19 to 0.94. Some of the highest CoAs were between fused females and their older speckled female offspring (which remained in their mother’s cluster). These older offspring

often had strong associations with their mother’s female associates and their older offspring. One speckled female lost her mother after 2000 and subsequently had strong associations (up to 0.74) with three other females in the Southern cluster. One selleckchem strong association between a fused mother and her mottled female offspring was observed and this pair had strong associations throughout the offspring’s development into adulthood (minimum CoA = 0.37, three times the population average). The majority of associations (59.0%–74.0%) were between different age classes in all years except 1997–1999, when it was 50.0%. Strong associations between speckled individuals were prevalent in all years except 1991–1993. CoA results indicated that reproductive status may have influenced strong female associations. In each pooled period, an average of about 30% of the strong female associations involved two reproductively active mottled and fused females. The majority (81%) of the strong associations were between reproductively active females in the same reproductive state (i.e., both had calves (majority), or both were pregnant, during

that time period). However there was no difference in average CoA of same reproductive state vs. different reproductive state (average CoA for both ~ 0.36). Out of all the possible combinations of mixed sex associations between

check details individuals, 63.2%–68.0% were observed (CoA >0). This was higher than observed female-female associations, but lower than observed male-male associations. Strong CoAs ranged from 0.19 to 0.97, with the two highest (and several MCE lower strong CoAs) between females and their older speckled male offspring. The majority of associations were mixed age class (between 58.3%–72.9%) through 1999, but in 2000–2002 mixed age class associations comprised only 46.6%. Generally, strong mixed sex associations were between individuals of the same cluster. Only 21.3% of the observed mixed sex associations were between individuals from different clusters. One Northern male, Rivet, had strong associations with Central females in every pooled period, and one association with a Southern female in 2000–2002. No other Northern-Southern strong associations were observed. Although other Northern and Southern males had a few strong associations, the majority of cross cluster associations were between Southern or Northern females and Central males. There were speckled and young mottled males involved in cross cluster associations but the vast majority involved fused males. The percentage of males involved in mixed sex associations (85.7%–100.0%) was always larger than the percentage of females involved (73.1%–84.1%).

Although staining for additional mesenchymal markers AZD2014 would have strengthened the conclusions, the data are nonetheless compelling in demonstrating in the CCl4 model that hepatocytes and their derivatives do not express FSP1, type I collagen, or α-SMA and thus do not undergo EMT. Why do the authors of the two lineage tracing articles on hepatocyte EMT reach such different conclusions? Taura et al. propose that technical limitations associated with β-Gal staining yielded false-positive results in the Zeisberg

study. This hypothesis is supported by the observation that detection of β-Gal expression by immunostaining does not coincide with detection of β-Gal activity by X-gal.12 I would suggest that failure to rigorously

define EMT is another reason for the divergent findings. GDC-0941 clinical trial Zeisberg et al. define EMT through expression of the controversial and potentially nonspecific marker FSP1 but do not examine collagen synthesis, the feature ultimately most relevant to fibrosis. Taura et al., although focused on collagen synthesis as a primary marker of EMT, also demonstrate that hepatocytes in the fibrotic liver fail to express α-SMA, a finding of key importance given the many demonstrations (including in their study) that α-SMA–positive cells make up a large percentage of fibrogenic cells. Does the work of Taura et al. lay to rest the concept of hepatocyte EMT? The answer is a qualified yes. There are caveats, including the reality that neither the genetic background of the mice nor the injury model (CCl4) accurately model human disease. Regardless, this study effectively refutes the published 上海皓元医药股份有限公司 data that support hepatocyte EMT. Although it is still theoretically possible that hepatocyte EMT occurs in human disease,
s of evidence will be required for this to reemerge as a viable concept. Interestingly,

an exhaustive study has recently been published calling into question EMT in the kidney. Using two different epithelial cell–specific drivers, two different reporters, and two different models of renal fibrosis, Humphreys et al. find no evidence that epithelial cells of the kidney contribute to the myofibroblast population in vivo (or express FSP1).16 Like Taura and colleagues, this group suggests that nonspecific methods to detect the β-Gal reporter could have contributed to discordant findings in the literature. Thus, there is now convincing evidence that neither hepatocyte nor renal epithelial cell EMT occurs in fibrosis. Whether cholangiocyte EMT contributes to fibrosis in the liver is still an open question. Several groups, making use of both animal models and human tissue, have reported that cholangiocytes in fibrotic livers (from bile duct–ligated mice as well as humans with primary biliary cirrhosis, biliary atresia, and several other diseases) coexpress multiple epithelial and mesenchymal markers by immunostaining and are therefore likely to be undergoing EMT.

