The total costs of preventive headache therapy by type of treatment were then evaluated and compared over time. Results.— During the initial months of treatment, PPT with inexpensive mediations (<0.75 $/day) represents the least costly regimen and is comparable to MCBT in expense until 6 months. After 6 months, PPT is expected to become more costly, particularly when medication cost exceeds 0.75$ a day. When using an expensive medication (>3 $/day),

preventive drug treatment becomes more expensive than CBBT after the first year. Long-term, and within year 1, MCBT was found to be the least costly approach to migraine prevention. Conclusions.— Through year 1 of treatment, Selleck SAHA HDAC inexpensive prophylactic medications (such as generically available beta-blocker or tricyclic antidepressant medications) and behavioral interventions utilizing limited delivery formats (MCBT) are the least costly of the empirically validated interventions. This analysis suggests that, relative to pharmacologic options, limited format behavioral interventions are cost-competitive in the early phases of treatment and become

more cost-efficient as the years of treatment accrue. “
“Glutamate (Glu) and FK506 clinical trial glutamine (Gln) are strongly compartmentalized (in neurons for Glu and in astrocytes for Gln). The visual cortex is the brain region with a higher neuron/astrocyte ratio (the highest neuronal density and the relatively lowest density of astrocytes). Elevations in extracellular Glu or potassium above certain thresholds are likely candidates to be the final common steps in the multiple distinct processes that can lead to cortical spreading depression. Astrocytes play a key role in this phenomenon, by acting as a sink for extracellular Glu and potassium, as well as generally acting as a buffer for the ionic and neurochemical changes that initiate and propagate cortical spreading depression. The purpose of this study was to MCE公司 quantify Glu

and Gln to generate Glu/Gln ratios in women with migraine during the interictal state compared with healthy control women. Twenty-seven patients with migraine (8 with aura and 19 without aura) and 19 matched healthy controls were included in the study. We performed proton magnetic resonance spectroscopy in the anterior paracingulate cortex and occipital cortex (OC). Spectral analysis was performed by LCModel, allowing a separation of Glu and Gln using a 3T machine. The main result was a significantly higher Glu/Gln ratio in the OC of migraine patients compared with healthy control subjects (4.87 for migraineurs [standard deviation (SD) = 2.74] and 3.42 for controls [SD = 1.52], P = .042). We also observed higher Glu levels (6.98 for migraineurs [SD = 0.85] and 6.22 for controls [SD = 0.97], P = .007) and Glu/creatine + phosphocreatine ratio (1.18 for migraineurs [SD = 0.18] and 1.00 for controls [SD = 0.16], P = .001) in anterior paracingulate cortex in migraine patients but saw no differences in Glu/Gln ratio (2.79 for migraineurs [SD = 1.11] and 2.

This study’s findings will alert researchers to review the impact of both the ‘seed’ (the research) and the ‘soil’ (the infrastructure) when planning studies in developing countries. The preparation of the ‘soil’ requires time – years – to mature the infrastructure, training and provision of education to patients and families. We wish to thank Bayer Healthcare (China) for donating rFVIII (Kogenate®) to support the prophylaxis portion of our project. We selleck chemicals also thank haemophilia centers in the following 12 hospitals for their cooperation and participation in our study: Wenzhou

No. 3 hospital (Dr./Prof. Bingshou XIE).Anhui province hospital (Dr./Prof. Jingsheng WU), No. 1 hospital affiliated to Xian communication university (Dr./Prof Mei ZHANG), People’s hospital of Xinjiang Uygur Autonomous region (Dr./Prof Xiaomin WANG), Hebei medical university affiliated hospital (Dr./Prof. Ling PAN), Jiangxi province children’s hospital (Dr. Zhongjin XU), No. 1 hospital affiliated to Lanzhou university (Dr./Prof. Yaming XI), No. 2 hospital affiliated to Chongqing Sirolimus clinical trial medical university (Dr./Prof. Shifeng LOU), Children’s hospital affiliated to Zhejiang university (Dr. Weiqun XU), Guiyang medical university affiliated hospital

