7 Hedgehog and ras-related C3 botulinum toxin substrate (Rac) signaling may regulate the EMT of HSCs.7, 8 However, no information selleck chemical was available about the significance of ECAD with respect to the inhibition of HSC activation. Our results demonstrate that ectopic ECAD expression prevents HSC activation. Thus, a deficiency of ECAD may facilitate the activation or motility of HSCs. Sometimes, increased expression of NCAD without a change in ECAD expression is called cadherin switching. In a study,18 increased motility of epithelial cells was claimed to be associated with NCAD up-regulation. Thus,

HSC activation may result in part from the increased expression of NCAD as well as the loss of ECAD. In addition to the fibrotic process in the liver, cadherin switching is involved in other physiological and pathological conditions such as the normal physiology of embryonic development, chronic inflammation, LY294002 and the invasion and metastasis of cancer cells.1, 2 In clinical studies, the loss of ECAD in many epithelium-derived cancer cells promotes the conversion of the epithelial phenotype into a more motile and less polarized mesenchymal phenotype.1, 19 Consistently, decreased ECAD expression has been observed in approximately 40% of hepatocellular carcinoma samples.20 Activated HSCs serve as liver-specific pericytes in hepatic carcinogenesis and may contribute to the remodeling and deposition of tumor-associated ECM.13

Because of the link between ECAD loss and the pathological process of EMT, information on the molecular basis of ECAD signaling may be helpful in understanding the development and progression of hepatocellular carcinoma. TGFβ1 represses the expression of ECAD and promotes the following temporal sequence: disassembly of cell junctions,

loss of epithelial polarity, cytoskeletal reorganization, and cell-matrix adhesion remodeling.9 Transcription factors such as Snail, Twist, Slug, and Zeb negatively regulate the expression of ECAD by binding to specific sequences within the ECAD gene, and Thalidomide these sequences are called E-boxes. These proteins are involved in the pathological process of EMT and thereby enhance the accumulation of ECM. Although ECAD deficiency or cadherin switching had been recognized during HSC activation in liver disease,7 the inhibitory role of ECAD in fibrogenesis had not been studied. Moreover, despite the well-known process of the disintegration and disassembly of cell-cell junctions by TGFβ1, information about whether ECAD has an inhibitory effect on TGFβ1 gene expression was not available. Our results demonstrate that ECAD prevents the induction of the TGFβ1 gene and its downstream genes, whereas the loss of ECAD initiates it and facilitates hepatic fibrosis. Sustained injury to hepatocytes activates fibrogenic mechanisms in patients with chronic liver diseases induced by any means. Fibrogenic cells (i.e.

7 Hedgehog and ras-related C3 botulinum toxin substrate (Rac) signaling may regulate the EMT of HSCs.7, 8 However, no information selleck chemicals was available about the significance of ECAD with respect to the inhibition of HSC activation. Our results demonstrate that ectopic ECAD expression prevents HSC activation. Thus, a deficiency of ECAD may facilitate the activation or motility of HSCs. Sometimes, increased expression of NCAD without a change in ECAD expression is called cadherin switching. In a study,18 increased motility of epithelial cells was claimed to be associated with NCAD up-regulation. Thus,

HSC activation may result in part from the increased expression of NCAD as well as the loss of ECAD. In addition to the fibrotic process in the liver, cadherin switching is involved in other physiological and pathological conditions such as the normal physiology of embryonic development, chronic inflammation, see more and the invasion and metastasis of cancer cells.1, 2 In clinical studies, the loss of ECAD in many epithelium-derived cancer cells promotes the conversion of the epithelial phenotype into a more motile and less polarized mesenchymal phenotype.1, 19 Consistently, decreased ECAD expression has been observed in approximately 40% of hepatocellular carcinoma samples.20 Activated HSCs serve as liver-specific pericytes in hepatic carcinogenesis and may contribute to the remodeling and deposition of tumor-associated ECM.13

