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Liver metastases are commonly detected in the advanced stages of various malignant tumors, representing a significant clinical challenge. Throughout the process of liver metastases formation, immune cells play a pivotal role, particularly in the pre-metastatic and metastatic niches within the liver. Immune cells establish extensive and intricate interactions with tumor cells and other components in the liver, collectively promoting and sustaining the growth of liver metastases. Despite the limited efficacy of existing therapeutic modalities against some advanced liver metastases, novel immune-based treatment approaches are continuously being explored and validated. Building on the systematic elucidation of the immunosuppressive characteristics of liver metastases, we explored the potential of novel immunotherapies applicable to patients with liver metastases from multiple dimensions., Competing Interests: Declarations Ethical approval Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Background: Targeting CD47/SIRPα axis has emerged as a promising strategy in cancer immunotherapy. Despite the encouraging clinical efficacy observed in hematologic malignancies through CD47-SIRPα blockade, there are safety concerns related to the binding of anti-CD47 antibodies to CD47 on the membrane of peripheral blood cells., Methods: In order to enhance the selectivity and therapeutic efficacy of the antibody, we developed a humanized anti-CD47 monoclonal antibody called Gentulizumab (GenSci059). The binding capacity of GenSci059 to CD47 was evaluated using flow cytometry and surface plasmon resonance (SPR) methods, the inhibitory effect of GenSci059 on the CD47-SIRPα interaction was evaluated through competitive ELISA assays. The anti-tumor activity of GenSci059 was assessed using in vitro macrophage models and in vivo patient-derived xenograft (PDX) models. To evaluate the safety profile of GenSci059, binding assays were conducted using blood cells. Additionally, we investigated the underlying mechanisms contributing to the weaker binding of GenSci059 to erythrocytes. Finally, toxicity studies were performed in non-human primates to assess the potential risks associated with GenSci059., Results: GenSci059 displayed strong binding to CD47 in both human and monkey, and effectively inhibited the CD47-SIRPα interaction. With doses ranging from 5 to 20 mg/kg, GenSci059 demonstrated potent inhibition of the growth of subcutaneous tumor with the inhibition rates ranged from 30.3% to complete regression. Combination of GenSci059 with 2.5 mg/kg Rituximab at a dose of 2.5 mg/kg showed enhanced tumor inhibition compared to monotherapy, exhibiting synergistic effects. GenSci059 exhibited minimal binding to hRBCs compared to Hu5F9-G4. The binding of GenSci059 to CD47 depended on the cyclization of N-terminal pyroglutamic acid and the spatial conformation of CD47, but was not affected by its glycosylation modifications. A maximum tolerated dose (MTD) of 450 mg/kg was observed for GenSci059, and no significant adverse effects were observed in repeated dosages up to 10 + 300 mg/kg, indicating a favorable safety profile., Conclusion: GenSci059 selectively binds to CD47, effectively blocks the CD47/SIRPα axis signaling pathway and enhances the phagocytosis effects of macrophages toward tumor cells. This monoclonal antibody demonstrates potent antitumor activity and exhibits a favorable safety profile, positioning it as a promising and effective therapeutic option for cancer., (© 2024. The Author(s).)

Backgrounds: Remarkable interindividual variability in clopidogrel response is observed, genetic polymorphisms in P2RY12 and its signal pathway is supposed to affect clopidogrel response in CHD patients., Methods: 539 CHD patients treated with clopidogrel were recruited. The platelet reaction index (PRI) indicated by VASP-P level were detected in 12-24 h after clopidogrel loading dose or within 5-7 days after initiation of maintain dose clopidogrel. A total of 13 SNPs in relevant genes were genotyped in sample A (239 CHD patients). The SNPs which have significant differences in PRI will be validated in another sample (sample B, 300 CHD patients)., Results: CYP2C19*2 increased the risk of clopidogrel resistance significantly. When CYP2C19*2 and CYP2C19*3 were considered, CYP2C19 loss of function (LOF) alleles were associated with more obviously increased the risk of clopidogrel resistance; P2RY12 rs6809699C > A polymorphism was also associated with increased risk of clopidogrel resistance (AA vs CC: P = 0.0398). This difference still existed after stratification by CYP2C19 genotypes. It was also validated in sample B. The association was also still significant even in the case of stratification by CYP2C19 genotypes in all patients (sample A + B)., Conclusion: Our data suggest that P2RY12 rs6809699 is associated with clopidogrel resistance in CHD patients. Meanwhile, the rs6809699 AA genotype can increase on-treatment platelet activity independent of CYP2C19 LOF polymorphisms., (© 2022. The Author(s).)

Background: Hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) is heterogeneous and frequently contains multifocal tumors, but how the multifocal tumors relate to each other in terms of HBV integration and other genomic patterns is not clear., Methods: To interrogate heterogeneity of HBV-HCC, we developed a HBV genome enriched single cell sequencing (HGE-scSeq) procedure and a computational method to identify HBV integration sites and infer DNA copy number variations (CNVs)., Results: We performed HGE-scSeq on 269 cells from four tumor sites and two tumor thrombi of a HBV-HCC patient. HBV integrations were identified in 142 out of 269 (53%) cells sequenced, and were enriched in two HBV integration hotspots chr1:34,397,059 (CSMD2) and chr8:118,557,327 (MED30/EXT1). There were also 162 rare integration sites. HBV integration sites were enriched in DNA fragile sites and sequences around HBV integration sites were enriched for microhomologous sequences between human and HBV genomes. CNVs were inferred for each individual cell and cells were grouped into four clonal groups based on their CNVs. Cells in different clonal groups had different degrees of HBV integration heterogeneity. All of 269 cells carried chromosome 1q amplification, a recurrent feature of HCC tumors, suggesting that 1q amplification occurred before HBV integration events in this case study. Further, we performed simulation studies to demonstrate that the sequential events (HBV infecting transformed cells) could result in the observed phenotype with biologically reasonable parameters., Conclusion: Our HGE-scSeq data reveals high heterogeneity of HCC tumor cells in terms of both HBV integrations and CNVs. There were two HBV integration hotspots across cells, and cells from multiple tumor sites shared some HBV integration and CNV patterns., (© 2022. The Author(s).)

