Statistical analyses were performed using Mann-Whitney’s U test (nonequal distribution) and the unpaired Student t test (equal distribution), respectively. Data are presented as means ± standard error of the mean (SEM). A P value <0.05 was considered significant. We used new TRAIL fusion proteins in which three TRAIL protomers were expressed as a single-polypeptide chain (scTRAIL) that were further fused to a humanized single-chain Fv fragment ICG-001 of the anti-EGFR Ab, cetuximab (αEGFR-scTRAIL). In initial experiments, we investigated EGFR expression in liver cancer (Huh7) cells and PHHs by flow cytometry. We also compared EGFR expression in HCC to healthy liver tissues using immunohistochemistry (IHC). Almost no EGFR

expression MK-1775 solubility dmso was found in PHH, whereas in Huh7 cells, EGFR was strongly up-regulated (Fig. 1A, B). Similarly, in healthy liver (n = 8), we found no EGFR expression, whereas HCC patients (n = 12) revealed strong EGFR expression on the cell membrane of tumor cells (Fig. 1C, D). This observation, in line with previous reports demonstrating increased EGFR expression in the majority

of HCC tissues,27 therefore suggests that EGFR is a valid tumor target in HCC. We next compared the apoptotic activity of nontargeted scTRAIL with the construct targeting human EGFR (αEGFR-scTRAIL). Because HCC cells, as with many solid tumor cells, reveal a weak TRAIL sensitivity, sensitizing agents, such as proteasome inhibitors, have been suggested to overcome TRAIL resistance.24 Therefore, we additionally analyzed the effects

of both TRAIL proteins in combination with the proteasome inhibitor BZB in Huh7 HCC cells and PHHs. Initial dose-finding experiments revealed a concentration of 100 ng/mL of the two TRAIL proteins to be the most effective for inducing apoptotic caspase-3 activation, when combined with a nontoxic concentration of BZB (500 ng/mL). Compared to BZB alone, which showed almost no effect on caspase activity, scTRAIL significantly increased caspase-3 activation (5.21- ± 1.01-fold) in Huh7 cells, which was further enhanced by BZB (17.06- ± 2.34-fold; Fig. 2A). In contrast to HCC cells, no significant medchemexpress caspase-3 activity was induced by treatment of PHHs with either scTRAIL alone or in combination with BZB. Compared to scTRAIL, EGFR-targeted scTRAIL even more potently increased caspase-3 activity in HCC cells (6.24- ± 1.07-fold, compared to untreated control), which was most strongly enhanced by cotreatment with BZB (50.63- ± 13.97-fold, P < 0.01; Fig. 2B). Importantly, neither αEGFR-scTRAIL alone nor its combination with BZB significantly induced caspase-3 activation in PHHs (2.19- ± 0.76- and 1.88- ± 0.77-fold; Fig. 2B). In contrast, CD95L, which served as a positive control, induced strong caspase-3 activation in PHHs (38.87- ± 10.51-fold; Fig. 2C). We then compared apoptosis induction by nontargeted and EGFR-targeted scTRAIL in the presence or absence of BZB.

Statistical analyses were performed using Mann-Whitney’s U test (nonequal distribution) and the unpaired Student t test (equal distribution), respectively. Data are presented as means ± standard error of the mean (SEM). A P value <0.05 was considered significant. We used new TRAIL fusion proteins in which three TRAIL protomers were expressed as a single-polypeptide chain (scTRAIL) that were further fused to a humanized single-chain Fv fragment selleck chemicals of the anti-EGFR Ab, cetuximab (αEGFR-scTRAIL). In initial experiments, we investigated EGFR expression in liver cancer (Huh7) cells and PHHs by flow cytometry. We also compared EGFR expression in HCC to healthy liver tissues using immunohistochemistry (IHC). Almost no EGFR

