2008). The impact of tuber late blight on potato production occurs at different levels: on seed production as the potential source of new epidemics, on volunteers that serve as sources of inoculum for tomato and potato crops and on quality and yield of seed, tablestock (or ware) and processing tubers (Bonde and Schultz 1943; Kirk et al. 2009). Latent infections on seed and volunteer tubers are an important mechanism of long-term dispersion and introduction of new genotypes of P. infestans (Abad and Abad 1997; Nyankanga et al. 2010). The resistance of tubers against P. infestans and development of tuber blight are conditioned by the ability of the pathogen to penetrate the tuber tissue and the localization

of the infection within the tuber. The tuber has different components

involved in resistance including the periderm, HIF pathway outer cortical cells, medulla, lenticels and eyes (meristematic tissue) and all may respond differently to the pathogen (Pathak and Clarke 1987; Flier et al. 2007; Nyankanga et al. 2008). Different cultivars also vary in these resistance components, and there is variation in the aggressiveness of P. infestans genotypes (Kirk et al. 2001a, 2009, 2010). Potato breeding has focused on resistance of foliage with little effort Cobimetinib in vitro on tuber blight resistance. This trend has changed over time due to the importance of tuber blight that can result in storage rot losses and transmission from season to season through seed (Johnson and Cummings 2009; Kirk et al. 2009, 2010). Therefore, it is important to compare tuber disease development caused by isolates of new genotypes of P. infestans with isolates of the existing genotypes to commonly produced cultivars and those with known tuber resistance to P. infestans. The late blight epidemics of 2009–2010 in this website the Eastern United States were characterized by the appearance of a new genotype, designated as US-22. The genotype US-22 was initially reported in Florida in 2007 (Ristaino 2010; Hu et al. 2012) and then found in infected potato and tomato along the Eastern US coast (Hu et al. 2012). This

new genotype is complex and temporally displaced the US-8 genotype in Michigan (Rojas and Kirk 2011). The change in the genetic structure of the P. infestans population in Michigan necessitates the evaluation of currently available cultivars and recently released late blight resistant cultivars from breeding programmes. Therefore, the aim of this study was to compare the ability of the new genotype, US-22, as well as other P. infestans genotypes to cause tuber breakdown at 10°C, the storage temperature typically used for chip processing (potato crisp). Six cultivars of potato were selected for evaluation. The tubers for this study were obtained from the Michigan State University (MSU) potato breeding and genetics programme and commercial potato fields in Michigan.

2008). The impact of tuber late blight on potato production occurs at different levels: on seed production as the potential source of new epidemics, on volunteers that serve as sources of inoculum for tomato and potato crops and on quality and yield of seed, tablestock (or ware) and processing tubers (Bonde and Schultz 1943; Kirk et al. 2009). Latent infections on seed and volunteer tubers are an important mechanism of long-term dispersion and introduction of new genotypes of P. infestans (Abad and Abad 1997; Nyankanga et al. 2010). The resistance of tubers against P. infestans and development of tuber blight are conditioned by the ability of the pathogen to penetrate the tuber tissue and the localization

of the infection within the tuber. The tuber has different components

involved in resistance including the periderm, MG-132 outer cortical cells, medulla, lenticels and eyes (meristematic tissue) and all may respond differently to the pathogen (Pathak and Clarke 1987; Flier et al. 2007; Nyankanga et al. 2008). Different cultivars also vary in these resistance components, and there is variation in the aggressiveness of P. infestans genotypes (Kirk et al. 2001a, 2009, 2010). Potato breeding has focused on resistance of foliage with little effort PD0332991 on tuber blight resistance. This trend has changed over time due to the importance of tuber blight that can result in storage rot losses and transmission from season to season through seed (Johnson and Cummings 2009; Kirk et al. 2009, 2010). Therefore, it is important to compare tuber disease development caused by isolates of new genotypes of P. infestans with isolates of the existing genotypes to commonly produced cultivars and those with known tuber resistance to P. infestans. The late blight epidemics of 2009–2010 in click here the Eastern United States were characterized by the appearance of a new genotype, designated as US-22. The genotype US-22 was initially reported in Florida in 2007 (Ristaino 2010; Hu et al. 2012) and then found in infected potato and tomato along the Eastern US coast (Hu et al. 2012). This

new genotype is complex and temporally displaced the US-8 genotype in Michigan (Rojas and Kirk 2011). The change in the genetic structure of the P. infestans population in Michigan necessitates the evaluation of currently available cultivars and recently released late blight resistant cultivars from breeding programmes. Therefore, the aim of this study was to compare the ability of the new genotype, US-22, as well as other P. infestans genotypes to cause tuber breakdown at 10°C, the storage temperature typically used for chip processing (potato crisp). Six cultivars of potato were selected for evaluation. The tubers for this study were obtained from the Michigan State University (MSU) potato breeding and genetics programme and commercial potato fields in Michigan.

