10-40.0), only 2 as a result of non-liver-related death. The remaining 49 were alive after a median of 55 months (range, 0.7-69.0). Uni- and multivariable analysis for intervention-free

survival is detailed in Supporting Table 5. The Rotterdam score had an excellent prognostic value, and no further variable could significantly improve its prognostic ability. This validates the Rotterdam score as a useful prognostic tool in this post-therapeutic series of BCS. Supporting Fig. 2 shows survival curves for Rotterdam class I, II, and III. Because the Rotterdam score includes the INR, which could not be MK 1775 calculated in a substantial number of patients (already on oral anticoagulants), we performed a multivariable analysis without including scores or INR. Baseline ascites, bilirubin, and creatinine were independently associated with intervention or death (BCS-intervention-free survival prognostic score [BCIS score]: ascites

[yes = 1, no = 0]*1.675 + ln creatinine [umol/L]*0.613 + ln bilirubin [umol/L]*0.440). This data-driven new score showed an adequate discrimination Smad inhibitor (area under the curve [AUC] = 0.819), but it did not outperform the Rotterdam score (AUC, 0.821)9 (Supporting Fig. 3). The probability of intervention-free survival among different intervals of the BCIS score is shown in Supporting Table 7. Thirty-six patients (23%) died during the study. Median time to death was 10 months (range, 0.1-41.0). Main causes of death are reported in Table 2. Factors associated with mortality are shown in Supporting Table 6. The BCS-TIPS PI score was strongly associated with the risk of death, so that no other variable could improve its predictive capacity. Supporting

Table 8 shows survival among different ranges of BCS-TIPS PI scores. Because this score includes the INR, we performed a multivariable analysis excluding all scores and INR. Age, bilirubin, and creatinine were independently associated eltoprazine with survival [BCSurvival score: age/10*0.370 + ln creatinine [umol/L]*0.809 + ln bilirubin [umol/L]*0.496). The discriminative capacity was comparable to that of the BCS-TIPS PI score and better than the Rotterdam score (Supporting Fig. 4). BCS is a rare, life-threatening disorder caused by obstruction of hepatic venous outflow. Until recently, most evidence regarding BCS was generated in small retrospective studies of patients diagnosed over long periods and managed using heterogeneous strategies.7, 9, 14 However, an international initiative, funded by the Fifth Framework Program of the European Commission, entitled the EN-Vie, was able to prospectively gather a large multicenter cohort of consecutive patients with BCS diagnosed and treated following homogeneous criteria.4 Previous retrospective studies evaluating prognosis in BCS showed that fatal events occur throughout the first 5 years after diagnosis.

However, tolerance could be broken (or not achieved in the first place) if I22-inv patients were infused with a FVIII protein containing an immunogenic sequence variation, e.g. due to one or more ‘foreign’ amino residues resulting from allelically ‘mismatched’ ns-SNPs in their F8 gene. Structural differences between endogenous and therapeutic FVIII proteins meet the first and minimal requirement for eliciting an immune response, but such differences may or may not be immunogenic in a given individual. Pexidartinib in vivo Differences in the immune system

from one person to another are also of critical importance. FVIII inhibitor responses are mediated by helper T cells [40]. Therefore, the limited collection of MHC genes (and alleles) in a given patient will determine

whether a particular ‘mismatched’ FVIII sequence can be presented by the restricted repertoire of MHC class II molecules on antigen-presenting cells (APCs). Additional genetic variations may influence events following antigen presentation, including avidity of interactions with T-cell receptors on responding T cells. These variations, plus the presence Fostamatinib cost or absence of ‘danger signals’– and the co-stimulatory interactions they induce between APCs and T cells – will influence the evolution of the immune response, e.g. along tolerogenic or immunogenic pathways [41]. CD4+ T-cell epitopes are linear stretches of at least 9 amino acid residues that bind to a specific groove on the surface of an MHC class II molecule. Foreign proteins (together with ‘self’ proteins co-internalized from

the vascular space or other extracellular compartments [Correction made after online publication 11 July 2011: Addition of text critical to article]) are broken down into peptides by enzymes in the MHC class II compartment of APCs. Although large numbers of peptide fragments are released, only about 2% of all the fragments generated have permissive structures – based on their amino acid side chain and backbone conformation – that allow them to interact strongly with the residues comprising the binding groove of a given MHC molecule. A critical determinant of ADAMTS5 immunogenicity for a T-cell epitope is the strength of its binding to one or more MHC molecules. As alluded to above, the development of an antibody response also requires a ‘danger signal’; in the case of infectious immunity this is provided by repetitive structural components of bacteria or viruses that are recognized by toll-like receptors as non-self and thus dangerous to self [41]. The nature of danger signals that may accompany intravenous infusions of FVIII and their role in inhibitor development is poorly understood and is a subject of current research. The MHC proteins, which in humans comprise the human leucocyte antigen (HLA) system, are extremely polymorphic [42].

