Epigenetic modifications are involved in the pathogenesis of cancer, and histone deacetylase inhibitors are considered potential therapeutic agents. Histone tails undergo acetylation at lysine residues, which is associated with transcriptional activation. However, previous studies indicated that as histone deacetylase inhibitors, both (−)-epigallocatechin-3-gallate and valproic acid presented the effects of downregulation of amyloid precursor protein expression, which resulted in the induction of apoptosis. The downregulation of amyloid precursor protein, instead of conventionally activating gene expression as histone deacetylase inhibitor, was attractive. However, there was no relevant report on the correlation of the expression of amyloid precursor protein and histone deacetylase 1 in cancer. In the present study, we detected the expression of amyloid precursor protein and histone deacetylase 1 in hepatocellular carcinoma and adjacent tissues, as well as the correlations among histone deacetylase 1, amyloid precursor protein, and tumor stage. The results showed that the expressions of amyloid precursor protein and histone deacetylase 1 were significantly higher in hepatocellular carcinoma tissues than that in adjacent tissues ( P < .05), however, there was no statistical difference between amyloid precursor protein and histone deacetylase 1 with tumor stages. The present findings provided more foundation for the study on amyloid precursor protein metabolism in cancer, especially on the regulation of amyloid precursor protein by histone deacetylases.
Cervical cancer is mainly caused by infections of high-risk human papillomavirus (HR-HPV). Persistent expression of HR-HPV oncogenes E6 and E7 is implicated in malignant transformation. The aim was to provide proof-of-concept data to support use of zinc finger nucleases (ZFN) targeting HPV E7 to treat HPV-related cervical cancer.We designed and constructed ZFNs that could specifically recognize and cleave HPV16/18 E7 DNA. We tested the cleavage efficiency of selected ZFN16-E7-S2 and ZFN18-E7-S2 by using single-strand annealing (SSA) assay. Cell viability and colony formation assays were used to estimate the inhibition of cell growth that received treatments of ZFNs. Gene disruption of HPV E7 and downstream genes were examined by Western blotting. Cell apoptosis assay was used to test the specificity and efficiency of induction of HPV type-specific apoptosis. We also introduced xenograft formation assays to estimate the potential of inhibition of HPV-related disease.We found ZFN16-E7-S2 and ZFN18-E7-S2 disrupted HPV E7 oncogenes in HPV16/18-positive cervical cancer cells. Both ZFNs effectively led to inhibition of type-specific cervical cancer cell growth, and specifically induced apoptosis of corresponding HPV16- and HPV18-positive cervical cancer cell lines. ZFN16-E7-S2 and ZFN18-E7-S2 also repressed xenograft formation in vivo.ZFNs targeting HPV16/18 E7 could effectively induce disruption of E7 oncogenes and lead to type-specific and efficient growth inhibition and apoptosis of HPV-positive cells. ZFNs targeting HPV16/18 E7 oncogenes could be used as novel therapeutic agents for the treatment of HPV-related cervical cancer.