expression Staurosporine datasheet was found in PHH, whereas in Huh7 cells, EGFR was strongly up-regulated (Fig. 1A, B). Similarly, in healthy liver (n = 8), we found no EGFR expression, whereas HCC patients (n = 12) revealed strong EGFR expression on the cell membrane of tumor cells (Fig. 1C, D). This observation, in line with previous reports demonstrating increased EGFR expression in the majority

of HCC tissues,27 therefore suggests that EGFR is a valid tumor target in HCC. We next compared the apoptotic activity of nontargeted scTRAIL with the construct targeting human EGFR (αEGFR-scTRAIL). Because HCC cells, as with many solid tumor cells, reveal a weak TRAIL sensitivity, sensitizing agents, such as proteasome inhibitors, have been suggested to overcome TRAIL resistance.24 Therefore, we additionally analyzed the effects

of both TRAIL proteins in combination with the proteasome inhibitor BZB in Huh7 HCC cells and PHHs. Initial dose-finding experiments revealed a concentration of 100 ng/mL of the two TRAIL proteins to be the most effective for inducing apoptotic caspase-3 activation, when combined with a nontoxic concentration of BZB (500 ng/mL). Compared to BZB alone, which showed almost no effect on caspase activity, scTRAIL significantly increased caspase-3 activation (5.21- ± 1.01-fold) in Huh7 cells, which was further enhanced by BZB (17.06- ± 2.34-fold; Fig. 2A). In contrast to HCC cells, no significant MCE公司 caspase-3 activity was induced by treatment of PHHs with either scTRAIL alone or in combination with BZB. Compared to scTRAIL, EGFR-targeted scTRAIL even more potently increased caspase-3 activity in HCC cells (6.24- ± 1.07-fold, compared to untreated control), which was most strongly enhanced by cotreatment with BZB (50.63- ± 13.97-fold, P < 0.01; Fig. 2B). Importantly, neither αEGFR-scTRAIL alone nor its combination with BZB significantly induced caspase-3 activation in PHHs (2.19- ± 0.76- and 1.88- ± 0.77-fold; Fig. 2B). In contrast, CD95L, which served as a positive control, induced strong caspase-3 activation in PHHs (38.87- ± 10.51-fold; Fig. 2C). We then compared apoptosis induction by nontargeted and EGFR-targeted scTRAIL in the presence or absence of BZB.

Target genes regulated by MEG3 were detected with the Dual Luciferase reporter system and their expression levels were confirmed using qRT-PCR and Western blotting. Results: In contrast to matched adjacent non-neoplastic tissues, the expression of MEG3 was absent or decreased in most HCC tissues as well as in HepG2 cells. Low expression levels of MEG3 were associated with advanced pathologic stage, tumor size and a relatively

poor prognosis in HCC patients. Hypermethylation of MEG3 differentially methylated regions was identified by MSP in both HCC tissues and HepG2 cells and MEG3 expression was increased with the inhibition of DNA methyltransferase with 5-aza-2′-deoxycytidine treatment. MEG3 was overexpressed by transfection with pcDNA3.1-MEG3 in HepG2 cells. qRT-PCR analysis revealed that MEG3 expression was increased

by 51-fold in HepG2 cells, BMS-907351 price compared with the empty vector group. Overexpression of MEG3 decreased cell proliferation and increased 11% cell apoptosis ratio in vitro. MEG3 activated P53 and ILF-3 in HepG2 cells. Conclusion: Our data suggest that MEG3 is epigenetically silenced due to promoter hypermethylation, which may contribute to the development of HCC. MEG3 plays Selleck Navitoclax a tumor suppressor role by activating P53 and ILF-3 gene. Key Word(s): 1. MEG3; 2. hepatocellular arcinoma; 3. methylation; 4. prognosis; 5. p53 Presenting Author: LING FEI WU Additional Authors: MENG QI XIANG, WEI DENG, LI XUAN

