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1.
Phys Med Biol ; 2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34818638

RESUMEN

OBJECTIVE: Robustness is an important aspect to consider, when developing methods for medical image analysis. This study investigated robustness properties of deep neural networks (DNNs) for a lung nodule classification problem based on CT images and proposed a solution to improve robustness. APPROACH: We firstly constructed a class of four DNNs with different widths, each predicting an output label (benign or malignant) for an input CT image cube containing a lung nodule. These networks were trained to achieve Area Under the Curve of 0.891-0.914 on a testing dataset. We then added to the input CT image cubes noise signals generated randomly using a realistic CT image noise model based on a noise power spectrum at 100 mAs, and monitored the DNN's output change. We defined $SAR_{5} (\%)$ to quantify the robustness of the trained DNN model, indicating that for $5\%$ of CT image cubes, the noise can change the prediction results with a chance of at least $SAR_{5} (\%)$. To understand robustness, we viewed the information processing pipeline by the DNN as a two-step process, with the first step using all but the last layers to extract representations of the input CT image cubes in a latent space, and the second step employing the last fully-connected layer as a linear classifier to determine the position of the sample representations relative to a decision plane. To improve robustness, we proposed to retrain the last layer of the DNN with a Supporting Vector Machine (SVM) hinge loss function to enforce the desired position of the decision plane. MAIN RESULTS: $SAR_{5}$ ranged in $47.0\sim 62.0\%$ in different DNNs. The unrobustness behavior may be ascribed to the unfavorable placement of the decision plane in the latent representation space, which made some samples be perturbed to across the decision plane and hence susceptible to noise. The DNN-SVM model improved robustness over the DNN model and reduced $SAR_{5}$ by $8.8\sim 21.0\%$. SIGNIFICANCE: This study provided insights about the potential reason for the unrobustness behavior of DNNs and the proposed DNN-SVM model improved model robustness.

2.
ACS Appl Mater Interfaces ; 13(46): 55412-55419, 2021 Nov 24.
Artículo en Inglés | MEDLINE | ID: mdl-34756020

RESUMEN

Metal halide perovskites have attracted extensive attention in next-generation solid-state lighting and displays due to their fascinating optoelectronic properties. However, the toxicity of lead (Pb) impedes their practical application. Herein, we report an efficient Zn-alloyed quasi-two-dimensional (quasi-2D) pure-red perovskite light-emitting device (PeLED) by introducing zinc ions (Zn2+) into the perovskite lattice and partially substituting Pb2+. The substitution of Zn2+ is confirmed by X-ray diffraction, X-ray photoelectron spectroscopy, grazing-incidence wide-angle X-ray scattering, and transmission electron microscopy measurements. In addition, the vacancy defect density of Pb and the halogen is reduced by the introduction of Zn2+ in the PEA2(Cs0.3MA0.7)2(ZnxPb1-x)3I10 perovskite system, which leads to a more ordered crystal orientation, compact morphology, and increased photoluminescence quantum efficiency. Benefiting from the improved photoelectric properties, a maximum EQE of 9.5% and a luminescence of 453 cd m-2 are achieved for the Zn-alloyed PeLEDs, with a maximum emission peak of 658 nm and stable electroluminescence spectra under various applied biases.