Although staining for additional mesenchymal markers check details would have strengthened the conclusions, the data are nonetheless compelling in demonstrating in the CCl4 model that hepatocytes and their derivatives do not express FSP1, type I collagen, or α-SMA and thus do not undergo EMT. Why do the authors of the two lineage tracing articles on hepatocyte EMT reach such different conclusions? Taura et al. propose that technical limitations associated with β-Gal staining yielded false-positive results in the Zeisberg

study. This hypothesis is supported by the observation that detection of β-Gal expression by immunostaining does not coincide with detection of β-Gal activity by X-gal.12 I would suggest that failure to rigorously

define EMT is another reason for the divergent findings. MK-8669 order Zeisberg et al. define EMT through expression of the controversial and potentially nonspecific marker FSP1 but do not examine collagen synthesis, the feature ultimately most relevant to fibrosis. Taura et al., although focused on collagen synthesis as a primary marker of EMT, also demonstrate that hepatocytes in the fibrotic liver fail to express α-SMA, a finding of key importance given the many demonstrations (including in their study) that α-SMA–positive cells make up a large percentage of fibrogenic cells. Does the work of Taura et al. lay to rest the concept of hepatocyte EMT? The answer is a qualified yes. There are caveats, including the reality that neither the genetic background of the mice nor the injury model (CCl4) accurately model human disease. Regardless, this study effectively refutes the published 上海皓元 data that support hepatocyte EMT. Although it is still theoretically possible that hepatocyte EMT occurs in human disease,
s of evidence will be required for this to reemerge as a viable concept. Interestingly,

an exhaustive study has recently been published calling into question EMT in the kidney. Using two different epithelial cell–specific drivers, two different reporters, and two different models of renal fibrosis, Humphreys et al. find no evidence that epithelial cells of the kidney contribute to the myofibroblast population in vivo (or express FSP1).16 Like Taura and colleagues, this group suggests that nonspecific methods to detect the β-Gal reporter could have contributed to discordant findings in the literature. Thus, there is now convincing evidence that neither hepatocyte nor renal epithelial cell EMT occurs in fibrosis. Whether cholangiocyte EMT contributes to fibrosis in the liver is still an open question. Several groups, making use of both animal models and human tissue, have reported that cholangiocytes in fibrotic livers (from bile duct–ligated mice as well as humans with primary biliary cirrhosis, biliary atresia, and several other diseases) coexpress multiple epithelial and mesenchymal markers by immunostaining and are therefore likely to be undergoing EMT.

Total hepatic FA profiling revealed a higher palmitic acid/oleic acid (PA/OA) ratio in WT mice, compared to ATGL KO mice,

at baseline. Phosphoinositide-3-kinase inhibitor–known Erlotinib solubility dmso to be involved in FA-derived ER stress and blocked by OA–was increased in TM-treated WT mice only. In line with this, in vitro OA protected hepatocytes from TM-induced ER stress. Conclusions: Lack of ATGL may protect from hepatic ER stress through alterations in FA composition. ATGL could constitute a new therapeutic strategy to target ER stress in NAFLD. (HEPATOLOGY 2012;56:270–280 ) Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation (i.e., steatosis) and can progress to nonalcoholic steatohepatitis (NASH), advanced fibrosis,