LIU, XIAO TAO ZHOU, PEI RUI CHEN, LING FEI WU Corresponding Author: LING FEI WU Affiliations: Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University medchemexpress Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med, Second Affiliated Hospital, Shantou University Med Objective: To investigate the role of DNA methyltransferases (DNMTs) and methylation on adenosine (ADO)-induced apoptosis in human hepatocellular carcinoma HepG2 cells. Methods: HepG2 cells were treated with different concentrations of ADO alone or in combination with homocysteine (HCY) for different durations. 5-aza-2′-deoxycytidine (5-Aza-CdR) as a positive control. Cell proliferation inhibition rates were evaluated by CCK8 assay. Cell apoptosis was detected by AnnexinV-FITC/PI staining. The mitochondrial membrane potentials were measured by flow cytometry. The mRNA and protein expression of DNMT1, DNMT3a, DNMT3b, MDM-2, P53, caspase-3, caspase-9 and cytochrome C were detected by qRT-PCR and Western blotting, respectively. The mRNA expression of lncRNA-MEG3 was also detected by qRT-P CR. Results: ADO alone or in combination with HCY significantly suppressed the cell proliferation of HepG2 cells in a dose- and time-dependent manner.

Scanners were applied to record the usage, cleaning and sterilization of endoscope.

The time for cleaning and sterilization and the rates of mistakes were compared between the manual operation and the program. Results: Using the program, recording the cleaning and sterilization of endoscopes needed shorter time and had lower rate of mistakes than using manual operation (P < 0.05). Conclusion: Computerized information technology in monitoring the cleaning and sterilization of endoscope proved to be more accurate, effective and genuine. Key Word(s): 1. endoscope; 2. reprocessing; 3. monitoring; 4. computer; Presenting Author: HUIJUN XI Corresponding Author: HUIJUN XI Affiliations: Shanghai Changhai CAL-101 cell line Hospital Objective: The patients’ willingness

and impacted factors for the unsedated gastrointestinal endoscopy and ordinary gastrointestinal endoscopy have been evaluated in this study. Methods: The purpose of accepting gastrointestinal endoscopy, the understanding and selection of different ways of gastrointestinal endoscopy for patients in outpatient have been analyzed through questionnaires. The difference in anxiety between the unsedated gastrointestinal endoscopy and ordinary gastrointestinal endoscopy has been compared. Results: In all the 694 patients, 58.7% of the patients choose the ordinary gastrointestinal Vemurafenib cost endoscopy. Anesthesia-related risks and financial burden should be considered, which mainly caused the patients’ unwillingness for unsedated gastrointestinal endoscopy. The degree of anxiety

in patients with unsedated gastrointestinal endoscopy was significantly lower than those with ordinary gastrointestinal endoscopy. Conclusion: The choice of different ways of gastrointestinal endoscopy is affected by the interventional history and medical expenses, etc. Key Word(s): 1. anaesthesia; 2. Gastrointestinal; 3. willingness; 4. Endoscopy; Presenting Author: FUYUN HUI Corresponding Author: FUYUN HUI Affiliations: 上海皓元 hospital Objective: To investigate the value of NBI endoscopy in the diagnosis of colorectal tumor and non-neoplastic lesions. Methods: 105 polypoid lesions of the colon found in conventional endoscopy from January 2011 to January 2013 were enrolled in the study.These lesions were observed with conventional endoscopy and NBI mode.These lesions were classified by contour, pit pattern and capilary pattern which was assessed by reference to histopathology. Results: In 105 lesions,there were 9 cases,of hyperplastic polyps, 21 cases of inflammatory polyps,72 cases of adenoma and three cases of adenocarcinoma;The diagnostic accuracy rate, sensitivity, specificity of NBI endoscopy to identify lesions were 91.4%, 92.5%, 90.0%. Conclusion: NBI endoscopy is superior to conventional endoscopy in differentiation between colorectal neoplastic and non-neoplastic lesions, and the operation is simple and fast. Key Word(s): 1. NBI; 2. colorectal neoplas; 3. endoscopic; 4.