3.
Artículo en Inglés | MEDLINE | ID: mdl-34764998

RESUMEN

Objective: Coinfection of tuberculosis (TB) and viral hepatitis may increase the risk of antituberculosis treatment-induced hepatotoxicity, which is regarded as a common cause of termination of the first-line antituberculosis drugs. The study aimed at investigating the protective effects of antiviral therapy on the liver and innate immunity in patients with TB-HBV coinfection. Methods: A total of 100 patients with TB-HBV coinfection were recruited and split into antituberculosis and antiviral groups, 50 per group, according to odd or even date of hospital admission from December 2019 to October 2020. The patients in the anti-TB group received antituberculosis therapy, and those in the antiviral group received antiviral therapy. The clinical effectiveness; HBV-DNA negative conversion rate; liver function assessment involving alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL); immune function evaluation including CD4+, CD8+, CD4+/CD8+, and CD3+ T cells; inflammatory cytokines containing tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interferon-γ (IFN-γ); and intestinal microflora including bifidobacterium, lactobacillus, enterobacterium, enterococcus, and clostridium were main outcome measures after treatment. Results: It was found that the total response rate in the antiviral group was significantly higher than the anti-TB group after treatment (χ 2 = 3.157, P=0.017). There was a significant difference in HBV-DNA negative conversion rates between the antiviral group and anti-TB group (82% vs. 58%, χ 2 = 6.384, P=0.001). The ALT, AST, and TBIL in the two groups were all increased after treatment (P < 0.05), but the antiviral group indicated a rise of the above indices compared to the anti-TB group (P < 0.05). The two groups showed a rise on the concentration of CD3+, CD4+, and CD4+/CD8+ T cells and a decline on the CD8+ T cells after treatment (P < 0.05), but these changes in the antiviral group were more evident to those in the anti-TB group (P < 0.05). There was an increase on the IFN-γ level and decrease on the TNF-α and IL-6 levels in both groups after treatment (P < 0.05), but the antiviral group revealed a higher level of IFN-γ with lower levels of TNF-α and IL-6 compared to the anti-TB group (P < 0.05). After treatment, the number of bifidobacteria and lactobacilli was increased, and the number of enterobacteria, enterococci, and clostridium were decreased in the two groups (P < 0.05), while these changes in the antiviral group were more remarkable compared to the anti-TB group (P < 0.05). There was no significant difference in the incidence of adverse reactions between the two groups (χ2 = 0.267, P=0.731). Conclusion: Antiviral therapy for tuberculosis-HBV coinfected patients could inhibit HBV replication, providing protection against liver damage, improving innate immunity, and balancing intestinal microflora.

4.
EBioMedicine ; 74: 103712, 2021 Nov 25.
Artículo en Inglés | MEDLINE | ID: mdl-34839261

RESUMEN

BACKGROUND: Despite clinical success with anti-spike vaccines, the effectiveness of neutralizing antibodies and vaccines has been compromised by rapidly spreading SARS-CoV-2 variants. Viruses can hijack the glycosylation machinery of host cells to shield themselves from the host's immune response and attenuate antibody efficiency. However, it remains unclear if targeting glycosylation on viral spike protein can impair infectivity of SARS-CoV-2 and its variants. METHODS: We adopted flow cytometry, ELISA, and BioLayer interferometry approaches to assess binding of glycosylated or deglycosylated spike with ACE2. Viral entry was determined by luciferase, immunoblotting, and immunofluorescence assays. Genome-wide association study (GWAS) revealed a significant relationship between STT3A and COVID-19 severity. NF-κB/STT3A-regulated N-glycosylation was investigated by gene knockdown, chromatin immunoprecipitation, and promoter assay. We developed an antibody-drug conjugate (ADC) that couples non-neutralization anti-spike antibody with NGI-1 (4G10-ADC) to specifically target SARS-CoV-2-infected cells. FINDINGS: The receptor binding domain and three distinct SARS-CoV-2 surface N-glycosylation sites among 57,311 spike proteins retrieved from the NCBI-Virus-database are highly evolutionarily conserved (99.67%) and are involved in ACE2 interaction. STT3A is a key glycosyltransferase catalyzing spike glycosylation and is positively correlated with COVID-19 severity. We found that inhibiting STT3A using N-linked glycosylation inhibitor-1 (NGI-1) impaired SARS-CoV-2 infectivity and that of its variants [Alpha (B.1.1.7) and Beta (B.1.351)]. Most importantly, 4G10-ADC enters SARS-CoV-2-infected cells and NGI-1 is subsequently released to deglycosylate spike protein, thereby reinforcing the neutralizing abilities of antibodies, vaccines, or convalescent sera and reducing SARS-CoV-2 variant infectivity. INTERPRETATION: Our results indicate that targeting evolutionarily-conserved STT3A-mediated glycosylation via an ADC can exert profound impacts on SARS-CoV-2 variant infectivity. Thus, we have identified a novel deglycosylation method suitable for eradicating SARS-CoV-2 variant infection in vitro. FUNDING: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

