Combining FITs and HRFQ with colonoscopy improve the cost-effectiveness of a 9-year mass colorectal cancer screening program.

BACKGROUND: Colorectal cancer (CRC) incidence has been increasing. Colonoscopy is still a gold standard method for its early diagnosis but using colonoscopy alone as a mass screening method is unrealistic. This study is to investigate whether combining fecal immunochemical test (FIT) and high-risk-factors questionnaire (HRFQ) with colonoscopy improve the cost-effectiveness of a mass CRC screening. PATIENTS AND METHODS: CRC screening protocol combining FITs and HRFQ in the first stage and colonoscopy in the second stage was used in 50 villages/towns in 2007-2015. Residents aged 40-74 years were eligible for this free screening. A total of 160 210 (76.12%) participants completed first-stage screening, and 28 679 (17.90%) participants were defined as positive, among which 21 715 (75.72%) participants completed colonoscopy and were included in the final analysis. Outcomes were followed up until 2020. RESULTS: The compliance was 76.12% and 75.72% in the first and second screening stage, respectively. A total of 252 CRC, 4033 adenoma, 1234 advanced neoplasm, and 5534 total neoplasm cases were detected in the screening. The positive predictive values of CRC, adenoma, advanced neoplasm, and total neoplasm were higher in FITs+ than those in the HRFQ+ population, respectively. A total of 64.60% and 43.42% total neoplasm cases were found in FITs+ and HRFQ+ (8.02% for both), respectively. The total colorectal neoplasm and CRC cases detected by combining HRFQ and FITs increased by 55.08% and 40.00%, respectively, and their increases were higher compared to HRFQ. The detection cost per any neoplasm by combining HRFQ and FITs was <$5331, while that by FITs and HRFQ alone was <$4570 and $5380, respectively. CONCLUSIONS: Combining FITs and HRFQ with colonoscopy improve the cost-effectiveness of a mass CRC screening program. This protocol can be recommended for most populations, especially those in the countries and areas with high population density and low physician/population ratio.

Expression of CD4+CD25+ regulatory T cells and Foxp3 in peripheral blood of patients with gastric carcinoma.

The aim of this research was to study the clinical significance and expression of CD4+CD25+ regulatory T cells (Tregs) and p3Forkhead transcription factor-3 (Foxp3) in peripheral blood of patients with gastric carcinoma (GC) and to investigate the effects in the occurrence and development process of GC, to further comprehend their clinical values and provide a theoretical basis for the early diagnosis and immunotherapy of GC. The expression levels of CD4+CD25+Foxp3+Tregs in GC patients, at TNM staging, differentiated degree, lymphatic metastasis, cancer sites and cancer diameter of GC, were analyzed within the groups. The comparison of the expression levels of CD4+CD25+Foxp3+Tregs in peripheral blood between the GC group and the healthy control group showed a statistically significant difference. At TNM staging within the groups, pairwise comparisons of the expression levels of CD4+CD25+Foxp3+Tregs indicated that differences among the stage I+II group, stage III group and stage IV group were statistically significant. The expression levels of CD4+CD25+Foxp3+Tregs are closely relative to the occurrence and development of GC, providing theoretical bases and evidence for the early diagnosis, prognosis evaluation and immunotherapy of GC.

Synthetic lethality of Chk1 inhibition combined with p53 and/or p21 loss during a DNA damage response in normal and tumor cells.

Cell cycle checkpoints ensure genome integrity and are frequently compromised in human cancers. A therapeutic strategy being explored takes advantage of checkpoint defects in p53-deficient tumors in order to sensitize them to DNA-damaging agents by eliminating Chk1-mediated checkpoint responses. Using mouse models, we demonstrated that p21 is a key determinant of how cells respond to the combination of DNA damage and Chk1 inhibition (combination therapy) in normal cells as well as in tumors. Loss of p21 sensitized normal cells to the combination therapy much more than did p53 loss and the enhanced lethality was partially blocked by CDK inhibition. In addition, basal pools of p21 (p53 independent) provided p53 null cells with protection from the combination therapy. Our results uncover a novel p53-independent function for p21 in protecting cells from the lethal effects of DNA damage followed by Chk1 inhibition. As p21 levels are low in a significant fraction of colorectal tumors, they are predicted to be particularly sensitive to the combination therapy. Results reported in this study support this prediction.