Because of the link between ECAD loss and the pathological process of EMT, information on the molecular basis of ECAD signaling may be helpful in understanding the development and progression of hepatocellular carcinoma. TGFβ1 represses the expression of ECAD and promotes the following temporal sequence: disassembly of cell junctions,

loss of epithelial polarity, cytoskeletal reorganization, and cell-matrix adhesion remodeling.9 Transcription factors such as Snail, Twist, Slug, and Zeb negatively regulate the expression of ECAD by binding to specific sequences within the ECAD gene, and Ribose-5-phosphate isomerase these sequences are called E-boxes. These proteins are involved in the pathological process of EMT and thereby enhance the accumulation of ECM. Although ECAD deficiency or cadherin switching had been recognized during HSC activation in liver disease,7 the inhibitory role of ECAD in fibrogenesis had not been studied. Moreover, despite the well-known process of the disintegration and disassembly of cell-cell junctions by TGFβ1, information about whether ECAD has an inhibitory effect on TGFβ1 gene expression was not available. Our results demonstrate that ECAD prevents the induction of the TGFβ1 gene and its downstream genes, whereas the loss of ECAD initiates it and facilitates hepatic fibrosis. Sustained injury to hepatocytes activates fibrogenic mechanisms in patients with chronic liver diseases induced by any means. Fibrogenic cells (i.e.

We selected 4-PBA for these studies, because it is a clinically approved drug for treatment of a variety of human disorders originating or manifesting in the liver. These include urea cycle disorders, where 4-PBA is used short-term in dosages exceeding the concentration

used in this study. Importantly, this drug also ameliorates cell surface abundance of a number of misfolded and mislocalized membrane proteins with relevance to human liver disease. These include ABCB11 p.E297G and p.D482G, identified in PFIC2 patients, and CF transmembrane conductance regulator ΔF508, the most common mutation associated with CF.9, 22 Clinical trials demonstrated that 4-PBA treatment resulted

in increased chloride conductance in patients with CF.23 In our study, 4-PBA treatment stimulated the protein expression and/or cell surface abundance of ATP8B1 G308V, D454G, D554N, and I661T in vitro. PDGFR inhibitor Amelioration of cell surface expression was most prominent for the latter mutant, with a dramatic increase in ATP8B1 I661T accessible for biotinylation. However, using multiple assays, we could not detect ATP8B1-mediated internalization of fluorescently Pexidartinib cost labeled phosphatidylserine upon coexpression of ATP8B1 WT and CDC50A (data not shown). This prohibited verification whether ATP8B1 I661T at the cell surface is functional. Furthermore, it is currently Interleukin-2 receptor unclear to what level ATP8B1 cell surface abundance needs to be restored, and how much ATP8B1 catalytic activity is required, to relieve patients from an ATP8B1 deficiency phenotype. Given the episodic character of cholestatic attacks in BRIC1 patients, and the predominant absence of clinical symptoms in heterozygous carriers, we propose that partial restoration of cell surface expression by 4-PBA might already provide clinical improvement in BRIC1. A substantial proportion of BRIC1 patients carry at least one p.I661T allele, and many are homozygous for p.I661T. Whether the episodic

character of BRIC1 even precludes the need for long-term administration of 4-PBA in these patients, needs to be investigated in clinical trials once the in vivo efficacy has been ascertained. In conclusion, the results of this study investigating six missense and one nonsense mutation, indicate that future therapy aiming to restore ATP8B1 expression at the plasma membrane probably needs to be tailored to specific genetic defects, and emphasize the need for continued detailed and systematic analysis of ATP8B1 mutations that possibly result in folding defects. Treatment with pharmacological chaperones like 4-PBA, might present a clinically useful approach to increase the amount of ATP8B1 mutant protein at the cell surface, especially in patients with episodic presentation of ATP8B1 deficiency.