Background: Ingestion of fish bones leading to gastric perforation and inducing abscess formation in the caudate lobe of the liver is very rare., Case Presentation: A 67-year-old man presented to our hospital with a 2-day history of subxiphoid pain. There were no specific symptoms other than pain. Laboratory tests showed only an increase in the number and percentage of neutrophils. Contrast-enhanced Computerized tomography (CT) of the abdomen showed two linear dense opacities in the gastric cardia, one of which penetrated the stomach and was adjacent to the caudate lobe of the liver, with inflammatory changes in the caudate lobe. We finally diagnosed his condition as a caudate lobe abscess secondary to intestinal perforation caused by a fishbone based on the history and imaging findings. The patient underwent 3D laparoscopic partial caudate lobectomy, incision and drainage of the liver abscess, and fishbone removal. The procedure was successful and we removed the fishbone from the liver. The patient was discharged on the 9th postoperative day without other complications., Conclusions: Liver abscess caused by foreign bodies requires multidisciplinary treatment. Especially when located in the caudate lobe, we must detect and remove the cause of the abscess as early as possible. Foreign bodies that perforate the gastrointestinal tract can penetrate to the liver and cause abscess formation, as in this case. When exploring the etiology of liver abscesses, we should investigate the general condition, including the whole gastrointestinal tract., (© 2022. The Author(s).)

Background: Pancreatic resections are complex and technically challenging surgical procedures. They often come with potential limitations to high-volume centers. Distal pancreatectomy is a relatively simple procedure in most cases. It facilitates the development of up-to-date minimally invasive surgical procedures in pancreatic surgery including laparoscopic distal pancreatectomy and robot-assisted distal pancreatectomy., Main Body: To obtain a desirable long-term prognosis, R0 resection and adequate lymphadenectomy are crucial to the surgical management of pancreatic cancer, and they demand standard procedure and multi-visceral resection if necessary. With respect to combined organ resection, progress has been made in evaluating and determining when and how to preserve the spleen. The postoperative pancreatic fistula, however, remains the most significant complication of distal pancreatectomy, with a rather high incidence. In addition, a safe closure of the pancreatic remnant persists as an area of concern. Therefore, much efforts that focus on the management of the pancreatic stump have been made to mitigate morbidity., Conclusion: This review summarized the historical development of the techniques for pancreatic resections in recent years and describes the progress. The review eventually looked into the controversies regarding distal pancreatectomy for tumors in the body and tail of the pancreas.

Background: In China, ethnic minorities often live in frontier areas and have a relatively small population size, and tremendous social transitions have enlarged the gap between eastern and western China, with western China being home to 44 ethnic minority groups. These three disadvantages have health impacts. Examining ethnicity and health inequality in the context of western China is therefore essential., Methods: This paper is based on data from the 2010 China Survey of Social Change (CSSC2010), which was conducted in 12 provinces, autonomous regions and province-level municipalities in western China and had a sample size of 10,819. We examined self-rated health and disparities in self-rated health between ethnic minorities and Han Chinese in the context of western China. Self-rated health was coded as poor or good, and ethnicity was coded as ethnic minority or Han Chinese. Ethnic differences in self-rated health was examined by using binary logistic regression. Associations among sociodemographic variables, SES variable, health behaviour variable, health problem variables and self-rated health were also explored., Results: Fourteen percent of respondents reported their health to be poor. A total of 15.75% of ethnic minorities and 13.43% of Han Chinese respondents reported their health to be poor, indicating a difference in self-rated health between ethnic minorities and Han Chinese. Age, gender, marital status, education, alcohol, and health problems were the main factors that affected differences in self-rated health., Conclusion: In western China, there were obvious ethnic disparities in self-rated health. Elderly ethnic minorities, non-partnered ethnic minorities, ethnic minorities with an educational level lower than middle school, and ethnic minorities with chronic disease had higher odds of poor self-rated health.

In the original publication of this article [1], Fig. 6 is wrong and the updated figure is shown below.

Background: The value of magnetic resonance imaging (MRI), contrast-enhanced ultrasound (CEUS), and the combination of CEUS and MRI (CCWM) for the diagnosis of periampullary space-occupying lesions (PSOL) was investigated., Methods: A total of 102 patients diagnosed with PSOLs by surgery or biopsy were recruited retrospectively. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of MRI, CEUS, and CCWM were analyzed., Results: MRI, CEUS, and CCWM allowed for the accurate detection of 91.17, 92.15, and 99.01% of PSOLs, respectively. The specificity, PPV, and accuracy of CCWM were significantly different from MRI and CEUS (p < 0.05). However, there the sensitivity and NPV were not significantly different among the three diagnostic technologies. In addition, the specificity, PPV, and accuracy were not significantly different between MRI and CEUS (all p > 0.05)., Conclusions: CCWM is valuable for differentiating benign and malignant PSOL, which provides important guiding significances for the clinic.