5.
Front Cardiovasc Med ; 8: 730508, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34722663

RESUMEN

Purpose: A low ABI, ≦0.9, indicates peripheral artery disease (PAD) and physical activity (PA) represents an important non-surgical treatment for patients with PAD. However, as for the general population, the associations between PA, PAD, and their mutual dependence are not well-defined. Here we aimed to determine whether there is a dose-response relationship between PA and incidence of PAD in the general population using restricted cubic spline (RCS). Patients and methods: This study analyzed 1,370 adults aged ≧40 years who had participated in the National Health and Nutrition Examination Survey (NHANES) during 1999-2004. The ABI of the participants were measured by trained technicians, and PAD was defined as ABI ≦0.9. PA was obtained with a standard questionnaire, and metabolic equivalents (MET) were used to quantify the PA level. Logistic regression was used to assess the association between PA and incidence of PAD, and the dose-response relationship was analyzed with RCS. Results: PAD was present in 6.2% of the participants: 5.6% of males and 6.9% of females. After adjusting for potential confounders, compared with the first quartile (Q1) of MET, the odds ratios (ORs) of PAD for those with Q2, Q3, and Q4 of MET were 0.688 [95% confidence interval (CI) = 0.684-0.692], 0.463 (95% CI = 0.460-0.466), 0.816 (95% CI = 0.812-0.821), respectively (all p < 0.0001). The RCS regression showed that physical activity was related to the incidence of PAD in a non-linear manner (p for non-linearity < 0.0001). For females, the prevalence of PAD decreased as physical activity increased, reaching the minimum for activity at ~5,800 MET-min month-1 (OR = 0.425, 95% CI = 0.424-0.426), and for males, no plateau was found in this study. Conclusion: The prevalence of PAD is inversely associated with PA, and vigorous activities might help decrease PAD risk for general population. The prevalence of PAD reaches the minimum at ~5,800 MET-min month-1, representing a recommended PA value.

6.
Phys Med Biol ; 2021 Nov 09.
Artículo en Inglés | MEDLINE | ID: mdl-34753117

RESUMEN

Cone-beam CT (CBCT) in modern pre-clinical small-animal radiation research platforms provides volumetric images for image guidance and experiment planning purposes. In this work, we implemented multi-energy element-resolved (MEER) CBCT using three scans with different kVps on a SmART platform (Precision X-ray Inc.) We performed comprehensive calibration tasks achieve sufficient accuracy for this quantitative imaging purpose. For geometry calibration, we scanned a ball bearing phantom and used an analytical method together with an optimization approach to derive gantry-angle specific geometry parameters. Intensity calibration and correction included the corrections for detector lag, glare, and beam hardening. The corrected CBCT projection images acquired at 30, 40 and 60 kVp in multiple scans were used to reconstruct CBCT images using the Feldkamp-Davis-Kress reconstruction algorithm. After that, an optimization problem was solved to determine images of relative electron density (rED) and elemental composition (EC) that are needed for Monte Carlo-based radiation dose calculation. We demonstrated effectiveness of our CBCT calibration steps by showing improvements in image quality and successful material decomposition in cases with a small animal CT calibration phantom and a plastinated mouse phantom. It was found that artifacts induced by geometry inaccuracy, detector lag, glare and beam hardening were visually reduced. CT number mean errors were reduced from 19\% to 5\%. In the CT calibration phantom case, median errors in H, O, and Ca fractions for all the inserts were below 1\%, 2\%, and 4\% respectively, and median error in rED was less than 5\%. Compared to standard approach deriving material type and rED via CT number conversion, our approach improved Monte Carlo simulation-based dose calculation accuracy in bone regions. Mean dose error was reduced from 47.5\% to 10.9\%.

7.
J Environ Sci (China) ; 110: 38-47, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-34593193

RESUMEN

To assess groundwater nitrate contamination and its human health risks, 489 unconfined groundwater samples were collected and analyzed from Zhangjiakou, northern China. The spatial distribution of principle hydrogeochemical results showed that the average concentrations of ions in descend order was HCO3-, SO42-, Na+, Ca2+, Cl-, NO3-, Mg2+ and K+, among which the NO3- concentrations were between 0.25 and 536.73 mg/L with an average of 29.72 mg/L. In total, 167 out of 489 samples (~ 34%) exceeded the recommended concentration of 20 mg/L in Quality Standard for Groundwater of China. The high NO3- concentration groundwater mainly located in the northern part and near the boundary of the two geomorphic units. As revealed by statistical analysis, the groundwater chemistry was more significantly affected by anthropogenic sources than by the geogenic sources. Moreover, human health risks of groundwater nitrate through oral and dermal exposure pathways were assessed by model, the results showed that about 60%, 50%, 32% and 26% of the area exceeded the acceptable level (total health index>1) for infants, children, adult males and females, respectively. The health risks for different groups of people varied significantly, ranked: infants> children> adult males>adult females, suggesting that younger people are more susceptible to nitrate contamination, while females are more resistant to nitrate contamination than males. To ensure the drinking water safety in Zhangjiakou and its downstream areas, proper management and treatment of groundwater will be necessary to avoid the health risks associated with nitrate contamination.