We selected 4-PBA for these studies, because it is a clinically approved drug for treatment of a variety of human disorders originating or manifesting in the liver. These include urea cycle disorders, where 4-PBA is used short-term in dosages exceeding the concentration

used in this study. Importantly, this drug also ameliorates cell surface abundance of a number of misfolded and mislocalized membrane proteins with relevance to human liver disease. These include ABCB11 p.E297G and p.D482G, identified in PFIC2 patients, and CF transmembrane conductance regulator ΔF508, the most common mutation associated with CF.9, 22 Clinical trials demonstrated that 4-PBA treatment resulted

in increased chloride conductance in patients with CF.23 In our study, 4-PBA treatment stimulated the protein expression and/or cell surface abundance of ATP8B1 G308V, D454G, D554N, and I661T in vitro. Y-27632 cell line Amelioration of cell surface expression was most prominent for the latter mutant, with a dramatic increase in ATP8B1 I661T accessible for biotinylation. However, using multiple assays, we could not detect ATP8B1-mediated internalization of fluorescently Ibrutinib in vitro labeled phosphatidylserine upon coexpression of ATP8B1 WT and CDC50A (data not shown). This prohibited verification whether ATP8B1 I661T at the cell surface is functional. Furthermore, it is currently Glutamate dehydrogenase unclear to what level ATP8B1 cell surface abundance needs to be restored, and how much ATP8B1 catalytic activity is required, to relieve patients from an ATP8B1 deficiency phenotype. Given the episodic character of cholestatic attacks in BRIC1 patients, and the predominant absence of clinical symptoms in heterozygous carriers, we propose that partial restoration of cell surface expression by 4-PBA might already provide clinical improvement in BRIC1. A substantial proportion of BRIC1 patients carry at least one p.I661T allele, and many are homozygous for p.I661T. Whether the episodic

character of BRIC1 even precludes the need for long-term administration of 4-PBA in these patients, needs to be investigated in clinical trials once the in vivo efficacy has been ascertained. In conclusion, the results of this study investigating six missense and one nonsense mutation, indicate that future therapy aiming to restore ATP8B1 expression at the plasma membrane probably needs to be tailored to specific genetic defects, and emphasize the need for continued detailed and systematic analysis of ATP8B1 mutations that possibly result in folding defects. Treatment with pharmacological chaperones like 4-PBA, might present a clinically useful approach to increase the amount of ATP8B1 mutant protein at the cell surface, especially in patients with episodic presentation of ATP8B1 deficiency.

pylori)

are proton pump inhibitor, amoxacillin, and clarithromycin. Considering the convenience of the patient, it is more helpful to take the drugs at once postprandial compared to take the drugs dividing by preprandial and postprandial. But, proton pump inhibitor is more effective when taking preprandial. The aim of this study was to determine the difference in eradication rates according to the method of treatment of H.pylori. Methods: Between January 2008 and December 2012, a total 160 patients with positive by rapid urease test at our hospital were reviewed, retrospectively. We divided into two groups in accordance with the prescribed methods of H.pylori. learn more One group of people were prescribed the drugs at once postprandial (group A). Another group of people were prescribed proton pump inhibitor at preprandial with amoxicillin and clarithromycin at postprandial (group B). After 4 weeks, urea breath test was performed to validate eradication of H.pylori. Results: The rate of eradication of group A was 75% (60/80) and the rate of eradication

of group B was 72.5% (58/80). There was no Palbociclib significant difference between two groups (p = 0.719). Conclusion: To take the regimens for treatment of H.pylori at once postprandial or dividing by preprandial and postprandial was no significant difference in eradication rates of H.pylori. Therefore, to prescribe at once postprandial

maybe the better way, considering the convenience of the patient. Key Word(s): 1. PPI; 2. Pre-prandial; 3. H.Pyolori;   Group A Group B p-value Male: Female ratio 50:30 59:21 0.127 Mean age 51.45 53.34 0.334 Eradication rate of H.pylori 75% (60/80) 72.5% (58/80) 0.719 Presenting Author: KYU KEUN KANG Additional Authors: DONG HO LEE, DONG HYUN OH, NAYOUNG KIM, YOUNG SOO PARK, CHEOL MIN SHIN, HYUK YOON, JIN HYEOK HWANG Corresponding Author: DONG HO LEE Affiliations: Resveratrol Seoul National University Bundang Hospital Objective: There was a controversy the efficacy of eradication with moxifloxacin based triple therapy as second line treatment for Helicobacter pylori infection. And most of published papers focused on patients failed to treat with standard triple therapy. So, we investigated the efficacy of moxifloxacin as second line therapy and the eradication rates of that according to previous first-line regimen. Methods: A total of 298 patients who were failed to eradicate with first line treatment received 14 days moxifloxacin containing triple therapy (moxifloxacin 400 mg q.d, amoxicillin 1000 mg b.i.d, rabeprazole 20 mg b.i.d). As first line treatment, they were prescribed 7day-standard triple therapy (n = 184), 7day-bisthmus containing quadruple therapy (n = 29), 7day-concomitant therapy (n = 39) and 14day-sequential therapy (n = 46).

