Background
S‐adenosylmethionine decarboxylase proenzyme (AMD1) is a key enzyme involved in the synthesis of spermine (SPM) and spermidine (SPD), which are associated with multifarious cellular ...processes. It is also found to be an oncogene in multiple cancers and a potential target for tumor therapy. Nevertheless, the role AMD1 plays in hepatocellular carcinoma (HCC) is still unknown.
Methods
HCC samples were applied to detect AMD1 expression and evaluate its associations with clinicopathological features and prognosis. Subcutaneous and orthotopic tumor mouse models were constructed to analyze the proliferation and metastasis of HCC cells after AMD1 knockdown or overexpression. Drug sensitive and tumor sphere assay were performed to investigate the effect of AMD1 on HCC cells stemness. Real‐time quantitative PCR (qRT‐PCR), western blot, immunohistochemical (IHC) and m6A‐RNA immunoprecipitation (Me‐RIP) sequencing/qPCR were applied to explore the potential mechanisms of AMD1 in HCC. Furthermore, immunofluorescence, co‐IP (Co‐IP) assays, and mass spectrometric (MS) analyses were performed to verify the proteins interacting with AMD1.
Results
AMD1 was enriched in human HCC tissues and suggested a poor prognosis. High AMD1 level could promote SRY‐box transcription factor 2 (SOX2), Kruppel like factor 4 (KLF4), and NANOG expression of HCC cells through obesity–associated protein (FTO)‐mediated mRNA demethylation. Mechanistically, high AMD1 expression increased the levels of SPD in HCC cells, which could modify the scaffold protein, Ras GTPase‐activating‐like protein 1 (IQGAP1) and enhance the interaction between IQGAP1 and FTO. This interaction could enhance the phosphorylation and decrease the ubiquitination of FTO.
Conclusions
AMD1 could stabilize the interaction of IQGAP1 with FTO, which then promotes FTO expression and increases HCC stemness. AMD1 shows prospects as a prognostic predictor and a therapeutic target for HCC.
AMD1 could stabilize the interaction of IQGAP1 with FTO.
The interaction with IQGAP1 increases FTO phosphorylation and expression.
High level of FTO promotes pluripotency factors expression and elevates stem cell‐like property of HCC cells.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background The purpose of this study was to improve the deep learning (DL) model performance in predicting and classifying IMRT gamma passing rate (GPR) by using input features related to machine ...parameters and a class balancing technique. Methods A total of 2348 fields from 204 IMRT plans for patients with nasopharyngeal carcinoma were retrospectively collected to form a dataset. Input feature maps, including fluence, leaf gap, leaf speed of both banks, and corresponding errors, were constructed from the dynamic log files. The SHAP framework was employed to compute the impact of each feature on the model output for recursive feature elimination. A series of UNet++ based models were trained on the obtained eight feature sets with three fine-tuning methods including the standard mean squared error (MSE) loss, a re-sampling technique, and a proposed weighted MSE loss (WMSE). Differences in mean absolute error, area under the receiver operating characteristic curve (AUC), sensitivity, and specificity were compared between the different models. Results The models trained with feature sets including leaf speed and leaf gap features predicted GPR for failed fields more accurately than the other models (F(7, 147) = 5.378, p < 0.001). The WMSE loss had the highest accuracy in predicting GPR for failed fields among the three fine-tuning methods (F(2, 42) = 14.149, p < 0.001), while an opposite trend was observed in predicting GPR for passed fields (F(2, 730) = 9.907, p < 0.001). The WMSE_FS5 model achieved a superior AUC (0.92) and more balanced sensitivity (0.77) and specificity (0.89) compared to the other models. Conclusions Machine parameters can provide discriminative input features for GPR prediction in DL. The novel weighted loss function demonstrates the ability to balance the prediction and classification accuracy between the passed and failed fields. The proposed approach is able to improve the DL model performance in predicting and classifying GPR, and can potentially be integrated into the plan optimization process to generate higher deliverability plans. Trial registration: This clinical trial was registered in the Chinese Clinical Trial Registry on March 26th, 2020 (registration number: ChiCTR2000031276). Keywords: Deep learning, Prediction, Classification, Quality assurance, Machine parameters, Class imbalance