Asunto(s)
Agua Subterránea , Contaminantes Químicos del Agua , China , Monitoreo del Ambiente , Femenino , Humanos , Masculino , Nitratos/análisis , Medición de Riesgo , Contaminantes Químicos del Agua/análisis , Contaminantes Químicos del Agua/toxicidad
8.
J Magn Reson ; 332: 107062, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34601187

RESUMEN

Small animal radiation experiments are of paramount importance for the advancement of human radiation therapy. These experiments use a dedicated radiation platform to deliver radiation to small animals, such as mice and rats, similar to how human radiation therapy is performed. By acquiring images immediately before radiation delivery to guide positioning of the animals, image guidance plays a critical role to ensure accuracy of the experiments. Recently, MR-based image guidance has been enabled in human radiation therapy. This paper proposes a new concept using a unilateral magnet-based MRI scanner to realize image guidance for small animal radiation experiments. We reported our design, optimization, construction, and characterization of the magnet. The magnet was designed using eight 2-inch neodymium magnet cubes arranged in a modified Halbach ring configuration. The ring has an opening to allow for animal positioning. We considered a spherical region of interest (ROI) located outside of the ring's plane to allow radiation delivery to the ROI without obstruction of the magnet. An optimization problem was formulated and solved to determine the positions and orientations of the magnet cubes to generate a magnetic field with desired properties in the ROI. The optimization improved the average magnetic flux density from 55 mT to 72 mT and reduced variation from 1.2 T/m to 1.0 T/m. We constructed the magnet using 3D-printed templates to hold the neodymium magnet cubes with the optimized positions and orientations. We measured the spatial distribution of the magnetic flux density. The measurement results and computed results agreed with an average difference of 0.35% through the ROI.

9.
Am J Cancer Res ; 11(8): 3921-3934, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34522458

RESUMEN

The causal relationship between body mass index (BMI) and type 2 diabetes (T2D) and breast cancer prognosis is still ambiguous. The aim of this study was to investigate the prognostic effect of BMI and T2D on breast cancer disease-free survival (DFS) among Asian individuals. In this two-sample Mendelian randomization (MR) study, the instrumental variables (IVs) were identified using a genome-wide association study (GWAS) among 24,000 participants in the Taiwan Biobank. Importantly, the validity of these IVs was confirmed with a previous large-scale GWAS (Biobank Japan Project, BBJ). In this study, we found that a genetic predisposition toward higher BMI (as indicated by BMI IVs, F = 86.88) was associated with poor breast cancer DFS (hazard ratio [HR] = 6.11; P < 0.001). Furthermore, higher level of genetically predicted T2D (as indicated by T2D IVs) was associated with an increased risk of recurrence of and mortality from breast cancer (HR = 1.43; P < 0.001). Sensitivity analyses, including the weighted-median approach, MR-Egger regression, Radial regression and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) supported the consistency of our findings. Finally, the causal relationship between BMI and poor breast cancer prognosis was confirmed in a prospective cohort study. Our MR analyses demonstrated the causal relationship between the genetic prediction of elevated BMI and a greater risk of T2D with poor breast cancer prognosis. BMI and T2D have important clinical implications and may be used as prognostic indicators of breast cancer.

10.
Adv Mater ; 33(43): e2103268, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-34545631

RESUMEN

Quasi-2D perovskites have long been considered to have favorable "energy funnel/cascade" structures and excellent optical properties compared with their 3D counterparts. However, most quasi-2D perovskite light-emitting diodes (PeLEDs) exhibit high external quantum efficiency (EQE) but unsatisfactory operating stability due to Auger recombination induced by high current density. Herein, a synergetic dual-additive strategy is adopted to prepare perovskite films with low defect density and high environmental stability by using 18-crown-6 and poly(ethylene glycol) methyl ether acrylate (MPEG-MAA) as the additives. The dual additives containing COC bonds can not only effectively reduce the perovskite defects but also destroy the self-aggregation of organic ligands, inducing the formation of perovskite nanocrystals with quasi-core/shell structure. After thermal annealing, the MPEG-MAA with its CC bond can be polymerized to obtain a comb-like polymer, further protecting the passivated perovskite nanocrystals against water and oxygen. Finally, state-of-the-art green PeLEDs with a normal EQE of 25.2% and a maximum EQE of 28.1% are achieved, and the operating lifetime (T50 ) of the device in air environment is over ten times increased, providing a novel and effective strategy to make high efficiency and long operating lifetime PeLEDs.

