Abstract Extracellular cytokines are enriched in the tumor microenvironment and regulate various important properties of cancers, including autophagy. However, the precise molecular mechanisms underlying the link between autophagy and extracellular cytokines remain to be elucidated. In the present study, we demonstrate that IL-6 activates autophagy through the IL-6/JAK2/BECN1 pathway and promotes chemotherapy resistance in colorectal cancer (CRC). Mechanistically, IL-6 triggers the interaction between JAK2 and BECN1, where JAK2 phosphorylates BECN1 at Y333. We demonstrate that BECN1 Y333 phosphorylation is crucial for BECN1 activation and IL-6-induced autophagy by regulating PI3KC3 complex formation. Furthermore, we investigate BECN1 Y333 phosphorylation as a predictive marker for poor CRC prognosis and chemotherapy resistance. Combination treatment with autophagy inhibitors or pharmacological agents targeting the IL-6/JAK2/BECN1 signaling pathway may represent a potential strategy for CRC cancer therapy.
BACKGROUND Previous studies highlight viral shedding using cycle threshold (Ct) with the RT-PCT for epidemic trajectories of SARS-CoV-2 infection, but assessing Ct values transition kinetics before recovery for surveillance using individual repeated Ct values data is rare. OBJECTIVE We propose a new Ct-enshrined compartment model for understanding viral shedding kinetics in susceptible, pre-symptomatic, and symptomatic compartments before recovery or death. METHODS A series of useful recovery indices are developed to quantify the kinetic movement of Ct-up-down viral shedding toward recovery and are demonstrated with two scenarios, one is small-scale community-acquired Alpha VOC infection under the “zero-COVID-19” policy without available vaccine in May 2021, and the other is large-scale community-acquired Omicron infection with high booster vaccination but lifting the “zero-COVID-19” policy in April 2022 in Taiwan. RESULTS Kinetic indicators revealed Alpha's increased Ct-up transitions, indicative of reduced viral loads, especially among asymptomatic infections. In contrast, Omicron displayed swifter viral shedding and a higher asymptomatic recovery rate. Vaccination showed discernible effects; non-boosted individuals had a 19% higher pre-symptomatic incidence. Sensitivity analysis affirmed the chosen Ct values of 18 and 25, ensuring robust results across recovery phases. CONCLUSIONS The study provides a new insight into the dynamic CT transitions with the notable finding that Ct-up transitions toward recovery outpace Ct-down and symptom-surfacing transitions during the pre-symptomatic phase. The Ct-up against Ct-down transition varies with variants and vaccination status. The proposed Ct-enshrined compartment model is useful for the surveillance of emerging infectious diseases in the future to prevent community-acquired outbreaks.
The association between osteoporosis and periodontal disease (PD) has been revealed by previous studies, but there have been few studies on the association in younger adults. We enrolled a total of 7298 adults aged 40 to 44 who underwent PD screening between 2003 and 2008. Data on quantitative ultrasound for the measurement of bone mineral density (BMD) were collected for the diagnostic criteria of osteopenia and osteoporosis. The Community Periodontal Index (CPI) was measured for defining PD. A multiple logistic regression model was used to assess the effect of low bone mass on the risk of PD. Of 7298 enrollees, 31% had periodontal pockets >3 mm, 36.2% had osteopenia, and 2.1% had osteoporosis. The 39.8% of PD prevalence was high in adults with osteoporosis, followed by 33.3% in osteopenia. A negative association was found between BMD and CPI value (p < 0.0001). Low bone mass was associated with the risk of PD (adjusted OR: 1.13; 95% CI:1.02–1.26) after adjusting the confounding factors, including age, gender, education level, overweight, smoking status, past history of osteoporosis, and diabetes mellitus. An association between BMD and PD among young adults was found. An intervention program for the prevention of PD and osteoporosis could be considered starting in young adults.