cirrhosis, and cancer.1, 2 As a result of the pandemic Selleck Talazoparib of obesity and diabetes, NAFLD has become a leading cause of liver disease in the Western world.3 As such, more than 20% of the general population4 and 75% of obese individuals5 suffer from NAFLD. Though adipose tissue has the capacity to deposit excess free fatty acids (FAs) as triglycerides (TGs) in lipid droplets, nonadipocyte cell types, such as hepatocytes, have a more limited capacity for lipid storage. When the FA-buffering capacity of a cell is exceeded, the resultant increase in FA levels can become cytotoxic in a series of events termed lipotoxicity.6 Previous studies have demonstrated hepatic endoplasmic reticulum (ER) stress in several animal models of steatosis7, 8 and human NAFLD patients,9, 10 suggesting that ER stress 上海皓元医药股份有限公司 may be associated with lipotoxicity. In response to ER stress, three main pathways are activated, which, in turn, mediate the unfolded protein response (UPR).11 Pancreatic ER eukaryotic translational initiation factor (eIF)-2α kinase (PERK) and inositol-requiring

enzyme (IRE)-1α are transmembrane kinases leading to the phosphorylation of eIF2α, which inhibits the translation and production of X-box-binding protein (XBP)-1 transcription factor by a splicing mechanism. Concomitantly, activating transcription factor (ATF)-6α, a transmembrane transcription factor released by stress, regulates intramembrane proteolysis. Each pathway activates transcriptional regulators of gene expression and contributes to the preservation of cellular integrity during ER stress.12 Constituent genes of the UPR, such as the transcription factor, XBP1,13 and the translational regulator, eIF2α,14 have also been proposed to directly regulate lipid metabolic pathways. ATF6α up-regulates chaperones, such as binding immunoglobulin protein/glucose-regulated protein (BiP/Grp78) and the ER-associated protein degradation (ERAD) machinery, and therefore protects ER function during stress.

ISC is a rare disease, and its exact prevalence is not yet known. According to a previous report,10 a substantial portion (17%) of bile duct resection for presumed hilar CCC was finally proven not to be malignant, and significant lymphoplasmacytic infiltration was also identified histologically in half of those benign strictures. The prevalence of hilar or intrahepatic strictures as biliary manifestations see more of IgG4-related systemic disease in patients with AIP has been reported to be 8–13%11,12 to 46–49%.3,5 In our data, these proximal biliary strictures were observed only in 14% of patients with AIP (16/118). The wide range of prevalence of ISC in reports might be related

to the heterogeneity of the study population, including ethnic differences and undetermined natural courses of the disease, at which time, ISC develops along the clinical course of IgG4-related systemic disease in each individual patient. ISC can be preceded, accompanied, or followed by AIP.13 Among our patients, two patients exhibited a long disease interval gap between ISC and AIP, with ISC preceding AIP by 9 years, and ISC following AIP by 8 years. Concurrent AIP was

observed in one-third of patients with ISC (6/16). It is already well known that IgG4-positive cell infiltration in the bile duct specimen and serum IgG4 elevation are characteristic findings in ISC. Since ISC is a rare disease, however, it might not Cytoskeletal Signaling inhibitor be practical or cost-effective that serological evaluation for serum IgG4 and histological evaluation with IgG4 immunostaining MCE are routinely

performed in all patients with hilar or intrahepatic biliary strictures. This strategy might be appropriate only when ISC is suspected clinically and radiologically. Our case series revealed several characteristic radiological findings, which were likely to be useful for differential diagnosis between ISC and hilar CCC. First, bile duct wall thickening, especially at the hilum, was prominent, but the luminal surface was smooth, with relatively preserved luminal patency. Thus, it looked like a doughnut (Fig. 2a). A plausible explanation for the smooth luminal surface and preserved luminal patency, despite marked bile duct wall thickening, could be that the bile duct epithelium is relatively intact, while the bile duct wall is thickened by extensive lymphoplasmacytic infiltration and fibrosis.14 In addition, the bile duct wall was a thickened in a concentric pattern in our patients with ISC,12 in contrast to the abrupt and eccentric strictures with a irregular surface in CCC.15 Second, proximal biliary dilatation was relatively mild in ISC, despite the marked bile duct wall thickening, in contrast to the marked proximal dilatation in CCC. Third, multifocal strictures with intervening normal-looking branches were observed in most of our ISC patients, in comparison to a single, localized stricture in CCC.