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objectives We aimed to elucidate the temporal and spatial characteristics of tumor evolution in an oral squamous cell carcinoma (OSCC) mouse model with higher burden of lymphatic metastasis through ...high-throughput sequencing. Methods The OSCC model was established in 9 mice. DNA was extracted from the tumors of primary tongue lesions and disseminated tumor cells (DTCs) of submandibular gland lymph nodes and bone marrow, and then whole genome sequencing was performed. After bioinformatics analysis, somatic single-nucleotide variants (SSNVs) and copy number variations (CNVs) data were obtained. Based on SSNVs, clonal architecture and ancestor-descendant relationships among tumor cell subclones were elucidated. Results A total of 238 tumor-related SSNVs with 120 high-frequency mutated genes were obtained from 36 samples of 9 mice by whole-genome sequencing. The number of unique SSNVs in the primary lesion, submandibular lymph node and bone marrow was greater than the number of shared SSNVs. Furthermore, the primary lesion-originated subclones, which were identified by SSNVs, were also detected in submandibular lymph nodes in the early stage of oral carcinogenesis. Moreover, at different histopathological stages, unique subclones were also identified in DTCs isolated from lymph nodes. Conclusion Tumor heterogeneity is significant in primary tumor cells and disseminated tumor cells. OSCC cells probably disseminate to lymph nodes in the early stage of oral carcinogenesis. OSCC is characterized by polyclonal dissemination, and the evolutionary trajectory of DTCs is potentially dominated by the tumor microenvironment. Keywords: Oral squamous cell carcinoma (OSCC), Disseminated tumor cells (DTCs), Tumor evolution, Whole genome sequencing, Genetic heterogeneity, Tumor microenvironment
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The present study presents the tertiary assembly of a POM, peptide, and biogenic amine, which is a concept to construct new hybrid bio-inorganic materials for antibacterial applications and will help ...to promote the development of antivirus agents in the future. To achieve this, a Eu-containing polyoxometalate (EuW
) was first co-assembled with a biogenic amine of spermine (Spm), which improved both the luminescence and antibacterial effect of EuW
. Further introduction of a basic peptide from HPV E6, GL-22, induced more extensive enhancements, both of them being attributed to the cooperation and synergistic effects between the constituents, particularly the adaptive responses of assembly to the bacterial microenvironment (BME). Further intrinsic mechanism investigations revealed in detail that the encapsulation of EuW
in Spm and further GL-22 enhanced the uptake abilities of EuW
in bacteria, which further improved the ROS generation in BME via the abundant H
O
involved there and significantly promoted the antibacterial effects.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background In people with prediabetes, the link between developing type 2 diabetes (T2D) and cancer risk among those with impaired glucose tolerance (IGT) remains uncertain. We examined this ...association in IGT individuals from primary care in South and West Auckland, New Zealand, spanning 1994-2019, assessing 5- and 10-year cancer risks. Methods Study cohorts were extracted from the Diabetes Care Support Service in Auckland, New Zealand, linking it with national registries for death, cancer, hospital admissions, pharmaceutical claims, and socioeconomic status. We compared cancer risks in individuals with IGT newly diagnosed with or without T2D within a 1-5-year exposure window. Employing tapered matching and landmark analysis to address potential confounding effects, we formed comparative IGT cohorts. Weighted Cox regression models were then employed to assess the association between T2D onset and 5- and 10-year cancer risks. Results The study included 26,794 patients with IGT, with 629 newly diagnosed with T2D within 5 years and 13,007 without such a diagnosis. Those progressing to T2D had similar 5-year cancer risk but significantly higher 10-year risk (HR 1.35; 95% CI 1.09-1.68). This association was stronger in older individuals, the socioeconomically deprived, current smokers, those with worse metabolic measures, and lower renal function. Patients with IGT of NZ European ethnicity had lower 10-year cancer risk. Conclusions T2D diagnosis influences cancer risk in individuals with IGT. Developing risk scores for high-risk IGT individuals and implementing cancer screening and structured diabetes prevention, especially in deprived or minority ethnic populations, is essential. Keywords: Impaired glucose tolerance, Type 2 diabetes, Cancer, Tapered matching, Landmark analysis, New Zealand
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In this paper, a fully automated microassembly methodology is proposed to assemble a slice micropart into a groupware in three-dimensional (3-D) space with the requirement of attitude adjustment. To ...accurately acquire the attitude of the slice micropart, we proposed an automated measurement method based on a laser triangulation measurement instrument (LTMI) guided by microscopic vision as well as an accurate calibration method for the telecentric vision system based on nonlinear damping least square method. To achieve automatic assembly, a three-stage microassembly strategy is presented: 1) attitude adjustment of the groupware based on multimicroscopic vision regarding the slice micropart's attitude as the target; 2) coarse-to-fine alignment of the slice micropart to the groupware in 3-D space on the basis of LTMI and microscopic vision; 3) remove microgripper of slice micropart until itis completely glued. Fully automated microassembly experiments are conducted, and the results demonstrate the reasonability of proposed approaches. The task has been performed with the following accuracy: 3 μm for the center position error, 2 μm for the depth error and 0.3° for the attitude error.