Background & AimsWe investigated whether 2 quantitative fecal immunochemical tests (FITs) with the same cutoff concentration of fecal hemoglobin perform equivalently in identifying patients with colorectal cancer (CRC).MethodsA total of 956,005 Taiwanese subjects, 50 to 69 years old, participated in a nationwide CRC screening program to compare results from 2 FITs; 78% were tested using the OC-Sensor (n = 747,076; Eiken Chemical Co, Tokyo, Japan) and 22% were tested using the HM-Jack (n = 208,929; Kyowa Medex Co Ltd, Tokyo, Japan), from 2004 through 2009. The cutoff concentration for a positive finding was 20 μg hemoglobin/g feces, based on a standardized reporting unit system. The tests were compared using short-term and long-term indicators of performance.ResultsThe OC-Sensor test detected CRC in 0.21% of patients, with a positive predictive value of 6.8%. The HM-Jack test detected CRC in 0.17% of patients, with a positive predictive value of 5.2%. The rate of interval cancer rate was 30.7/100,000 person-years among subjects receiving the OC-Sensor test and 40.6/100,000 person-years among those receiving the HM-Jack test; there was significant difference in test sensitivity (80% vs 68%, P = .005) that was related to the detectability of proximal CRC. After adjusting for differences in city/county, age, sex, ambient temperature, and colonoscopy quality, significant differences were observed between the tests in the positive predictive value for cancer detection (adjusted relative risk = 1.29; 95% confidence interval, 1.14–1.46) and the rates of interval cancer (0.75; 95% confidence interval, 0.62–0.92). Although each test was estimated to reduce CRC mortality by approximately 10%, no significant difference in mortality was observed when the 2 groups were compared.ConclusionsDifferent brands of quantitative FITs, even with the same cutoff hemoglobin concentration, perform differently in mass screening. Population-level data should be gathered to verify the credibility of quantitative laboratory findings. We investigated whether 2 quantitative fecal immunochemical tests (FITs) with the same cutoff concentration of fecal hemoglobin perform equivalently in identifying patients with colorectal cancer (CRC). A total of 956,005 Taiwanese subjects, 50 to 69 years old, participated in a nationwide CRC screening program to compare results from 2 FITs; 78% were tested using the OC-Sensor (n = 747,076; Eiken Chemical Co, Tokyo, Japan) and 22% were tested using the HM-Jack (n = 208,929; Kyowa Medex Co Ltd, Tokyo, Japan), from 2004 through 2009. The cutoff concentration for a positive finding was 20 μg hemoglobin/g feces, based on a standardized reporting unit system. The tests were compared using short-term and long-term indicators of performance. The OC-Sensor test detected CRC in 0.21% of patients, with a positive predictive value of 6.8%. The HM-Jack test detected CRC in 0.17% of patients, with a positive predictive value of 5.2%. The rate of interval cancer rate was 30.7/100,000 person-years among subjects receiving the OC-Sensor test and 40.6/100,000 person-years among those receiving the HM-Jack test; there was significant difference in test sensitivity (80% vs 68%, P = .005) that was related to the detectability of proximal CRC. After adjusting for differences in city/county, age, sex, ambient temperature, and colonoscopy quality, significant differences were observed between the tests in the positive predictive value for cancer detection (adjusted relative risk = 1.29; 95% confidence interval, 1.14–1.46) and the rates of interval cancer (0.75; 95% confidence interval, 0.62–0.92). Although each test was estimated to reduce CRC mortality by approximately 10%, no significant difference in mortality was observed when the 2 groups were compared. Different brands of quantitative FITs, even with the same cutoff hemoglobin concentration, perform differently in mass screening. Population-level data should be gathered to verify the credibility of quantitative laboratory findings.
Cognitive flexibility is a personality trait, which can influence how effectively a healthcare professional can manage a challenging clinical situation. This study explored the cognitive flexibility of undergraduate dental hygiene students at two universities in Asia to gather baseline information in order to consider whether there was an educational need for pre-clinical students with regards to this personality factor.