Gender disparities in dietary status and its risk factors in underserved populations.

OBJECTIVES: To examine dietary status and its risk factors among adults aged 40-74 years at high risk of colorectal cancer (CRC) in an economically and medically underserved population. STUDY DESIGN: Cross-sectional survey in 2007. METHODS: A survey was conducted among a random sample (n = 1844) nested in a screening cohort of a rural population in Jiashan County, China. Information about diet, family history of CRC and other factors was collected by questionnaire. The primary outcome was dietary status, assessed by consumption (servings/week) of plant-based food and unhealthy food. Linear or multinomial logistic regressions were used to determine risk factors for dietary status. RESULTS: On average, individuals with a family history of CRC ate 2.25 fewer servings of plant-based food each week compared with individuals without a family history of CRC. Individuals who smoked and drank alcohol ate less plant-based food. After stratification by gender, there were multiple determinants for consumption of plant-based food for men, including family history of CRC, smoking, alcohol consumption and income. For women, the only association was found for income. Consumption of unhealthy food was positively associated with high income and high body mass index. Determinants for an unhealthy diet were the same in both genders. CONCLUSIONS: There are gender disparities in the consumption of plant-based food and the risk factors for CRC in medically and economically underserved populations. Men's insufficient consumption of plant-based food and unhealthy lifestyle behaviours, such as smoking and drinking, may explain, in part, why men have a higher risk of CRC than women.

Lipopolysaccharide results in a marked decrease in hepatocyte nuclear factor 4 alpha in rat liver.

The acute-phase response can result in decreased liver-specific functions and death as a result of liver failure. We show here that lipopolysaccharide (LPS), an endotoxin that induces the acute-phase response, results in a marked decrease in the major isoforms of the transcription factor, hepatocyte nuclear factor 4 alpha (HNF-4 alpha), in livers of rats. HNF-4 alpha is a nuclear receptor that is critical for the expression of several liver-specific genes. This decrease in HNF-4 alpha is primarily the result of a posttranscriptional mechanism, because mRNA levels are normal, and there are no major changes in the splicing patterns. This decrease was of functional significance, because expression of a gene that is highly dependent on HNF-4 alpha, HNF-1 alpha, was reduced. Interleukin-1 beta (IL-1 beta) is a cytokine whose levels are increased in vivo in response to LPS. IL-1 beta resulted in a decrease in HNF-4 alpha levels in HepG2 cells. This IL-1 beta-induced decrease was likely caused by degradation via the proteasome, because it was prevented by the addition of the proteasome inhibitor, MG132. We conclude that the decrease in HNF-4 alpha that occurs in vivo after the administration of LPS may be the result of IL-1 beta-induced degradation, and likely contributes to the liver insufficiency that occurs. IL-1 beta antagonists or proteasome inhibitors might increase HNF-4 alpha protein levels in the acute-phase response, which could result in increased liver function and survival.

Quantitative variation in vascular endothelial growth factor mRNA expression during early flexor tendon healing: an investigation in a canine model.

Vascular endothelial growth factor (VEGF) is a potent mediator of angiogenesis, with direct mitogenic activity on cells of endothelial origin. We quantified the temporal accumulation of VEGF mRNA at the repair site of an in vivo canine intrasynovial flexor tendon repair and rehabilitation model by means of quantitative Northern blot analysis, in order to detail a molecular signal involved in the intrinsic angiogenic process that accompanies early flexor tendon healing. Significant accumulation of VEGF mRNA occurred at the flexor tendon repair site at 7 days post-operatively, with peak levels seen at post-operative days 7 and 10. Levels returned to baseline by day 14. Local VEGF mRNA accumulation at the repair site temporally precedes and is spatially distinct from the vascular ingrowth itself, which has been shown to occur maximally at day 17. These data suggest that cells within the flexor tendon repair site are involved in molecular processes other than the synthesis of extracellular matrix, such as modulation of angiogenesis.

Intramuscular injection of an adenoviral vector expressing hepatocyte growth factor facilitates hepatic transduction with a retroviral vector in mice.

