The presence of an intrahepatic cytotoxic T lymphocyte response is associated with low viral load in patients with chronic hepatitis C virus infection

BACKGROUND/AIMS: The role of cytotoxic T lymphocytes (CTL) in limiting viral replication and producing hepatocellular injury in patients with chronic hepatitis C virus (HCV) infection is controversial. METHODS: Intrahepatic and peripheral blood HCV-specific CTL activity against the entire HCV polyprotein was assessed in 26 patients. CTL responses were assessed after effector lymphocytes were re-stimulated for 6 days in vitro using HCV-vaccinia virus-infected autologous cells expressing HCV antigens. Serum and hepatic viral loads were measured and immunohistochemistry for CD3 and CD8 was performed to localise and enumerate effector cells in liver. RESULTS: A positive CTL response was detected in 39/52 (75%) of assays conducted with intrahepatic mononuclear cells and 21/52 (40%) of peripheral blood assays (P<0.001). The presence of an intrahepatic CTL response was associated with low hepatic viral load (P=0.004). Hepatic lobular infiltration by CD8(+)T cells correlated weakly with serum alanine aminotransferase levels (r=0.42, P=0.04) and no relationship was demonstrated between CTL activity and histological evidence of liver damage. CONCLUSIONS: HCV-specific CTL activity is found more commonly in liver than in blood. An inverse relationship between CTL responses and viral load supports the hypothesis that HCV-specific CTL limit viral replication in patients with chronic HCV infection.     

Noninvasive assessment of liver fibrosis with combined serum aminotransferase/platelet ratio index and hyaluronic acid in patients with chronic hepatitis B

AIM： To construct a noninvasive assessment model consisting of routine laboratory data to predict significant fibrosis and cirrhosis in patients with chronic hepatitis B （CHB）. METHODS： A total of 137 consecutive patients with CriB who underwent percutaneous liver biopsy were retrospectively analyzed. These patients were divided into two groups according to their aminotransferase （ALT） level. The sensitivity, specificity, positive predictive value （PPV）, negative predictive value （NPV）, the likelihood ratio （LR） of aminotransferase/platelet ratio index （APRI） ≥ 1.5 or 〈 1.5 in combination with different hyaluronic acid （HA） cut-off points were calculated for the presence of moderate to severe fibrosis/cirrhosis （fibrosis stages 2 and 4） and no to mild fibrosis/cirrhosis （fibrosis stages 0 and 1）. RESULTS： The APRI correlated with fibrosis stage in CriB patients. The APRI ≥1.5 in combination with a cut-off HA cut-off point 〉 300 ng/mL could detect moderate to severe fibrosis （stages 2-4） in Crib patients. The PPV was 93.7%, the specificity was 98.9%. The APRI 〈 1.5 in combination with different HA cut-off points could not detect no to mild fibrosis in CHB patients. CONCLUSION： The APRI ≥ 1.5 in combination with a HA cut-off point 〉 300 ng/mL can detect moderate to severe fibrosis （stages 2-4） in Crib patients.     

Gastrointestinal transit time (GITT) in normal Chinese and patients

Two kinds of radiopaque pellets were ingested as markers to determine GITT in 60 normal subjects, 7 patients with ulcerative colitis (UC), 10 patients with idiopathic constipation (IC) and 8 patients with other diseases. The food contained 10-20g dietary fiber per day. Besides, GITT was determined in 14 normal subjects whose dietary content was 40-50g or 10g MO YU and 10-20g dietary fiber per day. Results are expressed in hours as 50% transit time (mean +/- s) and the values or normal subjects are as the follows: total GITT 25.0 +/- 7.3h, mouth iteum TT 9.0 +/- 3.3h, colonic TT 15.9 +/- 7.5h. There was no difference in age or sex groups. However, in high dietary fiber or MO YU group, GITT shortened significantly. Abnormal GITT was shown in patients with UC, IC, other gut and systemic diseases. In conclusion, the method employed in the present study is simple, safe and useful in the clinical study of gastrointestinal motility; and may provide important information to elucidate the pathophysiology of the diseases related to disorders in motility of the digestive tract.     