A pathological diagnosis was also made for all 27 patients based on surgical or biopsied specimens. All 27 patients had serum IgG4 concentrations within the normal range. All ERCP and endoscopic biopsies were carried out during the hospital stay. ERCP was carried out using a duodenoscope (JF-240, TJF-240, TJF-260V; Olympus

Medical Systems Corp., Tokyo, Japan). A 1.7-mm-diameter cannula (PR-V416Q; LY2157299 Olympus Medical Systems) was inserted into the main pancreatic duct and bile ducts, cholangiopancreatograms were obtained and the location of stricture was carefully studied. After documenting the stricture, a 0.035-inch hydrophilic guidewire Palbociclib (stiff-type Jagwire; Boston Scientific Japan, Tokyo, Japan) was advanced to the tip of the cannula, through the stricture and into the bile duct beyond the stricture. After carrying out the ERCP, all

patients underwent endoscopic biopsies using side-opening biopsy forceps (FB-45Q-1; Olympus) from Vater’s ampulla and the common bile duct in the same session. The guidewire was left in place and the biliary biopsy forceps were passed along the guidewire and into the bile duct. Bile duct biopsies were taken from the lower and intrapancreatic bile ducts or other stenotic portions in IgG4-SC patients, the extrahepatic bile duct in PSC patients and the involved bile duct in pancreatobiliary malignancy patients under fluoroscopic guidance. In all 29 IgG4-SC patients, biopsies were obtained from Vater’s ampulla and the common bile duct before corticosteroid therapy. After carrying out the bile duct biopsies, Vater’s ampulla biopsies were taken from the

orifice of the common bile duct near the guidewire, but were not taken near the orifice of the pancreatic duct to avoid acute pancreatitis resulting from edema and reduced ductal flow. The procedures were finished without placing a pancreatic stent. All endoscopic procedures were carried out by the same experienced endoscopist (HK) while the patient was under conscious sedation with intravenous Baricitinib pethidine hydrochloride and diazepam. After the ERCP-related procedures, 50 000 units of ulinastatin were drip-infused twice (day of surgery and the next morning) over a period of 1–2 h. Antibiotics were drip-infused twice (once after the ERCP-related procedures and once the next morning) through a side tube. Histological examination was carried out by a pathologist (YZ) blinded to clinical information. The biopsied specimens were fixed in neutral formalin and embedded in paraffin. Sections (4 µm) were cut from each paraffin block and stained with hematoxylin–eosin or examined by immunohistochemistry.

In our study, the association was shown to be specific to active H. pylori infection. This association was not found with past H. pylori infection, suggesting that either past infection are not relevant, the school children can improve their iron INCB024360 status when the infection is cleared, or these are only false positive results. Some studies suggest that

active infection causes deterioration in nutritional iron status: A meta-analysis included 15 observational studies in which the infection was detected by UBT or by serological test. In the studies that detected the infection by UBT, the association between ID and H. pylori infection showed an OR of 5.88. In the studies where the infection was detected by serological test that quantitate whole-cell H. pylori antibodies, it was 2.16 [45]. The results show that serological test in the evaluation of this association may lead to misclassification of H. pylori status at the time when the blood sample is obtained and subsequently attenuate the association [23]. The cross-sectional Everolimus chemical structure nature of our study limited the possibility to make inferences about causality and the direction of associations.