Cardiovascular disease is the leading cause of death among patients receiving peritoneal dialysis. We aimed to develop and validate a risk prediction model for cardiovascular death within 2 years ...after the initiation of peritoneal dialysis (PD). A cohort including all patients registered with the Henan Peritoneal Dialysis Registry (HPDR) between 2007 and 2014. Multivariate logistic regression analysis was used to develop the risk prediction model. The HPDR data was randomly divided into two cohorts with 60% (1,835 patients) for model derivation, and 40% (1,219 patients) for model validation. The absolute rate of cardiovascular mortality was 14.2% and 14.4 in the derivation and validation cohort, respectively. Age, body mass index, blood pressure, serum lipids, fasting glucose, sodium, albumin, total protein, and phosphorus were the strongest predictors of cardiovascular mortality in the final model. Discrimination of the model was similar in both cohorts, with a C statistic above 0.70, with good calibration of observed and predicted risks. The new prediction model that has been developed and validated with clinical measurements that are available at the point of initiation of PD and could serve as a tool to screen for patients at high risk of cardiovascular death and tailor more intensive cardio-protective care.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The Systolic Blood Pressure Intervention Trial (SPRINT) showed significant reductions in death and cardiovascular disease (CVD) risk with a systolic blood pressure (SBP) goal of <120 mm Hg compared ...with a SBP goal of <140 mm Hg. Our study aimed to assess the applicability of SPRINT to Chinese adults. Additionally, we sought to predict the medical and economic implications of this intensive SBP treatment among those meeting SPRINT eligibility.
We used nationally representative baseline data from the China Health and Retirement Longitudinal Study (CHARLS) (2011-2012) to estimate the prevalence and number of Chinese adults aged 45 years and older who meet SPRINT criteria. A validated microsimulation model was employed to project costs, clinical outcomes, and quality-adjusted life-years (QALYs) among SPRINT-eligible adults, under 2 alternative treatment strategies (SBP goal of <120 mm Hg intensive treatment and SBP goal of <140 mm Hg standard treatment). Overall, 22.2% met the SPRINT criteria, representing 116.2 (95% CI 107.5 to 124.8) million people in China. Of these, 66.4%, representing 77.2 (95% CI 69.3 to 85.0) million, were not being treated for hypertension, and 22.9%, representing 26.6 (95% CI 22.4 to 30.7) million, had a SBP between 130 and 139 mm Hg, yet were not taking antihypertensive medication. We estimated that over 5 years, compared to standard treatment, intensive treatment would reduce heart failure incidence by 0.84 (95% CI 0.42 to 1.25) million cases, reduce CVD deaths by 2.03 (95% CI 1.44 to 2.63) million cases, and save 3.84 (95% CI 1.53 to 6.34) million life-years. Estimated reductions of 0.069 (95% CI -0.28, 0.42) million myocardial infarction cases and 0.36 (95% CI -0.10, 0.82) million stroke cases were not statistically significant. Furthermore, over a lifetime, moving from standard to intensive treatment increased the mean QALYs from 9.51 to 9.87 (an increment of 0.38 95% CI 0.13 to 0.71), at a cost of Int$10,997 per QALY gained. Of all 1-way sensitivity analyses, high antihypertensive drug cost and lower treatment efficacy for CVD death resulted in the 2 most unfavorable results (Int$25,291 and Int$18,995 per QALY were gained, respectively). Simulation results indicated that intensive treatment could be cost-effective (82.8% probability of being below the willingness-to-pay threshold of Int$16,782 1× GDP per capita in China in 2017), with a lower probability in people with SBP 130-139 mm Hg (72.9%) but a higher probability among females (91.2%). Main limitations include lack of specific SPRINT eligibility information in the CHARLS survey, uncertainty about the implications of different blood pressure measurement techniques, the use of several sources of data with large reliance on findings from SPPRINT, limited information about the serious adverse event rate, and lack of information and evidence for medication effectiveness on renal disease.