(Dr./Prof. Xiaoqin Zeng), No. 1 hospital affiliated to Zhengzhou university (Dr./Prof. Pingchong LEI), Hospital affiliated to Qingdao medical university (Dr./Prof. Lirong SUN). The authors stated that they had interests which might be perceived as posing a conflict or bias. “
“Summary.  The development of neutralizing antibodies against factor VIII (FVIII) is a major complication of treatment with FVIII in patients with severe haemophilia A. This study was designed to describe the relationship between the type and location of the factor 8 (F8) gene mutation and the development of clinically relevant inhibitors in patients with severe

haemophilia A. We conducted a single centre cohort study among 318 consecutive patients (baseline FVIII activity level <0.01 IU mL−1) born between 1934 and 2007 who were treated with FVIII on at least 50 exposure days. The primary outcome was clinically relevant inhibitor development, defined as the occurrence of at least two positive MCE公司 inhibitor titres and a decreased recovery. Clinically relevant inhibitors were diagnosed in 14% (43) of patients (30 high-titre). The cumulative incidence of inhibitor development was 18% (35 of 200) in high-risk gene defects (67% in patients with large deletions, 30% in patients with nonsense mutations, 15% in patients with intron 1 or 22 inversions) and 7% (8 of 118) in low-risk gene defects (7% in patients with small deletions and insertions, 6% in patients with missense mutations, 8% in patients with splice site mutations). In patients with point mutations, the cumulative risk of developing inhibitors was highest in patients with mutations in the A3 and C2 domains (13% and 17% respectively).

Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing. Conclusion: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of

hepatocytes, and the Pembrolizumab potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. (HEPATOLOGY 2009.) Human induced pluripotent stem cells (iPSCs) are reprogrammed mature somatic fibroblasts which represent a pluripotent cell population able to generate all primary cell types in vitro.1–3 The ability to derive iPSCs from an indefinite range of genotypes makes them an attractive resource on which to model liver function reflecting the complexity of polygenic influences on metabolism in vitro. Another Buparlisib cost facet of iPSC technology

is the ability to study the impact of gene polymorphisms in a native chromatin setting and model gene interactions with precision. Therefore iPSC-derived models hold great potential to develop a detailed understanding of human liver disease and metabolism including drug toxicity (for a review, see Dalgetty et al.4). Any methods which might streamline and standardize the process of drug and toxicology testing, which currently relies on primary human hepatocytes (PHHs), would represent a significant development. Therefore, an iPSC resource representative of polymorphic 上海皓元医药股份有限公司 variants and ethnic groups, unhindered by quality and supply, would revolutionize predictive drug toxicology assays and

have an effect on drug attrition. Presently, PHHs are the gold standard cell type used in predictive drug toxicology. Unfortunately, PHHs are a scarce, heterogeneous, and expensive resource which function only short-term in vitro. The generation of hepatic endoderm (HE) from iPSCs has the potential to fulfill the major challenge to acquire the reliable and clonal source of functional human hepatocyte cells for biotechnology purposes. To date, efficient models of deriving HE from iPSCs have not been described or developed. Capitalizing on our recent investigations that human embryonic stem cells (hESCs) can be stimulated to form HE,5 we have developed a parallel methodology for iPSCs; here, we describe the generation of functional HE from multiple human iPSC lines that can potentially model human drug metabolism.

Furthermore, iPSC-derived hepatocytes produced and secreted the plasma proteins, fibrinogen, fibronectin, transthyretin, and alpha-fetoprotein, an essential feature for functional HE. Additionally iPSC-derived HE supported both CYP1A2 and CYP3A4 metabolism, which is essential for drug and toxicology testing. Conclusion: This work is first to demonstrate the efficient generation of hepatic endodermal lineage from human iPSCs that exhibits key attributes of

hepatocytes, and the Erlotinib molecular weight potential application of iPSC-derived HE in studying human liver biology. In particular, iPSCs from individuals representing highly polymorphic variants in metabolic genes and different ethnic groups will provide pharmaceutical development and toxicology studies a unique opportunity to revolutionize predictive drug toxicology assays and allow the creation of in vitro hepatic disease models. (HEPATOLOGY 2009.) Human induced pluripotent stem cells (iPSCs) are reprogrammed mature somatic fibroblasts which represent a pluripotent cell population able to generate all primary cell types in vitro.1–3 The ability to derive iPSCs from an indefinite range of genotypes makes them an attractive resource on which to model liver function reflecting the complexity of polygenic influences on metabolism in vitro. Another find more facet of iPSC technology