Temporal ambiguity bias may be present. We can speculate that children with worse nutritional status have higher risk of H. pylori acquisition but, as it has been suggested by other authors, it is also possible that active H. pylori infection has negative effects on iron status and on growth rate velocity [17, 21, 23]. In this study, school children with evidence of past H. pylori infection had similar percentages

of iron deficiency and of low height for age than children without H. pylori infection. In this population, we have reported that spontaneous clearance of active infection is not rare [9]. It is possible that those children able to eradicate the infection have better nutritional and health status than children with persistent infection. But it is also possible that clearance of infection per se led to the improvement of these children’s nutritional status. ADAMTS5 In conclusion, the reported prevalence of H. pylori infection depends on the detection test utilized. The results obtained by different tests are in relation with the colonization status at the moment in which the samples are taken. Overall, results suggested that active H. pylori infection is associated with deficient nutritional status in school children. This study was supported in part by grants from the National Council of Science and Technology (project No. 69667) and from Fund of Health Research, Mexican Institute of Social Security (projects 2005/1/I/089 and 190). Competing interests: The authors have no conflicts of interest to declare. “
“Background:  The human bacterial pathogen Helicobacter pylori forms biofilms. However, the constituents of the biofilm have not been extensively investigated. In this study, we analyzed the carbohydrate and protein components of biofilm formed by H.

To study the function of Col1a1 within fibrocytes, BM from 5′StemLoop knockout mouse was transplanted into wildtype mice, which are deficient of Col1a1 expression in fibrocytes. METHODS: Inducible Col1a1-ER-Cre mice were crossed with Rosa26-YFP

NVP-LDE225 reporter mice and Rosa26-DTA mice and were used as donors for BM transplantation into wt mice to generate Fibrocyte deleted mice. Upon tamoxifen administration, fibrocytes were labeled by YFP expression in wt mice, while successful ablation of fibrocytes (>95%) was achieved in Fibrocyte deleted mice, as indicated by disappearance of YFP+ fibrocytes. To study the function of Col1a1 in fibrocytes, the BM from 5′SL knockout mice was transplanted into wt mice to generate Fibrocyte5′SL-Col1a1 mice. Mice were subjected

to CCl4 (6w), livers were analyzed for development of liver fibrosis. The transcriptome of fibrocytes selleck chemical were assessed by RNA-seq. RESULTS: Deletion of fibrocytes in mice resulted in attenuation of CCl4-induced liver fibrosis by 50%, as shown by reduced Sirius Red, and Col1a1, alpha-SMA, TIMP1 and TGFbeta1 mRNA expression. We determined that in fibrotic liver fibrocyte give rise to 10% of myofibroblasts. Meanwhile, majority of fibrocytes contributes to hepatic myeloid cells, which serve as a significant source of TGFb1, and inflammatory cytokines such as IL-6 and IL1b1, and also suppress anti-fibrogenic (M2) macrophages. We next hypothesized that upregulation of Col1a1

may be important for fibrocyte functions. Indeed, development of liver fibrosis was reduced in Fibrocyte5′SL-Col1a1 mice by 30%, and was associated with impaired activation and migration of HSCs and reduced TGFβ1 and CCL5 in liver. CONCLUSION: Fibrocyte contribute to myofibroblast population, but most importantly, they mediate differentiation of proinflammatory macrophage and secret profibrogenic cytokine TGFβ1. Furthermore, proper collagen expression is required for fibrocyte function. Disclosures: The following people have nothing to disclose: Jun Xu, Tae Jun Park, Min Cong, Xiao Liu, David A. Brenner, Tatiana Kisseleva Background: To accomplish cell therapy with higher efficiencies, insights into transplanted cell fates is critical. The ability of mature hepatocytes as well as LSEC to engraft and oxyclozanide proliferate in liver was of therapeutic benefit. However, early clearance of transplanted cells was a major restriction in both cases. Clearance of transplanted hepatocytes was largely due to secondary release of endothelin-1 (ET1) or of chemokines/cytokines/ receptors, e.g., TNF-a, from Kupffer cells and neutrophils, whereas endothelial disruption and release of hepatoprotective factors from hepatic stellate cells (HSC) benefited cell engraftment. Based on these considerations, we defined mechanisms for engrafting transplanted LSEC in liver.