Background: Global transmission from imported cases to domestic cluster infection is often the main route for the resultant community-acquired outbreaks facing the emerging SARS-CoV-2 variants. It is so important to monitor imported cases as to foretell outbreaks given various containment measures. Methods: We used Taiwanese COVID-19 epidemic data, mainly covering D614G and three VOCs (Alpha, Delta, and Omicron) from Jan 2020 to Jan 2022 to estimate the increased risk of domestic cluster infection per one imported case by type of variants given NPIs, test, and vaccination using an extra-Poisson regression model. The upper limit of predicted value one week before is used as the threshold for alerting community-acquired outbreak.Findings: An increase in one imported D614G case prior to one week led to 9·54% (95% CrI 6·44% to 12·59%) higher risk of domestic infection, yielding five clusters with the observed cases beyond the 95% upper limit but they did not lead to any outbreak due to effective contact tracing of infectives and the elevation to NPI level two. The risk of domestic cluster infections in Jan 2021 was gradually elevated to 14·14% (95% CrI 5·41% to 25·10%) until the end of April. The failure of timely contact tracing together with the loose of NPI led to the outbreak of Alpha VOC in mid-May 2021. After stamping out the outbreak with raising level three of NPI and rolling out of vaccination, surveillance of imported cases of Delta VOCs prevented any outbreak until Nov 2021. During Omicron pandemic from mid-Dec 2021 onwards, surveillance of imported cases found the observed cases exceeding the alert threshold around early Jan 2022, leading to a small-scale community-acquired outbreak.Interpretation: The proposed model for monitoring imported cases can be used as a global surveillance tool for forestalling large-scale community-acquired outbreak once SARS-CoV-2 VOCs emerges.Funding Information: This study was funded by Ministry of Science and Technology, Taiwan (MOST 108-2118-M-002-002-MY3; MOST 108-2118-M-038-001-MY3; MOST 108-2118-M-038 -002 -MY3; MOST 109-2327-B-002-009). Declaration of Interests: All authors declare no competing interests.Ethics Approval Statement: This study uses publicly available case line list without any private and identifiable information and does not require IRB approval.
Objectives To summarize debate and research in the Swedish Two-County Trial of mammographic screening on key issues of trial design, endpoint evaluation, and overdiagnosis, and from these to infer promising directions for the future. Methods A cluster-randomized controlled trial of the offer of breast cancer screening in Sweden, with a single screen of the control group at the end of the screening phase forms the setting for a historical review of investigations and debate on issues of design, analysis, and interpretation of results of the trial. Results There has been considerable commentary on the closure screen of the control group, ascertainment of cause of death, and cluster randomization. The issues raised were researched in detail and the main questions answered in publications between 1989 and 2003. Overdiagnosis issues still remain, but methods of estimation taking full account of lead time and of non-screening influences on incidence (taking place mainly before 2005) suggest that it is a minor phenomenon. Conclusion Despite resolution of issues relating to this trial in peer-reviewed publications dating from years, or even decades ago, issues that already have been addressed continue to be raised. We suggest that it would be more profitable to concentrate efforts on current research issues in breast cancer diagnosis, treatment, and prevention.
Abstract Background: Treating marginalized populations with hepatitis C presents a difficult challenge in achieving the 2025 goal of hepatitis C elimination in Taiwan. We report the novel experience of Changhua county in Taiwan in characterizing and treating these populations. Methods: The Changhua integrated program to stop HCV infection (CHIPS-C) adopted a multidisciplinary care approach within marginalized populations and enrolled patients from 2019 Jan to 2020 Dec. This model incorporated active collaboration between different teams with gastroenterologists, psychologists, infectious disease doctors, and nursing coordinators. Results: There were 303 patients who attended methadone clinics, 3222 persons in correctional institutions, 2853 persons within the national HIV surveillance program (noted as “People under surveillance program”), and 731 HIV-positive patients recruited during the study period. 25.41% (73/303) of methadone clinic patients, 17.65% (129/731) of HIV clinic patients, and 44.3% (41/93) of Group B (deferred prosecuted or probationary people under protective parole) within the “People under surveillance program” category were also recruited into other settings during this period of time. Patients in methadone clinics have the highest seroprevalence of HCV (86%), followed by prisoners (45.23%), patients who attended HIV clinics (35%), and patients within groups of the “People under surveillance program” category (2.94% to 59.52%). Overall, the HCV RNA positivity rate is 70% and the treatment rate is 85%. The proportions of RNA testing and treatment are similar among groups. Conclusion: Overlapping characteristics were observed in these populations which highlights that a simultaneous rapid scale-up of treatment was important in these cohorts to lead to HCV elimination.
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