Goal 1: Promote Human Health

Mechanism of dietary polysaccharide/ sugars in averting CVD and cancer

CQ

Submitted by (@mayaraman)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Non-communicable diseases and their preventive measure are always of interest. But we always, face side-effects because of these new applications. And at times, these techniques fail.

Diet today is a attractive area of discussion. Everyday, we read or hear that control of diet has cured severe conditions.

In fact, as the saying goes, we are what we eat. Today, scientific communities can lay emphasis on the researches concerning these topics. Dietary polysaccharides/ polyphenols etc. have a promising role in deciding our health. We can include these in our diet but the mechanism of the action of these factors in preventing diseases has not be explored in detail. The role of specific factors in diet at specific sites, may assist in pin-point treatment with better results and no side-effects. Can this topic be considered for research!

Feasibility and challenges of addressing this CQ or CC :

Challenges include creating teams of researchers with basic research expertise and experienced researchers to collaborate and come up with plans to understand the action of system and to design strategies utilizing dietary carbohydrates to have healthier and long term benefits.

Name of idea submitter and other team members who worked on this idea : Raman M

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-8 net votes
6 up votes
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Goal 3: Advance Translational Research

Leveraging big data for T4 translation research

What approaches can help leverage the emerging big data in health and health care for observational and interventional implementation research in heart, lung, blood, sleep diseases?

Submitted by (@nhlbiforumadministrator)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

• Integration of big data analytics into T4 research study design and interventions development

• Innovative linkages across multiple health and non-health sector data

• Innovative methods to analyze big data linked across sectors

• Various communities are using big data analytics to understand population health data (e.g. electronic medical records s) and opportunities exist for consolidation of these efforts and standardization of methodologies

Feasibility and challenges of addressing this CQ or CC :

• NIH now has focus on big data in its formative stages

• Significant amount of NIH’s budget is/will be dedicated to big data research

• NHLBI can leverage NIH’s investment by foster research in D&I big data analytics and systems science

• Future investment in big data should yield opportunities and focus efforts

Name of idea submitter and other team members who worked on this idea : NHLBI Staff

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Goal 1: Promote Human Health

Epigenetics and Genomics

There is a need to target epigenetic mechanisms as new treatment options for hematologic disorders.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Advances in the field of epigenetics and the understanding of various epigenetic mechanisms has provided a completely new ensemble of therapeutic targets for treating hematologic disorders – both non-malignant and malignant. These mechanisms have enormous implications for understanding the molecular underpinnings of the normal orderly development of hematologic disorders. Although one of the greatest challenges in effectively treating hematologic disorders is the diversity of molecular abnormalities that underlie a disease, there are a number of common threads emerging, including alterations in proteins that function through epigenetic mechanisms. Additional research focusing on epigenetic alterations and emerging targets is needed to identify the role of such proteins in the development of hematologic disorders in order to design potential targeted treatments to counter their effects. This research will further lay the groundwork for precision medicine, and will help to provide more insight on potentially critical determinants of responsiveness to therapeutic regimens.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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-2 net votes
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15 down votes
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Goal 2: Reduce Human Disease

Development of right ventricular-targeted therapies in pulmonary arterial hypertension (PAH)

Pulmonary arterial hypertension (PAH) is a complex, progressive condition characterized by high blood pressure in the lungs and restriction of flow through the pulmonary arterial system. A great increase in the treatment armamentarium has been noted for this rare disease in the past 20 years, with 12 new PAH-targeted therapies. Though these therapies do improve cardiac performance, this is most likely due to their primary ...more »

Submitted by (@katherinek)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Since 2006, 12 medical therapies for PAH have been approved by the FDA, which have increased survival of this rare disease from around 2.8 years to approximately 9 years; these therapies primarily act by dilating the pulmonary arteries in order to reduce pulmonary vascular resistance to blood flow. However, patients continue to die from right ventricular failure, highlighting the important relationship of the pulmonary arterial system and right ventricle (RV). Despite patients ultimately dying from RV failure, little is known about the effect of the currently available PAH-targeted therapies on RV functional support. Prostacyclins, PDE5i, and sGC agonists are thought to enhance RV contractility—though the long-term effects remain unknown—while ERAs are thought to reduce it. The direct RV effect of some potential therapies targeting the pseudo-malignancy theory of PAH is a concern, as these therapies seek to reduce the hypertrophy and angiogenesis that may actually be supporting the adapting RV. Further, therapies targeting the ventricle directly have historically been centered on the LV—for example β-adrenergic receptor blockers and RAS inhibition—and either remain controversial or without data in the RV. There remains no identified RV-specific therapy to either provide support through increase contractility or molecularly prevent the progression from RV hypertrophy to ultimate failure.