Coronavirus disease 2019 (COVID-19) has significantly affected gastrointestinal (GI) endoscopy, with jurisdictions reporting up to a 95% reduction in procedure volumes compared to before the pandemic.1Rutter MD et al. Gut [published online July 20, 2020]. https://doi.org/10.1136/gutjnl-2020-322179.Google Scholar In Ontario, Canada, a large volume of colonoscopies not performed during the first wave of the pandemic (the backlog) must now be managed (Supplementary Table 1). Ontario Health (Cancer Care Ontario) oversees colonoscopies performed in hospitals (70% of those performed in the province). Ontario Health's "COVID-19 Tip Sheet for Facilities Performing Gastrointestinal Endoscopy" (June 2020) recommended that individuals originally scheduled for low-yield colonoscopies (ie, average-risk screening colonoscopy or surveillance colonoscopy in those with a history of low-risk adenoma [LRA]) should instead receive the fecal immunochemical test (FIT)2Ontario Health. https://www.ontariohealth.ca/sites/ontariohealth/files/2020-05/A%20Measured%20Approach%20to%20Planning%20for%20Surgeries%20and%20Procedures%20During%20the%20COVID-19%20Pandemic.pdf.Google Scholar, 3Tinmouth J. et al.Colorectal cancer screening in average risk populations: evidence summary. Program in evidence-based care evidence summary no. 15-14. Cancer Care Ontario, Toronto, Canada2015Google Scholar, 4Dubé C. et al.Am J Gastroenterol. 2017; 112: 1790-1801Crossref PubMed Scopus (78) Google Scholar and be referred for colonoscopy only if the FIT result is abnormal. Ontario Health's surveillance guidelines recommend FIT as the follow-up test in those with a history of LRA based on recent evidence that the risk of colorectal cancer in these individuals is less than in the general population.5Dubé C et al. https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/38506.Google Scholar, 6Loberg M. et al.N Engl J Med. 2014; 371: 799-807Crossref PubMed Scopus (226) Google Scholar, 7Wieszczy P. et al.Gastroenterology. 2020; 158: 875-883Abstract Full Text Full Text PDF PubMed Scopus (128) Google Scholar, 8Cross A.J. et al.Long-term colorectal cancer incidence after adenoma removal and the effects of surveillance on incidence: a multicentre, retrospective, cohort study.Gut. 2020; 69: 1645-1658Crossref PubMed Scopus (58) Google Scholar Our aims were to (1) estimate the volume of hospital-based outpatient colonoscopies not performed because of the pandemic and (2) compare the effect of 2 strategies, redirecting individuals from low-yield colonoscopy to FIT and increasing hospital colonoscopy capacity, on backlog recovery time. We used the GI Endoscopy Data Submission Portal, which receives monthly hospital colonoscopy data (including colonoscopy date and indication) to identify all outpatient hospital colonoscopies performed from January 2019 to August 2020. We estimated hospital-based outpatient colonoscopy volumes from March 2020 to February 2024 by calculating the difference between expected monthly colonoscopy volumes (derived from monthly 2019 volumes inflated by 1%/year) in the absence of the pandemic and observed or projected volumes during the pandemic. Volumes from March to August 2020 were obtained from the Gastrointestinal Endoscopy Data Sharing Portal ("observed") and projected for subsequent months by multiplying the expected volumes by assumptions of system capacity during the pandemic. We assumed that (1) colonoscopy volume in September 2020 would be 85% of that expected; (2) capacity would increase by 5%/month, reaching 100% in December 2020; and (3) the maximum capacity of 115% would be reached in March 2021, remaining stable thereafter. In any given year, 100% capacity was defined as the mean of expected monthly volumes for that year. Maximum system capacity was set at 115% based on the relative difference between the highest and average monthly volumes in 2019. Recovery time was defined as the number of months until the colonoscopy backlog was eliminated. Colonoscopies were added to the backlog after August 2020 in months where capacity was anticipated to be below 100%. We counted low-yield colonoscopies that would have been performed in the absence of the pandemic. All average-risk screening colonoscopies and 50% of surveillance colonoscopies were considered low yield. The latter assumption was required because we do not have data on pathology from the prior colonoscopy. A proportion of people redirected to FIT (OC-Sensor DIANA, Eiken Chemical Co) will have an abnormal result (Ontario target positivity range: 5%–6.5%) and require a colonoscopy (Ontario's prepandemic colonoscopy