1) and alcoholic cirrhosis (OR = 3.2), although obesity was not a significant predictor in patients with viral hepatitis, primary biliary cirrhosis, or autoimmune hepatitis. In a recent study, Ohki et al. followed 62 patients with HCC in the setting of non-HBV, non-HCV, nonalcoholic HCC after curative ablation. The analysis demonstrated older age and the accumulation of visceral fat as independent risk factors for recurrence of HCC. Patients with very high visceral fat areas (>130 cm2 in males and >90 cm2 in females) had significantly higher rates of recurrence of HCC (75.1% versus 43.1% at 3 years). The recurrence of HCC was also more likely to develop de novo in the setting of

high visceral fat.66 Although these results are in the setting of HCC recurrence, this increased visceral fat accumulation is possibly involved in both tumor initiation and promotion of progression. Obesity has definitively PS-341 mw been established as a risk Microtubule Associated inhibitor factor for the development of HCC, with a 1.5-4 times increased risk (Fig. 2).60-63 This risk is likely conferred by two factors: the increased risk for NAFLD with subsequent progression to NASH and the carcinogenic potential of obesity alone.7 Large population-based cohort studies from Sweden, Denmark, and Greece demonstrate a 1.86-fold to 4-fold increase in risk of HCC among patients with diabetes (Fig. 3), which

is closely associated with obesity and NAFLD.67-69 More recently, a case-control study in the United

States showed that diabetes was associated with an increased risk for HCC, but only in patients with concomitant HCV-related, HBV-related, or alcohol-related cirrhosis.70 In a larger longitudinal study, the same group compared 173,643 diabetic patients with 650,620 nondiabetic controls over 10-15 years.71 The incidence of HCC increased more than two-fold among diabetic patients with higher increase among those with longer duration of follow-up. The risk of HCC with diabetes remained elevated even after excluding patients who were subsequently diagnosed with HCV, HBV, alcohol use, and/or fatty liver disease at any time during the follow-up.71 The risk for HCC was attributable to diabetes, and could not 上海皓元 be explained by the presence of underlying liver disease or other risk factors. Diabetes is clearly established as an independent risk factor for HCC. The risk of HCC from diabetes may be decreased with the use of statins. Experimental and indirect human data suggest that statin use may reduce the progression of HCC as well as increase survival in advanced HCC.72-74 More recently, statins have been shown to significantly reduce the risk of HCC among patients with diabetes.75 A total of 1303 cases and 5212 controls were compared in a nested, matched, case-control study in patients with diabetes given the known higher risk of developing HCC.

Endoscopic retrograde pancreatography (ERP) Selleck AZD6244 can be a useful adjunct to diagnose AIP. In a recent study, the ERP

features of AIP included the presence of a long, narrow stricture (>1/3 of the main pancreas duct), lack of upstream dilation from the stricture; side branches arising from the strictured portion of the duct; and multiple, non-contiguous strictures (Fig. 1,2).25 Collectively, these features are more suggestive of AIP than the presence of any one of these items. Although magnetic resonance cholangiopancreatography (MRCP) is an attractive minimally-invasive way of visualizing the pancreatic duct, ERP and MRCP have not been compared head to head. Endoscopic ultrasound (EUS) is a very useful test in diagnosing AIP. The classic EUS feature of AIP is that of a diffusely-hypoechoic Rapamycin gland. However, the greatest advantage of EUS is the ability to obtain tissue. Tissue sampling via fine-needle aspiration is sufficient for diagnosing pancreatic cancer, but inadequate for diagnosing AIP. A core biopsy of the pancreas is needed for the latter. Only such a core biopsy is likely to have all the features