is the ability to study the impact of gene polymorphisms in a native chromatin setting and model gene interactions with precision. Therefore iPSC-derived models hold great potential to develop a detailed understanding of human liver disease and metabolism including drug toxicity (for a review, see Dalgetty et al.4). Any methods which might streamline and standardize the process of drug and toxicology testing, which currently relies on primary human hepatocytes (PHHs), would represent a significant development. Therefore, an iPSC resource representative of polymorphic 上海皓元医药股份有限公司 variants and ethnic groups, unhindered by quality and supply, would revolutionize predictive drug toxicology assays and

have an effect on drug attrition. Presently, PHHs are the gold standard cell type used in predictive drug toxicology. Unfortunately, PHHs are a scarce, heterogeneous, and expensive resource which function only short-term in vitro. The generation of hepatic endoderm (HE) from iPSCs has the potential to fulfill the major challenge to acquire the reliable and clonal source of functional human hepatocyte cells for biotechnology purposes. To date, efficient models of deriving HE from iPSCs have not been described or developed. Capitalizing on our recent investigations that human embryonic stem cells (hESCs) can be stimulated to form HE,5 we have developed a parallel methodology for iPSCs; here, we describe the generation of functional HE from multiple human iPSC lines that can potentially model human drug metabolism.

Under low shear conditions (shear 0.08 dyne/cm2) no increase in ATP release was observed; however, increasing

shear to 0.64 dyne/cm2 caused a rapid relative increase in ATP release in both MLCs and MSCs, and again the magnitude of the peak response was significantly greater in MSCs versus MLCs (P < 0.05, Fig. 5B,C). No difference was noted in lactate dehydrogenase measurements before or after stimulus, for either hypotonic or shear exposure, excluding cell lysis as contributing to measured ATP (data not shown). In other biliary models, ATP release has been linked to exocytosis.18 To determine if exocytosis contributes to ATP release in MLCs and MSCs, studies were performed in the presence or absence of monensin, a carboxylic ionophore known to dissipate the transmembrane pH gradients in Golgi and lysosomal compartments and disrupt vesicular trafficking. In both MLCs and MSCs, monensin significantly inhibited RXDX-106 swelling-induced (33% hypotonic exposure) ATP release (Fig. 5D). Thus, both MSCs and MLCs exhibit mechanosensitive ATP release which is dependent on intact vesicular trafficking pathways. Additionally, the magnitude of mechanosensitive ATP release is significantly greater (∼two-fold) in MSCs compared to MLCs. To determine if the difference in ATP release BMS-777607 observed between MSCs and MLCs are the result of generalized

differences in total cellular exocytosis, rates of exocytosis were measured 上海皓元医药股份有限公司 in response to mechanical stimuli in both cell types. After equilibration with FM1-43, cells were exposed to hypotonic buffer (33%) which was associated with a rapid increase in fluorescence, reflecting an increase in exocytosis (Fig. 6). In separate studies, exposure to shear (0.64 dyne/cm2) also resulted in an increase in exocytosis (Fig. 6). These findings suggest a functional link between exocytosis and ATP release in both MLCs and MSCs. There was no significant difference noted in the

rate or magnitude of exocytosis between MLCs and MSCs in response to either of these mechanical stimuli. The concentration of extracellular ATP in bile is regulated not only through the rate of ATP release, but also through degradation pathways.23 To determine if differences exist in the kinetics of ATP degradation between MSCs and MLCs, the media bathing confluent cells was loaded with exogenous ATP (10 nM). Changes in bioluminescence were monitored continuously until relative ALU returned to basal levels. As shown in Fig. 7, addition of ATP (10 nM) to MLCs increased relative bioluminescence 2.7-fold. The time course of degradation was described by a single exponential (y = ae−0.038 min, r = 0.99). By comparison, addition of ATP to MSCs increased bioluminescence 2.5-fold with a similar rate of degradation described by a single exponential (y = ae−0034min, r = 0.99). Thus, MLCs and MSCs display functionally similar ATP degradation pathways.