11.
Front Immunol ; 12: 692263, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34497603

RESUMEN

IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.

13.
Phys Med Biol ; 66(11)2021 05 31.
Artículo en Inglés | MEDLINE | ID: mdl-34061043

RESUMEN

Adaptive-radiation-therapy (ART) is applied to account for anatomical variations observed over the treatment course. Daily or weekly cone-beam computed tomography (CBCT) is commonly used in clinic for patient positioning, but CBCT's inaccuracy in Hounsfield units (HU) prevents its application to dose calculation and treatment planning. Adaptive re-planning can be performed by deformably registering planning CT (pCT) to CBCT. However, scattering artifacts and noise in CBCT decrease the accuracy of deformable registration and induce uncertainty in treatment plan. Hence, generating from CBCT a synthetic CT (sCT) that has the same anatomical structure as CBCT but accurate HU values is desirable for ART. We proposed an unsupervised style-transfer-based approach to generate sCT based on CBCT and pCT. Unsupervised learning was desired because exactly matched CBCT and CT are rarely available, even when they are taken a few minutes apart. In the proposed model, CBCT and pCT are two inputs that provide anatomical structure and accurate HU information, respectively. The training objective function is designed to simultaneously minimize (1) contextual loss between sCT and CBCT to maintain the content and structure of CBCT in sCT and (2) style loss between sCT and pCT to achieve pCT-like image quality in sCT. We used CBCT and pCT images of 114 patients to train and validate the designed model, and another 29 independent patient cases to test the model's effectiveness. We quantitatively compared the resulting sCT with the original CBCT using the deformed same-day pCT as reference. Structure-similarity-index, peak-signal-to-noise-ratio, and mean-absolute-error in HU of sCT were 0.9723, 33.68, and 28.52, respectively, while those of CBCT were 0.9182, 29.67, and 49.90, respectively. We have demonstrated the effectiveness of the proposed model in using CBCT and pCT to synthesize CT-quality images. This model may permit using CBCT for advanced applications such as adaptive treatment planning.


Asunto(s)
Aprendizaje Profundo , Tomografía Computarizada de Haz Cónico Espiral , Tomografía Computarizada de Haz Cónico , Humanos , Planificación de la Radioterapia Asistida por Computador
14.
Cancers (Basel) ; 13(10)2021 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-34069208

RESUMEN

In this study we aim to examine gene-environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10-3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10-4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.

15.
Phys Med Biol ; 66(13)2021 Jun 23.
Artículo en Inglés | MEDLINE | ID: mdl-34107460

RESUMEN

Purpose.We have previously proposed an intelligent automatic treatment planning (IATP) framework that builds a virtual treatment planner network (VTPN) to operate a treatment planning system (TPS) to generate high-quality radiation therapy (RT) treatment plans. While the potential of IATP in automating RT treatment planning has been demonstrated, its poor scalability caused by an almost linear growth of network size with the number of treatment planning parameters (TPPs) is a bottleneck, preventing its application in complicate, but clinically relevant treatment planning problems. The decision-making behavior of the trained network is hard to understand. Motivated by the decision-making process of a human planner, this study proposes a hierarchical IATP framework.Methods and materials.The hierarchical VTPN (HieVTPN) consists of three networks, i.e. Structure-Net, Parameter-Net, and Action-Net. When interacting with a TPS, the networks are employed in a sequential order in each step to decide the structure to adjust, the TPP to adjust for the selected structure, and the specific adjustment manner for the parameter, respectively. We developed an end-to-end hierarchical deep reinforcement learning scheme to simultaneously train the three networks. We then evaluated the effectiveness of the proposed framework in the treatment planning problems for prostate cancer intensity modulated RT (IMRT) and stereotactic body RT (SBRT). We benchmarked the performance of our approach by comparing plans made by VTPN of a parallel architecture, and the human plans submitted for competition in the 2016 American Association of Medical Dosimetrist (AAMD)/Radiosurgery Society (RSS) Plan Study. We analyzed scalability of the network size with respect to the number of TPPs. Numerical experiments were also performed to understand the rationale of the decision-making behaviors of the trained HieVTPN.Results.Both HieVTPNs for prostate IMRT and SBRT were trained successfully using 10 training patient cases and 5 validation cases. For IMRT, HieVTPN was able to generate high-quality plans for 59 testing patient cases that were not included in training process, achieving an average plan score of 8.62 (±0.83), with 9 being the maximal score. The score was comparable to that of the VTPN, 8.45 (±0.48). For SBRT planning, HieVTPN achieved an average plan score of 139.07 on five testing patient cases compared to the score of 132.21 averaged over the human plans summited for competition in AAMD/RSS plan study. Different from VTPN with network size linearly scaling with the number of TPPs, the network size of HieVTPN is almost independent of the number of TPPs. It was also observed that the decision-making behaviors of HieVTPN were understandable and generally agreed with the human experience.Conclusions.With the scalability and explainability, the hierarchical IATP framework is more favorable than the previous framework in terms of handling treatment planning problems involving a large number of TPPs.