of LPSP.26 This said, a core biopsy of the pancreatic head is technically challenging, especially in the focal form of AIP. The mainstay of serology in AIP is the fact that a subtype of IgG, IgG4, is elevated. Initial studies showed that elevated IgG4 上海皓元医药股份有限公司 had a >95% sensitivity and specificity in diagnosing AIP.4 More recent studies reveal a much lower sensitivity (70%) and specificity (90%).27,28 The accuracy of IgG4 elevation depends on the extent of the increase. Thus, twice-the-upper-limit-of-normal elevation is highly suggestive of AIP. It must be borne in mind that 10% of pancreatic cancers can also have elevated IgG4 levels.29,30 It follows that an elevated IgG4 level alone should not be the sole criterion used to

diagnose AIP. Although a host of other autoantibodies has been purportedly elevated in AIP, to date, none has proved more informative than serum IgG4. As already stated, type 1 AIP is the pancreatic manifestation of a multisystem disease. Because all tissues involved have characteristic infiltration of IgG4-positive cells, the term “IgG4-associated systemic disease” has been proposed. The most common site of extrapancreatic involvement in AIP is the bile duct, followed by salivary glands, retroperitoneal fibrosis, orbital pseudotumors, lymphadenopathy, and renal parenchyma.5,31 The presence of other organ involvement can lead to characteristic clinical features, such as dry eyes and a dry mouth (Sjögren’s syndrome), jaundice (bile ducts), and groin swelling (regional lymphadenopathy). Often these symptoms improve with treatment, and such changes can serve as indicators of response to treatment.

Endoscopic retrograde pancreatography (ERP) selleck inhibitor can be a useful adjunct to diagnose AIP. In a recent study, the ERP

features of AIP included the presence of a long, narrow stricture (>1/3 of the main pancreas duct), lack of upstream dilation from the stricture; side branches arising from the strictured portion of the duct; and multiple, non-contiguous strictures (Fig. 1,2).25 Collectively, these features are more suggestive of AIP than the presence of any one of these items. Although magnetic resonance cholangiopancreatography (MRCP) is an attractive minimally-invasive way of visualizing the pancreatic duct, ERP and MRCP have not been compared head to head. Endoscopic ultrasound (EUS) is a very useful test in diagnosing AIP. The classic EUS feature of AIP is that of a diffusely-hypoechoic selleck chemicals gland. However, the greatest advantage of EUS is the ability to obtain tissue. Tissue sampling via fine-needle aspiration is sufficient for diagnosing pancreatic cancer, but inadequate for diagnosing AIP. A core biopsy of the pancreas is needed for the latter. Only such a core biopsy is likely to have all the features

of LPSP.26 This said, a core biopsy of the pancreatic head is technically challenging, especially in the focal form of AIP. The mainstay of serology in AIP is the fact that a subtype of IgG, IgG4, is elevated. Initial studies showed that elevated IgG4 上海皓元医药股份有限公司 had a >95% sensitivity and specificity in diagnosing AIP.4 More recent studies reveal a much lower sensitivity (70%) and specificity (90%).27,28 The accuracy of IgG4 elevation depends on the extent of the increase. Thus, twice-the-upper-limit-of-normal elevation is highly suggestive of AIP. It must be borne in mind that 10% of pancreatic cancers can also have elevated IgG4 levels.29,30 It follows that an elevated IgG4 level alone should not be the sole criterion used to

diagnose AIP. Although a host of other autoantibodies has been purportedly elevated in AIP, to date, none has proved more informative than serum IgG4. As already stated, type 1 AIP is the pancreatic manifestation of a multisystem disease. Because all tissues involved have characteristic infiltration of IgG4-positive cells, the term “IgG4-associated systemic disease” has been proposed. The most common site of extrapancreatic involvement in AIP is the bile duct, followed by salivary glands, retroperitoneal fibrosis, orbital pseudotumors, lymphadenopathy, and renal parenchyma.5,31 The presence of other organ involvement can lead to characteristic clinical features, such as dry eyes and a dry mouth (Sjögren’s syndrome), jaundice (bile ducts), and groin swelling (regional lymphadenopathy). Often these symptoms improve with treatment, and such changes can serve as indicators of response to treatment.

