Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes... more Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c-/- ) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c-/- mice, associated with loss of active Lgr5+ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt ...
There is a geographic inequality in the incidence of colorectal cancer, lowest in developing coun... more There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents.
Enterotoxigenic E. coli (ETEC) cause ∼20% of the acute infectious diarrhea (AID) worldwide, often... more Enterotoxigenic E. coli (ETEC) cause ∼20% of the acute infectious diarrhea (AID) worldwide, often by producing heat-stable enterotoxins (STs) which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion are defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog linaclotide, an FDA-approved oral secretagogue, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced dia...
Obesity has emerged as a principle cause of mortality worldwide reflecting co-morbidities includi... more Obesity has emerged as a principle cause of mortality worldwide reflecting co-morbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. GUCY2C, a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cyclic (c)GMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis which activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that diet-induced obesity suppressed guanyl...
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks o... more Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells...
An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developm... more An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developmental programs indelibly imprint restricted repertoires of homeostasis, forming the substrate for lineage-dependent tumor induction by dysregulation of survival pathways. GUCY2C, the intestinal receptor for the paracrine hormones guanylin and uroguanylin whose early loss universally characterizes colorectal transformation, has emerged as a component of homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis, and its dysregulation promotes tumorigenesis through hyperproliferation and genetic instability. Here we identify GUCY2C as a switch for lineage-dependent tumorigenesis whose disruption reprograms survival circuits essential for regenerative homeostasis and universally required for tumorigenesis. Eliminating GUCY2C expression in mice expands proliferating crypts, accelerating the cell cycle by regulating mediators of the G1/S transition, including cyclin D1, pRb, and p27. Further, loss of GUCY2C produces an increase in aerobic glycolysis, reflected by elevated glucose transport and lactate production associated with increased expression of rate-limiting glycolytic proteins universally up-regulated in tumors, including glucose transporter I, hexokinase II, phosphofructokinase, and pyruvate kinase. Conversely, there is a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, reflected by a decrease in mitochondrial genome, proteins, and organelles associated with reduced mitochondrial oxygen consumption, dehydrogenase activity and ATP production, recapitulating the tumor metabolic phenotype. Conversely, GUCY2C signaling restores replicative and metabolic homeostatic circuits in colon cancer cells, recapitulating the phenotype of normal enterocytes. Moreover, oral administration of the proximal downstream mediator of GUCY2C, cyclic GMP, reverses crypt hyperplasia and restores proliferative and metabolic programs in mice deficient in GUCY2C. Coordination of survival circuits by GUCY2C is orchestrated through the oncogene AKT, whose inhibition mimics, and activation eliminates, GUCY2C regulation of proliferation and metabolism. AKT modulation by GUCY2C involves the tumor suppressor PTEN, whose silencing eliminates GUCY2C regulation of AKT, proliferation and metabolism. Thus, disruption of developmentally restricted signaling by GUCY2C, reflecting loss of paracrine hormones, induces maladaptive survival pathways essential for crypt-surface homeostasis whose tissue-specific deregulation contributes to lineage dependency in intestinal tumorigenesis. With the role of guanylin and uroguanylin loss in transformation, the universal compensatory over-expression of GUCY2C by colorectal tumors offers a unique therapeutic opportunity for cancer prevention through oral hormone supplementation. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4412.
Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is stil... more Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is still in its infancy for treatment of childhood malignancies such as acute lymphoblastic leukemia (ALL). Nanotherapy offers multiple advantages over conventional therapy. It facilitates targeted delivery and enables controlled release of drugs to reduce treatment-related side effects. Here, we demonstrate, that doxorubicin (DOX) encapsulated in polymeric nanoparticles (NPs) modified with targeting ligands against CD19 (CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive ALL cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. We suggest that targeted delivery of dru...
Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decad... more Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics.
The guanylyl cyclase C (GCC) receptor posseses several well-established properties ideal for use ... more The guanylyl cyclase C (GCC) receptor posseses several well-established properties ideal for use as a biomarker in gastrointestinal malignancies. The GCC receptor is constitutively expressed in the apical membranes of the intestine and its expression is universally preserved in primary colorectal tumors and their metastases. Moreover, receptor binding is retained by GCC's cognate ligand, the bacterial enterotoxin ST, even after conjugation to functional moieties. Selective tumor, but not gastrointestinal, uptake of ST in mice bearing GCC-expressing colon cancer xenografts demonstrates the potential of exploiting ST-GCC interaction for diagnostic imaging and targeted therapy of metastatic colorectal cancer. We expect this specific targeting provided by ST-GCC interaction to improve diagnosis, staging and management of colorectal cancer metastases, and ultimately prolong patient survival in this disease.
