Intestinal Disease

Coding Dimension ID: 
299
Coding Dimension path name: 
Intestinal Disease

Mechanism of Tissue Engineered Small Intestine Formation

Funding Type: 
New Faculty II
Grant Number: 
RN2-00946
ICOC Funds Committed: 
$3 415 000
Disease Focus: 
Intestinal Disease
Pediatrics
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
Short Bowel Syndrome is an expensive, morbid condition with an increasing incidence. Fundamental congenital and perinatal conditions such as gastroschisis, malrotation, atresia, and necrotizing enterocolitis (NEC) may lead to short bowel syndrome (SBS). NEC is the most common gastrointestinal emergency in neonates and primarily occurs in premature infants As rates of prematurity are increasing, so are the numbers of children with SBS and NEC. In addition, prevalence is increased for other diagnoses such as gastroschisis, which has nearly doubled. Medical and surgical treatment options carry high dollar and human costs and morbidities including multiple infections and hospitalizations for vascular access, liver failure in conjunction with parenteral nutrition-associated cholestasis, and death. Small bowel transplant has a reported 5 year graft survival of 48%, but is attended by rejection, the morbidity of major surgery, and a lifelong need for anti-rejection medication. A report on 989 grafts in 923 patients by the Intestine Transplant Registry reveals improving outcomes, but one year graft/ patient survival rates are 65%/77%. Tissue engineered small intestine (TESI) offers a potential alternative durable autologous therapy that avoids the problems of donor graft supply for intestinal transplant and long term immunosuppression. TESI exactly recapitulates native intestine histology. All four epithelial lineages are seen in conjunction with a lamina propria, nerve elements, and muscularis mucosa. OU, when reduced to single cells or the single cell fraction obtained in the purification of OU do not form TESI. This multicellular OU transplantation strategy is distinctive in producing full-thickness TESI that recapitulates all the layers of native intestine, and in the Lewis rat, intact function. In order to meet regulatory requirements and to guarantee the best chance of success by optimizing all conditions, we must define the necessary and sufficient progenitor cell population that will be transplanted. In addition, defining the mechanisms by which TESI forms and therefore can be impelled will underpin the best chance of success in human trials. This grant proposal seeks to identify and surpass the barriers to using TESI as a human therapy for SBS.
Statement of Benefit to California: 
Short Bowel Syndrome is an expensive, morbid condition with an increasing incidence. Fundamental congenital and perinatal conditions such as gastroschisis, malrotation, atresia, and necrotizing enterocolitis (NEC) may lead to short bowel syndrome (SBS). NEC is the most common gastrointestinal emergency in newborn babies in California and primarily occurs in premature infants As rates of prematurity are increasing, so are the numbers of children with SBS and NEC. In addition, more babies in California are getting SBS associated with other diagnoses such as gastroschisis, which has recently nearly doubled. Medical and surgical treatment options carry high dollar and human costs and children suffer from problems such as infections and hospitalizations for vascular access, liver failure, and death. The only therapy currently is small bowel transplant, but a recent study showed that the transplant only has a 65% chance of surviving in the first year, and the child has only a 77% chance of surviving that same year. We need to give these children a better future measured in decades. Tissue engineered small intestine (TESI) offers a potential therapy. This would come from the patient's own cells, and therefore would avoid the problems of finding a donor for small bowel transplant, and also would not require life-long medicine for immunosuppression as children must take who have had a transplant. In this proposal, we seek to identify and surpass the barriers to using TESI as a human therapy for SBS. This would benefit the children of California as well as the field of Regenerative medicine as these advances might also help with further somatic stem cell-based therapies to treat a wide range of problems for both children and adults.
Progress Report: 
  • Short Bowel Syndrome (SBS) is an expensive, morbid condition with an increasing
  • incidence. Fundamental congenital and perinatal conditions such as gastroschisis, volvulus,
  • atresia, and necrotizing enterocolitis (NEC) may lead to SBS. NEC is the most common
  • gastrointestinal emergency in neonates and primarily occurs in premature infants. Rates of
  • prematurity are increasing, as are the numbers of children with SBS and NEC. In addition,
  • prevalence is increasing for other diagnoses such as gastroschisis. Medical and surgical
  • treatments are partial and carry high dollar and human costs including multiple infections and
  • hospitalizations for vascular access, liver failure in conjunction with intravenous nutrition, and