鼠疫菌Pgm因子在阿拉善黄鼠体内的突变试验观察

用阿拉善黄鼠(Citellus alsachanicus)鼠疫疫源地的鼠疫菌Pgm~+和Pgm~-株,连续通过阿拉善黄鼠进行传代试验。在传代前后用阿拉善黄鼠测其毒力。Pgm~+株连续传代15代后未发现突变,其主要生化特性、抗原结构和毒力都没有发生改变。而含有0.1～0.3％Pgm~+鼠疫菌个体的Pgm~-株在连续传代5代后即突变为Pgm~+株,且毒力增强。但生化特性和抗原结构仍无改变。纯系Pgm~-株在连续传代8～11代后可突变为Pgm~+株,至20代仍未完全突变为Pgm~+,其他生化特性和抗原结构亦没有改变,但其毒力逐渐增强。作者分析鼠疫菌Pgm细胞突变与阿拉善黄鼠动物鼠疫流行和间歇有密切关系,这对研究该疫源地内鼠疫菌的保存机制及流行病学分析提供了参考资料。     

Immune evasion in HPV− head and neck precancer–cancer transition is driven by an aneuploid switch involving chromosome 9p loss

An aneuploid-immune paradox encompasses somatic copy-number alterations (SCNAs), unleashing a cytotoxic response in experimental precancer systems, while conversely being associated with immune suppression and cytotoxic-cell depletion in human tumors, especially head and neck cancer (HNSC). We present evidence from patient samples and cell lines that alterations in chromosome dosage contribute to an immune hot-to-cold switch during human papillomavirus-negative (HPV⁻) head and neck tumorigenesis. Overall SCNA (aneuploidy) level was associated with increased CD3⁺ and CD8⁺ T cell microenvironments in precancer (mostly CD3⁺, linked to trisomy and aneuploidy), but with T cell-deficient tumors. Early lesions with 9p21.3 loss were associated with depletion of cytotoxic T cell infiltration in TP53 mutant tumors; and with aneuploidy were associated with increased NK-cell infiltration. The strongest driver of cytotoxic T cell and Immune Score depletion in oral cancer was 9p-arm level loss, promoting profound decreases of pivotal IFN-γ-related chemokines (e.g., CXCL9) and pathway genes. Chromosome 9p21.3 deletion contributed mainly to cell-intrinsic senescence suppression, but deletion of the entire arm was necessary to diminish levels of cytokine, JAK-STAT, and Hallmark NF-κB pathways. Finally, 9p arm-level loss and JAK2-PD-L1 codeletion (at 9p24) were predictive markers of poor survival in recurrent HPV⁻ HNSC after anti–PD-1 therapy; likely amplified by independent aneuploidy-induced immune-cold microenvironments observed here. We hypothesize that 9p21.3 arm-loss expansion and epistatic interactions allow oral precancer cells to acquire properties to overcome a proimmunogenic aneuploid checkpoint, transform and invade. These findings enable distinct HNSC interception and precision-therapeutic approaches, concepts that may apply to other CN-driven neoplastic, immune or aneuploid diseases, and immunotherapies.

