Unraveling the interplay between RAS/RAF/MEK/ERK signaling pathway and autophagy in cancer: From molecular mechanisms to targeted therapy.

RAS/RAF/MEK/ERK signaling pathway is one of the most important pathways of Mitogen-activated protein kinases (MAPK), which widely participate in regulating cell proliferation, differentiation, apoptosis and signaling transduction. Autophagy is an essential mechanism that maintains cellular homeostasis by degrading aged and damaged organelles. Recently, some studies revealed RAS/RAF/MEK/ERK signaling pathway is closely related to autophagy regulation and has a dual effect in tumor cells. However, the specific mechanism by which RAS/RAF/MEK/ERK signaling pathway participates in autophagy regulation is not fully understood. This article provides a comprehensive review of the research progress with regard to the RAS/RAF/MEK/ERK signaling pathway and autophagy, as well as their interplay in cancer therapy. The impact of small molecule inhibitors that target the RAS/RAF/MEK/ERK signaling pathway on autophagy is discussed in this study. The advantages and limitations of the clinical combination of these small molecule inhibitors with autophagy inhibitors are also explored. The findings from this study may provide additional perspectives for future cancer treatment strategies.

Identification of Balanol As a Potential Inhibitor of PAK1 That Induces Apoptosis and Cytoprotective Autophagy in Colorectal Cancer Cells.

Colorectal cancer (CRC) is a common malignancy of the gastrointestinal tract, often accompanied by poor prognosis and high incidence and mortality. p21 activated kinases (PAKs) have been used as therapeutic targets because of their central role in many oncogenic signaling networks. By exploring tumor databases, we found that PAK1 overexpression is associated with poor prognosis in colorectal cancer, and therefore, PAK1-targeted inhibition is a new potential therapeutic strategy for colorectal cancer. We identified that Balanol (compound 6, DB04098) can effectively target PAK1 by high-throughput virtual screening. In vitro, compound 6 exhibited favorable PAK1 inhibition with potent anti-proliferative and anti-migration activity in SW480 cells. Additionally, we also found that compound 6 induced apoptosis and cytoprotective autophagy in SW480 cells. Together, these results indicate that compound 6 is a potential novel PAK1 inhibitor, which would be utilized as a candidate compound for future CRC treatment.

Long-term outcomes of administration of intravitreal triamcinolone acetonide after posterior vitreous detachment during pars plana vitrectomy for proliferative diabetic retinopathy.

AIM: To evaluate the long-term outcomes of intravitreal triamcinolone acetonide (TA) administration after posterior vitreous detachment (PVD) during pars plana vitrectomy (PPV) for patients with proliferative diabetic retinopathy (PDR). METHODS: A total of 189 eyes (152 patients) who underwent PPV for severe PDR were reviewed. Intravitreal injection of TA (IVTA) was administered during PPV in 118 eyes (PPV+IVTA group), and 71 eyes did not receive IVTA (PPV group). Immediately after PVD, when most of the vitreous and proliferative membranes were removed, 0.1 mL TA (40 mg/mL) was injected into the vitreous cavity in the PPV+IVTA group. All patients were followed-up for least 12 months. Visual outcomes and postoperative complications were recorded and compared between the two groups. RESULTS: IVTA was helpful for proliferative membrane peeling and haemostasis during PPV. In the PPV+IVTA group, best-corrected visual acuity had significantly improved and the intraocular pressure was controlled well during the follow-up. The incidence of early recurrent vitreous haemorrhage after PPV was significantly lower in the PPV+IVTA group (1.7%) than in the PPV group (9.9%) (p=0.028). CONCLUSION: The administration of IVTA after PVD during PPV can effectively improve the final visual outcomes and prevent postoperative complications in patients with severe PDR.

Epidemiology of Sports-Related Eye Injuries Among Athletes in Tianjin, China.