  • death. Tissue-engineered small intestine (TESI) offers a potential durable autologous therapy. In the human, engineered intestine from autologous cells would avoid the problems of transplant: immunosuppression and donor supply. Because engineered small and large intestine, esophagus, stomach and specific portions of the gastrointestinal tract such as the GE junction, form by the same process, in addition to SBS engineered intestine could aid in future treatments of trauma, vascular
  • accidents, and gastrointestinal cancer resection. In this year's work, we were able to identify the donor contributions to TESI in a novel murine model that will allow us to make the formation of tissue-engineered small intestine much more efficient. This progress will help us to progress toward a safe human therapy.
  • Current treatment for children with Short Bowel Syndrome (SBS) has a 30% 5 year mortality rate and serious morbidities that destroy the quality of life. Surgical and medical therapies are inadequate. Tissue- engineered small intestine (TESI) may offer an alternative and superior means for restoring intestinal length and function. We recently transitioned this model in order to make use of the tools available in the mouse. The long-term goal of this project is a human cure for SBS. TESI will be formed from autologous cells, and after formation, be connected to the shortened intestinal tract to salvage patients. In order to meet regulatory requirements and to increase the chance of success in humans, we must define the necessary and sufficient progenitor cell population by defining the fate of transplanted OU. A knowledge of the serial process of TESI formation from the seeded OU will inform us about cell spreading, time of vascularization, when and how mature mucosa forms, and allow us to manipulate these processes for successful TESI formation in larger animals and humans. In addition, we can expand the crucial progenitor(s) prior to implantation. As another strategy to enhance TESI formation, we are investigating the role of FGF10, a necessary molecule during organogenesis, homeostasis, and injury repair in postnatal life. FGF10 may increase the proliferation of intestinal epithelial progenitor cells, and therefore improve the growth of TESI. We are conducting parallel studies with murine and human tissue, with success with each.
  • In order to treat children or adult patients who lose part of their gastrointestinal system from trauma, birth defect, or surgery for cancer, we are working on growing parts of the intestine for replacement. This tissue-engineered intestine is now growing well in our laboratory models, and further studying this model we have found ways to make the tissue grow faster while still confirming that the tissue is still growing in a healthy way. We published these findings and presented them at national and international meetings.
  • Transition to the mouse model for the generation of Tissue-Engineered Small Intestine (TESI) was accomplished in year 1, and in year 2 the efficiency and reproducibility of TESI formation in the mouse was markedly improved. For 2012, the work resulted in 4 invited national lectures, and 10 nationally presented abstracts. The lab also has 1 abstract accepted for presentation in 2013 and three papers in press. In year 4 of this grant, we determined that FGF10 overexpression enhances the formation of tissue-engineered small intestine, and these results were just accepted for publication. We also demonstrated two critical steps toward human therapy: generation of tissue-engineered large and small intestine from human progenitor cells.
  • Transition to the mouse model for the generation of Tissue-Engineered Small Intestine (TESI) was accomplished in year 1, and in year 2 the efficiency and reproducibility of TESI formation in the mouse was markedly improved. In year 3, we showed improved tissue generation with VEGF administration and in year 4 of this grant, we determined that FGF10 overexpression enhances the formation of tissue-engineered small intestine and published those data. We also demonstrated two critical steps toward human therapy: generation of tissue-engineered large and small intestine from human progenitor cells. In Year 5, we further developed and published the generation of tissue-engineered small and large intestine, investigated the role of FGF10 in the homeostasis of the small intestine in order to determine its utility as a growth factor for engineered intestine, and began work on the request for designation to the FDA for future translation. In addition, we developed a body of data that we are submitting for publication showing that we have developed a cryopreservation and storage solution, vitrification, which results in the growth of tissue-engineered intestine with excellent viability post-thaw. We further determined that tissue-engineered intestine demonstrates numerous functional markers that are necessary for human translation.
  • For 2013, the work resulted in 6 invited national lectures, and 13 nationally or internationally presented abstracts. The lab also has 6 abstracts accepted for presentation in 2014 and published 5 papers this year.