Dysfunctional CD8+ T (TCD8+) cells lacking cytokine production have been identified in many viral... more Dysfunctional CD8+ T (TCD8+) cells lacking cytokine production have been identified in many viral infections, but their genesis is not well understood. Established results indicate that such cells could be either high avidity that enter a refractory state due to overstimulation or low avidity that are only partially stimulated. Using an acute, resolving infection model that results in rapid production of dysfunctional cells, we show that this IL2 unresponsive phenotype emerges from the low end of the avidity spectrum and is characterized by broad TCR usage and a reduced proliferation rate. Furthermore, the dysfunctional population is extremely fluid, being sustained by high Ag dose but virtually eliminated following low dose boosting. Together, these results suggest that persistence of dysfunctional cells generated in this manner depends upon continual exposure to high Ag levels and that such cells may ultimately predominate if functional cells become exhausted.
International Journal of Radiation Oncology*Biology*Physics, 2013
Conclusions: Results provide evidence that, besides prolonging survival with a good safety profil... more Conclusions: Results provide evidence that, besides prolonging survival with a good safety profile, Ra-223 delays time to first SRE, in particular, time to first use of EBRT and use of opioids. In addition, Ra-223 reduces pain and opioid use in CRPC patients with bone mets. Importantly, the study showed that Ra-223 could be given safely with concomitant EBRT. Author Disclosure: J. Michalski: None. O. Sartor: G. Consultant; Bayer, Algeta. C. Parker: F. Honoraria; Amgen, Astellas, Bayer, Janssen, SanofiAventis, Takeda.G.Consultant; Algeta,Bayer, BNIT.M.Shan:A.Employee; Bayer HealthCare. K. Stock; Bayer HealthCare. J. Garcia-Vargas: A. Employee; Bayer HealthCare. K. Stock; Bayer HealthCare. A. Aksnes: A. Employee; Algeta ASA. N.J. Vogelzang: G. Consultant; Algeta, Bayer.
Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes... more Long-lived multipotent stem cells (ISCs) at the base of intestinal crypts adjust their phenotypes to accommodate normal maintenance and post-injury regeneration of the epithelium. Their long life, lineage plasticity, and proliferative potential underlie the necessity for tight homeostatic regulation of the ISC compartment. In that context, the guanylate cyclase C (GUCY2C) receptor and its paracrine ligands regulate intestinal epithelial homeostasis, including proliferation, lineage commitment, and DNA damage repair. However, a role for this axis in maintaining ISCs remains unknown. Transgenic mice enabling analysis of ISCs (Lgr5-GFP) in the context of GUCY2C elimination (Gucy2c-/- ) were combined with immunodetection techniques and pharmacological treatments to define the role of the GUCY2C signaling axis in supporting ISCs. ISCs were reduced in Gucy2c-/- mice, associated with loss of active Lgr5+ cells but a reciprocal increase in reserve Bmi1+ cells. GUCY2C was expressed in crypt ...
There is a geographic inequality in the incidence of colorectal cancer, lowest in developing coun... more There is a geographic inequality in the incidence of colorectal cancer, lowest in developing countries, and greatest in developed countries. This disparity suggests an environmental contribution to cancer resistance in endemic populations. Enterotoxigenic bacteria associated with diarrheal disease are prevalent in developing countries, including enterotoxigenic E. coli (ETEC) producing heat-stable enterotoxins (STs). STs are peptides that are structurally homologous to paracrine hormones that regulate the intestinal guanylyl cyclase C (GUCY2C) receptor. Beyond secretion, GUCY2C is a tumor suppressor universally silenced by loss of expression of its paracrine hormone during carcinogenesis. Thus, the geographic imbalance in colorectal cancer, in part, may reflect chronic exposure to ST-producing organisms that restore GUCY2C signaling silenced by hormone loss during transformation. Here, mice colonized for 18 weeks with control E. coli or those engineered to secrete ST exhibited normal growth, with comparable weight gain and normal stool water content, without evidence of secretory diarrhea. Enterotoxin-producing, but not control, E. coli, generated ST that activated colonic GUCY2C signaling, cyclic guanosine monophosphate (cGMP) production, and cGMP-dependent protein phosphorylation in colonized mice. Moreover, mice colonized with ST-producing E. coli exhibited a 50% reduction in carcinogen-induced colorectal tumor burden. Thus, chronic colonization with ETEC producing ST could contribute to endemic cancer resistance in developing countries, reinforcing a novel paradigm of colorectal cancer chemoprevention with oral GUCY2C-targeted agents.