In that study, high HIF2α expression was also correlated with VEGF expression, microvessel density, and decreased survival.97 Multiple studies have suggested that HIF1α is a prognostic factor for tumor recurrence in human and murine HCC.98, 99 Some studies have shown that high expression of HIF1α in nonmalignant liver tissue adjacent to resected HCC is a negative predictor of disease-free survival, and may correlate with up-regulation

of HIF1α-dependent genes involved in cell migration and invasion.100 Lastly, patients with HCC whose tumors had high levels of expression of p28(GANK) had a high risk of recurrence, metastasis, and high mortality; interestingly, high p28(GANK) Gamma-secretase inhibitor expression correlated with higher levels of HIF1α.101 These observations imply that HIF1α inhibition may play a role in anticancer therapeutics. RNA-mediated inhibition of HIF1α was able to slow tumor growth.102 The antitumor efficiency of doxorubicin was increased Ivacaftor ic50 when combined with an HIF1α antisense oligonucleotide.103 Rapamycin inhibits signaling by the mammalian target of rapamycin (mTOR) complex pathway, and has shown some efficacy against HCC. The prevention of HCC tumor growth by rapamycin in a rodent model was correlated with suppression of HIF1α by rapamycin.104 Another compound, silibinin, was demonstrated to have some antitumor efficacy through phosphorylation of mTOR, and was also associated

with suppression of HIF1α signaling.105 Hypoxia has been implicated in the pathogenesis of a broad range of hepatic disease. In most of these models, some data exist to implicate a role for hypoxia inducible factors. Consideration of the role of HIFs in liver diseases should include multiple cell types, as HIF1α

activity has been implicated in hepatocytes as well as myeloid (Kupffer cells) and lymphoid (T-cells) lineage immune cells. Taken collectively, these findings strongly suggest that anti-HIF therapies promise useful interventions in the management of hepatic diseases of various etiologies. “
“Fanconi anemia (FA) is an inherited bone marrow failure syndrome due to defective DNA inter-strand cross-link repair. Hematopoietic stem cell transplantation (HSCT) is curative for pancytopenia, but Decitabine nmr may not prevent the development of non-hematological malignancies. We describe a 26-year-old male patient with FA and Marfan syndrome who in 1994 underwent successful HSCT with bone marrow stem cells from his human leukocyte antigen (HLA)-identical sister. In 2006, three lesions in the liver were detected and resected. The three lesions all showed activation of the β-catenin pathway and were histologically characterized by a highly differentiated steatotic hepatocellular carcinoma (HCC) with remnants of the underlying adenoma from which it arose, a hepatocellular adenoma with foci of well-differentiated HCC, and a cholestatic adenoma.

A full repertoire analysis of the BCR heavy chain was performed using GS-FLX/454 and customized bioinformatics algorithms (>10,000 sequences/sample; clones with a frequency ≥0.5% were considered dominant). We found that the most dominant clones within the IgG+ BCRheavy repertoire of the peripheral blood at baseline were IgG4+ only in IAC patients. In all IAC patients, but none of the controls, IgG4+ BCR clones were among the 10 most dominant BCR clones of any immunoglobulin isotype

(IgA, IgD, IgM, and IgG) in blood. Selleck Lapatinib The BCR repertoires of the duodenal papilla comprised the same dominant IgG4+ clones as the paired peripheral blood samples. In all IAC patients, after 4 and 8 weeks of corticosteroid therapy selleck the contribution of these IgG4+ clones to the IgG+ repertoire as well as to total BCR repertoire was marginalized, mirroring sharp declines in serum IgG4 titers and regression of clinical symptoms. Conclusion: The novel finding of highly abundant IgG4+

BCR clones in blood and tissue of patients with active IAC, which disappear upon corticosteroid treatment, suggests that specific B cell responses are pivotal to the pathogenesis of IAC. (HEPATOLOGY 2013 ) Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a common denominator for incompletely understood organ abnormalities associated with IgG4+ B-cell and plasma cell infiltrates and/or elevated serum IgG4 titres.1–6 Although the list of possibly affected organs in IgG4-RD is expanding, the pancreas in the form of autoimmune pancreatitis and biliary tree in the form of IgG4-associated cholangitis (IAC, also known as IgG4-related (sclerosing)

cholangitis) are thus far the most frequently involved localizations. The diagnosis of IgG4-RD is currently made by exclusion of other causes and organ-specific diagnostic criteria, of which the histology, Epothilone B (EPO906, Patupilone) imaging, serology, other organ involvement, and response to steroid therapy (HISORt) criteria that were originally developed for the diagnosis of autoimmune pancreatitis are arguably the most generally applied. Nevertheless, diagnosing IgG4-related disease of the biliary tree is challenging, because this rare disease often mimics malignancies of the bile ducts or pancreatic head as well as primary sclerosing cholangitis (PSC) and forms of secondary sclerosing cholangitis, mainly in terms of symptoms and imaging. The number of IAC patients diagnosed after histological evaluation of surgical specimens, either obtained in diagnostic procedures or during extended resections for suspected malignancies, is far from negligible.7 IgG4-RD derived its name from the elevated serum levels of IgG4 that were found in the original cohorts.