Purpose: To investigate the incidence, characteristics, and risk factors of sports-related eye injuries among athletes in Tianjin, China. Methods: A cross-sectional study was carried out from March 2018 to October 2018. In this study, the athletes from Tianjin University of Sports, Tianjin Vocational College of Sports, and Tianjin provincial sports teams were selected for general investigation. In total, 1,673 athletes were invited and 1,413 participated in the study (response rate of 84.5%). Results: In total, 1,413 athletes were enrolled; 151 had suffered from sports-related eye injuries, with an incidence of 10.7% (95% CI: 9.1-12.0%). Handball (38.5%) was the sport with the highest incidence of eye injuries, followed by water polo (36.4%) and diving (26.7%). Overall, 42.4% of the athletes were injured by ball and 22.5% of injuries came from teammates. The eye injuries usually occurred during training (64.2%) and competitions (14.6%). Adnexa wound (51.7%) was the most common type of injury. About 11.9% of the athletes with eye injuries had the impaired vision; 66.7% failed to see doctors on time. The athletes <18 years of age had a higher risk of eye injuries (odds ratio [OR] =1.60, 95% CI: 1.06-2.40). The athletes with lower family income (<1,000 RMB) were at risk population for sports-related eye injuries (OR = 3.91, 95% CI: 2.24-6.82). Training >4 h a day increased the risk of eye injuries (OR = 2.21, 95% CI: 1.42-3.43). Conclusion: The incidence of sports-related eye injuries among athletes was 10.7% in Tianjin, China. Handball, water polo, and diving were the most common activities of injury. Age, family income, and training time were the risk factors for sports-related eye injuries.

Prevalence and causes of bilateral visual impairment in rural areas of Tianjin, China - The Tianjin Eye Study.

PURPOSE: To estimate the prevalence, causes and risk factors of bilateral visual impairment in rural areas of Tianjin, China. METHODS: A large population-based, cross-sectional study. A stratified random cluster sampling method was used to investigate 12 233 participants in all age groups living in rural Tianjin. Participants completed questionnaires and received professional ophthalmology examinations. RESULTS: According to World Health Organization best-corrected visual acuity (BCVA) criteria, the crude prevalence of bilateral visual impairment (BCVA < 20/63), bilateral low vision (BCVA < 20/63 to ≥20/400) and bilateral blindness (BCVA < 20/400) was 2.53%, 2.40% and 0.14% (age- and gender-standardized prevalence was 1.86%, 1.76% and 0.11%). The prevalence increased with age and was higher in women than men. The most common causes of bilateral visual impairment in the total population were cataract (48.39%), refractive error/amblyopia (17.74%), age-related macular degeneration (AMD) (10.00%), diabetic retinopathy (5.81%) and glaucoma (3.87%). For participants younger than 50 years, refractive error/amblyopia was the leading cause of low vision and blindness, while cataract was the major cause in the participants over 50. Female gender, older age and self-reported diabetes were associated with increased risks of visual impairment. CONCLUSION: The age- and gender-standardized prevalence of low vision, especially in the older group (50+), was higher in this study compared with previous studies in China. Refractive error/amblyopia was the leading cause of bilateral visual impairment in younger group, while cataract was the primary cause in the older group. These findings will provide useful information for planning comprehensive eye healthcare programmes in China.

Dexmedetomidine Alleviates CCI-Induced Neuropathic Pain via Inhibiting HMGB1-Mediated Astrocyte Activation and the TLR4/NF-κB Signaling Pathway in Rats.