Stem cell therapy for inflammatory bowel disease

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06525
ICOC Funds Committed: 
$3 259 000
Disease Focus: 
Intestinal Disease
Stem Cell Use: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
One of the most promising approaches that physicians foresee for treating human disease is regenerative medicine. A major aim in this field is to restore function by repairing damaged organs. Inflammatory bowel disease (IBD) is a chronic disease characterized by intermittent episodes of intestinal inflammation and disruption of the intestinal epithelial barrier. It causes significant morbidity and can lead to multiple complications, including growth impairment, intestinal failure, malnutrition, and cancer. IBD has increased in incidence and prevalence globally over the past several decades, and the increasing number of patients suffering from IBD has translated into growing health care costs. Our goal is to bring regenerative medicine approaches to the treatment of IBD by making intestinal structures called “organoids” from human embryonic stem cells. These organoids will be delivered to the intestines in order to repair damage. If the aims of the application are achieved, our findings will make a critical contribution to development of a needed therapeutic.
Statement of Benefit to California: 
The promise of stem cell biology lies in the ability of these remarkable cells to give rise to more differentiated cell types that can repair damaged or diseased tissues. We propose to develop translational approaches that will enable the utilization of human embryonic stem cells for therapeutic applications in inflammatory bowel disease. We anticipate that our research will be a significant step towards making the promise of regenerative medicine from stem cells a reality. Eventually, stem cell-based therapies will reduce health care costs for Californians by improving treatment for diseases for which we currently do not have effective therapies. Our work could provide economic benefits to the state by helping to lay the groundwork for commercial efforts to repair diseased tissues using stem cells. Such developments would be of great benefit to California by making the state a leader in a field that is poised to become economically important in the future.
Progress Report: 
  • The objective of the project is to test regenerative medicine approaches using human embryonic and adult stem cells in the treatment of inflammatory bowel disease (IBD). The strategy that we have proposed is to target the epithelial components of the disease and explore the potential of using hESCs as a cell-based therapy for IBD. The underlying hypotheses for this application are: (1) hESC-derived organoids can be used to ameliorate or cure colitis, (2) enriching these organoids for committed intestinal progenitors/stem cells will improve engraftment and regeneration, and (3) expansion and activation of endogenous ISCs can improve regeneration and re-establishment of the epithelial barrier in IBD. In the first year, as described in detail in the progress report, we have set up our systems and generated data for each of the Aims. We are preparing publications reporting data from Aims 1 and 3 for submission during the next reporting period.

The generation and expansion of tissue-engineered small intestine from human stem/ progenitor cells: a preclinical study of functional translation

Funding Type: 
New Faculty Physician Scientist
Grant Number: 
RN3-06425
ICOC Funds Committed: 
$3 583 000
Disease Focus: 
Intestinal Disease
Stem Cell Use: 
Adult Stem Cell
Cell Line Generation: 
Adult Stem Cell
oldStatus: 
Active
Public Abstract: 
This proposal aims to complete the preclinical steps to develop tissue-engineered intestine (TESI) as a functional replacement of the small intestine to treat short bowel syndrome (SBS). Common birth conditions especially those associated with prematurity result in SBS wherein 50-75% of the small intestine is gone. SBS children cannot get adequate nutrition and supportive medical care is morbid with liver failure a common problem. Small bowel transplants, the only current salvage therapy have many problems including poor graft survival, rejection, limited donor supply, surgical morbidity, and lifelong immunosuppression. We hypothesize that TESI from the patient's own cells offers a potential, durable human progenitor-cell based treatment option for SBS. We have shown that TESI forms when autologous cells are implanted on a polymer scaffold, and that TESI exactly recapitulates native intestine: all four differentiated epithelial cell types in conjunction with the key supporting structure such as nerves, and muscle, grow from the transplanted OU. Importantly, Lewis rats recover from massive small bowel resection with TESI. Other regions of the gut can also reengineered via this approach. Our goal is to translate TESI from rodents to an autologous human cell based therapy. Patients who needed emergency surgery for their intestine, which might leave the remaining amount of intestine too short to absorb enough nutrition could potentially be treated with TESI.
Statement of Benefit to California: 
In the pediatric population, the incidence of SBS is estimated to be 24.5 per 100,000 live births and associated with a 30% 5-year mortality. To put this in perspective, the NCI reports the cumulative incidence of all invasive childhood cancers is 14.5 per 100,000. In addition, cancer, inflammatory bowel disease and mesenteric ischemia put the adult population at risk. In fact, the incidence of SBS is increasing with a striking 30% 5-year mortality. Annual cost per patient in Europe ranges from $100,000 – 150,000 and is double that in the US [1]. SBS is an unsolved problem with unacceptable human and financial cost. An autologous engineered tissue approach would surpass current therapies. Usable engineered intestine would be far less expensive, more durable, and require less maintenance than any current therapy. California would benefit from this research in many ways- we have a large population and improved and less expensive medical care with less suffering for patients would be the most important benefit to the state and to the people of California. In addition, being at the leading edge of this translational approach will make our state and our institutions experts in the translation of stem cell research, a focus point for attracting scientists and innovators to the state and opening up future therapies building on these results. Finally, this approach will generate intellectual property that can be protected and will also benefit the state and its economy.