2008). The impact of tuber late blight on potato production occurs at different levels: on seed production as the potential source of new epidemics, on volunteers that serve as sources of inoculum for tomato and potato crops and on quality and yield of seed, tablestock (or ware) and processing tubers (Bonde and Schultz 1943; Kirk et al. 2009). Latent infections on seed and volunteer tubers are an important mechanism of long-term dispersion and introduction of new genotypes of P. infestans (Abad and Abad 1997; Nyankanga et al. 2010). The resistance of tubers against P. infestans and development of tuber blight are conditioned by the ability of the pathogen to penetrate the tuber tissue and the localization

of the infection within the tuber. The tuber has different components

involved in resistance including the periderm, find more outer cortical cells, medulla, lenticels and eyes (meristematic tissue) and all may respond differently to the pathogen (Pathak and Clarke 1987; Flier et al. 2007; Nyankanga et al. 2008). Different cultivars also vary in these resistance components, and there is variation in the aggressiveness of P. infestans genotypes (Kirk et al. 2001a, 2009, 2010). Potato breeding has focused on resistance of foliage with little effort Metabolism inhibitor on tuber blight resistance. This trend has changed over time due to the importance of tuber blight that can result in storage rot losses and transmission from season to season through seed (Johnson and Cummings 2009; Kirk et al. 2009, 2010). Therefore, it is important to compare tuber disease development caused by isolates of new genotypes of P. infestans with isolates of the existing genotypes to commonly produced cultivars and those with known tuber resistance to P. infestans. The late blight epidemics of 2009–2010 in this website the Eastern United States were characterized by the appearance of a new genotype, designated as US-22. The genotype US-22 was initially reported in Florida in 2007 (Ristaino 2010; Hu et al. 2012) and then found in infected potato and tomato along the Eastern US coast (Hu et al. 2012). This

new genotype is complex and temporally displaced the US-8 genotype in Michigan (Rojas and Kirk 2011). The change in the genetic structure of the P. infestans population in Michigan necessitates the evaluation of currently available cultivars and recently released late blight resistant cultivars from breeding programmes. Therefore, the aim of this study was to compare the ability of the new genotype, US-22, as well as other P. infestans genotypes to cause tuber breakdown at 10°C, the storage temperature typically used for chip processing (potato crisp). Six cultivars of potato were selected for evaluation. The tubers for this study were obtained from the Michigan State University (MSU) potato breeding and genetics programme and commercial potato fields in Michigan.

By binding to FXR, Alectinib concentration bile acids inhibit their synthesis and hepatocellular import in a feedback loop and induce their detoxification and excretion in a feedforward fashion. FXR represses transcription of CYP7A1, the enzyme mediating the rate-limiting step in conversion of cholesterol into bile acids, by induction of SHP111,112 (Fig. 3). In the intestine, FXR induces Fgf-15, which signals to the liver and activates hepatic FGF receptor 4

(FGFR-4) signaling to inhibit bile acid synthesis in the liver.62,113 FXR also represses hepatocellular basolateral bile acid uptake by way of the Na+/taurocholate cotransporter (NTCP) in an SHP-dependent manner114 (Fig. 3). In contrast to these inhibitory effects, FXR stimulates orthograde bile acid excretion into the canaliculus by way of the bile salt export pump BSEP and retrograde bile acid export back into portal blood by way of heteromeric organic solute transporter OSTα/β (Fig. 3).115-117 The canalicular bilirubin export pump MRP2 is also induced by FXR ligands.118 Preserved expression or induction of MRP2 may be important during cholestasis, because this protein is able to transport tetrahydroxylated bile acids that accumulate during cholestasis.119