To investigate the effects of dexmedetomidine on chronic constriction injury (CCI)-induced neuropathic pain and to further explore its mechanism. A CCI rat model was established and treatment with dexmedetomidine. The paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) were monitored at different time points, and the effects of hematoxylin-eosin staining on the sciatic nerve morphology of rats were observed. Immunohistochemical and immunofluorescence analyses were used to detect the expression of high mobility group box-1 (HMGB1) protein and glial fibrillary acidic protein (GFAP), and protein fluorescence intensity of GFAP in spinal cord tissue, respectively. Moreover, the expression of HMGB1 and Toll-like receptor-4/nuclear factor kappa-B (TLR4/NF-κB) pathway-related proteins were detected by western blot assay. To verify whether dexmedetomidine alleviates CCI-induced neuropathic pain by inhibiting HMGB1-mediated astrocyte activation and the TLR4/NF-κB signaling pathway, the rats were further treated with an HMGB1 activator or antagonist. Dexmedetomidine was found to improve the pathological changes of the sciatic nerve and alleviate pain in the CCI rats. The expression of HMGB1, GFAP, TLR4, TRAF6, MyD88, and p-P65 were greatly downregulated in the spinal cord tissues of the CCI rats. In addition, a further study showed that an HMGB1 activator can reverse the inhibition of neuropathic pain behaviors of dexmedetomidine. Overexpression of HMGB1 downregulated the PWMT and PWTL and enhanced the astrocyte activity and the TLR4/NF-κB signaling pathway in CCI rats. These results indicated that dexmedetomidine can alleviate neuropathic pain in CCI rats by inhibiting HMGB1-mediated astrocyte activation and the TLR4/NF-κB signaling pathway.

Susceptibilities of Malassezia strains from pityriasis versicolor, Malassezia folliculitis and seborrheic dermatitis to antifungal drugs.

The human pathogenic yeast genus Malassezia may be an etiological agent of skin disorders and has received considerable attention from dermatologists in recent years. To investigate the different susceptibilities of Malassezia species to four antifungal drugs, we isolated a total of 244 Malassezia strains and identified six species of Malassezia from patients with clinical skin diseases. The minimum inhibitory concentration (MIC) of the four antifungal drugs was obtained by comparing the susceptibility of the isolated Malassezia strains to four antifungal drugs (ketoconazole (KTZ), itraconazole (ITZ), fluconazole (FLC) and amphotericin B (Am B)). We demonstrated that M. furfur, M. sympodialis, M. pachydermatis and M. globosa are the most common Malassezia species in the three skin diseases. The MICs of KTZ, ITZ, FLC and Am B against M. furfur, M. sympodialis, M. pachydermatis and M. globosa ranged from 0.03 - 16 mg/L, 0.03 - 2.0 mg/L, 0.03 - 8 mg/L, and 13 - 64 mg/L, respectively. The sensitivities of Malassezia to the four antifungal drugs from high to low were ITZ ≥ KTZ > Am B > FLC. The susceptibilities of the various Malassezia species to the four antifungal drugs were different, and the susceptibility of M. furfur to KTZ was significantly different from those of the three skin diseases (pityriasis versicolor, Malassezia folliculitis and seborrheic dermatitis). Our results suggested that the MIC analysis of the four antifungal drugs would be helpful in preventing drug resistance in the clinical screening of Malassezia and choosing better antifungal drugs to treat Malassezia-associated skin diseases.

Bis-benzylidine Piperidone RA190 treatment of hepatocellular carcinoma via binding RPN13 and inhibiting NF-κB signaling.

BACKGROUND: According to GLOBOSCAN, hepatocellular carcinoma (HCC) claimed 782,000 lives in 2018. The tyrosine kinase inhibitor sofafenib is used to treat HCC, but new anticancer agents targeting different pathways are urgently needed to improve outcomes for patients with advanced disease. The aberrant metabolism and aggressive growth of cancer cells can render them particularly susceptible to proteasome inhibition, as demonstrated by bortezomib treatment of multiple myeloma. However, resistance does emerge, and this 20S proteasome inhibitor has not proven active against HCC. The bis-benzylidine piperidone RA190 represents a novel class of proteasome inhibitor that covalently binds to cysteine 88 of RPN13, an ubiquitin receptor subunit of the proteasome's 19S regulatory particle. RA190 treatment inhibits proteasome function, causing rapid accumulation of polyubiquitinated proteins. Considerable evidence suggests that nuclear factor κB (NF-κB) signaling, which is dependent upon the proteasome, is a major driver of inflammation-associated cancers, including HCC. METHODS: Human HCC cell lines were treated with titrations of RA190. The time course of endoplasmic reticulum stress and NF-κB-related mechanisms by which RA190 may trigger apoptosis were assessed. The therapeutic activity of RA190 was also determined in an orthotopic HCC xenograft mouse model. RESULTS: RA190 is toxic to HCC cells and synergizes with sofafenib. RA190 triggers rapid accumulation of polyubiquitinated proteins, unresolved endoplasmic reticulum stress, and cell death via apoptosis. RA190 blocks proteasomal degradation of IκBα and consequent release of NF-κB into the nuclei of HCC cells. Treatment of mice bearing an orthotopic HCC model with RA190 significantly reduced tumor growth. CONCLUSIONS: RA190 has therapeutic activity in a xenograft model, and with sorafenib exhibited synergetic killing of HCC cells in vitro, suggesting further exploration of such a combination treatment of HCC is warranted.

Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease.

BACKGROUND: Wilson's disease (WD) is an autosomal recessive genetic disease caused by mutations in ATP7B and characterized by copper metabolism disorders. METHODS: Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method. Fourteen probands with WD and 12 family members participated in this study. The ATP7B gene was analyzed by direct sequencing. RESULTS: Twenty-nine different variants (27 substitutions, 1 duplication, 1 deletion) were found. Of the 23 reported variants, nine nondisease variants, 11 disease variants, one silent variant, and two variants with uncertain functions were identified. The six novel variants included c.1875T>A, c.2306T>C, c.3028A>G, c.3243G>A, c.3437_3438 delTG, and c.3903+5G>A. CONCLUSION: These findings will assist in the diagnosis of WD. The novel variants have enriched the WD database.

Role of microRNA-145 in protection against myocardial ischemia/reperfusion injury in mice by regulating expression of GZMK with the treatment of sevoflurane.

This study aims to investigate the role of microRNA-145 (miR-145) in protection against myocardial ischemia/reperfusion (I/R) injury in mice by regulating expression of granzyme K (GZMK) with the treatment of sevoflurane. The mice model of myocardial I/R injury was established by left coronary artery ligation. The expression of miR-145 and GZMK in myocardial tissues of mice was detected by Reverse transcription quantitative polymerase chain reaction and western blot analysis. The changes of the cardiac function and hemodynamics, pathological changes of myocardial tissues, the ultrastructure of cardiomyocytes, myocardial infarction area, and cardiomyocyte apoptosis were observed. The expression of the apoptosis-related protein cleaved-caspase-3, Bax, and Bcl-2 was detected by western blot analysis. The levels of malondialdehyde, myeloperoxidase, superoxide dismutase in myocardial tissues were detected by spectrophotometric colorimetry. The levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α in the serum of mice were detected by the enzyme-linked immunosorbent assay. The level of oxidative stress and the expression of inflammatory factors increased in mice with myocardial I/R injury. Sevoflurane postconditioning could reduce myocardial I/R injury in mice. Sevoflurane postconditioning may protect myocardial I/R injury through miR-145-regulation of GZMK in mice. Inhibition of miR-145 expression could reduce the protective effect of sevoflurane posttreatment on myocardial I/R injury in mice. Low expression of GZMK could attenuate the inhibitory effect of miR-145 on myocardial I/R injury after sevoflurane treatment in mice. Our study suggests that sevoflurane postconditioning may protect against myocardial I/R injury by upregulating miR-145 expression and downregulating GZMK expression.

Neuroprotective effects of artemisinin against isoflurane-induced cognitive impairments and neuronal cell death involve JNK/ERK1/2 signalling and improved hippocampal histone acetylation in neonatal rats.