follow-up rate: 90%). Beginning in September 2020, redirected low-yield colonoscopies were subtracted, and abnormal FIT result colonoscopies resulting from redirection were added to expected hospital colonoscopy volumes. Corresponding recovery times, varying the proportion of low-yield colonoscopies redirected to FIT (25%, 50%, and 75%), were calculated. An alternative strategy for managing the backlog is to increase hospital endoscopy capacity. Again, we assumed (1) 85% capacity in September 2020 and (2) that capacity would increase by a constant rate each month until March 2021, when the maximum capacity would be reached and maintained thereafter. We then calculated the maximum expected increase in system capacity required to match the recovery times achieved by redirecting 25%, 50%, and 75% of low-yield colonoscopies to FIT. Before the pandemic, 18% and an estimated 13% of all colonoscopies were performed for average-risk screening and LRA surveillance, respectively (Supplementary Table 1). Estimated recovery times vary depending on the proportion of persons scheduled for low-yield colonoscopies who are redirected to FIT. The backlog is projected to take 41 months to recover without redirection, but redirecting 25%, 50%, and 75% low-yield colonoscopies to FIT will reduce recovery times to 28, 22, and 19 months, respectively (Figure 1A). If there was no redirection to FIT, hospitals would need to increase colonoscopy capacity to 124%, 134%, and 145% to recover the backlog in 28, 22, and 19 months, respectively (Figure 1B). As in other jurisdictions,1Rutter MD et al. Gut [published online July 20, 2020]. https://doi.org/10.1136/gutjnl-2020-322179.Google Scholar GI endoscopy services in Ontario have been profoundly affected by the COVID-19 pandemic, leading to a colonoscopy backlog that, absent any intervention, is estimated to take 41 months to recover. The impact to patients is consequential, particularly in terms of delays in diagnosis. The UK estimated 2828 fewer colorectal cancers diagnosed using lower endoscopy during the pandemic compared to the months leading up to COVID-19, representing a 72% absolute decrease.1Rutter MD et al. Gut [published online July 20, 2020]. https://doi.org/10.1136/gutjnl-2020-322179.Google Scholar We have presented 2 strategies to address the colonoscopy backlog and shown that redirecting persons originally scheduled for low-yield colonoscopy to FIT can substantially reduce the colonoscopy backlog and recovery time. To achieve a similar effect, colonoscopy capacity would need to exceed mean historical volumes by as much as 45%, which would be costly and challenging to achieve due to the constraints in the delivery of care introduced by COVID-19 (eg, physical distancing in recovery rooms). Limitations to this work include that we did not account for subsequent pandemic waves or for reduction in demand for colonoscopy during the study period because of patients' reluctance to undergo a colonoscopy, including follow-up procedures after an abnormal FIT result. Furthermore, although the FIT cutoff used to define a positive test can be adjusted to local colonoscopy capacity, we did not vary this cutoff in our analyses. Other jurisdictions facing a similar backlog in colonoscopy should consider redirecting individuals waiting for low-yield colonoscopy to FIT to mitigate the impact of the pandemic on access to colonoscopy. Other members of the ColonCancerCheck/Gastrointestinal Endoscopy COVID Working Group: Melissa Coulson, Julia Gao, Dan He, Nathaniel Jembere, Bronwen R. McCurdy, and Justine Wallace, all of Prevention and Cancer Control, Ontario Health (Cancer Care Ontario), Toronto, Ontario. Jill Tinmouth, MD, PhD (Conceptualization: Equal; Formal analysis: Supporting; Methodology: Lead; Supervision: Lead; Writing – original draft: Lead); Steven Dong, MA (Conceptualization: Supporting; Formal analysis: Lead; Writing – original draft: Equal); Christine Stogios, MSc (Project administration: Lead; Writing – original draft: Equal); Linda Rabeneck, MD, MPH (Conceptualization: Equal; Methodology: Equal; Writing – review & editing: Equal); Michelle Rey, MSc, PhD (Methodology: Supporting; Supervision: Supporting; Writing – review & editing: Equal); Catherine Dubé, MD, MSc (Conceptualization: Equal; Methodology: Equal; Writing – review & editing: Equal). Supplementary Table 1Impact of the COVID-19 Pandemic on Hospital Outpatient Colonoscopy Volumes in OntarioColonoscopy indicationHospital outpatient colonoscopy volumesBefore Pandemic, March–June 2019 n (%)Pandemic, March–June 2020 n (%)% change, 2020 vs 2019gFOBT+/FIT+4390 (4)4758 (13)8Symptomatic44,651 (42)19,501 (54)–56Family historyaIndividuals at increased risk due to a family history in 1 or more first degree relative(s) with colorectal cancer.10,855 (10)2134 (6)–80SurveillancebIndividuals with a prior polypectomy or colorectal cancer. Prior histology (ie, low- or high-risk adenoma) is not known.28,107 (26)6033 (17)–79Average-risk screeningcIndividuals at average risk for colorectal cancer (ie, no first degree relatives with colorectal cancer).19,031 (18)3603 (10)–81All colonoscopies107,034 (100)36,029 (100)–66FIT, fecal immunochemical test; gFOBT, guaiac fecal occult blood test.a Individuals at increased risk due to a family history in 1 or more first degree relative(s) with colorectal cancer.b Individuals with a prior polypectomy or colorectal cancer. Prior histology (ie, low- or high-risk adenoma) is not known.c Individuals at average risk for colorectal cancer (ie, no first degree relatives with colorectal cancer). Open table in a new tab FIT, fecal immunochemical test; gFOBT, guaiac fecal occult blood test.
Background Spinal tuberculosis is the most common form of musculoskeletal tuberculosis. The expression of matrix metalloproteinase‐1 ( MMP ‐1) is increased in cells with Mycobacterium tuberculosis infection. MMP ‐1 plays a curial role in extracellular matrix degradation during the progression of tuberculosis. Although the 1G/2G polymorphism in MMP ‐1 ‐1607 influences its transcription, its role in spinal tuberculosis remains unknown. Methods Healthy controls and patients with spinal tuberculosis of Han ethnicity were recruited between January 2010 and May 2016. The MMP ‐1 ‐1607 1G/2G polymorphism was genotyped using the Sequenom mass Array polymorphism analysis system. Results The genotypes of 1G/1G, 1G/2G, and 2G/2G were found in 13.7%, 53.6%, and 32.8% of patients, and 12.2%, 37.4%, and 50.4% of controls, respectively. The 1G/2G genotype were more common in cases than in controls ( P =2.05E‐04). The 1G allele showed an association with an increased risk for spinal tuberculosis when compared to 2G allele ( P =.004). 1G genotypes, having at least one 1G allele, were associated with the risk of developing spinal tuberculosis (1G/1G+1G/2G vs 2G/2G: OR =2.084, 95% CI =1.401‐3.100, P =2.65E‐04). Conclusion 1G genotypes of the MMP ‐1 ‐1607 may be associated with susceptibility to spinal tuberculosis in Southern Chinese Han population.
Abstract BACKGROUND Septic shock is a life-threatening subset of sepsis, and blood urea nitrogen (BUN) and serum albumin are inexpensive and easily available biomarkers. BUN to serum albumin ratio (BAR) has been identified as a valuable prognostic marker in various diseases. Therefore, we conducted a retrospective study to explore the relationship between BAR and mortality risk in septic shock. METHODS From 2008 to 2019, we enrolled 3, 220 patients diagnosed with septic shock from the MIMIC-IV database. Restricted cubic spline (RCS) was used to visualize the relationship between BAR and mortality. Kaplan-Meier survival curves were generated to evaluate differences in survival rates among three groups: low-BAR (<9.6), medium-BAR (≥9.6, <20.0), and high-BAR (≥20.0). Box plot analysis was performed to compare the distribution of BAR between survivors and non-survivors. Cox regression analysis was used to estimate the independent association between BAR and all-cause mortality. The receiver operating characteristic (ROC) curve analysis was conducted to assess the performance of BAR for predicting mortality. RESULTS The mean age was 66.1 years. The 28-day mortality risk increased non-linearly with BAR values as shown by RCS. Compared to the low-BAR or medium-BAR group, the high-BAR group had significantly higher mortality according to Kaplan-Meier curves for in-hospital, 28-day, 90-day, and 1-year mortalities. The boxplot demonstrated that patients who survived had lower BAR compare to non-survived in terms of in-hospital, 28-day, 90-day, and 1-year. The results of both the univariate and multivariate Cox regression analysis showed that BAR was an independent risk factor for predicting in-hospital, 28-day, 90-day, and 1-year mortalities, with higher BAR values associated with increasing mortality. For sensitivity analysis, the Cox regression analysis also showed that compared with the low-BAR group, the high-BAR group had a higher risk of in-hospital, 28-day, 90-day, and 1-year mortality rates in both the unadjusted and adjusted models. Conclusions The study showed that BAR was an independent risk factor for predicting both short-term and 1-year mortality rates in septic shock patients.