The genetic bases for predisposition, and neoplastic transformation, to cancer have been increasingly well described. However, it remains less clear how early, precancer cells employ these genetic alterations to acquire the characteristic features and properties (1) of malignant disease. For example, studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent, metastatic head and neck squamous cell carcinoma (HNSC) therapy (2–4). This underscores the importance of immune modulation in these tumors, despite a still suboptimal overall response rate of less than 20% in advanced cancers. Immune response within tumors has been observed to be strongest at the earliest neoplastic stages, as reported recently in lung adenocarcinoma precursors (5). As such, new, immune-based strategies could be developed to reduce the high global burden of HNSC, by intercepting the most common precursor of the most common HNSC presentation: HPV⁻ oral squamous cell carcinomas (6–8).Studies of chromosome somatic copy-number (CN) alteration (SCNA) profiles have reported the impact of 3p14, 9p21, or 17p13 loss in molecular models of HNSC progression (9) and risk (10–15). Early studies reported that patients with oral precancers harboring 9p21 and/or 3p14 loss were at significantly greater cancer risk than those with retention at these loci (10, 16). A comprehensive, prospective validation study examined the relative contribution of six candidate chromosome-arm regions. 9p21 loss had the greatest influence on cancer risk (13). The mechanism underlying the association between CN and malignant transformation of precancers, however, is unclear (17–20). Studies of CN-altered neoplastic cells have shown that SCNAs can trigger a cytotoxic response in experimental precancer systems (21, 22) but, paradoxically, were associated with immune evasion (23) and suppression (24) in computational studies of naturally occurring human cancers. The latter, in melanoma, found that nonresponders to PD-1 and CTLA-4 blockade had higher CN alteration and loss burdens, which correlated with immunologically cold tumors, characterized by cytotoxic-cell, marker, and metric reductions, and suppressive microenvironment cell, network, and signal increases (23–26). This SCNA-cold association was particularly strong in our previous, pan-The Cancer Genome Atlas (TCGA) computational study in HNSC (23). These data point to a putative in vivo switch from immune hot-to-cold in the precancer–cancer transition, and raise the hypothesis that SCNAs in precursor lesions contribute to malignant transformation through genomic events and mechanisms that enable the acquisition of immune-suppressive, evasive properties. To test this hypothesis, we evaluated CN influence on immune profiles and outcomes in a large prospective oral precancer patient cohort, and HPV⁻ HNSC (tissue specimens and cell lines) and anti–PD-1–treated recurrent-disease cohorts.     

心血管病高危与非高危人群的生存质量比较:倾向评分匹配分析

目的探究心血管病高危与非高危人群生存质量差异。方法采用2015-2017年国家心血管病高危人群早期筛查与综合干预项目江苏省项目点调查数据,对调查对象进行问卷调查和体格检查,运用倾向评分匹配分析(PSM)方法,按照1∶1匹配心血管病高危组与非高危组间性别和年龄,采用多重线性回归模型分析心血管病高危对生存质量[欧洲五维度健康量表(EQ-5D)]得分及其中的直观相似尺度(EQ-VAS)评分的影响。结果调查对象40 243(高危组20 839,非高危组19 404)人,倾向评分匹配后得到调查对象31 605(高危组15 948,非高危组15 657)人,EQ-5D指数得分0.97±0.07,EQ-VAS评分79.83±9.36,高危组行动能力、自理能力、日常生活能力和疼痛/不适报告有困难率高于非高危组(1.9%比1.0%、0.6%比0.3%、1.5%比0.8%、16.8%比15.7%,均P<0.05);高危组与非高危组焦虑/不适报告有困难率差异无统计学意义(4.5%比4.4%,P=0.785);女性、高龄、不在婚、初中及以下学历、不吸烟、不饮酒、肥胖、患有高血压、患有血脂异常的调查对象EQ-5D指数得分和EQ-VAS评分低于不在此状态或不患有此疾病人群(P<0.05),家庭年收入≤5万元、患有糖尿病的调查对象EQ-VAS评分低于不在此状态或不患有此疾病人群(P<0.001);多因素线性回归分析显示,调整基本情况和主要慢性病情况后,高危组EQ-VAS评分降低(β=-0.054, 95 CI-1.264^-0.766,P<0.001)。结论高危组人群的EQ-VAS评分低,应关注心血管病高危人群的生存质量。     

Impact of follow-up visits on disease outcome in Chinese systemic lupus erythematosus