Feasibility and challenges of addressing this CQ or CC :

The primary challenge of addressing this CC on the lack of RV-targeted therapies for the treatment of PAH is the comprehensive analysis and support that will need to be provided, spanning from basic to clinical science. To begin, strong support of biologic characterization of the right ventricle needs to be provided. The RV is distinctly different from the more comprehensively studied left ventricle, and subsequently responds differently to autocrine, paracrine, neuroendocrine, pressure, and pharmaceutical changes to name only a few. However, when identified, these RV biologic distinctions can be translated and tested clinically to more comprehensively and appropriately treat the RV-arterial uncoupling ultimately leading to right heart failure: through both reduction in afterload and an increase in contractility.

Name of idea submitter and other team members who worked on this idea : Katherine Kroner, Michael Patrick Gray, PHA

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Goal 3: Advance Translational Research

To find specific medical therapies to treat the wide array of human vascular malformations and vascular tumors.

Vascular malformations and vascular tumors, together referred to as vascular anomalies, comprise a complex and wide array of diseases in which there is a fundamental disruption in blood and lymphatic vasculature. The lesions disrupt organ function, destroy tissue, cause bleeding, increase infections and can threaten life. At present, there are some medical therapies but none are specifically targeted to an underlying ...more »

Submitted by (@joyce.bischoff)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Deciphering the cellular and molecular basis of human vascular anomalies will have a critical impact for patients with these lesions and it will also have a broad, far-reaching impact on cardiovascular research because the mechanisms and insights learned from these specific vascular anomalies will teach us the fundamental rules that are needed, and must be followed, to build and maintain a stable functional vasculature in humans. This will have an impact on a variety of areas of research including regenerative medicine.

Feasibility and challenges of addressing this CQ or CC :

With the enormous advances in next generations sequencing technologies, the time is ripe for a concerted push to find the gene mutations that cause human vascular malformations and vascular tumors, both the most common and the rare. Cellular models for human endothelial cells are vastly improved and far superior to murine endothelial models, making research on patient-derived cells highly feasible.

The challenges will be to develop animal models of the individual human vascular anomalies that reflect as closely as possible the critical and specific features of the vascular malformation or vascular tumor. Such animal models, as well as relevant cellular in vitro models, would then be ideal for screen drug libraries for ability to reverse or slow the formation of the malformation or tumor. Such drugs might then be candidates to test in pilot clinical trials.

Name of idea submitter and other team members who worked on this idea : Joyce Bischoff

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Goal 3: Advance Translational Research

Genome Profiling

What structural changes need to be implemented in the health-care community in order to support the use of genomic information in clinical trials and drug development for hematologic diseases?

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

In various blood disorders, including hematologic malignancies, there are both inherited and somatic genetic alterations that contribute to predisposition, transformation, disease progression, responsiveness to therapy, and treatment complications. The presence of such genetic alterations underscore the need for the identification of rare but traceable mutations as well as the integration of such genomic information into clinical trials. By implementing a few structural changes in the healthcare sector, a clinical trial infrastructure can be established that accounts for proper application of sequencing technology. Some examples include the creation of genome diagnostic networks that address accrual of sufficient patients, procurement of suitable tumor/non-tumor material for sequencing, as well as pharmacodynamic and correlative biology studies in hematologic diseases.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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11 net votes
22 up votes
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Goal 2: Reduce Human Disease

Transplantation across HLA barriers in aplastic anemia

Allogeneic stem cell transplantation is curative in aplastic anemia with much less intrinsic toxicity than transplantation in hematologic malignancies. The recent BMT-CTN trial demonstrated 97% survival at one year with little subsequent decline. However patients without matched related or unrelated donors have graft-rejection rates of up to 50%. Preliminary data from the Netherlands suggests that anti-thymocyte globulin ...more »

Submitted by (@jantin)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

The use of umbilical cord blood or haploidentical donors has proven effective in patients with hematologic malignancies, but in non-malignant disorders outcomes are limited by graft rejection. Overcoming rejection in this context would be applicable to other non-malignant disorders such as thalassemia, sickle cell anemia, and other congenital disorders of hematopoiesis.