pylori)

are proton pump inhibitor, amoxacillin, and clarithromycin. Considering the convenience of the patient, it is more helpful to take the drugs at once postprandial compared to take the drugs dividing by preprandial and postprandial. But, proton pump inhibitor is more effective when taking preprandial. The aim of this study was to determine the difference in eradication rates according to the method of treatment of H.pylori. Methods: Between January 2008 and December 2012, a total 160 patients with positive by rapid urease test at our hospital were reviewed, retrospectively. We divided into two groups in accordance with the prescribed methods of H.pylori. PLX-4720 supplier One group of people were prescribed the drugs at once postprandial (group A). Another group of people were prescribed proton pump inhibitor at preprandial with amoxicillin and clarithromycin at postprandial (group B). After 4 weeks, urea breath test was performed to validate eradication of H.pylori. Results: The rate of eradication of group A was 75% (60/80) and the rate of eradication

of group B was 72.5% (58/80). There was no GDC-0973 nmr significant difference between two groups (p = 0.719). Conclusion: To take the regimens for treatment of H.pylori at once postprandial or dividing by preprandial and postprandial was no significant difference in eradication rates of H.pylori. Therefore, to prescribe at once postprandial

maybe the better way, considering the convenience of the patient. Key Word(s): 1. PPI; 2. Pre-prandial; 3. H.Pyolori;   Group A Group B p-value Male: Female ratio 50:30 59:21 0.127 Mean age 51.45 53.34 0.334 Eradication rate of H.pylori 75% (60/80) 72.5% (58/80) 0.719 Presenting Author: KYU KEUN KANG Additional Authors: DONG HO LEE, DONG HYUN OH, NAYOUNG KIM, YOUNG SOO PARK, CHEOL MIN SHIN, HYUK YOON, JIN HYEOK HWANG Corresponding Author: DONG HO LEE Affiliations: Thalidomide Seoul National University Bundang Hospital Objective: There was a controversy the efficacy of eradication with moxifloxacin based triple therapy as second line treatment for Helicobacter pylori infection. And most of published papers focused on patients failed to treat with standard triple therapy. So, we investigated the efficacy of moxifloxacin as second line therapy and the eradication rates of that according to previous first-line regimen. Methods: A total of 298 patients who were failed to eradicate with first line treatment received 14 days moxifloxacin containing triple therapy (moxifloxacin 400 mg q.d, amoxicillin 1000 mg b.i.d, rabeprazole 20 mg b.i.d). As first line treatment, they were prescribed 7day-standard triple therapy (n = 184), 7day-bisthmus containing quadruple therapy (n = 29), 7day-concomitant therapy (n = 39) and 14day-sequential therapy (n = 46).

In both cases FXIII activity and FXIII-A antigen were undetectable in the plasma and platelet lysate. In the plasma no FXIII-A2B2 antigen was found, while FXIII-B antigen was >30% in both cases. Proband1 was a compound heterozygote possessing a known missense mutation (c.980G>A, p.Arg326Gln) and a novel splice–site mutation (c.1112+2T>C). Proband2 was homozygote for a novel single nucleotide deletion (c.212delA) leading to early stop codon. The discovered

mutations explain the severity of clinical symptoms and the laboratory data. Methods precise in the low activity/antigen range are required to draw valid conclusion on phenotype–genotype relationship. “
“Summary.  Hepatitis C is a major co-morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non-invasive way of assessing the extent of liver fibrosis. selleck chemical This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant Trichostatin A difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of

infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement

of LSM results of more than 2 kPa. These results are comparable with those of ifenprodil paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM. “
“Summary.  Muscle haematoma represents 10–25% of bleeds in patients with severe haemophilia. There is limited consensus on diagnostic or treatment strategies and little knowledge about the natural history of muscle haematoma and optimal treatment goals. The aim of this review was to perform a systematic description of the natural history of muscle haematoma in healthy athletes, focusing on diagnosis, classification and treatment options. Publications and educational textbooks on management of sports injuries were used as data source. Muscle haematomas occur following contusion, strain, or laceration and can be categorized as mild, moderate, or severe. Muscle haematoma may be inter- or intramuscular. In healthy athletes, the healing process takes 20–40 days.