Background: The influence of DNMT3A R882 mutations on adult acute myeloid leukemia (AML) prognosis is still controversial presently. The influence of R882 allele ratio on drug response and prognosis of AML is unknown yet. Besides, it is obscure whether anthracyclines are involved in chemoresistance resulted from R882 mutations., Methods: DNMT3A R882 mutations in 870 adult AML patients receiving standard induction therapy were detected by pyrosequencing. Associations of the mutants with responses to induction therapy and disease prognosis were analyzed., Results: DNMT3A R882 mutations were detected in 74 (8.51%) patients and allele ratio of the mutations ranged from 6 to 50% in the cohort. After the first and second courses of induction therapy including aclarubicin, complete remission rates were significantly lower in carriers of the DNMT3A R882 mutants as compared with R882 wildtype patients (P = 0.022 and P = 0.038, respectively). Compared with R882 wild-type patients, those with the R882 mutations showed significantly shorter overall survival (OS) and disease-free survival (DFS) (P = 1.92 × 10 -4 and P = 0.004, respectively). Patients with higher allele ratio of R882 mutations showed a significantly shorter OS as compared with the lower allele ratio group (P = 0.035)., Conclusion: Our results indicate that the impact of DNMT3A R882 mutations on AML prognosis was determined by the mutant-allele ratio and higher allele ratio could predict a worse prognosis, which might improve AML risk stratification. In addition, DNMT3A R882 mutations were associated with an inferior response to induction therapy with aclarubicin in Chinese AML patients.

Background: Gliomas are the most common primary tumors in central nervous system. Despite advances in diagnosis and therapy, the prognosis of glioma remains gloomy. Autophagy is a cellular catabolic process that degrades proteins and damaged organelles, which is implicated in tumorigenesis and tumor progression. Autophagy related 4C cysteine peptidase (ATG4C) is an autophagy regulator responsible for cleaving of pro-LC3 and delipidation of LC3 II. This study was designed to investigate the role of ATG4C in glioma progression and temozolomide (TMZ) chemosensitivity., Methods: The association between ATG4C mRNA expression and prognosis of gliomas patients was analyzed using the TCGA datasets. The role of ATG4C in proliferation, apoptosis, autophagy, and TMZ chemosensitivity were investigated by silencing ATG4C in vivo. Ectopic xenograft nude mice model was established to investigate the effects of ATG4C on glioma growth in vivo., Results: The median overall survival (OS) time of patients with higher ATG4C expression was significantly reduced (HR: 1.48, p = 9.91 × 10 - 7 ). ATG4C mRNA expression was evidently increased with the rising of glioma grade (p = 2.97 × 10 - 8 ). Knockdown ATG4C suppressed glioma cells proliferation by inducing cell cycle arrest at G1 phase. ATG4C depletion suppressed autophagy and triggered apoptosis through ROS accumulation. Depletion of ATG4C suppressed TMZ-activated autophagy and promoted sensitivity of glioma cells to TMZ. Additionally, ATG4C knockdown suppressed the growth of glioma remarkably in nude mice., Conclusion: ATG4C is a potential prognostic predictor for glioma patient. Targeting ATG4C may provide promising therapy strategies for gliomas treatment.

Background & Aims: Although the prognosis of patients with occult hepatitis B virus (HBV) infection (OBI) is usually benign, a small portion may undergo cirrhosis and subsequently hepatocellular carcinoma (HCC). We studied the mechanism of life-long Integration of virus DNA into OBI host's genome, of which may induce hepatocyte transformation., Methods: We applied HBV capture sequencing on single cells from an OBI patient who, developed multiple HCC tumors and underwent liver resection in May 2013 at Tongji Hospital in China. Despite with the undetectable virus DNA in serum, we determined the pattern of viral integration in tumor cells and adjacent non-tumor cells and obtained the details of the viral arrangement in host genome, and furthermore the HBV integrated region in cancer genome., Results: HBV captured sequencing of tissues and individual cells revealed that samples from multiple tumors shared two viral integration sites that could affect three host genes, including CSMD2 on chr1 and MED30/EXT1 on chr8. Whole genome sequencing further indicated one hybrid chromosome formed by HBV integrations between chr1 and chr8 that was shared by multiple tumors. Additional 50 poorly differentiated liver tumors and the paired adjacent non-tumors were evaluated and functional studies suggested up-regulated EXT1 expression promoted HCC growth. We further observed that the most somatic mutations within the tumor cell genome were common among the multiple tumors, suggesting that HBV associated, multifocal HCC is monoclonal in origin., Conclusion: Through analyzing the HBV integration sites in multifocal HCC, our data suggested that the tumor cells were monoclonal in origin and formed in the absence of active viral replication, whereas the affected host genes may subsequently contribute to carcinogenesis.

Background: Previous studies reported that low level of oestradiol (E2) was associated with higher risk of cardiovascular disease (CVD). However, little study examined the relationship between E2 and CVD in longevous women, which were deficient in serum E2 for the post-menopausal status. Therefore, this study aims to explore the association between E2 and CVD risk factors in a group of female centenarians of Hainan, China., Methods: A total of 413 female centenarians (aged from 100 to 115) from China Hainan Centenarian Cohort Study (CHCCS) were enrolled in this study. Home interviews were conducted to collected data on demographic characteristics, health-related lifestyles, and anthropometrics. The level of serum E2 was assessed in the Clinical Laboratory of Hainan branch of PLA General Hospital. The variables of CVD risk factors, including blood pressures, lipids and blood glucose, were measured through standard procedures., Results: Significant negative correlations between levels of serum E2 and TC, HDL-C, and LDL-C were observed in this study. Compared with the highest group of E2, the odds ratio and 95% confidence intervals of high LDL-C in groups 3, 2 and 1 were OR1.94 (CI0.82-4.62), OR3.61 (CI1.27-10.25) and OR9.29 (CI2.08-41.53), respectively. Similarly, the prevalence of hypertension was decreased with the increase of serum E2. The odds ratio and 95% confidence intervals of stage-2 hypertension in groups 3, 2 and 1 versus highest E2 group were OR1.34 (CI0.49-3.72), OR1.36 (CI0.47-3.99) and OR1.38 (CI0.45-4.20), respectively., Conclusions: This study examined the relationship between E2 and CVD risk factors in a group of community-based female centenarians. A negative correlations between serum E2 levels and CVD risk factors, i.e. high level of LDL-C, TC, and hypertension were observed in this population. Besides, the level of serum E2 is also negatively correlated with HDL-C. Further studies on the correlation between serum E2 and CVD risk factors, especially dyslipidemia, in longevous and post-menopausal women are warranted.