Specifically, in both BCLC B and C patients the ICERs for QALY progressively increased from log-normal, to Weibull and further to exponential and log-logistic survival distributions. Further sensitivity analysis was performed to evaluate whether the increase of the expected survival of HCC patients treated with

full-dose sorafenib allowed achieving the willingness-to-pay threshold of €38,000 per QALY. Specifically, we observed that full-dose sorafenib reached cost-effectiveness if survival increased from 11.1 to 19.2 months (percentage increase of 74%) in BCLC B and C considered together, from 16.3 to 27 months (percentage increase of 67%) in BCLC B, and from 10 to 17.4 months (percentage increase of 74%) in BCLC C patients. Varying all variables simultaneously in the Monte Carlo simulation, and using a willingness-to-pay threshold of €38,000 per QALY, dose-adjusted strategies were cost-effective in 68% and 9% of the simulations, in BCLC B and BCLC C RG7422 manufacturer HCC patients, respectively (Fig. 4). In a best-case scenario, the model generated an ICER of €16,464 per QALY for BCLC C and an ICER of €24,407 per QALY for BCLC B HCC. In a worst-case scenario, the model generated an ICER of €119,673 per QALY for BCLC C and an ICER of €1,295,276 per QALY for BCLC

B HCC. In the present study, we show that in patients with advanced/intermediate HCC included in the SOFIA study, 6 sorafenib at the recommended dose of 800 mg daily is not a cost-effective medchemexpress treatment compared with BSC. Our analysis, in agreement with the NICE recommendation,7 relies on data from the single GS1101 available manufacturer-sponsored SHARP trial4 demonstrating that sorafenib, within its licensed dose and indication, is not recommended

for the treatment of patients with advanced HCC. In addition, we showed that full-dose sorafenib was not cost-effective also when considering separately BCLC B and BCLC C HCC patients. However, we demonstrated that in field practice dose-adjusted sorafenib is cost-effective compared with BSC in the treatment of BCLC B and C HCC patients considered together, improving survival by about 0.59 LYG and 0.44 QALY. This gain came at an acceptable cost, resulting in an ICER of €34,000 per QALY gained, which was lower than the generally accepted societal threshold for willingness to pay.12 According to the SOFIA study, which differs from the SHARP trial 4 in terms of rates of poor tolerability, leading to dose reduction or discontinuation, and that provides indirect evidence of effectiveness of half-dose sorafenib, we hypothesized that sorafenib could be utilized in a more cost-effective manner in the setting of intermediate/advanced HCC. Specifically, the key issue is the identification for both BCLC B and C HCC of an effective but not toxic sorafenib dose. The availability of individual patients’ data makes it possible to assess the cost-effectiveness of treatment according to sorafenib dose and BCLC stage.

Specifically, in both BCLC B and C patients the ICERs for QALY progressively increased from log-normal, to Weibull and further to exponential and log-logistic survival distributions. Further sensitivity analysis was performed to evaluate whether the increase of the expected survival of HCC patients treated with

full-dose sorafenib allowed achieving the willingness-to-pay threshold of €38,000 per QALY. Specifically, we observed that full-dose sorafenib reached cost-effectiveness if survival increased from 11.1 to 19.2 months (percentage increase of 74%) in BCLC B and C considered together, from 16.3 to 27 months (percentage increase of 67%) in BCLC B, and from 10 to 17.4 months (percentage increase of 74%) in BCLC C patients. Varying all variables simultaneously in the Monte Carlo simulation, and using a willingness-to-pay threshold of €38,000 per QALY, dose-adjusted strategies were cost-effective in 68% and 9% of the simulations, in BCLC B and BCLC C Small molecule library purchase HCC patients, respectively (Fig. 4). In a best-case scenario, the model generated an ICER of €16,464 per QALY for BCLC C and an ICER of €24,407 per QALY for BCLC B HCC. In a worst-case scenario, the model generated an ICER of €119,673 per QALY for BCLC C and an ICER of €1,295,276 per QALY for BCLC