In addition to transport and synthesis, phase I and phase II detoxification pathways are also regulated by FXR (Supporting Table 5). Phase I bile acid hydroxylation and phase II sulfation and glucuronide conjugation renders bile acid

more hydrophilic, less toxic, and more amenable to urinary excretion. Bile acid-activated MI-503 mw FXR induces expression of CYP3A4 (phase I bile acid hydroxylation), positively regulates SULT2A1 (phase II sulfoconjugation), and UGT2B4 (phase II bile acid glucuronidation)120 (Fig. 3). Master regulators of these phase I and II detoxification pathways are the classical drug receptors PXR and CAR. Both PXR and CAR are key regulators of CYP3A4, SULT2A1, glutathione S-transferases, selleck chemicals and UDP-glucuronosyltransferases expression (reviewed120) (Fig. 3). CAR is a central regulator of bile acid sulfation and their subsequent basolateral export by way of MRP4.121 These protective pathways are activated under conditions with high intracellular bile acid load in animal models of cholestasis and deletion of one or both receptors results in increased liver injury. Most important, the appearance of hydroxylated, sulfated, and glucuronidated bile acids in the urine of patients with cholestatic diseases indicates that these mechanisms are also activated in human liver disease.120 Unfortunately, this intrinsic adaptation to increased hepatic bile acid load cannot fully prevent liver damage and biliary fibrosis and cirrhosis in patients with longstanding cholestasis may ensue. PXR and CAR have been therapeutically targeted with “enzyme inducers” including rifampicin and phenobarbital, respectively, even long before NRs were discovered.

6 ± 12 g. For the remaining newborn seals in which both CC and brM were measured (n = 6), mean CC and brM were 387.2 ± 13 cm3 and 387.4 ± 12 g, respectively. Mean pup brM represented 69% of mean adult brM measured in this study, and 70% taking

into account all published values (Table 2). In pups, there was no correlation between measured CC and estimated age at death (range 0–8 d, Pearson correlation P = 0.49, n = 10). 1 1 563.2 501.5 estimated from cranial capacity estimated from AZD8055 cost cranial capacity Relatively few data are available on brain mass in Weddell seals (Table 2). Our measured adult brM of 563 g (n = 2) agrees well with previous estimates of 562 g (Bininda-Emonds 2000) and 550 g (Sacher and Staffeldt 1974, Elsner and Gooden 1983;2 Table 2). Zapol et al. (1979) reported the sum of this website major brain components to be 588 g for six adult Weddell seals

ranging in BM from 334 to 496 kg. Estimated brM based on CC of adult skulls from the UC collection (n = 9) was 627 ± 21 g. Even though this last result was not significantly different from brM measured directly, it is possible that average adult brM of Weddell may be somewhat underestimated in our sample of directly measured brains (n = 2) and in previous studies due to small sample sizes (Table 2). The accuracy of estimates of neonatal brain mass depends on sampling at or shortly after birth, before any significant postnatal brain growth has taken place. Our results for neonatal brM of Weddell seals (387 ± 12 g; n = 6) are similar to a previously reported brM of 400 g based on data from one full-term fetus and two newborn pups (Sacher and Staffeldt 1974, Elsner and Gooden 1983; Table 2). Our sample includes stillborn animals and pups ranging from 0 to 8 d of age (2.7 ± 1.1 d), and causes

learn more of death were known only for a subset (see Methods). Even after omission of one undersized, apparently premature pup (7547; Table 1), there was considerable variance in brain mass (coefficient of variation = 7.4%). Given the small sample size, and variable age and condition of the pups, our data set may contain bias. Pups that were stillborn or succumbed at a young age may have been smaller, and may have had smaller brains than average, contributing a negative bias. On the other hand, we have no data on the rate of brain growth in Weddell seals and so it is possible that inclusion of animals up to 8 d old produced a positive bias. However, there was no significant correlation between estimated age at death and CC (n = 10) in our data set. More data are needed for both Weddell seals and other species to obtain a more accurate picture of brain growth in pinnipeds. The ontogeny of brain growth has not been quantitatively described in any pinniped, or indeed any marine mammal, but is presumably similar to other mammals.

