-1084.

6.         Mintz B, Cronmiller C: Normal blood cells of anemic genotype in teratocarcinoma-derived mosaic mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(12):6247-6251.

7.         Watanabe T, Dewey MJ, Mintz B: Teratocarcinoma cells as vehicles for introducing specific mutant mitochondrial genes into mice. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(10):5113-5117.

8.         Mintz B, Cronmiller C, Custer RP: Somatic cell origin of teratocarcinomas. Proceedings of the National Academy of Sciences of the United States of America 1978, 75(6):2834-2838.

 

 

Other articles on this site on “PERSONALIZED MEDICINE” and “CANCER” and “OMICS” include:

Personalized medicine-based diagnostic test for NSCLC

Personalized medicine and Colon cancer

Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center

Systems Diagnostics – Real Personalized Medicine: David de Graaf, PhD, CEO, Selventa Inc.

Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

Personalized Medicine: Clinical Aspiration of Microarrays

Understanding the Role of Personalized Medicine

Directions for Genomics in Personalized Medicine

Paradigm Shift in Human Genomics – Predictive Biomarkers and Personalized Medicine – Part 1

Rewriting the Mathematics of Tumor Growth; Teams Use Math Models to Sort Drivers from Passengers

Diagnosing Diseases & Gene Therapy: Precision Genome Editing and Cost-effective microRNA Profiling

Breast Cancer: Genomic profiling to predict Survival: Combination of Histopathology and Gene Expression Analysis

Proteomics and Biomarker Discovery

 

 Also please see our upcoming e-book “Genomics Orientations for Individualized Medicine” in our Medical E-book Series at http://pharmaceuticalintelligence.com/biomed-e-books/genomics-orientations-for-personalized-medicine/volume-one-genomics-orientations-for-personalized-medicine/

 

 

 

 

 

 

 

 

 

 

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Vasoplegia in Orthotopic Heart Transplant Patients

Posted in Ecosystems & Industrial Concentration in the Medical Device Sector, FDA Regulatory Affairs, International Global Work in Pharmaceutical, Medical Devices R&D and Inventions, Nitric Oxide in Health and Disease, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, tagged BMI, cardiothoracic surgery, Cheyne-Stokes Respiration, Conditions and Diseases, Heart Failure, Heart Lung Transplant, Larry H. Bernstein, mechanical support, surgery, thyroid disease, vasoplegia on June 30, 2013| Leave a Comment »

Pre-operative Risk Factors and Clinical Outcomes Associated with Vasoplegia in Recipients of Orthotopic Heart Transplantation in the Contemporary Era.

Writer and Curator: Larry H. Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN 

 

 Patarroyo M, Simbaqueba C, Shrestha K, Starling RC, Smedira N, Tang WH, Taylor DO.

J Heart Lung Transplant. 2012 Mar;31(3):282-7.  http://dx.doi.org/10.1016/j.healun.2011.10.010  Epub 2011 Nov

 

BACKGROUND:  Patients who underwent orthotopic heart transplant (OHT) can develop vasoplegia, which is

• associated with high mortality and morbidity.

Herein we examine the per-operative risk in OHT recipients at Cleveland Clinic.  Vasoplegic syndrome is

• low systemic vascular resistance ( SVR index <1,600 dyn∙seg/cm5/m2 ) and
• high cardiac output ( cardiac index >2.5 l/min/m2 )
• within the first 4 postoperative hours.

VPS occurs more frequently after on pump CABG surgery versus off pump CABG surgery.

Methylene blue and vasoplegia: who, when, and how?

Stawicki SP, Sims C, Sarani B, Grossman MD, Gracias VH.

Department of Surgery, Division of Surgical Critical Care, University of Pennsylvania School of Medicine

Mini Rev Med Chem. 2008 May;8(5):472-90.  http://www.ncbi.nlm.nih.gov/pubmed/18473936

Vasoplegia or vasoplegic syndrome (VS) is thought to be due to

• dysregulation of endothelial homeostasis and subsequent endothelial dysfunction
• secondary to direct and indirect effects of multiple inflammatory mediators.

Vasoplegia has been observed in all age groups and in various clinical settings, such as anaphylaxis (including protamine reaction), sepsis, hemorrhagic shock, hemodialysis, and cardiac surgery. Among mechanisms thought to be contributory to VS, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway appears to play a prominent role.

Methylene blue (MB),

• an inhibitor of nitric oxide synthase (NOS) and guanylate cyclase (GC),

has been found to improve

• the refractory hypotension associated with endothelial dysfunction of VS.

METHODS:  We reviewed peri-operative data from 311 consecutive adult patients who underwent OHT between January 2003 and June 2008.

Vasoplegia was defined as

1. persistent low systemic vascular resistance,
2. despite multiple intravenous pressor drugs at high dose,
3. between 6 and 48 hours after surgery.

RESULTS:  In our cohort of 311 patients, 35 (11%) patients developed vasoplegia syndrome; these patients were more likely to be UNOS Status 1A, with

• a higher body surface area (1.8 ± 0.25 vs 1.63 ± 0.36, p = 0.0007),
• greater history of thyroid disease (38.2% vs 18.5%, p = 0.0075) and
• a higher rate of previous cardiothoracic surgery (79% vs 48%, p = 0.0006).

Pre-operatively,

• they were more frequently treated with aspirin (73% vs 48%, p = 0.005) and
• mechanical assist devices (ventricular assist devices [VADs]: 45% vs 17%, p < 0.0001;
• total artificial hearts: 8.6% vs 0%, p < 0.0001), and
• less treated with milrinone (14.7% vs 45.8%, p = 0.0005).

Bypass time (118 ± 37 vs 142 ± 39 minutes, p = 0.0002) and

donor heart ischemic time (191 ± 46 vs 219 ± 51 minutes, p = 0.002) were longer, with

• higher mortality (3.2% vs 17.1%, p = 0.0003) and morbidity in the first 30 days after transplant.

In the multivariate analysis, history of thyroid disease (odds ratio [OR] = 2.7, 95% CI 1.0 to 7.0, p = 0.04) and VAD prior to transplant (OR = 2.8, 95% CI 1.07 to 7.4, p = 0.03)

• were independent risk factors for development of vasoplegia syndrome.

CONCLUSIONS:

1. High body mass index,
2. long cardiopulmonary bypass time,
3. prior cardiothoracic surgery,
4. mechanical support,
5. use of aspirin, and
6. thyroid disease

are risk factors associated with development of vasoplegia syndrome.

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Space-filling model of the cyclic guanosine monophosphate molecule, also known as cGMP, a nucleotide. This image shows the anionic (negatively charged) form. Colour code (click to show) : Black: Carbon, C : White: Hydrogen, H : Red: Oxygen, O : Blue: Nitrogen, N : Orange: Phosphorus, P (Photo credit: Wikipedia)

Ball-and-stick model of the cyclic guanosine monophosphate molecule, also known as cGMP, a nucleotide. This image shows the anionic (negatively charged) form. Colour code (click to show) : Black: Carbon, C : White: Hydrogen, H : Red: Oxygen, O : Blue: Nitrogen, N : Orange: Phosphorus, P (Photo credit: Wikipedia)

English: Drawing showing targets of cGMP in cells (Photo credit: Wikipedia)

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