B HCC. In the present study, we show that in patients with advanced/intermediate HCC included in the SOFIA study, 6 sorafenib at the recommended dose of 800 mg daily is not a cost-effective MCE公司 treatment compared with BSC. Our analysis, in agreement with the NICE recommendation,7 relies on data from the single Mitomycin C available manufacturer-sponsored SHARP trial4 demonstrating that sorafenib, within its licensed dose and indication, is not recommended

for the treatment of patients with advanced HCC. In addition, we showed that full-dose sorafenib was not cost-effective also when considering separately BCLC B and BCLC C HCC patients. However, we demonstrated that in field practice dose-adjusted sorafenib is cost-effective compared with BSC in the treatment of BCLC B and C HCC patients considered together, improving survival by about 0.59 LYG and 0.44 QALY. This gain came at an acceptable cost, resulting in an ICER of €34,000 per QALY gained, which was lower than the generally accepted societal threshold for willingness to pay.12 According to the SOFIA study, which differs from the SHARP trial 4 in terms of rates of poor tolerability, leading to dose reduction or discontinuation, and that provides indirect evidence of effectiveness of half-dose sorafenib, we hypothesized that sorafenib could be utilized in a more cost-effective manner in the setting of intermediate/advanced HCC. Specifically, the key issue is the identification for both BCLC B and C HCC of an effective but not toxic sorafenib dose. The availability of individual patients’ data makes it possible to assess the cost-effectiveness of treatment according to sorafenib dose and BCLC stage.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide.1 Although the incidence of this cancer is rising in many countries of the developed world, most deaths occur in Asia and the developing world. Traditionally, external beam radiotherapy has had Angiogenesis antagonist a very limited role in the treatment

of HCC and is rarely considered in current treatment recommendations of the major Asia–Pacific regions, American and European societies.2,3 There are many reasons for the current lack of interest in radiotherapy. The discouraging early experience with radiotherapy for HCC was a key factor leading to the current widespread belief that HCC is not a ‘radiosensitive’ tumor and that radiotherapy is too ‘toxic’ for the liver. During this era, large HCC were treated with large volume or whole liver radiotherapy, which was associated with high rates of radiation-induced liver disease and poor tumor response rates. As will

be discussed, an understanding of the relationship between the volume of normal tissue (liver) irradiated and tolerable dose is necessary. We are usually mainly concerned about the late radiation effects. Recent developments have concentrated on means of identifying and treating small volumes, because tolerance of liver to radiation is very volume dependant. These developments include the use of radioactive 90Y microspheres locally introduced, stereotactic selleck screening library radiotherapy, the use of intensity modulated X-ray beams and the more exotic and expensive heavy 上海皓元 ion therapy. Other means of delivering a local effect include surgery, chemotherapy and percutaneous techniques for tumor ablation. In our view, the roles of radiotherapy, especially

external beam fractionated treatment using standard multifield treatment techniques and modern 3-D computer planning, have been undervalued. It is essential that the radiobiological base for treatment be understood. To help address this problem, the current radiobiology data for HCC and normal liver have been reviewed. These data have been used to describe radiosensitivity of HCC and normal liver and the fundamental concepts of liver tolerance and growth rates of HCC. Tumor control probability when conventional fractionated external beam radiotherapy was used was also examined. The medical published work was reviewed using a computer-based Medline search supplemented by relevant references from primary articles (http://medline.cos.com). These searches were particularly directed to volume doubling times (Tvol) and growth rate of HCC, radiosensitivity of HCC and normal liver and the radiobiology of normal tissue responses. Graphs and associated calculations were generated using Mathcad 2001 software (MathSoft, Cambridge, MA, USA).

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality worldwide.1 Although the incidence of this cancer is rising in many countries of the developed world, most deaths occur in Asia and the developing world. Traditionally, external beam radiotherapy has had Sirolimus nmr a very limited role in the treatment

of HCC and is rarely considered in current treatment recommendations of the major Asia–Pacific regions, American and European societies.2,3 There are many reasons for the current lack of interest in radiotherapy. The discouraging early experience with radiotherapy for HCC was a key factor leading to the current widespread belief that HCC is not a ‘radiosensitive’ tumor and that radiotherapy is too ‘toxic’ for the liver. During this era, large HCC were treated with large volume or whole liver radiotherapy, which was associated with high rates of radiation-induced liver disease and poor tumor response rates. As will