Endoscopic retrograde pancreatography (ERP) selleck chemicals llc can be a useful adjunct to diagnose AIP. In a recent study, the ERP

features of AIP included the presence of a long, narrow stricture (>1/3 of the main pancreas duct), lack of upstream dilation from the stricture; side branches arising from the strictured portion of the duct; and multiple, non-contiguous strictures (Fig. 1,2).25 Collectively, these features are more suggestive of AIP than the presence of any one of these items. Although magnetic resonance cholangiopancreatography (MRCP) is an attractive minimally-invasive way of visualizing the pancreatic duct, ERP and MRCP have not been compared head to head. Endoscopic ultrasound (EUS) is a very useful test in diagnosing AIP. The classic EUS feature of AIP is that of a diffusely-hypoechoic Erastin purchase gland. However, the greatest advantage of EUS is the ability to obtain tissue. Tissue sampling via fine-needle aspiration is sufficient for diagnosing pancreatic cancer, but inadequate for diagnosing AIP. A core biopsy of the pancreas is needed for the latter. Only such a core biopsy is likely to have all the features

of LPSP.26 This said, a core biopsy of the pancreatic head is technically challenging, especially in the focal form of AIP. The mainstay of serology in AIP is the fact that a subtype of IgG, IgG4, is elevated. Initial studies showed that elevated IgG4 MCE had a >95% sensitivity and specificity in diagnosing AIP.4 More recent studies reveal a much lower sensitivity (70%) and specificity (90%).27,28 The accuracy of IgG4 elevation depends on the extent of the increase. Thus, twice-the-upper-limit-of-normal elevation is highly suggestive of AIP. It must be borne in mind that 10% of pancreatic cancers can also have elevated IgG4 levels.29,30 It follows that an elevated IgG4 level alone should not be the sole criterion used to

diagnose AIP. Although a host of other autoantibodies has been purportedly elevated in AIP, to date, none has proved more informative than serum IgG4. As already stated, type 1 AIP is the pancreatic manifestation of a multisystem disease. Because all tissues involved have characteristic infiltration of IgG4-positive cells, the term “IgG4-associated systemic disease” has been proposed. The most common site of extrapancreatic involvement in AIP is the bile duct, followed by salivary glands, retroperitoneal fibrosis, orbital pseudotumors, lymphadenopathy, and renal parenchyma.5,31 The presence of other organ involvement can lead to characteristic clinical features, such as dry eyes and a dry mouth (Sjögren’s syndrome), jaundice (bile ducts), and groin swelling (regional lymphadenopathy). Often these symptoms improve with treatment, and such changes can serve as indicators of response to treatment.

There is wide variability in inter-individual response to these treatments with regard to both efficacy and toxicity, and there is also usually a delay of weeks to months before efficacy can be determined. Therefore, there has been great interest in applying pharmacogenetic

research to these drugs with the aim of predicting response to treatment, with the ultimate goal of individualizing drug type and dose for each patient. This article reviews our current understanding of the role genetic polymorphisms play in thiopurine, methotrexate and TNFα drug-based treatment of CD. The many enzymatic steps in the thiopurine pathway (Fig. 1) confer a high likelihood of genetic variability influencing drug efficacy and toxicity. The importance of genetic variability in determining patient response to the thiopurine drugs was first recognized with the discovery that approximately H 89 20% of myelosuppression cases caused by thiopurine treatment were the direct result of a genetic deficiency in the enzyme thiopurine S-methyltransferase (TPMT; EC 2.1.1.67).1 Today TPMT deficiency represents one of the few pharmacogenetic phenomena that are used to guide prescribing in CD. The Food and Drug Administration (FDA), the 2010 European Science Foundation—Universitat de Barcelona (ESF-UB) conference on pharmacogenetics and pharmacogenomics, and the National Academy of Clinical Biochemistry (NACB) all recommend