Pluripotent and Somatic Stem Cell Models to Study Inherited Diarrheal Disorders

Funding Type: 
Tools and Technologies II
Grant Number: 
RT2-01985
ICOC Funds Committed: 
$1 783 250
Disease Focus: 
Intestinal Disease
Pediatrics
Genetic Disorder
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
oldStatus: 
Active
Public Abstract: 
Our research group at [REDACTED] has had a long-standing interest in understanding the cause of several disorders that result in severe, and often times fatal forms of diarrhea in children. These diarrheal disorders are inherited, and somehow lead to poor absorption of nearly all forms of nutrients, including protein, sugars and fats. Why children with these disorders have impaired absorption of nutrients is one of the main unsolved mysteries, but they generally require life-long the daily infusion of intravenous nutrients or an intestinal transplantation to sustain proper growth and nutrition. The goal of this grant application is to develop personalized disease-in-a-dish models that can be used to solve these and other gastrointestinal disorders that are poorly understood. Specifically, we propose to develop custom-made "diarrhea-in-a-dish" models that will use pluripotent stem (iPS) cells derived from skin biopsies of individuals with various forms of diarrhea. These iPS cells will be induced to form gut epithelium that we believe will resemble various characteristics of the subjects native intestine. We will also develop methods that are already established in mice, to isolate and expand human intestinal (somatic) stem cells in cell incubators and in fat compartments of immunodeficient mice. We believe that the resulting intestinal units can be manipulated using various commonly used tools to introduce and/or suppress genes that might control the histology and function of the gut. We are also using newly developed genetic tools where the entire important (coding) region of the human genome is sequenced to identify genes that are defective, and thereby may account for the diarrheal disorder under investigation. This new approach generally identifies several genes that are defective, and we propose to introduce the normal forms of these various genes into the stem cell derived gut tissue to see which gene might reverse the abnormality. We believe that the combination of these various approaches will likely assist us in defining the cause of various forms of diarrhea. While short-term bouts (acute) of diarrhea are very common, approximately 5% individuals experience chronic (>2 weeks) diarrheal symptoms, and some may be life-long. Unfortunately, Physicians and Scientist alike have a very poor understanding of why so many patients experience chronic diarrhea. While the congenital diarrheal disorders under investigation in this grant are rare conditions, improving our understanding of these types of genetic disorders will undoubtedly provide new insight into how nutrients are absorbed, and may enhance our understanding of several common but poorly understood disorders, including IBD, IBS, drug-induced and other idiopathic forms of chronic diarrhea. Developing, refining and expanding the tools described here may also set the foundation to study other common disorders, and to screen for novel drug discovery.
Statement of Benefit to California: 
Chronic diarrheal disorders are common aliments among Californians, and result in frequent and prolonged hospitalizations, outpatient doctor visits and lost wages from sick leave. A subset of young children develop diarrhea shortly after birth, and some will require either daily life-long intravenous nutrition and/or intestinal transplantation. While the medical cost incurred from all forms of chronic diarrhea is daunting, we have a very poor understanding of the basis of most diarrheal conditions, and currently available drug therapies have limited efficacy. In this grant application, we propose to use pluripotent and somatic stem cells to assist us in solving the cause of several forms of congenital diarrheal disorders. We believe that these "diarrhea-in-a-dish models" can be used in the future to understand the cause of other common forms of diarrhea, and to screen for potential drug targets. Furthermore, the approaches taken here may provide alternative advances to small bowel transplantation in these more difficult cases of chronic diarrhea. Public and private insurers spend hundreds of millions of dollars in the diagnosing and management of children and adults with various forms of chronic diarrhea. More importantly, patients and their families are frequently immersed in the consequences of suffering from chronic aliments that are debilitating, hamper quality of life, and require frequent medical attention. Given our incomplete understanding of these conditions, the limited therapeutic options available, and the direct and indirect cost to the state of California and its citizens, novel approaches only recently available with the use of stem cell technology may provide new insight, and possible solutions and hope for those affected by these conditions.