Under low shear conditions (shear 0.08 dyne/cm2) no increase in ATP release was observed; however, increasing

shear to 0.64 dyne/cm2 caused a rapid relative increase in ATP release in both MLCs and MSCs, and again the magnitude of the peak response was significantly greater in MSCs versus MLCs (P < 0.05, Fig. 5B,C). No difference was noted in lactate dehydrogenase measurements before or after stimulus, for either hypotonic or shear exposure, excluding cell lysis as contributing to measured ATP (data not shown). In other biliary models, ATP release has been linked to exocytosis.18 To determine if exocytosis contributes to ATP release in MLCs and MSCs, studies were performed in the presence or absence of monensin, a carboxylic ionophore known to dissipate the transmembrane pH gradients in Golgi and lysosomal compartments and disrupt vesicular trafficking. In both MLCs and MSCs, monensin significantly inhibited Acalabrutinib datasheet swelling-induced (33% hypotonic exposure) ATP release (Fig. 5D). Thus, both MSCs and MLCs exhibit mechanosensitive ATP release which is dependent on intact vesicular trafficking pathways. Additionally, the magnitude of mechanosensitive ATP release is significantly greater (∼two-fold) in MSCs compared to MLCs. To determine if the difference in ATP release RG7204 supplier observed between MSCs and MLCs are the result of generalized

differences in total cellular exocytosis, rates of exocytosis were measured MCE公司 in response to mechanical stimuli in both cell types. After equilibration with FM1-43, cells were exposed to hypotonic buffer (33%) which was associated with a rapid increase in fluorescence, reflecting an increase in exocytosis (Fig. 6). In separate studies, exposure to shear (0.64 dyne/cm2) also resulted in an increase in exocytosis (Fig. 6). These findings suggest a functional link between exocytosis and ATP release in both MLCs and MSCs. There was no significant difference noted in the

rate or magnitude of exocytosis between MLCs and MSCs in response to either of these mechanical stimuli. The concentration of extracellular ATP in bile is regulated not only through the rate of ATP release, but also through degradation pathways.23 To determine if differences exist in the kinetics of ATP degradation between MSCs and MLCs, the media bathing confluent cells was loaded with exogenous ATP (10 nM). Changes in bioluminescence were monitored continuously until relative ALU returned to basal levels. As shown in Fig. 7, addition of ATP (10 nM) to MLCs increased relative bioluminescence 2.7-fold. The time course of degradation was described by a single exponential (y = ae−0.038 min, r = 0.99). By comparison, addition of ATP to MSCs increased bioluminescence 2.5-fold with a similar rate of degradation described by a single exponential (y = ae−0034min, r = 0.99). Thus, MLCs and MSCs display functionally similar ATP degradation pathways.

Poland has introduced prophylaxis for children in the last 3 years with no adults having access to long-term prophylaxis. These differences enable us to further examine the inequalities in medical outcomes and quality of life in patients who had full access to prophylaxis from birth and those who received prophylaxis for a period as a child and then switched to on-demand as well as those who continued entirely with varying levels of on-demand therapy. National Haemophilia organizations in Canada, France, Ireland, the Netherlands, Poland and

the UK were asked to participate by randomly selecting 20 severe haemophilia patients, with FVIII/IX Torin 1 research buy (levels <1 IU dL−1) aged 18–35 years and by asking them to complete a survey. This sample of young adults with severe haemophilia was chosen as at the age of 18, patients usually chose to continue on prophylaxis or change regimen. The age of 35 was chosen as this was the eldest possible age for a patient from the countries asked to participate Selleck LEE011 to in the survey. Data on co-morbidities were not collected. Sweden and Romania that were also included

in the study but did not reply. The data collection was performed by e-mail or phone interview in the period between October and November 2011. In total, MCE 124 responses were received. The Netherlands provided 16 responses (one moderate, three inhibitors), Ireland 17 (one inhibitor), Poland 24 (two moderate, two inhibitors), the UK 13 (one moderate), France 14 (one inhibitor) and Canada 40 (four moderate, six inhibitors). Eight responders with moderate haemophilia were excluded from the analysis in spite of severe bleeding phenotype. Of 116 responders with severe disease 13 had a previous history

of inhibitors and were examined separately as the level of the inhibitor and current status was unknown. One non-inhibitor respondent did not provide information on his treatment regimen and was excluded from the therapy analysis. The data collected was sociodemographic data (age, country and work or college status), medical data and responses to the EQ-5D questionnaire. The medical data collected were, the type of haemophilia, severity, treatment regime (prophylaxis vs. on demand, length of time on each regimen, dose of each infusion and number of infusions per week), current regimen, history of inhibitors, bleeding episodes per year, target joints, serious bleeding episodes (head or soft tissue (e.g. ilio-psoas, forearm) bleeding episodes, mobility, recurring bleeding episodes, surgery, pain and use of pain medication, and days missed from work due to haemophilia as total number of days missed from work per year.