that consideration should be given to TPMT status when prescribing azathioprine or 6-mercaptopurine. Furthermore, ESF-UB offers guidance on dosing by stating that patients with two loss-of-function alleles Enzalutamide cost should have

alternative therapy or 10% of the recommended dose, while CD patients with one loss-of-function allele should receive 50% of the recommended dose at commencement of therapy. Dose escalation is possible in these patients if guided by therapeutic drug monitoring.2 While TPMT deficiency is a robust predictor of thiopurine-induced myelosuppression,1 it neither predicts other 上海皓元医药股份有限公司 dose-dependent adverse effects (e.g. hepatotoxicity), dose-independent adverse effects (e.g. pancreatitis, flu-like symptoms, nausea and vomiting, rash), nor preferential metabolism of azathioprine and 6-mercaptopurine to 6-MMPR,3 a metabolite that increases the risk of hepatotoxicity. This raises the question of whether other genetic polymorphisms within the purine biosynthesis pathway may also have a clinically relevant effect on thiopurine drug response. In the following sections we will briefly summarize what is known about TPMT deficiency and then explore whether there is evidence to support a role of other polymorphisms in thiopurine adverse effects, non-response, and altered metabolism. Thiopurine S-methyltransferase deficiency.  Weinshilboum and Sladek4 were the first to report the large inter-individual variations in TPMT activity.

There is wide variability in inter-individual response to these treatments with regard to both efficacy and toxicity, and there is also usually a delay of weeks to months before efficacy can be determined. Therefore, there has been great interest in applying pharmacogenetic

research to these drugs with the aim of predicting response to treatment, with the ultimate goal of individualizing drug type and dose for each patient. This article reviews our current understanding of the role genetic polymorphisms play in thiopurine, methotrexate and TNFα drug-based treatment of CD. The many enzymatic steps in the thiopurine pathway (Fig. 1) confer a high likelihood of genetic variability influencing drug efficacy and toxicity. The importance of genetic variability in determining patient response to the thiopurine drugs was first recognized with the discovery that approximately Roscovitine 20% of myelosuppression cases caused by thiopurine treatment were the direct result of a genetic deficiency in the enzyme thiopurine S-methyltransferase (TPMT; EC 2.1.1.67).1 Today TPMT deficiency represents one of the few pharmacogenetic phenomena that are used to guide prescribing in CD. The Food and Drug Administration (FDA), the 2010 European Science Foundation—Universitat de Barcelona (ESF-UB) conference on pharmacogenetics and pharmacogenomics, and the National Academy of Clinical Biochemistry (NACB) all recommend

that consideration should be given to TPMT status when prescribing azathioprine or 6-mercaptopurine. Furthermore, ESF-UB offers guidance on dosing by stating that patients with two loss-of-function alleles Proteases inhibitor should have

alternative therapy or 10% of the recommended dose, while CD patients with one loss-of-function allele should receive 50% of the recommended dose at commencement of therapy. Dose escalation is possible in these patients if guided by therapeutic drug monitoring.2 While TPMT deficiency is a robust predictor of thiopurine-induced myelosuppression,1 it neither predicts other 上海皓元医药股份有限公司 dose-dependent adverse effects (e.g. hepatotoxicity), dose-independent adverse effects (e.g. pancreatitis, flu-like symptoms, nausea and vomiting, rash), nor preferential metabolism of azathioprine and 6-mercaptopurine to 6-MMPR,3 a metabolite that increases the risk of hepatotoxicity. This raises the question of whether other genetic polymorphisms within the purine biosynthesis pathway may also have a clinically relevant effect on thiopurine drug response. In the following sections we will briefly summarize what is known about TPMT deficiency and then explore whether there is evidence to support a role of other polymorphisms in thiopurine adverse effects, non-response, and altered metabolism. Thiopurine S-methyltransferase deficiency.  Weinshilboum and Sladek4 were the first to report the large inter-individual variations in TPMT activity.