OBJECTIVE: This study was performed to assess the effect of artemisinin against isoflurane-induced neuronal apoptosis and cognitive impairment in neonatal rats. METHODS: Artemisinin (50, 100 or 200 mg/kg b.wt/day; oral gavage) was administered to separate groups of neonatal rats starting from postnatal day 3 (P3) to postnatal day 21 (P21). On postnatal day 7 (P7), animals were exposed to inhalation anaesthetic isoflurane (0.75%) for 6 h. KEY FINDINGS: Neuronal apoptosis following anaesthetic exposure was significantly reduced by artemisinin. Isoflurane-induced upregulated cleaved caspase-3, Bax and Bad expression were downregulated. Western blotting analysis revealed that treatment with artemisinin significantly enhanced the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL, c-IAP-1, c-IAP-2, xIAP and survivin). Artemisinin increased the acetylation of H3K9 and H4K12 while reducing the expression of histone deacetlyases (HDACs) - HDAC-2 and HDAC-3. Isoflurane-induced activation of JNK signalling and downregulated ERK1/2 expression was effectively modulated by artemisinin. General behaviour of the animals in open-field and T-maze test were improved. Morris water maze test and object recognition test revealed better learning, working memory and also better memory retention on artemisinin treatment. CONCLUSIONS: Artemisinin effectively inhibited neuronal apoptosis and improved cognition and memory via regulating histone acetylation and JNK/ERK1/2 signalling.

Asymptomatic oral yeast carriage and antifungal susceptibility profile of HIV-infected patients in Kunming, Yunnan Province of China.

BACKGROUND: Oral Candida colonization and its relation with predisposing factors in HIV-infected patients have received wide concerns during recent decades. In this study, we investigated asymptomatic oral Candida carriage rate, species distribution and antifungal susceptibility of 604 HIV-infected patients and 851 healthy individuals in Kunming, Yunnan Province of China. METHODS: Mucosal swab sampling was taken from each subject and CHROMagar Candida agar medium and API 20C AUX system were used to identify yeast isolates. In vitro antifungal susceptibility was tested by the broth microdilution method according to the M27-A2 document of the Clinical and Laboratory Standard Institute (CLSI). RESULTS: The oral yeast colonization rate in HIV-infected patients (49.5%) was higher than that of healthy subjects (20.7%). Candida albicans constituted the most frequent species, accounting for 82.2% of yeast isolates. The remaining species were composed of C. glabrata, C. parapsilosis, C. krusei, C. tropicalis, C. rugosa, C. norvegensis, Pichia ohmeri and Saccharomyces cerevisiae. In HIV-infected patients, asymptomatic oral yeast colonization was associated with low CD4 cell count (<200 cells/mm3) and lack of highly active antiretroviral therapy (HAART). Different Candida species isolated from our samples presented different susceptibility to voriconazole, fluconazole and itraconazole. Amphotericin B had the best inhibiting effect for all isolates. CONCLUSION: Oral yeast colonization in Han Chinese patients with HIV from Kunming had common and unique features and was associated with CD4 cell number and HARRT. Amphotericin B should be used with first priority in controlling Candida infection in Han Chinese patients from Kunming. Our results provide first hand information on monitoring oral yeasts colonization in HIV-infected patients from Kunming, China.

[The characteristic of T cells response to HBV-specific antigen proteins in patients with HBV infection].

OBJECTIVE: To analyze the characteristic of T cell response to specific antigen proteins in patients with hepatitis B virus infection. METHODS: 76 cases were recruited, including four groups, acute hepatitis B (AHB), active phase of chronic hepatitis B (CHB), inactive HBV carriers (AsC) and past HBV infection. T cell responses stimulated by 3 antigen specific proteins of HBV were detected using enzyme linked immunospot (ELISPOT) assay. RESULTS: (1) There were no significant difference in frequencies to HBsAg, HBcAg and HBeAg in AHB and CHB. The frequencies to HBsAg and HBcAg in AsC were lower than that to HBeAg, and the frequencies to HBsAg in group of past HBV infection were significantly lower than that to HBcAg and HBeAg. (2) The frequencies to HBsAg in AHB and CHB both were higher than in group of past HBV infection. The frequencies to HBcAg of AHB, CHB and AsC were higher than that of group of past HBV infection. (3) There were no significant difference in magnitude to HBsAg, HBcAg and HBeAg in AHB and AsC. In CHB, the magnitude to HBsAg was lower than that to HBcAg. The magnitude of in group of past HBV infection were HBcAg > HBeAg > HBsAg. (4) In four groups, the sequence of the magnitude to HBsAg from high to low was AHB, CHB, group of past HBV infection and AsC. The magnitude to HBcAg in of AsC was lower than other three groups. As to the magnitude to HBeAg, the difference was no significant between any two groups except between AHB and CHB. CONCLUSIONS: The T cell responses in group of AsC to HBeAg were the highest, while the T cell responses to HBcAg were the highest in group of other groups.