16.
Cancers (Basel) ; 13(11)2021 May 25.
Artículo en Inglés | MEDLINE | ID: mdl-34070538

RESUMEN

Elevated expression of C-X-C motif chemokine receptor 4 (CXCR4) correlates with chemotaxis, invasion, and cancer stem cell (CSC) properties within several solid-tumor malignancies. Recent studies reported that microRNA (miRNA) modulates the stemness of embryonic stem cells. We aimed to investigate the role of miRNA, via CXCR4-modulation, on CSC properties in breast cancer using cell lines and xenotransplantation mouse model and evaluated miR-193 levels in 191 patients with invasive ductal carcinoma. We validated miR-139 directly targets the 3'-untranslated region of CXCR4. Hoechst 33342 fluorescence-activated cell sorting (FACS) and sphere-forming assay were used to identify CSCs. MiR-139 suppressed breast CSCs with mesenchymal traits; led to decreased migration and invasion abilities through down-regulating CXCR4/p-Akt signaling. In lung cancer xenograft model of nude mice transplanted with human miR-139-carrying MDA-MB-231 cells, metastatic lung nodules were suppressed. Clinically, microdissected breast tumor tissues showed miR-139 reduction, compared to adjacent non-tumor tissues, that was significantly associated with worse clinicopathological features, including larger tumor size, advanced tumor stage and lymph node metastasis; moreover, reduced miR-139 level was predominately occurred in late-stage HER2-oreexpression tumors. Collectively, our findings highlight miR-139-mediated suppression of CXCR4/p-Akt signaling and thereby affected mesenchymal stem-cell genesis, indicating its potential as a therapeutic target for invasive breast cancer.

17.
Hepatology ; 74(4): 1994-2006, 2021 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33942350

RESUMEN

BACKGROUND AND AIMS: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes. CONCLUSIONS: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC.

18.
J Viral Hepat ; 28(9): 1265-1273, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34003538

RESUMEN

Information on genetic variants associated with elevated serum alanine aminotransferase (ALT) levels remains limited. A genome-wide association study was performed to identify single-nucleotide polymorphisms (SNPs) associated with ALT levels. The ALT-associated SNP was further evaluated for hepatocellular carcinoma (HCC) risk. A cohort of 892 anti-HCV seropositive patients was used for genome-wide SNP array to examine the associations with baseline ALT levels. SNPs <10-5 were further tested for associations with serial ALT levels then validated in 486 anti-HCV seropositives. Multinomial logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals of SNPs associated with ALT. The SNP was evaluated for HCC risk by using Cox's proportional hazards models. After quality control, 803 participants with 564,464 SNPs were included in the analysis. Of these, 12 SNPs were associated with ALT (p < 10-5 ). Among the participants, 158 (19.7%) had ALT persistently ≤15 U/L, 327 (40.7%) ever >15 U/L but never >45 U/L, and 318 (39.6%) ever >45 U/L during follow-up. The rs568800 was associated with serial ALT levels, and this was replicated in the external population significantly (p < .05). The A allele (vs C) of rs568800 was associated with ALT >15 U/L but ≤45 U/L and ALT >45 U/L, with the adjusted ORs of 1.41 (1.11-1.78) and 1.86 (1.34-2.60), respectively. The adjusted HRs for HCC were 2.09 (0.90-4.89) for AC and 2.64 (1.13-6.17) for AA (CC as a reference). In conclusion, the rs568800 was associated with serum ALT levels and HCC risk. Clinical utility should be evaluated among patients who have received antivirals.