Esophageal varices grade 2 or 3 (p = 0.003), refractory ascites (p = 0.01), an increase in the portosystemic gradient (p = 0.008) were significantly more frequently in the TIPS group. Total mortality was not significantly different between the 2 groups. Median follow up was 12 months. Median survival was 26 months (TIPS) vs 27 months (ns). Conclusion: in

this series, TIPS with covered stents for refractory ascites or recurrent bleeding varices restore a survival comparable to a control group with a first decompensation of cirrhosis, without severe portal hypertension Key Word(s): 1. refractory ascites; 2. cirrhosis; 3. covered TIPS; 4. meld score; Presenting Author: WANG DI Additional Authors: GUO XIAO-ZHONG, LI HONG-YU, SHAO XIAO-DONG, CUI ZHONG-MIN, REN LI-NAN, GS-1101 research buy ZHAO JIA-JUN Corresponding

Author: GUO XIAO-ZHONG Affiliations: General Hospital of Shenyang Military Area Command Objective: To evaluate the safety of autologous bone-marrow stern cells mobilization by intravenous injection of granulocyte colony stimulating factor (G-CSF) in patients with decompensated liver cirrhosis patien. Methods: Fifty-one patients with decompensated cirrhosis patients were received intravenous injection of G-CSF (4 μg/kg.d) before treatment Acalabrutinib for 2 days. During the period of treatment, attention was paid to the following side effects bone pain, fever, gastrointestinal effects, and laboratory examination. Results: The incidence of complications during G-CSF treatment was 45.5%, including that of bone pain being of 13.6%, fever being of 27.2%, reinfarction being of 5%. Conclusion: In patients with cirrhosis, intravenous injection of G-CSF to mobilize autologous bone-marrow stem cells is feasible and safe. Key Word(s): 1. liver cirrhosis; 2. Stem cell; 3. Transplantation; 4. G-CSF; Presenting Author: FENG SHI Additional Authors: WENHUA HE, LU CHEN, WEN HUANG, TAO CHEN, DEQIANG HUANG, XUAN ZHU Corresponding Author: XUAN ZHU Affiliations: Telomerase Nanchang University Objective: To observe the effects of ursolic acid (UA) on the expression of NOX

subunit and its regulation on PI3K/Akt and P38MAPK pathways in rat activated hepatic stellate cells (HSCs), and explore the underlying mechanism. Methods: HSC-T6 cells (rat hepatic stellate cells) in the exponential growth phase were divided into six groups: normal control group; leptin (100 ng/ml) treated; leptin treated together with UA (50 μM); leptin treated together with NOX inhibitor DPI (20 μM); leptin treated together with P38MAPK inhibitor SB203580 (10 μM) and leptin treated together with PI3K inhibitor LY294002 (10 μM). HSC-T6 were treated with medicine and the protein expression of NOX subunit gp91phox, p22phox, p67phox, Rac1and PI3K, p-Akt, p-P38MAPK and TIMP-1, MMP-1 were analyzed with Western blotting.

4D). Furthermore, EphrinA2-induced activation of NF-κB was blocked by LY294002, NSC23766, dominant-negative Akt, and dominant-negative Rac1, respectively, despite varied inhibitory effects (Fig. 6D). These results indicated that the Rac1/Akt pathway participates in

the modulation of NF-κB activity stimulated by EphrinA2, thus revealing an exquisite regulatory network between EphrinA2, Rac1, Akt, and NF-κB. We identified the relationship between EphrinA2 expression and the development of HCC. The level of EphrinA2 was lowest in normal hepatocytes and increased in primary HCC cells, and it reached the highest level in portal vein tumor thrombus cells. This gradually increasing expression pattern paralleled with deterioration ABC294640 datasheet of this disease, suggesting a potential role of EphrinA2 in the progression of HCC. In fact, an emerging body of evidence suggests an increasing role of Eph/Ephrins in cancer. For example, EphA2 can