6 ± 12 g. For the remaining newborn seals in which both CC and brM were measured (n = 6), mean CC and brM were 387.2 ± 13 cm3 and 387.4 ± 12 g, respectively. Mean pup brM represented 69% of mean adult brM measured in this study, and 70% taking

into account all published values (Table 2). In pups, there was no correlation between measured CC and estimated age at death (range 0–8 d, Pearson correlation P = 0.49, n = 10). 1 1 563.2 501.5 estimated from cranial capacity estimated from learn more cranial capacity Relatively few data are available on brain mass in Weddell seals (Table 2). Our measured adult brM of 563 g (n = 2) agrees well with previous estimates of 562 g (Bininda-Emonds 2000) and 550 g (Sacher and Staffeldt 1974, Elsner and Gooden 1983;2 Table 2). Zapol et al. (1979) reported the sum of Selleck PF 01367338 major brain components to be 588 g for six adult Weddell seals

ranging in BM from 334 to 496 kg. Estimated brM based on CC of adult skulls from the UC collection (n = 9) was 627 ± 21 g. Even though this last result was not significantly different from brM measured directly, it is possible that average adult brM of Weddell may be somewhat underestimated in our sample of directly measured brains (n = 2) and in previous studies due to small sample sizes (Table 2). The accuracy of estimates of neonatal brain mass depends on sampling at or shortly after birth, before any significant postnatal brain growth has taken place. Our results for neonatal brM of Weddell seals (387 ± 12 g; n = 6) are similar to a previously reported brM of 400 g based on data from one full-term fetus and two newborn pups (Sacher and Staffeldt 1974, Elsner and Gooden 1983; Table 2). Our sample includes stillborn animals and pups ranging from 0 to 8 d of age (2.7 ± 1.1 d), and causes

selleckchem of death were known only for a subset (see Methods). Even after omission of one undersized, apparently premature pup (7547; Table 1), there was considerable variance in brain mass (coefficient of variation = 7.4%). Given the small sample size, and variable age and condition of the pups, our data set may contain bias. Pups that were stillborn or succumbed at a young age may have been smaller, and may have had smaller brains than average, contributing a negative bias. On the other hand, we have no data on the rate of brain growth in Weddell seals and so it is possible that inclusion of animals up to 8 d old produced a positive bias. However, there was no significant correlation between estimated age at death and CC (n = 10) in our data set. More data are needed for both Weddell seals and other species to obtain a more accurate picture of brain growth in pinnipeds. The ontogeny of brain growth has not been quantitatively described in any pinniped, or indeed any marine mammal, but is presumably similar to other mammals.

6 ± 12 g. For the remaining newborn seals in which both CC and brM were measured (n = 6), mean CC and brM were 387.2 ± 13 cm3 and 387.4 ± 12 g, respectively. Mean pup brM represented 69% of mean adult brM measured in this study, and 70% taking

into account all published values (Table 2). In pups, there was no correlation between measured CC and estimated age at death (range 0–8 d, Pearson correlation P = 0.49, n = 10). 1 1 563.2 501.5 estimated from cranial capacity estimated from DNA Damage inhibitor cranial capacity Relatively few data are available on brain mass in Weddell seals (Table 2). Our measured adult brM of 563 g (n = 2) agrees well with previous estimates of 562 g (Bininda-Emonds 2000) and 550 g (Sacher and Staffeldt 1974, Elsner and Gooden 1983;2 Table 2). Zapol et al. (1979) reported the sum of C646 in vitro major brain components to be 588 g for six adult Weddell seals

ranging in BM from 334 to 496 kg. Estimated brM based on CC of adult skulls from the UC collection (n = 9) was 627 ± 21 g. Even though this last result was not significantly different from brM measured directly, it is possible that average adult brM of Weddell may be somewhat underestimated in our sample of directly measured brains (n = 2) and in previous studies due to small sample sizes (Table 2). The accuracy of estimates of neonatal brain mass depends on sampling at or shortly after birth, before any significant postnatal brain growth has taken place. Our results for neonatal brM of Weddell seals (387 ± 12 g; n = 6) are similar to a previously reported brM of 400 g based on data from one full-term fetus and two newborn pups (Sacher and Staffeldt 1974, Elsner and Gooden 1983; Table 2). Our sample includes stillborn animals and pups ranging from 0 to 8 d of age (2.7 ± 1.1 d), and causes