Poland has introduced prophylaxis for children in the last 3 years with no adults having access to long-term prophylaxis. These differences enable us to further examine the inequalities in medical outcomes and quality of life in patients who had full access to prophylaxis from birth and those who received prophylaxis for a period as a child and then switched to on-demand as well as those who continued entirely with varying levels of on-demand therapy. National Haemophilia organizations in Canada, France, Ireland, the Netherlands, Poland and

the UK were asked to participate by randomly selecting 20 severe haemophilia patients, with FVIII/IX BMN 673 cost (levels <1 IU dL−1) aged 18–35 years and by asking them to complete a survey. This sample of young adults with severe haemophilia was chosen as at the age of 18, patients usually chose to continue on prophylaxis or change regimen. The age of 35 was chosen as this was the eldest possible age for a patient from the countries asked to participate Selleckchem KU-57788 to in the survey. Data on co-morbidities were not collected. Sweden and Romania that were also included

in the study but did not reply. The data collection was performed by e-mail or phone interview in the period between October and November 2011. In total, 上海皓元医药股份有限公司 124 responses were received. The Netherlands provided 16 responses (one moderate, three inhibitors), Ireland 17 (one inhibitor), Poland 24 (two moderate, two inhibitors), the UK 13 (one moderate), France 14 (one inhibitor) and Canada 40 (four moderate, six inhibitors). Eight responders with moderate haemophilia were excluded from the analysis in spite of severe bleeding phenotype. Of 116 responders with severe disease 13 had a previous history

of inhibitors and were examined separately as the level of the inhibitor and current status was unknown. One non-inhibitor respondent did not provide information on his treatment regimen and was excluded from the therapy analysis. The data collected was sociodemographic data (age, country and work or college status), medical data and responses to the EQ-5D questionnaire. The medical data collected were, the type of haemophilia, severity, treatment regime (prophylaxis vs. on demand, length of time on each regimen, dose of each infusion and number of infusions per week), current regimen, history of inhibitors, bleeding episodes per year, target joints, serious bleeding episodes (head or soft tissue (e.g. ilio-psoas, forearm) bleeding episodes, mobility, recurring bleeding episodes, surgery, pain and use of pain medication, and days missed from work due to haemophilia as total number of days missed from work per year.

These data suggest that AIB1 up-regulates Bcl-2 expression at least in part

through activation of Akt signaling, which contributes to CCA chemoresistance. Recently, we reported that SRC-3/AIB1-deficient macrophages exhibit increased AZD1152HQPA ROS levels and a concomitant reduced expression of Bcl-2,10 and it has been reported that ROS can suppress the expression of Bcl-2.11 Therefore, we examined whether the levels of ROS in CCA cells is affected by AIB1. As shown in Fig. 5D and Supporting Fig. 5, AIB1 knockdown significantly increased ROS accumulation and further enhanced the levels of ROS induced by cisplatin in QBC939 and SK-ChA-1 cells, whereas overexpression of AIB1 markedly decreased the levels of ROS and suppressed cisplatin-induced ROS levels in HCCC9810 cells (Fig. 5E). In addition, rescue of AIB1 expression was able to decrease the levels of ROS and to increase Bcl-2 expression in AIB1-knockdown QBC939 cells (Supporting Fig. 6). To confirm that ROS plays a role in regulating Bcl-2 expression, we examined the expression of Bcl-2 in QBC939 cells treated with antioxidant glutathione (GSH). The results revealed that GSH treatment increased Bcl-2 expression in AIB1-knockdown cells (Fig. 5F), indicating that