promote growth of breast, prostate, and pancreas cancer cells, perhaps by activating mitogen-activated protein kinases (MAPKs).7, 8 Likewise, EphA2 and EphB4 can stimulate cancer cell migration and invasion.28 The Eph/Ephrins also can enhance angiogenesis during cancer progression.29, 30 In our study, we demonstrated that EphrinA2 could endow the HCC cells with resistance to both basal and cytokine-induced apoptosis, thus providing a growth advantage to cancer cells, which consequently enhanced the development and progression Carnitine dehydrogenase of HCC. Because the mechanism underlying the regulation of cell survival and apoptosis by Eph/Ephrins in cancer cells remains largely unknown,31 our study provides click here novel insights into this mechanism. HCCs are often associated with chronic hepatitis, especially in Asia. TNF-α has been reported to be closely involved in the pathogenesis of chronic liver disease.22, 32, 33 Released by infiltrating lymphocytes,

TNF-α can trigger both pro-survival and pro-apoptosis signaling through the NF-κB pathway and the caspase8 pathway. The cell fate determination mainly depends on the balance between these two pathways. We found that overexpression of EphrinA2 in HCC cells could activate NF-κB, leading to a shift from apoptosis to survival in the circumstance of TNF-α. This may explain how HCC cells tolerate the high level of such potential apoptotic factors. A series of previous studies have suggested that TNF-α is a promising cytokine for cancer therapy34, 35; however, the clinical outcome was disappointing, mainly because of the nonspecific toxicity of this factor at high dose. Efforts have been made to improve its application, such as modification of TNF-α to ameliorate its specificity aiming at tumor tissues.36 Another potential strategy is to increase the sensitivity of cancer cells to TNF-α, which will decrease the effective dose of the cytokine and avoid unexpected systemic toxicity.

4D). Furthermore, EphrinA2-induced activation of NF-κB was blocked by LY294002, NSC23766, dominant-negative Akt, and dominant-negative Rac1, respectively, despite varied inhibitory effects (Fig. 6D). These results indicated that the Rac1/Akt pathway participates in

the modulation of NF-κB activity stimulated by EphrinA2, thus revealing an exquisite regulatory network between EphrinA2, Rac1, Akt, and NF-κB. We identified the relationship between EphrinA2 expression and the development of HCC. The level of EphrinA2 was lowest in normal hepatocytes and increased in primary HCC cells, and it reached the highest level in portal vein tumor thrombus cells. This gradually increasing expression pattern paralleled with deterioration Ferroptosis inhibition of this disease, suggesting a potential role of EphrinA2 in the progression of HCC. In fact, an emerging body of evidence suggests an increasing role of Eph/Ephrins in cancer. For example, EphA2 can

promote growth of breast, prostate, and pancreas cancer cells, perhaps by activating mitogen-activated protein kinases (MAPKs).7, 8 Likewise, EphA2 and EphB4 can stimulate cancer cell migration and invasion.28 The Eph/Ephrins also can enhance angiogenesis during cancer progression.29, 30 In our study, we demonstrated that EphrinA2 could endow the HCC cells with resistance to both basal and cytokine-induced apoptosis, thus providing a growth advantage to cancer cells, which consequently enhanced the development and progression Idoxuridine of HCC. Because the mechanism underlying the regulation of cell survival and apoptosis by Eph/Ephrins in cancer cells remains largely unknown,31 our study provides selleck inhibitor novel insights into this mechanism. HCCs are often associated with chronic hepatitis, especially in Asia. TNF-α has been reported to be closely involved in the pathogenesis of chronic liver disease.22, 32, 33 Released by infiltrating lymphocytes,

TNF-α can trigger both pro-survival and pro-apoptosis signaling through the NF-κB pathway and the caspase8 pathway. The cell fate determination mainly depends on the balance between these two pathways. We found that overexpression of EphrinA2 in HCC cells could activate NF-κB, leading to a shift from apoptosis to survival in the circumstance of TNF-α. This may explain how HCC cells tolerate the high level of such potential apoptotic factors. A series of previous studies have suggested that TNF-α is a promising cytokine for cancer therapy34, 35; however, the clinical outcome was disappointing, mainly because of the nonspecific toxicity of this factor at high dose. Efforts have been made to improve its application, such as modification of TNF-α to ameliorate its specificity aiming at tumor tissues.36 Another potential strategy is to increase the sensitivity of cancer cells to TNF-α, which will decrease the effective dose of the cytokine and avoid unexpected systemic toxicity.