Feasibility and challenges of addressing this CQ or CC :

It will require a large coordinated network like BMT-CTN to obtain sufficient patients studied in a uniform fashion to provide consistent reproducible data. .

Name of idea submitter and other team members who worked on this idea : Joseph Antin

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137 up votes
27 down votes
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Goal 1: Promote Human Health

Iron Loss after Blood Donation and Its Effect on Donors’ Health

What is the effect of donation-induced iron deficiency on blood donor health?

Submitted by (@anne.eder)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Blood donation removes iron, and frequent blood donors commonly have low or absent iron stores. Donation frequency remains the strongest predictor of iron depletion among all donors, after controlling for body mass, race/ethnicity, and polymorphisms affecting iron metabolism. Less well documented is the effect of iron depletion on blood donor health and well-being. Iron deficiency may have a broad spectrum of physical and neurologic consequences, including impaired work capacity, altered cognitive function, pica and restless legs syndrome. The prevalence, duration, and severity of these conditions in blood donor populations are poorly elucidated. In contrast, modest iron deficits may be protective against cancer and cardiovascular disease. Some investigators have demonstrated the feasibility to connect donor information with clinical databases to study whether donation behavior and iron status have long-term consequences for donor health.

Feasibility and challenges of addressing this CQ or CC :

Studying the short-term clinical impact of donation-induced iron deficiency presents logistical and methodological challenges. Many outcomes of interest are not observable by blood center staff under routine procedures; further, such studies are subject to selection bias due to donor failure to return to donate following low hemoglobin deferral or adverse outcomes they associate with donation. However, given the size and demographic diversity of donor populations, even uncommon outcomes can be successfully studied under a multi-center approach. A prospective approach that doesn’t condition enrollment or completion of the study on return to donate, may avoid the methodological pitfalls. A wide array of clinical or neurological outcomes can feasibly be studied with sufficient blood centers and/or donor follow-up.

Name of idea submitter and other team members who worked on this idea : Dana Devine PhD and Anne Eder MD PhD for the 2015 NHLBI State of the Science in Transfusion Medicine

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19 up votes
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Goal 3: Advance Translational Research

Genome Editing and Gene Therapy

There is a critical need for the establishment of strategies that will determine the efficacy, safety, and toxicity of genome editing techniques specifically in hematologic diseases.

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Inherited monogenic hematologic diseases such as hemophilia, beta-thalassemia and sickle cell disease are prime targets for future application of genome editing technology. However, studies are still needed to advance our understanding of the biology of genome editing as well as determine which other disorders are amenable to genome editing correction. Emphasis on preclinical research that focuses on determining the accuracy, safety and efficiency of this technology in order to help minimize off-target mutations and reduce toxicity, is essential for effective translation of this technology into the clinic. Once preclinical efficacy is established, support will be needed for clinical vector production, toxicity testing of the vectors/reagents used, and the performance of clinical trials. The gene correction strategies developed for inherited disorders will also be attractive for other hematologic diseases, and autoimmune disorders like lupus, rheumatoid arthritis, and type I diabetes). There is also a critical need for supporting preclinical validation studies, scale-up and GMP cell manufacturing, all of which could be shared infrastructures across multiple diseases in the NHLBI portfolio.

Name of idea submitter and other team members who worked on this idea : Alice Kuaban on behalf of the American Society of Hematology (ASH)

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69 net votes
87 up votes
18 down votes
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Goal 3: Advance Translational Research

Genomics in transfusion medicine

How can RBC genomics be utilized to improve outcomes with transfusion?

Submitted by (@barbarak)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Prevention of alloimmunization with transfusion

Improved understanding of RBC epitope diversity

Feasibility and challenges of addressing this CQ or CC :

Utilize advances in genomics medicine to better understand impact of transfusion and to improve outcomes.

Limited donor pool, particularly in minority populations, presents challenges

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Goal 3: Advance Translational Research

Develop alternatives for patients for whom routine red cell transfusion is unavailable or impractical

There is a compelling need to advance research to understand the physiology governing the safety and efficacy of hemoglobin-based oxygen therapeutics functioning outside the red cell.