Asunto(s)
Carcinoma Hepatocelular , Hepatitis C , Neoplasias Hepáticas , Alanina Transaminasa , Carcinoma Hepatocelular/genética , Estudio de Asociación del Genoma Completo , Hepacivirus/genética , Hepatitis C/genética , Humanos , Neoplasias Hepáticas/genética
19.
J Adv Res ; 30: 147-158, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-34026292

RESUMEN

Introduction: A population-specific genomic reference is important for research and clinical practice, yet it remains unavailable for Han Chinese (HC) in Taiwan. Objectives: We report the first whole genome sequencing (WGS) database of HC (1000 Taiwanese genome (1KTW-WGS)) and demonstrate several applications to cardiovascular medicine. Methods: Whole genomes of 997 HC were sequenced to at least 30X depth. A total of 20,117 relatively healthy HC individuals were genotyped using a customized Axiom GWAS array. We performed a genome-wide genotype imputation technique using IMPUTE2. Results: We identified 26.7 million single-nucleotide variants (SNVs) and 4.2 million insertions-deletions. Of the SNVs, 16.1% were novel relative to dbSNP (build 152), and 34.2% were novel relative to gnomAD. A total of 18,450 healthy HC individuals were genotyped using a customized Genome-Wide Association Study (GWAS) array. We identified hypertension-associated variants and developed a hypertension prediction model based on the correlation between the WGS data and GWAS data (combined clinical and genetic models, AUC 0.887), and also identified 3 novel hyperlipidemia-associated variants. Each individual carried an average of 16.42 (SD = 3.72) disease-causing variants. Additionally, we established an online SCN5A (an important cardiac gene) database that can be used to explore racial differences. Finally, pharmacogenetics studies identified HC population-specific SNVs in genes (CYP2C9 and VKORC1) involved in drug metabolism and blood clotting. Conclusion: This research demonstrates the benefits of constructing a population-specific genomic reference database for precision medicine.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Enfermedades Cardiovasculares/genética , Secuenciación Completa del Genoma/métodos , Enfermedades Cardiovasculares/sangre , China , Bases de Datos Factuales , Femenino , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Hiperlipidemias/genética , Hipertensión/genética , Mutación INDEL , Masculino , Polimorfismo de Nucleótido Simple , Taiwán , Vitamina K Epóxido Reductasas/genética
20.
Ann Vasc Surg ; 75: 294-300, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-33819595

RESUMEN

OBJECTIVE: Isolated true subclavian artery aneurysm (SAA) without aberrant subclavian artery or coarctation of descending aorta is a rare peripheral aneurysm. Herein, the experience of our medical center in the treatment of this disease is presented. METHODS: The Division operative log was queried to identify cases of SAA repair between January 2012 and September 2019 that were not associated with coarctation of the aorta or the presence of an aberrant subclavian artery. A total of 22 cases were identified. The characteristics, treatment and clinical outcomes of these cases were assessed. RESULTS: The mean age of patients was 53.5 ± 14.3 years and 14 patients were male (63.6%). Half of the cases were attributed to atherosclerotic degeneration. The clinical symptoms of aneurysms were varied, including asymptomatic, pulsatile mass of supraclavicular fossa, local pain, upper limb embolism, Horner's syndrome and hoarseness. Aneurysms were located on the right in 17 cases, on the left in 3 cases and on both sides in 2 cases. Fifteen (68%) patients underwent an intervention, of which 11 (50%) underwent an open surgical repair, and 4 (18%) underwent endovascular repair. The mean diameter of the aneurysms was 39.5 ± 20.7 mm in the open surgery group, and 24.0 ± 4.7 mm in the endovascular group. The follow-up duration ranged from 2 months to 12 years. One patient died of cardiogenic disease in the untreated group. Patients undergoing open operative repair had 100% patency of the reconstruction. In the endovascular group, one patient had stent occlusion 2 years after the operation. CONCLUSIONS: The most common cause of isolated subclavian aneurysm without aberrant subclavian artery or coarctation of descending aorta is atherosclerosis. The clinical symptoms of aneurysms are varied, and the aneurysms tend to occur on the right side. Based on the anatomical conditions of SAAs, open surgery and endovascular repair can be used for treatment.

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