The objective of this study is to determine whether the frequency of visits would affect disease activity and disease damage in patients with systemic lupus erythematosus (SLE). We recruited 147 patients who met the 1997 American College of Rheumatology (ACR) criteria for SLE. Patients were divided into three groups based on follow-up frequency: ≤ 6 visits/year (group 1), 6–12 visits/year (group 2), and > 12 visits/year (group 3). Disease activity and organ damage were evaluated using the SLE disease activity index (SLEDAI) and Systemic Lupus International Collaborative Clinics (SLICC)/ACR criteria, respectively. Data on disease features, patient characteristics, and treatment were retrospectively reviewed. We found that the SLICC score was significantly lower in patients with > 12 visits/year (P = 0.008), while the SLEDAI score showed no significant difference. The age at symptom onset (32.68 ± 13.53) and the age at SLE diagnosis (33.32 ± 13.81) in group 3 were significantly older than those in the other two groups. In univariate regression analysis, the frequency of visits, the age at symptom onset, and the age at SLE diagnosis were found to be associated with the SLICC scores. Visit frequency has no impact on SLE disease activity, but may be associated with less disease damage, an important outcome.     

Melatonin suppresses NO-induced apoptosis via induction of Bcl-2 expression in PGT-beta immortalized pineal cells

In the present study, we investigated whether melatonin would prevent nitric oxide (NO)-induced apoptotic death of PGT-beta immortalized pineal cells. To examine the protective effect of melatonin, cytotoxicity assay, DNA fragmentation analysis, caspase-3 activity assay, and Western blotting for caspase-3 and poly(ADP-ribose) polymerase (PARP) were performed. Treatment of cells with S-nitroso-N-acetylpenicillamine (SNAP), an NO donor, was shown to induce apoptotic cell death in a dose-dependent manner, and pretreatment with melatonin (0.1 mm) attenuated the occurrence of NO-induced apoptotic cell death. DNA fragmentation in response to NO was also arrested by melatonin. Caspase-3 activity induced by NO was decreased with melatonin treatment. Furthermore, the active fragments of caspase-3 and PARP were almost completely absent following exposure to melatonin. To elucidate the protective mechanisms of action of melatonin, Western blot analyses for Bcl-2 expression and cytochrome c release were carried out. Pretreatment with melatonin (0.1 mm) induced the expression of Bcl-2 and suppressed the release of cytochrome c into the cytosol, thereby arresting NO-induced apoptotic cell death. These results suggest that the antiapoptotic effect of melatonin is associated with induction of Bcl-2 expression in PGT-beta cells, which in turn blocks caspase-3 activation and inhibits cytochrome c release into the cytosol.     

Relationship between insulin resistance and serum alanine aminotransferase as a surrogate of NAFLD (nonalcoholic fatty liver disease) in obese Korean children

There has been increasing number of obese children who accompany obesity-related comorbidities. It has been known that nonalcoholic fatty liver disease (NAFLD) as one of obesity-related comorbidities is related with insulin resistance. So, we investigated the relation between insulin resistance and NAFLD, using serum alanine aminotransferase (ALT) as a surrogate of NAFLD among obese children in Korea. The study subjects were 909 obese children aged 9–12 years (boys 613, girls 296). Body mass index (BMI), waist circumference (WC), blood pressure, fasting blood glucose, fasting insulin, lipid profile were measured. ALT, liver enzyme was used as a surrogate of NAFLD and homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index of insulin resistance. The prevalence of elevated serum ALT (≥40 mg/dl) was 33.4% in boys, and 19.6% in girls respectively. In boys, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, HDL-cholesterol, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (≥40 mg/dl) was 1.061 (95% confidence interval, 1.020–1.103, P = 0.003). In girls, ALT was correlated with BMI, waist circumference, total cholesterol, triglyceride, glucose, systolic and diastolic blood pressure, HOMA-IR, fasting serum insulin. Odds ratio for HOMA-IR against the elevated ALT (≥40 mg/dl) was 1.042 (95% confidence interval, 0.998–1.088, P = 0.063). Among obese Korean children, insulin resistance and ALT, lipid profile, BMI, WC, blood pressure showed significant correlation. Especially, in boys, higher ALT is founded to be independently associated with insulin resistance.