Background: Posterior transfacet approach has been proved to be a safe and effective access to treat thoracic disc herniation. However, the therapeutic effect and safety of modified transfacet approach for treating thoracic spinal tuberculosis (TST) has not been reported in the clinical literature. In this study, the clinical efficacy and safety of a single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion for treating TST were retrospectively evaluated., Patients and Methods: From 2009 to 2014, 37 patients with TST underwent a posterior modified transfacet debridement, interbody fusion following posterior instrumentation, under the cover of 18 months of antituberculosis chemotherapy. The patients were evaluated preoperatively and postoperatively in terms of Frankel Grade, visual analog scale (VAS) pain score, kyphotic Cobb angle, and bony fusion., Results: The follow-up time was 39.8 ± 5.1 months (29-50 months). No postoperative complication or recurrence of spinal tuberculosis was observed. Definitive bony fusion was achieved in all patients. At the final follow-up, 2 cases were rated as Frankel grade D, 35 as grade E. VAS was recovered from 8.4 ± 1.0 cm to 0.4 ± 0.8 cm. The kyphotic angles were corrected from 29.4 ± 10.9° to 17.6 ± 6.3°. Using the Kirkaldy-Willis criteria, functional outcome was excellent in 29 patients, good in 7, and fair in 1., Conclusions: Our preliminary results showed that single-stage posterior modified transfacet debridement, posterior instrumentation, and interbody fusion are effective and safe surgical options for treating TST.

Background: Synchronous primary cancers in gallbladder and liver are rarely reported. Here we report an unusual case of synchronous cancers of gallbladder carcinoma and combined hepatocellular cholangiocarcinoma., Case Presentation: Several lesions in the gallbladder and in adjacent parenchyma of liver were discovered in a 65-years-old woman by imaging examination. Surgical resection was performed following a diagnosis of primary gallbladder carcinoma with local hepatic metastasis. Histological examination confirmed the diagnosis of primary gallbladder carcinoma, and the lesions in the liver consisted of hepatocellular carcinoma simultaneously with cholangiocarcinoma. Adjuvant chemoradiation therapy was not performed due to the patient's refusal of the treatment. Unfortunately, the patient died of widespread metastasis 8 months after the operation., Conclusions: The disease needed to be differentially diagnosed from gallbladder carcinoma with hepatic metastasis. Aggressive surgical approach should be based on a balance between the risk of surgery (morbidity and mortality) and the outcome.

Background: This study explored the effect of liver resection on perioperative circulating tumor cells (CTCs) and found that the prognostic significance of surgery was associated with changes in CTC counts in patients with hepatocellular carcinoma (HCC)., Methods: One hundred thirty-nine patients with HCC were consecutively enrolled. The time-points for collecting blood were one day before operation and three days after operation. CTCs in the peripheral blood were detected by the CellSearch™ System., Results: Both CTC detection incidence and mean CTC counts showed greater increases postoperatively (54%, mean 1.54 cells) than preoperatively (43%, mean 1.13 cells). The postoperative CTC counts increased in 41.7% of patients, decreased in 25.2% of patients and did not change in 33.1% of patients. The increase in postoperative CTC counts was significantly associated with the macroscopic tumor thrombus status. Patients with increased postoperative CTC counts (from preoperative CTC < 2 to postoperative CTC ≥ 2) had significantly shorter disease-free survival (DFS) and overall survival (OS) than did patients with persistent CTC < 2. Patients with persistent CTC levels of ≥2 had the worst prognoses., Conclusions: Surgical liver resection is associated with an increase in CTC counts, and increased postoperative CTC numbers are associated with a worse prognosis in patients with HCC.

Backgrounds: UDP-glucuronosyltransferase 1A subfamily (UGT1A) enzymes can inactivate cytarabine (Ara-C) by glucuronidation, and thus serves as candidate genes for interindividual difference in Ara-C response. UGT1A1 is a major UGT1A isoform expressed in human liver., Methods: UGT1A1*6 and *28 polymorphisms resulting in reduced UGT1A1 activity were genotyped in 726 adult acute myeloid leukemia (AML) patients treated with Ara-C based regimens. Influences of both polymorphisms on chemosensitivity and disease prognosis of the patients were evaluated., Results: After one or two courses of Ara-C based induction chemotherapy, the complete remission (CR) rate was significantly higher in patients carrying the UGT1A1*6 (77.0%) or the UGT1A1*28 (76.4%) alleles as compared with corresponding wild-type homozygotes (66.9 and 68.5%, respectively). Carriers of the UGT1A1*6 or *28 alleles showed significantly decreased risk of non-CR (OR = 0.528, 95% CI 0.379-0.737, P = 1.7 × 10 -4 ) and better overall survival (HR = 0.787, 95% CI 0.627-0.990, P = 0.040) as compared with homozygotes for both polymorphisms., Conclusion: Our results suggest that UGT1A1*28 and UGT1A1*6 are associated with improved clinical outcomes in Chinese AML patients treated with Ara-C.