[The impact of antiviral therapy on virus-specific T-cell reactivity in patients with chronic hepatitis B].

OBJECTIVE: To investigated the impact of viral load decline on virus-specific T-cell reactivity on patients with chronic hepatitis B. METHODS: 23 cases of patients with chronic hepatitis B were recruited randomized to therapy with nucleoside analogue or alpha interferon from January 2009 to April 2010. Peripheral blood mononuclear cells (PBMCs) were collected longitudinally at baseline and the time of HBV DNA undetected. T-cell reactivity to HBV core antigens were tested using Elispot assays and Luminex. RESULTS: (1) The frequency of T cell reactivity induced by HBcAg in patients with chronic hepatitis B were 91.3% at the time of HBV DNA undetected, which significantly higher than The frequency of 69.6% at baseline. The frequency between nucleoside analogue treatment group and alpha interferon treatment group was no significant difference. (2) The average response magnitude was expressed as spot forming unit (SFU) per million input cells. SFU of T cell responses to HBcAg was 120 SFU/10(6) PBMCs at baseline, much lower than SFU of 1060 SFU/10(6) PBMCs at the time of HBV DNA undetected. No significant difference between patients with negative T cell reactivity at baseline and patients with positive T cell reactivity at baseline was found. In patients with initial virological response (IVR) to therapy and patients with early virological response (EVR), no significant difference was found in the magnitude at baseline as well as at the time of HBV DNA undetected. (3) The average response magnitude of nucleoside analogue treatment group was 1713 SFU/10(6) PBMCs at the time the time of HBV DNA undetected, higher than 189 SFU/10(6) PBMCs at baseline. But in interferon treatment group, the average response magnitude was no significant difference, 120 SFU/10(6) PBMCs at the baseline and 305 SFU/10(6) PBMCs at the time the time of HBV DNA undetected respectively. The average response magnitude in nucleoside analogue treatment group was greater than that in interferon treatment group. (4) As to compare difference of IFN-γ concentration in supernatant of T cell culture solution stimulated by HBcAg, IFN-γ secreted by T cell at the time of HBV DNA undetected was clearly higher than IFN-γ secreted at baseline, (38 ± 9) ng/L and (90 ± 9) ng/L respectively. CONCLUSIONS: Antiviral therapy made profit to improve virus-specific T-cell reactivity in patients with chronic hepatitis B, suggesting the importance to investigate HBV specific T cell responses.

[Clinical characteristics of drug-induced liver injury in 31 pediatric cases].

OBJECTIVE: To investigate the clinical characteristics and responsible agents of drug-induced liver injury (DILI) in pediatric patients. METHODS: Thirty-one cases of DILI treated in our hospital's pediatric ward were retrospectively analyzed. The clinical data for each patient were extracted from the patient's medical records, and included reported causes, physical and biochemical features, natural history, blood examination results, and hepatic pathology findings. RESULTS: The 31 pediatric cases of DILI accounted for 1.7% of the 1831 total cases of drug-induced liver injury treated at our hospital between February 2002 to June 2011. The pediatric DILI population was composed of 20 males and 11 females, with an average age of 8.8+/-3.9 years old (range, 0.3-14.0). The liver injury patterns represented among the cases were: hepatocellular (25.8%), cholestasis (25.8%), and mixed hepatocellular-cholestatic (48.4%). Antimicrobials were the most common cause (41.9%) of DILI, followed by the herbal medicine (29.0%) and febrifuge drugs (19.4%). A single drug was implicated in nine cases (29.0%), and two or more drugs were implicated in 22 cases (71%). Most of the children had good prognosis, but those with pre-existing disease had poor prognosis. One child died of hepatic failure, making the death rate 3.23%. The average hospitalization time was 25.2 days, and the patients with hepatocellular injury had shorter hospitalization time than those with mixed injury. CONCLUSION: Drug-induced liver injury in our pediatric population was most often caused by antimicrobials, followed by herbal medicine and febrifuge drugs. Most patients presented with mixed hepatocellular-cholestatic injury. Children with pre-existing diseases or hepatic failure had poor prognosis.