Objective To construct a rat model of nonalcoholic fatty liver disease (NAFLD) by feeding rats fat-rich diet and analyze the effect of insulin resistance (IR)in the development of NAFLD. Methods Male SD rats were randomly divided into normal diet group (NG, n =24) and fat-rich diet group (FG, n =24). At the end of feeding for2 weeks, 4 weeks, 6 weeks or 8weeks, 6 rats in NG and FG were randomly took out. Their weight were recorded, then the serum fasting blood sugar, fasting insulin, triglyceride, total cholesterol, ala-nine aminotransferase and aspartate aminotransferase were measured, and the fasting insulin resistance index and liver index (liver weight (g)/body weight(g) × 100%)was calculated. Then liver tissues were homogenized, and muleic dialdehyde and superoxide dismutase were determined. The hepatic steatosis in all rats was assessed according to the results under light microscope. Results The body weight of rats in NG increased faster than those in FG after six weeks. The liver index of rats in FG was markedly higher than that in NG since the second weekend. The rats in FG began to have hepatocyte steatosis from the second weekend, had insulin resistance, hyperlipidemia, dysfunction of liver and lipid peroxide of liver from the fourth weekend, suffered mild fatty liver from the sixth weekend, and developed to moderate fatty liv-er from the eighth weekend. Conclusions NAFLD with IR model was successfully developed by feeding SD rats with an improved rich-fat diet for 6 weeks. IR may play an important role in the development of NAFLD.
Key words:
Dietary fats; Disease models,animal; Fatty liver; Insulin resistance
Intrahepatic cholangiocarcinoma (iCCA) is the second most common cancer in liver, with a high recurrence rate after surgery. Recently, we identified a CD11b-CD169-based myeloid response score (MRS), which showed remarkable prognostic potential in hepatocellular carcinoma (HCC). Here, we aimed to verify the prognostic value of the MRS in iCCA and establish an MRS-based nomogram to predict the postoperative prognosis of iCCA patients. From April 2005 to March 2017, a total of 84 patients from the Third Affiliated Hospital of Sun Yat-sen University were enrolled. Preoperative clinical information and surgical specimens of enrolled patients were collected. Among these, tissues from 75 patients passed the clinical data quality control and the staining quality control. The protein expression of CD11b and CD169 in iCCA samples were detected by immunohistochemistry (IHC). Kaplan-Meier analysis and receiver operating characteristic (ROC) curves revealed that the MRS had a high discriminatory ability for predicting the time to recurrence (TTR) of iCCA patients after surgery. Three independent risk factors selected by a Cox proportional hazards regression analysis, namely, the MRS, the tumor size and the status of vascular invasion, were included to construct a nomogram to predict the recurrence of iCCA after resection surgery. ROC curves, calibration analysis and decision curve analysis (DCA) suggested that this nomogram had notable discriminatory power, stability and clinical usefulness in predicting the postoperative recurrence. Together, we explored the prognostic value of the MRS in iCCA, and constructed an MRS-based nomogram which may help to predict postoperative recurrence and aid clinical decisions for iCCA patients.
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