Background: Centenarians refer to a special group who have outlived most of their fellows. Body shape and abdominal obesity have been identified as cardiovascular disease (CVD) risk factors. Our study aimed to evaluate the relationship between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) and CVD risk factors among male and female centenarians in Hainan province., Methods: Five hundred thirty-seven centenarians aged between 100 and 115 (Mage = 107 years old) years participated in this study. Each participant received a standardized questionnaire and physical examination. We measured anthropometric variables (BMI, WC, WHR, WHtR, SBP and DBP) and serum lipid (TC, TG, HDL-C and LDL-C)., Results: 76.9% (n = 413) of the study subjects were female. TC, TG, LDL-C and HDL-C were significantly higher in female group than that of male group. BMI, WC and WHtR were well-correlated with the CVD risk factors. The anthropometric measures were negatively related with HDL-C levels and positively related with the other CVD risk factors., Conclusions: Hainan centenarians were short in stature and underweight. Moreover, female centenarians were often pear-shaped, while male centenarians were often apple-shaped. Further, BMI, WC and WHtR were well-correlated with the serum lipid, and TC, TG, LDL-C and HDL-C were significantly higher in females than males. Also, BMI, WC and WHtR were closely related to the incidence of dyslipidemia in females, including high TG, high LDL-C and low HDL-C.

Background: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara-CTP., Methods: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed., Results: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients., Conclusion: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China.

Background: Erythropoietin (EPO) is a hypoxia-inducible stimulator of erythropoiesis. Besides its traditional application in anemia therapy, it offers an effective treatment in the cancer patients, especially those who receive chemotherapy. Several reports indicated that it could promote the tumor cell proliferation through its specific receptor (EPOR). Unfortunately, the role of EPO/EPOR in hepatocellular carcinoma (HCC) progressing is still uncertain., Methods: Protein in tumor tissue from HCC patients or H22 tumor-bearing mice was detected with immunohistochemistry. Cells were cultured under 1% oxygen to establish hypoxia. RT-PCR and western blotting were used to measure mRNA and protein of EPO/EPOR, respectively. MTT, flow cytometry and PCNA staining were used to detect cell proliferation. Immunofluorescence staining was applied to study the expression and location of cellular EPOR. The EPOR binding studies were performed with 125 I-EPO radiolabeling assay., Results: EPO and EPOR protein were up-regulated in HCC tissue of patients and H22-bearing mice. These were positively correlated with hypoxia-inducible factor -1 α and ki-67. Hypoxia up-regulated the expression of EPO and EPOR in HepG2 cells. It also induced the proliferation and increased the percentage of divided cells after 24, 48 and 72 h treatment. These were inhibited in cells pre-treated with 0.5 μg/mL soluble-EPOR. Immunofluorescence staining presented that EPOR was obviously translocated from nucleus to cytoplasm and membrane under hypoxia. EPOR binding activity was also increased after exposure to hypoxia. Recombinant human erythropoietin obviously elevated cell proliferation rate and the percentage of divided under hypoxia but not normoxia, which were also inhibited by soluble-EPOR., Conclusions: Our result indicated for the first time that EPO promoted the proliferation of HCC cells through hypoxia induced translocation of it specific receptor. Trial registration TJC20141113, retrospectively registered.

Background: Coagulase-negative staphylococci (CoNS) are recognized as a large reservoir of staphylococcal cassette chromosome mec (SCCmec) harboured by Staphylococcus aureus. However, data of SCCmec in CoNS are relatively absent particularly in China., Methods: Seventy-eight CoNS clinical and 47 community isolates were collected in Beijing. PCR was performed to classify SCCmec types. Under oxacillin treatment, quantitative real-time reverse transcription PCR (qRT-PCR) was performed to compare mecA mRNA levels and mRNA half-life between isolates with single SCCmec element and those with multiple one. Their growth curves were analysed. Their bacterial cell wall integrity was also compared by performing a Gram stain. All ccr complex segments were sequenced and obtained ccr segments were analysed by phylogenetic analyses., Results: All 78 clinical isolates had mecA segments compared with 38% in community isolates (total 47). Only 29% clinical isolates and 33% community isolates (among mecA positive isolates) harboured a single previously identified SCCmec type; notably, 17% clinical isolates and 28% community isolates had multiple SCCmec types. Further studies indicated that isolates with multiple SCCmec elements had more stable mecA mRNA expression compared with isolates with single SCCmec elements. CoNS with multiple SCCmec elements demonstrated superior cell wall integrity. Interestingly, phylogenetic analyses of obtained 70 ccr segments indicated that horizontal gene transfer of the ccr complex might exist among various species of clinical CoNS, community CoNS and S. aureus., Conclusions: CoNS recovered from patients carried extremely diverse but distinctive SCCmec elements compared with isolates from the community. More attention should be given to CoNS with multiple SCCmec not only because they had superior cell wall integrity, but also because CoNS and S. aureus might acquire multiple SCCmec through the ccr complex.

Recently, studies on the extent to which spaceflight affects the psychology of individuals has received attention. In order to reveal the mental challenges that humans face in space, we need practical viewpoints to integrate the psychological effects, behavior, performance and the environment itself for space exploration. The present review discusses the individual variables related to space psychology and manned spaceflight, in addition to their growing trends. These items include patterns of emotional changes in extreme environments and the approaches to evaluating emotions. Moreover, the review concludes with suggested future research on emotion during spaceflight and its analogs. These data and information are needed to plan for the exploration of the Moon and Mars, along with contributions to the construction of the international space station (ISS) and astronaut training.