In both cases FXIII activity and FXIII-A antigen were undetectable in the plasma and platelet lysate. In the plasma no FXIII-A2B2 antigen was found, while FXIII-B antigen was >30% in both cases. Proband1 was a compound heterozygote possessing a known missense mutation (c.980G>A, p.Arg326Gln) and a novel splice–site mutation (c.1112+2T>C). Proband2 was homozygote for a novel single nucleotide deletion (c.212delA) leading to early stop codon. The discovered

mutations explain the severity of clinical symptoms and the laboratory data. Methods precise in the low activity/antigen range are required to draw valid conclusion on phenotype–genotype relationship. “
“Summary.  Hepatitis C is a major co-morbidity in patients with inherited bleeding disorders, leading to progressive liver fibrosis and eventually cirrhosis. Liver stiffness measurement (LSM) is a non-invasive way of assessing the extent of liver fibrosis. Selumetinib research buy This article describes our experience with serial LSM to assess prospectively progression of fibrosis in a cohort of patients with inherited bleeding disorders and chronic hepatitis C. A total of 84 patients underwent serial LSMs, with a median interval of 3.7 years. The change in LSM results over time was assessed. Overall, there was no significant GS-1101 mw difference between the median results of LSM 1 and LSM 2. The median result of LSM 2 was low (6.6 kPa), after a median duration of

infection of 37 years. On the individual level, deterioration of LSM results of more than 2 kPa was seen in 13 patients (16%), 44 patients (52%) remained stable and 27 patients (32%) showed improvement

of LSM results of more than 2 kPa. These results are comparable with those of Alanine-glyoxylate transaminase paired liver biopsy studies. LSM appears to be a good alternative for liver biopsies in patients with hepatitis C and inherited bleeding disorders, although the interpretation of the unexpected improvement we found in some of our patients is not straightforward. LSMs will be repeated in our patient population in a few years to be able to better assess the value of serial LSM. “
“Summary.  Muscle haematoma represents 10–25% of bleeds in patients with severe haemophilia. There is limited consensus on diagnostic or treatment strategies and little knowledge about the natural history of muscle haematoma and optimal treatment goals. The aim of this review was to perform a systematic description of the natural history of muscle haematoma in healthy athletes, focusing on diagnosis, classification and treatment options. Publications and educational textbooks on management of sports injuries were used as data source. Muscle haematomas occur following contusion, strain, or laceration and can be categorized as mild, moderate, or severe. Muscle haematoma may be inter- or intramuscular. In healthy athletes, the healing process takes 20–40 days.

Compared with densely populated city centres, suburbs and towns support greater natural resources and therefore provide more opportunity for urban carnivores. Thirdly, Iossa et al. (2010) pointed out that there is a high prevalence of populations of feral and stray dogs in developing countries, which might limit the presence of carnivore species (e.g. Vanak & Gompper, 2009; Vanak, Thaker & Gompper, 2009). Finally, across the globe, people will respond differently to carnivores entering urban environments,

which may contribute to differences in reporting ratio. In India, culturally based tolerance towards carnivores allows many small carnivores and even leopards Panthera pardus, wolves, sloth bears Melursus ursinus and striped check details hyaenas to persist among high human population densities, albeit in agricultural landscapes (Karanth & Chellam, Enzalutamide in vitro 2009). In south China, large and small carnivore species have been extirpated or greatly reduced in numbers; ironically, it is in mostly highly urbanized Hong Kong, with strong legal protection, where surviving species can be most easily encountered (Lau, Fellowes & Chan, 2010). Outside of anecdotal information, we could find no reports of carnivores living in African cities,