Retroviral vectors can result in therapeutic and stable levels of expression of proteins from the liver. However, most retroviral vectors transduce only dividing cells, and hepatocytes are normally quiescent. The goal of this study was to determine if an adenoviral vector could transiently express hepatocyte growth factor (HGF) in order to induce hepatocyte replication and facilitate retroviral vector transduction of the liver. Intramuscular injection of an adenoviral vector that expressed human HGF from the cytomegalovirus promoter (Ad.CMV.HGF) resulted in moderate levels of HGF in blood and liver, and replication of 3 to 12% of hepatocytes. No cytopathic effect was observed in the liver, and a control adenoviral vector induced no or lower levels of replication. When a retroviral vector expressing beta-galactosidase cDNA was injected into a peripheral vein during the peak period of hepatocyte replication induced by intramuscularly administered Ad.CMV.HGF, 8% of hepatocytes were transduced. We conclude that intramuscular injection of Ad.CMV.HGF is a safe and effective way to induce transient systemic expression of HGF and hepatocyte replication, and to facilitate transduction of hepatocytes with a retroviral vector.

Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy.

Protein C deficiency results in a thrombotic disorder that might be treated by expressing a normal human protein C (hPC) gene in patients. An amphotropic retroviral vector with a liver-specific promoter and the hPC cDNA was delivered to rat hepatocytes in vivo during liver regeneration. Expression of hPC varied from 55 to 203 ng/ml (1.3-5.0% of normal) for 2 wk after transduction. Expression increased to an average of 900 ng/ml (22% of normal) in some rats and was maintained at stable levels for 1 yr. All of these rats developed anti-hPC antibodies and exhibited a prolonged hPC half-life in vivo. The hPC was functional as determined by a chromogenic substrate assay after immunoprecipitation. We conclude that most rats achieved hPC levels that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment for patients with severe homozygous hPC deficiency. Anti-hPC antibodies increased the hPC half-life and plasma levels in some rats, but did not interfere with its functional activity. Thus, the development of antibodies against a plasma protein does not necessarily abrogate its biological effect in gene therapy experiments.

Therapeutic levels of functional human factor X in rats after retroviral-mediated hepatic gene therapy.

Factor X deficiency results in a rare but serious bleeding disorder that might be treated by expressing a normal factor X gene in patients. We generated an amphotropic retroviral vector with the human FX cDNA and delivered it to rat hepatocytes in vivo during liver regeneration. The human alpha1-antitrypsin promoter was chosen to direct expression because it was the most efficient of several tested in yielding expression of alpha1-antitrypsin protein from a retroviral vector in hepatocytes in vivo. We achieved expression of factor X in four rats at levels sufficient to maintain hemostasis in humans (10% to 43% of normal). The factor X was determined to be functional by using a chromogenic substrate assay after immunoprecipitation with human specific antibodies. Expression of factor X remained stable for more than 10 months in two rats. It is likely that expression will be maintained for the life of the animals, because retroviral vectors integrate into the chromosome and hepatocytes are long-lived. The high and stable levels of expression achieved using this liver-specific promoter overcomes one of the two major obstacles to successful human gene therapy for hemophilia.

Portal branch occlusion safely facilitates in vivo retroviral vector transduction of rat liver.

Hepatic gene therapy might correct the clinical manifestations of several genetic disorders in patients. Although retroviral vectors with a strong liver-specific promoter can result in stable and therapeutic levels of expression of genes from the liver, application of these techniques in humans is limited by the need to perform one or more invasive procedures to achieve ex vivo or in vivo transduction of hepatocytes. In vivo delivery involves injection of retrovirus into the portal vein during liver regeneration. Although transduction is efficient and specific for the liver, induction of hepatocyte replication requires a 70% partial hepatectomy or administration of a liver toxin. An alternative method for inducing hepatocyte replication is to occlude branches of the portal vein. This results in apoptosis of hepatocytes in the occluded lobes and compensatory replication of the hepatocytes in the nonoccluded lobes. We demonstrate here that portal branch occlusion is nearly as effective as partial hepatectomy at facilitating retroviral vector transduction in vivo and has a lower morbidity. Portal branch occlusion could be performed in larger animals by minimally invasive techniques and has been used safely to treat human patients with liver cancer. Portal branch occlusion might ultimately be used in humans to facilitate retroviral vector transduction in vivo for the treatment of genetic diseases.