[Clinical significance of liver function and autoantibodies in patients with acute or chronic drug-induced liver injury].

OBJECTIVE: To investigate the clinical significance of liver function and autoantibodies in patients with acute or chronic drug-induced liver injury. METHODS: 51 patients with drug-induced liver injury were divided into acute drug induced liver injury group and chronic drug induced liver injury group, liver function and autoantibodies were compared between these two groups. RESULTS: There was no significant difference (P more than 0.05) in alanine aminotransferase [(412.1+/-387.5) U/L and (376.0+/-319.7) U/L], aspartate aminotransferase [(352.5+/-457.9) U/L and (198.8+/-142.7) U/L], total bilirubin [(109.7+/-104.80)micromol/L and(102.4+/-135.7)micromol/L], direct bilirubin [(66.4+/-73.3)micromol/L and (61.2+/-72.1)micromol/L], alkaline phosphatase [(133.4+/-50.1) U/L and (147.4+/-97.3) U/L], gamma-glutamyltransferase [(139.9+/-134.1) U/L and (180.6+/-227.9) U/L], and albumin [(41.3+/-4.9) g/L and (39.8+/-5.3)g/L] between these two groups, however, the level of globulin [(25.1+/-5.3) g/L and (28.6+/-5.1) g/L] was significantly different between these two groups (P less than 0.05). The titers of Anti-nuclear antibody (ANA) and smooth muscle antibody (SMA) were less than or equal to 1:320 in patients with acute drug induced liver injury. The titers of ANA, antimitochondrial antibody (AMA), and SMA were more than or equal to 1:320 in most of the patients with chronic drug induced liver injury. CONCLUSION: Liver function has no value in the diagnosis of acute or chronic drug induced liver injury. High titer autoantibodies are found in patients with chronic drug induced liver injury.

[Genetic polymorphisms of MxA protein and eIF-2a-reg2 and their responses to interferon treatment in patients with chronic hepatitis B].

OBJECTIVES: To identify the host single nucleotide polymorphisms (SNP) of myxovirus resistance A (MxA) protein and eukaryote initiation factor 2alfa regulatory region 2(eIF-2a-reg2) and to predict interferon (IFN) treatment responses in patients with chronic hepatitis B. METHODS: Two hundred sixty-two patients with chronic hepatitis B (CHB) were treated with interferon alfa (IFN ) for 12 months. Six months later the therapeutic effectiveness was evaluated. All the patients had signed a formal consent form. The patients were grouped into a sustained response (SR) group and a non-sustained response (NSR) group according to their responses to the IFNa treatment. Single nucleotide polymorphisms of the antiviral protein MxA promoter -88,-123 and protein kinase(PKR) activated eIF-2a-reg2 sites were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and were compared with the responsiveness to IFN treatment of these CHB patients. RESULTS: Among the 262 patients, 212 (80.9%) were non-sustained responders to IFNa and 50 (19.1%) were sustained responders. The rate of sustained responders with GT heterozygote at MxA promoter -88 was higher than that of the GG genotype (OR: 5.3, 95% CI: 2.46-11.43, P less than 0.01) and also higher than that of the TT genotype (OR: 4.1, 95% CI: 1.86-9.09, P less than 0.01). There were no statistically significant differences in IFN therapeutic effectiveness among the patients with different genotypes at MxA promoter -123, eIF-2a-reg2 and haplotypes made by MxA promoter -88 G/T, and -123 C/A alleles (P more than 0.05). CONCLUSION: Patients with GT genotype at MxA promoter -88 responded well to IFN treatment. SNP as a potential marker could be used to predict IFN treatment responses of patients with chronic hepatitis B.