despite a vast array of carnivore species on the continent. This may reflect the nature of urbanization or the nature of predator guilds in Africa: large expanses pheromone of adjacent rural or undeveloped habitat may provide sufficient alternative resources,

while human self-preservation or protection of livestock may preclude the establishment of some carnivore species close to urban areas. All major terrestrial carnivore families have representatives that show some degree of association with human settlement (Fig. 3a). There appears to be no taxonomic restriction in terms of an ability to exploit urban environments. The major restrictions may therefore be in terms of body size and dietary flexibility. Body size plays an important part in determining whether a carnivore species uses the urban environment. The proportion of species that utilize human habitat – from villages through to cities – is not spread evenly across the range of eutherian terrestrial carnivore body masses (Fig. 3; χ26 = 12.60, P = 0.05). Both small and large carnivores are under-represented in the urban environment. Body size is important in terms of how a species is able to deal with the habitat fragmentation implicit with urban environments. Larger body size is a benefit in human-fragmented agricultural landscapes if it aids the animals’ ability to move in and out of the fragment matrix (e.g. coyotes), but body size should not be too large that viable populations cannot survive in small habitat fragments (Gehring & Swihart, 2003).

Baumert, Eric Robinet PURPOSE: To determine the intracellular metabolism of a novel anti-HCV β-D-2′-C-methyl-2,6-diaminopurine ribonucleoside (DAPN) phosphoramidate (RS-1389) in comparison to BMS-986094 (formerly know as INX-189), a related ribonucleoside analog which was halted in phase IIb due

to cardiac adverse effects. METHODS: RS-1389 was compared to BMS-986094 and IDX-184 side-by-side for interspecies plasma stability and intracellular metabolism in primary hepatocytes and human cardiomyocytes. RESULTS: In human plasma, all three compounds had half-lives longer than 24 hr. However, in mouse and rat plasma, RS-1389 Atezolizumab cost and BMS-986094 were rapidly metabolized (TV2 were less than 5 min). In dog and monkey plasma, the half-live of RS-1389 was shorter when compared with those of BMS-986094 and IDX-184. In Huh-7, HepG2 cells and all five species (mouse, rat, dog, monkey and human) of primary hepatocytes, RS-1389 was metabolized into two nucleoside triphosphates: 2′-C-methyl-DAPN-TP and 2′-C-meth- yl-GTP. BVD-523 solubility dmso In Huh-7 and HepG2 cells, BMS-986094 produced

the highest levels of 2′-C-methyl-GTP within 4 hr, more than 78-fold higher than the total nucleoside 5′-triphosphate inhibitors (NI-TP) from RS-1389 or IDX-184. However, in primary human hepatocytes, RS-1389 produced more NI-TP than BMS- 986094 and IDX-184, with the novel 2′-C-methyl-DAPN-TP as the predominant metabolite. Notably, in human cardiomyo-cytes, BMS-986094 generated extremely high levels (> 8-fold) of 2′-C-methyl-GTP, when compared to RS-1389 and IDX-184. CONCLUSIONS: RS-1389 demonstrated comparable stability in human plasma to BMS-986094 and IDX-184; delivered predominantly 2′-C-methyl-DAPN-TP ADP ribosylation factor and a relatively small amount of 2′-C-methyl-GTP in primary human hepatocytes. Importantly, less NI-TP levels were produced with RS-1389 in human cardio-myocytes, suggesting greater safety compared to BMS-986094 and IDX-184, and warranting

further investigation as an anti-HCV preclinical purine nucleoside candidate. Disclosures: Steven J. Coats – Employment: RFS Pharma Raymond F. Schinazi – Board Membership: RFS Pharma, LLC; Stock Shareholder: RFS Pharma, LLC The following people have nothing to disclose: Sijia Tao, Zhou Longhu, Hong-wang Zhang, Shaoman Zhou, Sheida Amiralaei, Jadd Shelton For decades, the chimpanzee model has been the only system for studying HCV infection and evaluation of antiviral compounds. However limited availability, significant costs, and ethical considerations make the chimpanzee model increasingly impractical today. A simple, reproducible noninfectious HCV mouse efficacy model would provide valuable information for compounds before entering clinical testing.