Background: It has been well accepted that glycans present in schistosomes are highly antigenic. However, it is not clear what kind of worm glycans can affect the infected host to mount IgG responses and whether mounted anti-glycan IgG responses are protective., Methods: The contribution of antigenicity by glycans was measured by using competitive ELISA assay in sera from infected mice and humans. Monoclonal antibodies towards soluble Schistosoma japonicum egg antigens (SjEA) were generated from SjEA immunizated mice. The expression of glycans on surfaces of cercaria or young worm and their distributions were examined by immunofluorescence assay. The protective roles of glycans-specific mAbs were assayed by determination of the worm and egg burden in infected mice., Results: Both periodate-resistant glycans and periodate-sensitive glycans are antigenic in schistosome infections. When monoclonal antibodies against either periodate-sensitive or periodate-resistant glycans were administered prior to schistosome infections in mice, both kinds of anti-glycan antibodies were found to successfully provide protective immunity to infected mice., Conclusions: Both periodate-resistant and periodate-sensitive glycans are antigenic, and dominant anti-glycan IgG responses can play important roles in protective immunity in schistosome infected hosts.

Liver fibrosis is a wound-healing response to chronic liver injury characterized by progressive inflammation and deposition of extracellular matrix components. The pathological condition of liver fibrosis involves secretion of extracellular matrix proteins and formation of scar tissue. The major regulators involved in hepatic fibrogenesis are the transforming growth factor (TGF)-β1/SMAD and toll-like receptor 4 (TLR4)-initiated myeloid differentiation primary response 88 gene (MyD88)/NF-ĸB cell signaling pathways. This article reviews natural products and herbal medicines that have demonstrated activity against liver fibrosis through different mechanisms of action, including anti-hepatitis B and C virus activity, anti-inflammation, inhibition of cytokine production and nuclear receptor activation, and free radical scavenging.

Hepatocellular carcinoma is the third leading cause of cancer-related death in the world, and cirrhosis is the main cause of hepatocellular carcinoma and adversely affects surgical outcomes. Liver resection, liver transplantation, and local ablation are potentially curative therapies for early hepatocellular carcinoma (HCC). There exists an obvious histological variability of severity within cirrhosis which has different clinical stages. For patients with Child-Pugh B cirrhosis and/or portal hypertension and HCC within Milan criteria, consensus guidelines suggest that liver transplantation is the best treatment of choice; liver resection is widely accepted as first-line treatment for patients with early-stage HCC and preserved liver function; and local ablation is the treatment of choice in patients with small tumors who are not candidates for surgery or can be used as a temporary treatment during the waiting period for transplantation. For patients with compensated cirrhosis or Child A cirrhosis, the selection of surgical modality based on subclassification of cirrhosis remains unclear. This review examines the current status of the selection of surgical modality for hepatocellular carcinoma treatment in cirrhotic patients and aims to emphasize the effects of the severity of cirrhosis on the selection of surgical modality for the treatment of hepatocellular carcinoma.

The circadian clock and sleep are essential for human physiology and behavior; deregulation of circadian rhythms impairs health and performance. Circadian clocks and sleep evolved to adapt to Earth's environment, which is characterized by a 24-hour light-dark cycle. Changes in gravity load, lighting and work schedules during spaceflight missions can impact circadian clocks and disrupt sleep, in turn jeopardizing the mood, cognition and performance of orbiting astronauts. In this review, we summarize our understanding of both the influence of the space environment on the circadian timing system and sleep and the impact of these changes on astronaut physiology and performance.

Background: The expression of heparanase (HPSE) was associated with postoperative metastatic recurrence in patients with hepatocellular carcinoma (HCC). The six E-box binding sites in the core promoter of the HPSE gene suggested that transcription factors of E-box such as upstream stimulatory factor (USF) might regulate the transcription of the HPSE gene. The aim of our study is to measure the levels of HPSE and USF expression and investigate the relationship between USF expression and clinicopathological parameters in patients with HCC., Methods: HPSE, USF1 and USF2 expressions in human HCC cell lines (BEL-7402, HepG2 and HCCLM3) and 15 fresh human HCC tissue samples were measured by real-time reverse transcriptase-PCR and Western blot analysis. The normal liver cell line QSG7701 or fresh normal liver tissue samples obtained from 15 additional surgical patients with hepatic rupture was used as a control. The protein expressions were determined by immunohistochemistry in paraffin-embedded human HCC tissues and corresponding non-neoplastic tumor surrounding tissues (NTST) of 57 patients., Results: HPSE, USF1 and USF2 mRNA expressions were increased in HCC cell lines and HCC tissues compared with normal liver cell line and normal liver tissue. The protein expressions of HPSE, USF1 and USF2 in HCC cell lines and HCC tissues were also increased. Both USF1 and USF2 expressions were positively correlated with HPSE. USF1 and USF2 expressions were increased in patients with liver cirrhosis, worse tissue differentiation, advanced HCC stages and metastatic recurrence., Conclusions: Increased USF in HCC is associated with HPSE expression. USF might be an important factor in regulating HPSE expression and act as a novel marker of metastatic recurrence of HCC patients.