selleck inhibitor of death were known only for a subset (see Methods). Even after omission of one undersized, apparently premature pup (7547; Table 1), there was considerable variance in brain mass (coefficient of variation = 7.4%). Given the small sample size, and variable age and condition of the pups, our data set may contain bias. Pups that were stillborn or succumbed at a young age may have been smaller, and may have had smaller brains than average, contributing a negative bias. On the other hand, we have no data on the rate of brain growth in Weddell seals and so it is possible that inclusion of animals up to 8 d old produced a positive bias. However, there was no significant correlation between estimated age at death and CC (n = 10) in our data set. More data are needed for both Weddell seals and other species to obtain a more accurate picture of brain growth in pinnipeds. The ontogeny of brain growth has not been quantitatively described in any pinniped, or indeed any marine mammal, but is presumably similar to other mammals.

Due to the small numbers within subgroups, no further prognostic factors were explored for TTP. Survival was determined PD0325901 ic50 from the day of first Y-90 treatment. Figure 3 shows the Kaplan-Meier estimator with a median survival rate for the entire sample of 16.4 months (95% CI 12.1-inf. months). The corresponding survival probability at 6 months was 75% (95% CI 66%-85%), whereas it was 59% (95% CI 47%-75%) 1 year after treatment initiation. Significant differences were observed with respect to the survival times of patients with

Child A liver cirrhosis as compared to patients with Child B (Fig. 4A, P = 0.013). Although the estimated median survival rate in the Child A group was 17.2 months (95% CI 12.1-∞ months), the median survival rate in patients with Child B was only 6 months (95% CI 4.2-∞ months). Accordingly, the 6-month survival probability for Child A patients is 79% (95% CI 70%-90%) as compared to 16% (95% CI 23%-92%) for Child B patients. Another important element

that determines prognosis in patients with advanced HCC is the presence of macrovascular invasion. Figure 4B shows the difference in survival between patients with (31%) and without (69%) PVT. Survival probability in the PVT group at 6 months was 65% (95% CI 46%-92%) with a median survival rate of 10.0 months (95% CI 6.0-∞ months). In contrast, patients without detectable PVT had a survival probability EGFR signaling pathway of 76% (95% CI 65%-88%) and a median survival of 16.4 months (95% CI 12.1-∞ months). When the tumor stage was used to stratify survival (Fig. 4C), we observed that patients with BCLC stage B had a median survival rate of 16.4 months (95% CI 12.1-∞ months). For patients with stage C no median survival rate was assessable, as the last estimate of survival probability selleck compound in this group was 51% (95% CI 33%-81%). The corresponding survival probabilities at 6 months were 75% (95% CI 63%-89%) and 72% (95% CI 57%-87%), respectively. The most commonly reported clinical AE was a transient fatigue syndrome with a maximum between day 3 and

7 posttherapy in 61% of patients and a vague abdominal pain reported by 56% of patients. A single case with radiation cholecystitis was the only relevant gastrointestinal AE; the patient was treated by cholecystemtomy 10 days after Y-90 microsphere application. No patient experienced treatment-induced ulcerations in stomach or duodenum. In addition, we detected no patients with radiation-induced pneumonitis or other grade 3/4 AEs related to the lungs. One patient showed dissection of the proper hepatic artery during treatment, resulting in a functional stenosis of the vessel. Due to preexisting collaterals by way of the gastroduodenal artery, this dissection remained without clinical consequences. All bilirubin elevations that were observed within the observation period were considered treatment-related hepatotoxicity.

Due to the small numbers within subgroups, no further prognostic factors were explored for TTP. Survival was determined 3MA from the day of first Y-90 treatment. Figure 3 shows the Kaplan-Meier estimator with a median survival rate for the entire sample of 16.4 months (95% CI 12.1-inf. months). The corresponding survival probability at 6 months was 75% (95% CI 66%-85%), whereas it was 59% (95% CI 47%-75%) 1 year after treatment initiation. Significant differences were observed with respect to the survival times of patients with