Enterotoxigenic E. coli (ETEC) cause ∼20% of the acute infectious diarrhea (AID) worldwide, often... more Enterotoxigenic E. coli (ETEC) cause ∼20% of the acute infectious diarrhea (AID) worldwide, often by producing heat-stable enterotoxins (STs) which are peptides structurally homologous to paracrine hormones of the intestinal guanylate cyclase C (GUCY2C) receptor. While molecular mechanisms mediating ST-induced intestinal secretion are defined, advancements in therapeutics have been hampered for decades by the paucity of disease models that integrate molecular and functional endpoints amenable to high-throughput screening. Here, we reveal that mouse and human intestinal enteroids in three-dimensional ex vivo cultures express the components of the GUCY2C secretory signaling axis. ST and its structural analog linaclotide, an FDA-approved oral secretagogue, induced fluid accumulation quantified simultaneously in scores of enteroid lumens, recapitulating ETEC-induced intestinal secretion. Enteroid secretion depended on canonical molecular signaling events responsible for ETEC-induced dia...
Obesity has emerged as a principle cause of mortality worldwide reflecting co-morbidities includi... more Obesity has emerged as a principle cause of mortality worldwide reflecting co-morbidities including cancer risk, particularly in colorectum. Although this relationship is established epidemiologically, molecular mechanisms linking colorectal cancer and obesity continue to be refined. GUCY2C, a membrane-bound guanylyl cyclase expressed in intestinal epithelial cells, binds the paracrine hormones guanylin and uroguanylin, inducing cyclic (c)GMP signaling in colorectum and small intestine, respectively. Guanylin is the most commonly lost gene product in sporadic colorectal cancer and its universal loss early in transformation silences GUCY2C, a tumor suppressor, disrupting epithelial homeostasis underlying tumorigenesis. In small intestine, eating induces endocrine secretion of uroguanylin, the afferent limb of a novel gut-brain axis which activates hypothalamic GUCY2C-cGMP signaling mediating satiety opposing obesity. Recent studies revealed that diet-induced obesity suppressed guanyl...
Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks o... more Obesity is a well-known risk factor for colorectal cancer but precisely how it influences risks of malignancy remains unclear. During colon cancer development in humans or animals, attenuation of the colonic cell surface receptor guanylyl cyclase C (GUCY2C) that occurs due to loss of its paracrine hormone ligand guanylin contributes universally to malignant progression. In this study, we explored a link between obesity and GUCY2C silencing in colorectal cancer. Using genetically engineered mice on different diets, we found that diet-induced obesity caused a loss of guanylin expression in the colon with subsequent GUCY2C silencing, epithelial dysfunction, and tumorigenesis. Mechanistic investigations revealed that obesity reversibly silenced guanylin expression through calorie-dependent induction of endoplasmic reticulum stress and the unfolded protein response in intestinal epithelial cells. In transgenic mice, enforcing specific expression of guanylin in intestinal epithelial cells...
An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developm... more An evolving paradigm expanding the genetic basis of cancer suggests that tissue-specific developmental programs indelibly imprint restricted repertoires of homeostasis, forming the substrate for lineage-dependent tumor induction by dysregulation of survival pathways. GUCY2C, the intestinal receptor for the paracrine hormones guanylin and uroguanylin whose early loss universally characterizes colorectal transformation, has emerged as a component of homeostatic programs organizing spatiotemporal patterning along the crypt-surface axis, and its dysregulation promotes tumorigenesis through hyperproliferation and genetic instability. Here we identify GUCY2C as a switch for lineage-dependent tumorigenesis whose disruption reprograms survival circuits essential for regenerative homeostasis and universally required for tumorigenesis. Eliminating GUCY2C expression in mice expands proliferating crypts, accelerating the cell cycle by regulating mediators of the G1/S transition, including cyclin D1, pRb, and p27. Further, loss of GUCY2C produces an increase in aerobic glycolysis, reflected by elevated glucose transport and lactate production associated with increased expression of rate-limiting glycolytic proteins universally up-regulated in tumors, including glucose transporter I, hexokinase II, phosphofructokinase, and pyruvate kinase. Conversely, there is a reciprocal reduction in mitochondrial biogenesis and oxidative phosphorylation, reflected by a decrease in mitochondrial genome, proteins, and organelles associated with reduced mitochondrial oxygen consumption, dehydrogenase activity and ATP production, recapitulating the tumor metabolic phenotype. Conversely, GUCY2C signaling restores replicative and metabolic homeostatic circuits in colon cancer cells, recapitulating the phenotype of normal enterocytes. Moreover, oral administration of the proximal downstream mediator of GUCY2C, cyclic GMP, reverses crypt hyperplasia and restores proliferative and metabolic programs in mice deficient in GUCY2C. Coordination of survival circuits by GUCY2C is orchestrated through the oncogene AKT, whose inhibition mimics, and activation eliminates, GUCY2C regulation of proliferation and metabolism. AKT modulation by GUCY2C involves the tumor suppressor PTEN, whose silencing eliminates GUCY2C regulation of AKT, proliferation and metabolism. Thus, disruption of developmentally restricted signaling by GUCY2C, reflecting loss of paracrine hormones, induces maladaptive survival pathways essential for crypt-surface homeostasis whose tissue-specific deregulation contributes to lineage dependency in intestinal tumorigenesis. With the role of guanylin and uroguanylin loss in transformation, the universal compensatory over-expression of GUCY2C by colorectal tumors offers a unique therapeutic opportunity for cancer prevention through oral hormone supplementation. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4412.
Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is stil... more Nanomedicine has advanced to clinical trials for adult cancer therapy. However, the field is still in its infancy for treatment of childhood malignancies such as acute lymphoblastic leukemia (ALL). Nanotherapy offers multiple advantages over conventional therapy. It facilitates targeted delivery and enables controlled release of drugs to reduce treatment-related side effects. Here, we demonstrate, that doxorubicin (DOX) encapsulated in polymeric nanoparticles (NPs) modified with targeting ligands against CD19 (CD19-DOX-NPs) can be delivered in a CD19-specific manner to leukemic cells. The CD19-DOX-NPs were internalized via receptor-mediated endocytosis and imparted cytotoxicity in a CD19-dependent manner in CD19 positive ALL cells. Leukemic mice treated with CD19-DOX-NPs survived significantly longer and manifested a higher degree of agility indicating reduced apparent systemic toxicity during treatment compared to mice treated with free DOX. We suggest that targeted delivery of dru...
Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decad... more Antitumor immunotherapy for colorectal cancer has been studied at the bench and bedside for decades. Some clinical trials of cancer immunotherapy have demonstrated a potential benefit for patients with colorectal cancer, yet immunotherapy remains only an experimental option for this disease. Here, we review the major immunotherapeutic approaches currently under investigation for colorectal cancer, including cancer vaccines and adoptive cell therapy. Weakness and advantages of each strategy and progress in clinical trials will be described. Examination of previous and ongoing research in colorectal cancer therapy should define a path towards identification, approval, and mainstream adoption of colorectal cancer immunotherapeutics.
The guanylyl cyclase C (GCC) receptor posseses several well-established properties ideal for use ... more The guanylyl cyclase C (GCC) receptor posseses several well-established properties ideal for use as a biomarker in gastrointestinal malignancies. The GCC receptor is constitutively expressed in the apical membranes of the intestine and its expression is universally preserved in primary colorectal tumors and their metastases. Moreover, receptor binding is retained by GCC's cognate ligand, the bacterial enterotoxin ST, even after conjugation to functional moieties. Selective tumor, but not gastrointestinal, uptake of ST in mice bearing GCC-expressing colon cancer xenografts demonstrates the potential of exploiting ST-GCC interaction for diagnostic imaging and targeted therapy of metastatic colorectal cancer. We expect this specific targeting provided by ST-GCC interaction to improve diagnosis, staging and management of colorectal cancer metastases, and ultimately prolong patient survival in this disease.
Dysfunctional CD8+ T (TCD8+) cells lacking cytokine production have been identified in many viral... more Dysfunctional CD8+ T (TCD8+) cells lacking cytokine production have been identified in many viral infections, but their genesis is not well understood. Established results indicate that such cells could be either high avidity that enter a refractory state due to overstimulation or low avidity that are only partially stimulated. Using an acute, resolving infection model that results in rapid production of dysfunctional cells, we show that this IL2 unresponsive phenotype emerges from the low end of the avidity spectrum and is characterized by broad TCR usage and a reduced proliferation rate. Furthermore, the dysfunctional population is extremely fluid, being sustained by high Ag dose but virtually eliminated following low dose boosting. Together, these results suggest that persistence of dysfunctional cells generated in this manner depends upon continual exposure to high Ag levels and that such cells may ultimately predominate if functional cells become exhausted.
International Journal of Radiation Oncology*Biology*Physics, 2013
Conclusions: Results provide evidence that, besides prolonging survival with a good safety profil... more Conclusions: Results provide evidence that, besides prolonging survival with a good safety profile, Ra-223 delays time to first SRE, in particular, time to first use of EBRT and use of opioids. In addition, Ra-223 reduces pain and opioid use in CRPC patients with bone mets. Importantly, the study showed that Ra-223 could be given safely with concomitant EBRT. Author Disclosure: J. Michalski: None. O. Sartor: G. Consultant; Bayer, Algeta. C. Parker: F. Honoraria; Amgen, Astellas, Bayer, Janssen, SanofiAventis, Takeda.G.Consultant; Algeta,Bayer, BNIT.M.Shan:A.Employee; Bayer HealthCare. K. Stock; Bayer HealthCare. J. Garcia-Vargas: A. Employee; Bayer HealthCare. K. Stock; Bayer HealthCare. A. Aksnes: A. Employee; Algeta ASA. N.J. Vogelzang: G. Consultant; Algeta, Bayer.
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Papers by Scott Waldman