Although adoption of the SPRINT treatment strategy would increase the number of Chinese adults requiring SBP treatment intensification, this approach has the potential to prevent CVD events, to produce gains in life-years, and to be cost-effective under common thresholds.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study is focused on the uptake of PLGA particles with different coatings and its influences on the functions and toxicity of human endothelial cells. The PLGA particles coated with ...polyethyleneimine (PEI) or bovine serum albumin (BSA) were prepared via a one-step emulsion method, which had a similar diameter of ∼420 nm in water and ∼170 nm in a dry state but oppositely charged surfaces. Both types of the particles were readily internalized into cells within a short time regardless of their surface chemistry. Uptake of the positively charged particles caused apparently a decrease in cell viability, but did not significantly influence mitochondrial membrane potential and activity of caspase-3. The cell adhesion and migration were significantly affected, especially after uptake of the PLGA-PEI particles. The secretion levels of von Willebrand factor (vWF) and 6-k-PGF1α were not significantly influenced regardless of the surface coating.
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IJS, KILJ, NUK, PNG, UL, UM
New Zealand (NZ) research into type 1 diabetes mellitus (T1DM) mortality can inform policy and future research. In this study we aimed to quantify the magnitude to which ethnicity and socioeconomic ...disparities influenced mortality at the population level among people with Type 1 diabetes (T1DM) in Auckland, New Zealand (NZ).
The cohort data were derived from the primary care diabetes audit program the Diabetes Care Support Service (DCSS), and linked with national primary care, pharmaceutical claims, hospitalisation, and death registration databases. People with T1DM enrolled in DCSS between 1994-2018 were included. All-cause, premature, and cardiovascular mortalities were estimated by Poisson regression models with adjustment for population-level confounders. The mortality rates ratio (MRR) was standardized against the DCSS type 2 diabetes population. Mortality rates were compared by ethnic group (NZ European (NZE) and non-NZE) and socioeconomic deprivation quintile. The population attributable fraction (PAF) was estimated for ethnic and socioeconomic disparities by Cox regression adjusting for demographic, lifestyle, and clinical covariates. The adjusted slope index inequality (SII) and relative index of inequality (RII) were used to measure the socioeconomic disparity in mortalities.
Overall, 2395 people with T1DM (median age 34.6 years; 45% female; 69% NZE) were enrolled, among whom the all-cause, premature and CVD mortalities were 6.69 (95% confidence interval: 5.93-7.53), 3.30 (2.77-3.90) and 1.77 (1.39-2.23) per 1,000 person-years over 25 years. The overall MRR was 0.39 (0.34-0.45), 0.65 (0.52-0.80), and 0.31 (0.24-0.41) for all-cause, premature and CVD mortality, respectively. PAF attributable to ethnicity disparity was not significantly different for mortality. The adjusted PAF indicated that 25.74 (0.84-44.39)% of all-cause mortality, 25.88 (0.69-44.69)% of premature mortality, 55.89 (1.20-80.31)% of CVD mortality could be attributed to socioeconomic inequality. The SII was 8.04 (6.30-9.78), 4.81 (3.60-6.02), 2.70 (1.82-3.59) per 1,000 person-years and RII was 2.20 (1.94-2.46), 2.46 (2.09-2.82), and 2.53 (2.03-3.03) for all-cause, premature and CVD mortality, respectively.
Our results suggest that socioeconomic disparities were responsible for a substantial proportion of all-cause, premature and CVD mortality in people with T1DM in Auckland, NZ. Reducing socioeconomic barriers to management and self-management would likely improve clinical outcomes.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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