Submitted by (@chintamani.atreya)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Critical Challenge (CC)

Details on the impact of addressing this CQ or CC :

Adequate numbers of red blood cells are required to sustain human life. Neurocognitive deficits and mortality in acutely anemic humans increase significantly at a hemoglobin level of below 5 g/dL even in the absence of significant cardiovascular disease. At extremely low hemoglobin levels, alternative treatments (supplemental or hyperbaric oxygen, sedation, muscle paralysis and mechanical ventilation) are of only limited benefit and are not without risk. Several classes of patients cannot be routinely transfused with red blood cells. These classes of patients for whom blood is not an option would include patients who will not accept transfusion for religious or personal reasons, patients who due to multiple prior transfusions have developed red cell antibodies without the option for compatible red cells, and massive trauma patients needing treatment in a remote location. The development of cell-free hemoglobin-based oxygen carriers, stable at room temperature and not requiring cross-matching prior to transfusion as a red cell substitute, has been a sought after goal for several decades, yet to date all attempts have met with failure during clinical trials. There is a compelling need to advance research to understand the physiology governing the safety and efficacy of hemoglobin-based oxygen therapeutics functioning outside the red cell.

Feasibility and challenges of addressing this CQ or CC :

Multiple physiologic insults and adverse events seen with earlier modified hemoglobins, compared to banked red blood cells, have been described and are now better, but not completely, understood. Advances in hemoglobin modification could allow for successful use in a variety of clinical scenarios with life-saving results. Additional clinical indications could be investigated and established, such as identification of clinical situations where additional oxygen delivery could modulate the effects of chronic ischemic conditions. In addition, the hemoglobin molecule could be modified to deliver additional therapeutic benefit.

Name of idea submitter and other team members who worked on this idea : Office of Blood Research and Review, CBER, FDA

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Goal 2: Reduce Human Disease

Evidence based approaches to Red Blood Cell transfusion

What are the optimal RBC transfusion thresholds for adult and pediatric cancer patients undergoing chemotherapy regimens that may improve functional status and quality of life?

Submitted by (@nareg.roubinian)

Is this idea a Compelling Question (CQ) or Critical Challenge (CC)? : Compelling Question (CQ)

Details on the impact of addressing this CQ or CC :

Cancer patients undergo intensive medical and surgical therapies to treat their underlying disease. Treatment commonly results in anemia requiring RBC and platelet transfusions to support the patient through the hypoproliferative phase of chemotherapy. This is particularly true for those patients requiring hematopoetic stem cell transplantation (HSCT). Following therapy, cancer outpatients commonly receive RBC transfusions for weeks to months to maintain their functional status.

 

Common causes of death in patients with hematological malignancies and other cancers are infections and bleeding. A meta-analysis of clinical trials suggested that liberal transfusion is associated with greater risk of infection. Conversely, restrictive transfusion could adversely affect quality of life and functional status in oncology populations. In addition, pre-clinical and clinical studies support that concomitant anemia and thrombocytopenia significantly compound bleeding risk, and that hemostasis can be optimized in thrombocytopenia by maintaining a higher hematocrit. Although bleeding risks in relation to platelet transfusion thresholds are well studied in patients with hematological malignancy, optimal hemoglobin levels in thrombocytopenic patients are not known. Despite the significant allocation of blood components to cancer patients as a whole, RBC transfusion practices are not well studied within this group.

Feasibility and challenges of addressing this CQ or CC :

Randomized controlled clinical trials and other studies investigating optimal transfusion thresholds and other measures of practice are required to provide health care providers with evidence to guide one of the most common therapies administered in the setting of malignancy. The clinically important end points of well-designed studies could include: 1) quality of life and functional status for both inpatients and outpatients; 2) neurocognitive development in pediatric populations; 3) bleeding events / bleeding scores; 4) impact on immunity including immunomodulation and infection; 5) reconstitution of hematopoiesis; and 6) survival and/or recurrence of disease.. Besides a generalizable study population, certain target populations of interest are those with high risk disease, HSCT patients, patients undergoing radiation therapy, and pediatric patients.

 

There are >1.6 million new cases of cancer annually in the USA, including >50,000 with leukemia and >6,000 with HSCT. Cancer therapies are rapidly advancing in the era of genomics and immunotherapy. Capitalizing on the tradition of research in cancer, single and multicenter studies of RBC transfusion are feasible using randomized controlled designs in conjunction with clinical trials of chemotherapeutic regimens. The results of these studies will impact a large patient population’s quality of life, and may ultimately impact healthcare cost and blood demand.

Name of idea submitter and other team members who worked on this idea : Nareg Roubinian, MD and Naomi Luban, MD for the 2015 NHLBI State of the Science in Transfusion Medicine

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18 down votes
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