Background: Bacteria of the order Rickettsiales (Alphaproteobacteria) are obligate intracellular parasites that infect species from virtually every major eukaryotic lineage. Several rickettsial genera harbor species that are significant emerging and re-emerging pathogens of humans. As species of Rickettsiales are associated with an extremely diverse host range, a better understanding of the historical associations between these bacteria and their hosts will provide important information on their evolutionary trajectories and, particularly, their potential emergence as pathogens., Results: Nine species of Rickettsiales (two in the genus Rickettsia, three in the genus Anaplasma, and four in the genus Ehrlichia) were identified in two species of hard ticks (Dermacentor nuttalli and Hyalomma asiaticum) from two geographic regions in Xinjiang through genetic analyses of 16S rRNA, gltA, and groEL gene sequences. Notably, two lineages of Ehrlichia and one lineage of Anaplasma were distinct from any known Rickettsiales, suggesting the presence of potentially novel species in ticks in Xinjiang. Our phylogenetic analyses revealed some topological differences between the phylogenies of the bacteria and their vectors, which led us to marginally reject a model of exclusive bacteria-vector co-divergence., Conclusions: Ticks are an important natural reservoir of many diverse species of Rickettsiales. In this work, we identified a single tick species that harbors multiple species of Rickettsiales, and uncovered extensive genetic diversity of these bacteria in two tick species from Xinjiang. Both bacteria-vector co-divergence and cross-species transmission appear to have played important roles in Rickettsiales evolution.

Background: It has been demonstrated that platycodin D (PD) exhibits anti-cancer activities. This study aims to investigate the anti-proliferative effects of the combination of PD and doxorubicin (DOX) on human breast cancer cells (MCF-7 and MDA-MB-231 cells)., Methods: The anti-proliferative effects of different dosages of PD, DOX, and PD + DOX on MCF-7 and MDA-MB-231 cells were determined by the MTT assay. The 10 μM PD, 5 μM DOX, and 10 μM PD + 5 μM DOX induced-protein expression of apoptosis-related molecules on MCF-7 and MDA-MB-231 cells were detected by western blot. The 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX-induced mitochondrial membrane potential changes on MCF-7 and MDA-MB-231 cells were stained with JC-1 before visual determination. The intracellular accumulations of DOX, induced by 10 μM PD, 5 μM DOX and 10 μM PD + 5 μM DOX, were detected by flow cytometry., Results: PD enhanced anti-cancer activities of DOX were observed in both MCF-7 and MDA-MB-231 cell lines. Compared with mono treatment, the combined treatment increased the protein expression of cleaved poly (ADP-ribose) polymerase and decreased the mitochondrial membrane potential. The combined treatment with PD did not obviously increase the accumulation of DOX in MCF-7 cells (1.66 ± 0.13 in DOX-treated group, and 1.69 ± 0.06 in PD + DOX-treated group, P = 0.76), but it significantly increased the accumulation of DOX in MDA-MB-231 cells (1.76 ± 0.17 in DOX-treated group, 2.09 ± 0.02 in PD + DOX-treated group, P = 0.027)., Conclusion: The combined treatment of DOX and PD exhibited stronger anti-proliferative effects on MCF-7 and MDA-MB-231 cells than DOX and PD treatment did.

Background: Activin A, an important member of transforming growth factor-β superfamily, is reported to inhibit proliferation of mature hepatocyte. However, the effect of activin A on growth of hepatic progenitor cells is not fully understood. To that end, we attempted to evaluate the potential role of activin A in the regulation of hepatic progenitor cell proliferation., Results: Using the 2-acetaminofluorene/partial hepatectomy model, activin A expression decreased immediately after partial hepatectomy and then increased from the 9th to 15th day post surgery, which is associated with the attenuation of oval cell proliferation. Activin A inhibited oval cell line LE6 growth via activating the SMAD signaling pathway, which manifested as the phosphorylation of SMAD2/3, the inhibition of Rb phosphorylation, the suppression of cyclinD1 and cyclinE, and the promotion of p21WAF1/Cip1 and p15INK4B expression. Treatment with activin A antagonist follistatin or blocking SMAD signaling could diminish the anti-proliferative effect of activin A. By contrast, inhibition of the MAPK pathway did not contribute to this effect. Antagonizing activin A activity by follistatin administration enhanced oval cell proliferation in the 2-acetylaminofluorene/partial hepatectomy model., Conclusion: Activin A, acting through the SMAD pathway, negatively regulates the proliferation of hepatic progenitor cells.

Background: Schistosomiasis is a chronic infection, where the host immune response to the parasite changes from a predominantly Th1 to Th2 phenotype, when parasite enters the egg stage, restraining the host inflammatory immune responses to achieve a longer survival in the host. On the other hand, the development of Th2 responses causes immunopathological changes such as liver fibrosis. Therefore identification of schistosome-derived Th2 inducing molecules is important in the understanding of pathogenesis of schistosomiasis. A cyclophilin A homologue of Schistosoma japonicum was reported to be an egg-stage specific antigen, but its immunogenicity and immunoregulatory activities remain unknown., Methods: We cloned and expressed the gene of cyclophilin A from Schistosoma japonicum (AY814078), named as SjCyP18 based on its molecular weight. The expression profiles in different stages of S. japonicum were examined by RT-PCR and immunofluorescence assay. The immunogenicity of SjCyP18 was measured by the presence of IgG in the sera from S. japonicum infected patients and animals, and the Th2-promting activities were examined by the subclass of immunoglobulins against SjCyP18 and by the IL-4 induction in T cells following footpad injection of SjCyP18., Results: The cloned SjCyP18 has 65% homology with human or mouse cyclophilin A at the amino acid level. In contrast to reports as an egg-stage specific antigen, the gene was found to be expressed in all stages of S. japonicum. IgG responses against SjCyP18 were found in some S. japonicum infected patients and were significantly induced when infection become patent and produce eggs in infected mice. Furthermore, the Th2-promoting subclass of IgG1 was the predominant isotype in S. japonicum infected mice. More importantly, footpad injection of SjCyP18 induced a greater production of IL-4 than that of IFN-γ by lymphocytes compared to responses from PBS injection controls., Conclusion: The cyclophilin A homologue found in S. japonicum is immunogenic and promotes Th2 responses in vivo which may contribute to the establishment of chronic infection by schistosomes.