be discussed, an understanding of the relationship between the volume of normal tissue (liver) irradiated and tolerable dose is necessary. We are usually mainly concerned about the late radiation effects. Recent developments have concentrated on means of identifying and treating small volumes, because tolerance of liver to radiation is very volume dependant. These developments include the use of radioactive 90Y microspheres locally introduced, stereotactic Trichostatin A research buy radiotherapy, the use of intensity modulated X-ray beams and the more exotic and expensive heavy 上海皓元医药股份有限公司 ion therapy. Other means of delivering a local effect include surgery, chemotherapy and percutaneous techniques for tumor ablation. In our view, the roles of radiotherapy, especially

external beam fractionated treatment using standard multifield treatment techniques and modern 3-D computer planning, have been undervalued. It is essential that the radiobiological base for treatment be understood. To help address this problem, the current radiobiology data for HCC and normal liver have been reviewed. These data have been used to describe radiosensitivity of HCC and normal liver and the fundamental concepts of liver tolerance and growth rates of HCC. Tumor control probability when conventional fractionated external beam radiotherapy was used was also examined. The medical published work was reviewed using a computer-based Medline search supplemented by relevant references from primary articles (http://medline.cos.com). These searches were particularly directed to volume doubling times (Tvol) and growth rate of HCC, radiosensitivity of HCC and normal liver and the radiobiology of normal tissue responses. Graphs and associated calculations were generated using Mathcad 2001 software (MathSoft, Cambridge, MA, USA).

Development of this method began in 1958 by Dr. F. H. Fay and was used during six surveys in the Chukchi Sea between 1981 and 1999. We estimate calf:cow ratios using beta-binomial models to allow for overdispersion and use Monte Carlo simulations to assess the reliability of prior surveys and quantify sample sizes required for future surveys. Calf:cow ratios did not vary by region, date, or by the number of cows in a group. However, higher ratios were

observed in the morning and evening than during the day, indicating haul out behavior of cows varies by reproductive status. Adjusted for solar noon, few calves were observed in 1981 (3:100), 1984 (6:100), and 1998 (5:100), while substantially more were observed in 1982 (15:100) and Dasatinib 1999 (13:100). Classifying between 200 and 300 groups with cows (~1,600–2,300 individual cows) will yield calf:cow ratios with ~20%–30% relative precision. Tagging studies that examine hauling-out behavior of cows with and without calves relative to time-of-day are necessary to better understand how to interpret calf:cow ratios. There is recent concern over the long-term viability of the Pacific walrus (Odobenus rosmarus divergens) population, mostly because of the way warming trends are expected to affect summer sea ice in the Chukchi Sea (Garlich-Miller et al. 2011). Pacific walruses range over the continental shelves

of the Bering and Chukchi Seas where they feed mostly on benthic invertebrates, Estrogen antagonist generally in waters less than 100 m deep (Fay 1982, Fay and Burns 1988, Jay et al. 2001). Pacific

walruses winter in the Bering Sea. In spring, most walruses follow sea ice north MCE and rest on sea ice in between foraging bouts. In years when sea ice retreats north of the continental shelf, where depths are greater than 100 m, walruses will use terrestrial haul-outs on Wrangel Island, along the northern coast of Chukotka (Fay 1982, Belikov et al. 1996), and, more recently, along the northwestern coast of Alaska (Jay et al. 2012). This behavior is believed to be energetically costly and exposes calves to higher risk of mortality (Garlich-Miller et al. 2011, Jay et al. 2011). The length of the ice-free season is projected to increase through the end of the century (Douglas 2010) and the use of terrestrial haul-outs in the Chukchi Sea is increasing, both in Russia (Kavry et al. 2008) and Alaska (Jay et al. 2012). A warming climate may also expose walruses to new pathogens or, via changes in oceanography, alter the availability of benthic prey (Grebmeier et al. 2006, Bluhm and Gradinger 2008, Garlich-Miller et al. 2011). Due to these concerns, listing of the Pacific walrus as threatened under the Endangered Species Act was recently found to be warranted. The listing, however, was precluded due to other higher priority listing actions by the U.S. Fish and Wildlife Service (U.S. Federal Register 2011).