Child A liver cirrhosis as compared to patients with Child B (Fig. 4A, P = 0.013). Although the estimated median survival rate in the Child A group was 17.2 months (95% CI 12.1-∞ months), the median survival rate in patients with Child B was only 6 months (95% CI 4.2-∞ months). Accordingly, the 6-month survival probability for Child A patients is 79% (95% CI 70%-90%) as compared to 16% (95% CI 23%-92%) for Child B patients. Another important element

that determines prognosis in patients with advanced HCC is the presence of macrovascular invasion. Figure 4B shows the difference in survival between patients with (31%) and without (69%) PVT. Survival probability in the PVT group at 6 months was 65% (95% CI 46%-92%) with a median survival rate of 10.0 months (95% CI 6.0-∞ months). In contrast, patients without detectable PVT had a survival probability selleck chemicals of 76% (95% CI 65%-88%) and a median survival of 16.4 months (95% CI 12.1-∞ months). When the tumor stage was used to stratify survival (Fig. 4C), we observed that patients with BCLC stage B had a median survival rate of 16.4 months (95% CI 12.1-∞ months). For patients with stage C no median survival rate was assessable, as the last estimate of survival probability selleckchem in this group was 51% (95% CI 33%-81%). The corresponding survival probabilities at 6 months were 75% (95% CI 63%-89%) and 72% (95% CI 57%-87%), respectively. The most commonly reported clinical AE was a transient fatigue syndrome with a maximum between day 3 and

7 posttherapy in 61% of patients and a vague abdominal pain reported by 56% of patients. A single case with radiation cholecystitis was the only relevant gastrointestinal AE; the patient was treated by cholecystemtomy 10 days after Y-90 microsphere application. No patient experienced treatment-induced ulcerations in stomach or duodenum. In addition, we detected no patients with radiation-induced pneumonitis or other grade 3/4 AEs related to the lungs. One patient showed dissection of the proper hepatic artery during treatment, resulting in a functional stenosis of the vessel. Due to preexisting collaterals by way of the gastroduodenal artery, this dissection remained without clinical consequences. All bilirubin elevations that were observed within the observation period were considered treatment-related hepatotoxicity.

Due to the small numbers within subgroups, no further prognostic factors were explored for TTP. Survival was determined BTK inhibitor library from the day of first Y-90 treatment. Figure 3 shows the Kaplan-Meier estimator with a median survival rate for the entire sample of 16.4 months (95% CI 12.1-inf. months). The corresponding survival probability at 6 months was 75% (95% CI 66%-85%), whereas it was 59% (95% CI 47%-75%) 1 year after treatment initiation. Significant differences were observed with respect to the survival times of patients with

Child A liver cirrhosis as compared to patients with Child B (Fig. 4A, P = 0.013). Although the estimated median survival rate in the Child A group was 17.2 months (95% CI 12.1-∞ months), the median survival rate in patients with Child B was only 6 months (95% CI 4.2-∞ months). Accordingly, the 6-month survival probability for Child A patients is 79% (95% CI 70%-90%) as compared to 16% (95% CI 23%-92%) for Child B patients. Another important element

that determines prognosis in patients with advanced HCC is the presence of macrovascular invasion. Figure 4B shows the difference in survival between patients with (31%) and without (69%) PVT. Survival probability in the PVT group at 6 months was 65% (95% CI 46%-92%) with a median survival rate of 10.0 months (95% CI 6.0-∞ months). In contrast, patients without detectable PVT had a survival probability JQ1 concentration of 76% (95% CI 65%-88%) and a median survival of 16.4 months (95% CI 12.1-∞ months). When the tumor stage was used to stratify survival (Fig. 4C), we observed that patients with BCLC stage B had a median survival rate of 16.4 months (95% CI 12.1-∞ months). For patients with stage C no median survival rate was assessable, as the last estimate of survival probability see more in this group was 51% (95% CI 33%-81%). The corresponding survival probabilities at 6 months were 75% (95% CI 63%-89%) and 72% (95% CI 57%-87%), respectively. The most commonly reported clinical AE was a transient fatigue syndrome with a maximum between day 3 and

7 posttherapy in 61% of patients and a vague abdominal pain reported by 56% of patients. A single case with radiation cholecystitis was the only relevant gastrointestinal AE; the patient was treated by cholecystemtomy 10 days after Y-90 microsphere application. No patient experienced treatment-induced ulcerations in stomach or duodenum. In addition, we detected no patients with radiation-induced pneumonitis or other grade 3/4 AEs related to the lungs. One patient showed dissection of the proper hepatic artery during treatment, resulting in a functional stenosis of the vessel. Due to preexisting collaterals by way of the gastroduodenal artery, this dissection remained without clinical consequences. All bilirubin elevations that were observed within the observation period were considered treatment-related hepatotoxicity.