Progress Report: 
  • We have made significant progress in accomplishing the overall goals of our grant application. We have obtained skin cell from 14 subjects with various inherited gastrointestinal disorders, and we are in the process of reprogramming these cells to generate pluripotent stem cells. These cells will eventually be used to generate intestines and other tissue that will allow us to model the disorders of these various subjects. We anticipate that this approach will allow us to further develop tools that will let us understand the basis of chronic diarrhea and intestinal failure in children.
  • We have also performed total genome (exome) sequencing of several subjects with unique forms of chronic diarrhea and intestinal failure, and have identified several excellent candidate genes that likely account for these disorders. We will continue to screen other subjects with similar disorders to determine the full range of genes that are likely associated with these disorders.
  • We have also made considerable progress in our attempt to grow human small intestinal mucosa. Prior to our work, the small intestine had never been successfully grown and maintained in culture for more than just a few days. We utilized our experience working with murine intestine, and developed a novel method to grow human small intestines in a petri dish. We are now working to adapt our methods to grow intestinal samples that are obtained from endoscopic biopsies. We believe that this advancement will improve the usefulness of our culture system to samples obtained at the time of biopsy.
  • Taken together, we have made considerable progress in developing the tools required to understand the genetic basis of chronic diarrhea and intestinal failure in children. We are using a combination of genome sequencing, pluripotent stem cells, and tissue (somatic) stem cells to decipher the biology of established disorders, and to discover new disorders that have a significant impact on the growth and well being of children severe gastrointestinal disorders.
  • We have made significant progress in accomplishing the overall goals of our grant application. We have obtained skin cell from 18 subjects with various inherited gastrointestinal disorders, and we are in the process of reprogramming these cells to generate pluripotent stem cells. These cells have been used to generate intestinal epithelium that is allowing us to model the disorders of patient with specific disorders of intestinal failure. We anticipate that this approach will allow us to further develop tools that will let us understand the basis of chronic diarrhea and intestinal failure in children.
  • We have also performed total genome (exome) sequencing of several subjects with unique forms of chronic diarrhea and intestinal failure, and have identified several excellent candidate genes that likely account for these disorders. We will continue to screen other subjects with similar disorders to determine the full range of genes that are likely associated with these disorders.
  • We have also made considerable progress in our attempt to grow human small intestinal epithelium. In the prior year we developed methods to grow intestinal epithelium obtained from human surgical samples by growing them in a petri dish on a feeder layer of cells. We have now improved this method by eliminating the need of a feeder layer of cells, and have developed ways of significantly expanding the gut stem cell in significant quantities to allow for modeling. We have also adopted these methods to grow intestinal samples that are obtained from endoscopic biopsies. We believe that this advancement will improve the usefulness of our culture system to samples obtained at the time of biopsy.
  • Taken together, we have made considerable progress in developing the tools required to understand the genetic basis of chronic diarrhea and intestinal failure in children. We are using a combination of genome sequencing, pluripotent stem cells, and tissue (somatic) stem cells to decipher the biology of established disorders, and to discover new disorders that have a significant impact on the growth and well being of children severe gastrointestinal disorders.