Background: A long-term existing schistosome infection can aid in maintaining immuno-homeostasis, thus providing protection against various types of autoimmune diseases to the infected host. Such benefits have often been associated with acute or egg stage infection and with the egg-induced Th2 response. However, since schistosome infection undergoes different stages, each associated with a specific induction of Th responses, the requirements for the ability of the different stages of schistosome infection to protect against autoimmune disease has not been elucidated. The present study was designed to study whether different stages of schistosome infection offer unique protection in collagen-induced arthritis and its mechanisms., Results: Arthritis susceptible strain DBA/1 male mice were infected with Schistosoma japonicum for either 2 weeks resulting in early stage infection or for 7 weeks resulting in acute or egg stage infection. Following Schistosoma japonicum infection, collagen II was administered to induce collagen-induced arthritis, an animal model for human rheumatoid arthritis. Infection by Schistosoma japonicum significantly reduced the severity and the incidence of experimental autoimmune collagen-induced arthritis. However, this beneficial effect can only be provided by a pre-established acute stage of infection but not by a pre-established early stage of the infection. The protection against collagen-induced arthritis correlated with reduced levels of anti-collagen II IgG, especially the subclass of IgG2a. Moreover, in protected mice increased levels of IL-4 were present at the time of collagen II injection together with sustained higher IL-4 levels during the course of arthritis development. In contrast, in unprotected mice minimal levels of IL-4 were present at the initial stage of collagen II challenge together with lack of IL-4 induction following Schistosoma japonicum infection., Conclusion: The protective effect against collagen-induced arthritis provided by Schistosoma japonicum infection is infection stage-dependent. Furthermore, the ability of schistosomiasis to negatively regulate the onset of collagen-induced arthritis is associated with a dominant as well as long-lasting Th2 response at the initiation and development of autoimmune joint and systemic inflammation.

KLF6 (Zf9, COPEB), an ubiquitous transcription factor, maps to chromosome 10p. Recently, KLF6 was found to have a more generalized role in tumorigenesis as a candidate tumor suppressor gene for some tumors. However, results from other published studies seem not to be in agreement with data from previous studies. Gene-expression analysis is increasingly important in biological research. Loss of expression is one of the mechanisms to functionally inactivate a tumor suppressor gene. To investigate the expression change of KLF6 gene associated with HCC as a step toward a better understanding of the molecular pathophysiology, and to provide the basis for analysis of KLF6 gene in HCC carcinogenesis. We analyzed the expression of KLF6 mRNA in 26 samples of HCC tissues and hepatoma cell lines(Hep3B and HepG2) detected by Real-Time quantitative RT-PCR (qRT-PCR) and conventional RT-PCR assay. To confirm and extend the data obtained at RNA level, we performed detailed immunoblotting analysis on HCC tissues and hepatoma cell lines using a rabbit polyclonal antibody specific for KLF6. NKLF6 detected by qRT-PCR from HCC and corresponding noncancerous tissues was 0.04+/-0.038 and 0.116+/-0.101, respectively. These data demonstrated that KLF6 mRNA level was significantly decreased in HCC, compared with corresponding noncancerous tissues (t =3.683 , P<0.001). The frequency of Hepatoma Cell Lines with KLF6 down-regulation detected by conventional PT-PCR, seems to be consistent with a previous study using real-time PCR assays in tumor samples. KLF6 expression levels were determined by Western blot. Compared to the matched surrounding tissues, a clear decrease of KLF6 protein levels in tumor tissues was observable (t=13.59, P<0.001). Hepatoma cell lines also showed low-level of KLF6 protein (P<0.01) expression. Immunohistochemistry and immunocytochemistry showed a faint diffused staining in the HCC tissues and hepatoma cell lines, and endogenous KLF6 protein was detected mostly in the cytoplasm. KLF6 gene appeared markedly reduced in HCC tissues and hepatoma cell lines. Frequent down-regulation of KLF6 strongly suggested that it is a candidate of tumor suppressor gene for HCC.

Aim of the study was to explore the influence of hypoxia on multidrug resistance related genes and the potential role of hypoxia-inducible factor-1-alpha (HIF-1alpha) in formation of multidrug resistance in HepG2 human hepatocellular carcinoma cell line. HepG2 cells were subjected to hypoxia in a cohort of exposed time. A cell model stably expressing HIF-1alpha was established by liposome-mediated transfection of plasmid pcDNA3/HIF-1alpha into HepG2 cells. Apoptosis of HepG2 cells exposed to hypoxia or transfected by plasmid pcDNA3/HIF-1alpha was detected by Flow Cytometry after administration of chemotherapeutic drug (5-Fu). Real-time fluorescent quantitative PCR and Western-blot technique were used to analyze the expressions of multidrug resistance related genes mdr1, MRP1 and LRP at mRNA and protein level, respectively. Apoptosis Index of HepG2 cells exposed to hypoxia stepped down as exposed time extended after administration of 5-Fu. The expression of mdr1, MRP1 and LRP gene and protein revealed a hypoxic time-dependent induction and was synchronous with the alterations of HIF-1alpha in HepG2 cells exposed to hypoxia. The expressions of these multidrug resistance related genes were remarkably increased in HIF-1alpha transfected HepG2 cells as compared to empty vector transfected cells. Apoptosis index of HIF-1alpha transfected cells was obviously less than that of control cells when they were simultaneously exposed to 5-Fu for 24hrs. In conclusion, ambient hypoxia might be one of the causes for the formation of multidrug resistance in HepG2 human hepatocellular carcinoma cell line. Hypoxia-elicited multidrug resistance related protein expression might be a pathway for resistance of HepG2 cells to chemotherapeutics and HIF-1alpha might be involved in this process.