AIB1 regulates Bcl-2 expression in CCA cells at least in part through modulation of intracellular ROS levels. Consistent with the in vitro results, the protein levels of DAPT ic50 p-Akt and Bcl-2 in AIB1-positive CCA specimens were significantly higher than that in AIB1-negative CCA specimens (Supporting Fig. 7), implying that overexpression of AIB1 in CCA may contribute to the up-regulation of p-Akt and Bcl-2, which enhances the proliferation and survival of CCA. To balance intracellular ROS, the endogenous hydrogen peroxide is reduced by antioxidant MCE公司 enzymes such as catalase, superoxide dismutase (SOD), and glutathione peroxidase (GPx). In addition, ROS is scavenged by GSH. Glutamate cysteine ligase (GCL), which consists of a catalytic (GCLC) subunit and a modifier

subunit (GCLM), is the rate-limiting enzyme for GSH synthesis.12 Thus, the levels of catalase, SOD1, SOD2, GPx1, GPx2, GCLC, and GCLM mRNAs in control and AIB1-knockdown QBC939 cells were measured. As shown in Fig. 6A, AIB1 knockdown significantly decreased the expression of GPx2, GCLC, and GCLM. Consistent with these data, the enzymatic activity of GPx and the content of GSH were significantly reduced in AIB1-knockdown cells compared with control cells (Supporting Fig. 8). These results demonstrate that AIB1 regulates the levels of ROS in CCA cells through modulating the expression of GPx2, GCLC, and GCLM. AIB1-regulated GPx2, GCLC, and GCLM have a common feature that the promoters of these genes contain antioxidant response element (ARE) motifs bound and activated by Nrf2.12, 13 Nrf2 is the most effective transcription factor that acts through the ARE motif.

006, Fig. 2A). The copy numbers for FGF3/FGF4 were 10.2 ± 0.8/6.7 ± 0.8, 26.7 ± 0.4/35.1 ± 3.1, and 162.5 ± 9.0/165.0 ± 12.5 copies in the amplified samples, whereas the copy numbers of FGF3 for all the other samples were below 5 copies. The correlation between the FGF3 locus and the FGF4 locus copy numbers was very high (R

= 0.998), indicating that the DNA copy number assay for FGF3/FGF4 was a sensitive and reproducible method. We examined the messenger RNA (mRNA) expression levels of FGF3/FGF4 in nine HCC samples that were available as frozen samples among the this website 48 sorafenib-treated samples, as shown in Fig. 2A. One amplified sample expressed extremely high mRNA levels of FGF3/FGF4 compared with nonamplified samples (Fig. 2B). The results demonstrated that FGF3/FGF4 gene amplification mediates the overexpression of FGF3/FGF4 mRNAs and proteins (Figs. 2B and 1D). We used FISH analysis to examine FGF3/FGF4 amplification and to verify the results of the above-described PCR-based DNA copy number assay. All FGF3/FGF4-amplified clinical samples were confirmed as exhibiting high-level FGF3 amplification using FISH analysis (Fig. 3). One patient showed multiple scattered signals, whereas two patients showed large clustered signals. Nonamplified HCC

yielded a negative result for gene amplification. These results clearly demonstrate the presence of FGF3/FGF4-amplified HCC among the clinical samples, and the FISH

analysis results were consistent with those for the copy number assay. To determine the frequency check details of FGF3/FGF4 gene amplification in HCC, we performed a copy number assay for HCC samples without sorafenib treatment in a series of surgical specimens. Two of the 82 (2.4%) HCC samples exhibited FGF3/FGF4 gene amplification, with copy numbers medchemexpress of 10.7/15.3 and 133.3/112.7 copies, respectively (Fig. 4). One amplified HCC was a poorly differentiated tumor, whereas the other was a moderately differentiated tumor. The clinico-pathological features of the sorafenib responders are shown in Table 1. A comparison of clinical factors (age, sex, viral status, alpha-fetoprotein level, PIVKA-II, clinical stage, primary tumor size, metastatic status, histological type, and tumor response between responders and nonresponders) is given in Table 2. Notably, multiple lung metastases over five nodules was significantly higher among responders to sorafenib (responders, 5/13 [38%]; nonresponders, 2/42 [5%]; P = 0.006). Although the difference was not significant, poorly differentiated HCC tended to be more common among responders to sorafenib (responders, 5/13 [38%]; nonresponders, 6/42 [14%]; P = 0.13). These results suggest that multiple lung metastases and a poorly differentiated histology may be clinical biomarkers for sorafenib treatment in patients with HCC.