Differentiation of Human Embryonic Stem Cells to Intestinal Fates

Funding Type: 
SEED Grant
Grant Number: 
RS1-00243
ICOC Funds Committed: 
$578 943
Disease Focus: 
Intestinal Disease
Pediatrics
Trauma
Stem Cell Use: 
Embryonic Stem Cell
oldStatus: 
Closed
Public Abstract: 
The roughly 25 feet of intestine in the adult human play numerous essential roles in daily life, such as nutrient absorption, secretion of hormones, and serving as a barrier to infection. Commensurate with these diverse roles, diseases of the intestine are a considerable source of human morbidity and mortality. Indeed, numerous pathologic conditions including inflammatory bowel diseases, mesenteric ischemia, congenital syndromes and trauma, with or without concomitant intestinal resection, all impair intestinal function to the extent that “short-gut” syndromes develop—resulting in effective intestinal failure. Current therapies rely on supportive measures such as total parenteral nutrition, in which patients receive all of their nutrition intravenously, or even intestinal transplantation. The adult intestine is populated by specialized but highly active intestinal stem cells, which ideally could be harnessed for stem cell therapies of these disabling conditions. However, despite intensive research, no methods currently exist for identifying, isolating, and growing these intestinal stem cells for therapeutic purposes. Our goal is to develop technologies enabling human embryonic stem (hES) cells to be reliably converted to intestinal cells in culture. Human ES cells can be readily grown in culture but represent a completely undifferentiated tabula rasa. Here, we propose studies to convert hES cells to intestinal stem cells and thence to mature intestinal cells. Towards this goal, we have developed the first methodology to induce intestinal cells to divide and expand as cultures, or “explants” outside of the body. This success has been reliant on the provision in our explants of a nutritive “niche”, a specialized area in which signals conductive to intestinal stem cell survival are highly concentrated. In this proposal, the hES cells will be placed in this niche of our explant culture, amidst signals that would promote their conversion from a naïve state into intestinal stem cells and their mature progeny. We will further refine these methods by coaxing hES cells along the first steps towards intestine prior to placing them in the explant niche, as well as by adding hormones to encourage growth of intestinal cells. The use of hES cells could greatly enhance the growth of our explant cultures, vastly expanding the yield of cultured intestine. The therapeutic applications of this work are clear. The combination of ES cell technology along with our explant culture system holds considerable promise for the eventual generation of large quantities of intestinal stem cells, or even artificial intestine. Hopefully, these will yield effective therapies for the numerous conditions resulting in effective intestinal failure, for which currently available therapies are decidedly suboptimal.
Statement of Benefit to California: 
The proposed research will develop new human embryonic stem cell-based technologies enabling the robust propagation of intestinal tissue and its associated stem cells outside of the human body, in laboratory culture. These studies have implications for the treatment of disabling conditions of the intestinal tract including inflammatory bowel disease, mesenteric ischemia and congentital intestinal disorders.
Progress Report: 
  • The human intestine participates in a tremendous array of processes that are essential for daily life, including absorption of nutrients, secretion of hormones, and function as an immune organ against bacteria, viruses and parasites. Because of this, diseases of the intestine such as inflammatory bowel diseases, mesenteric ischemia, congenital short gut syndromes and trauma can produce severe disability and even mortality. In extreme cases where the degree of intestinal compromise is extremely severe, patients may need receive all of their nutrition intravenously, or even undergo intestinal transplantation. The purpose of this research is to induce human embryonic stem cells to develop into intestinal derivatives, to provide a replacement tissue these disorders of severe intestinal dysfunction.
  • The first goal has been to place human embryonic stem cells into a nurturing enviroment, or niche, where they would be exposed to the same signals that intestinal cells receive in the human body. Accordingly, human embryonic stem cells have been injected into cultures of mouse intestine in which such signals are operative. Under these conditions, the embryonic stem cells incorporate adjacent to the mouse intestine as well as to supporting stromal cells, and undergo a dramatic change in morphology, although they do not acquire an intestinal identity. Injections of embryonic stem cells that have been induced to become endoderm, a precursor tissue to the intestine, appear more encouraging. The second goal has examined the ability of stimulation of the Wnt pathway to induce intestinal growth and differentiation of human embryonic stem cells. These studies have confirmed that Wnt pathway stimulation greatly promotes growth of intestinal cultures, suggesting that such a strategy could feasibly promote the differentiation of human embryonic stem cells to become intestine. Finally, the third goal is to develop niches for intestinal differentiation of human embryonic stem cells that are fully comprised of mouse tissue. Here, a variety of strategies of tissue preparation and culture are under evaluation.
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