Assessment of human leukocyte antigen-based neoantigen presentation to determine pan-cancer response to immunotherapy.

Despite the central role of human leukocyte antigen class I (HLA-I) in tumor neoantigen presentation, quantitative determination of presentation capacity remains elusive. Based on a pooled pan-cancer genomic dataset of 885 patients treated with immune checkpoint inhibitors (ICIs), we developed a score integrating the binding affinity of neoantigens to HLA-I, as well as HLA-I allele divergence, termed the HLA tumor-Antigen Presentation Score (HAPS). Patients with a high HAPS were more likely to experience survival benefit following ICI treatment. Analysis of the tumor microenvironment indicated that the antigen presentation pathway was enriched in patients with a high HAPS. Finally, we built a neural network incorporating factors associated with neoantigen production, presentation, and recognition, which exhibited potential for differentiating cancer patients likely to benefit from ICIs. Our findings highlight the clinical utility of evaluating HLA-I tumor antigen presentation capacity and describe how ICI response may depend on HLA-mediated immunity.

Delivery and Transcriptome Assessment of an In Vitro Three-Dimensional Proximal Tubule Model Established by Human Kidney 2 Cells in Clinical Gelatin Sponges.

The high prevalence of kidney diseases and the low identification rate of drug nephrotoxicity in preclinical studies reinforce the need for representative yet feasible renal models. Although in vitro cell-based models utilizing renal proximal tubules are widely used for kidney research, many proximal tubule cell (PTC) lines have been indicated to be less sensitive to nephrotoxins, mainly due to altered expression of transporters under a two-dimensional culture (2D) environment. Here, we selected HK-2 cells to establish a simplified three-dimensional (3D) model using gelatin sponges as scaffolds. In addition to cell viability and morphology, we conducted a comprehensive transcriptome comparison and correlation analysis of 2D and 3D cultured HK-2 cells to native human PTCs. Our 3D model displayed stable and long-term growth with a tubule-like morphology and demonstrated a more comparable gene expression profile to native human PTCs compared to the 2D model. Many missing or low expressions of major genes involved in PTC transport and metabolic processes were restored, which is crucial for successful nephrotoxicity prediction. Consequently, we established a cost-effective yet more representative model for in vivo PTC studies and presented a comprehensive transcriptome analysis for the systematic characterization of PTC lines.

The impact of different temporal resolution rainfall data on biosphere model of long-term safety assessment in groundwater release scenario for radioactive waste disposal in the tropical monsoon zone.

The impact of different temporal resolutions of rainfall data on the Biosphere assessment for radioactive waste disposal in the tropical monsoon region with concentrated rainfall is evaluated in this research. Two scenarios are considered to verify the effect of release location. A simplified surface water budget model is used to generate the surface water flow rates for the biosphere model, which is implemented using three different temporal averaging intervals to consider the uncertainty caused by short-term impact. Kaohsiung in Taiwan is chosen as an example because of its extreme rainfall distribution. The results show that it is improper to use the annual rainfall data for this case, and it is suggested to consider a 20% margin to cover the underestimation of dose if the monthly rainfall data are used. The results of the biosphere models built with different timesteps show that a non-negligible difference occurs for radionuclides with a low Kd value in the river water release scenario and no difference for the well water release scenario.

Statistical Assessment of High-Performance Scaled Double-Gate Transistors from Monolayer WS2.

Scaling of monolayer transition metal dichalcogenide (TMD) field-effect transistors (FETs) is an important step toward evaluating the application space of TMD materials. Although some work on ultrashort channel monolayer (ML) TMD FETs has been published, there exist no comprehensive studies that assess their performance in a statistically relevant manner, providing critical insights into the impact of the device geometry. Part of the reason for the absence of such a study is the substantial variability of TMD devices when processes are not carefully controlled. In this work, we show a statistical study of ultrashort channel double-gated ML WS2 FETs exhibiting excellent device performance and limited device-to-device variations. From a detailed analysis of cross-sectional scanning transmission electron microscopy (STEM) images and careful technology computer aided design (TCAD) simulations, we evaluated, in particular, an unexpected deterioration of the subthreshold characteristics for our shortest devices. Two potential candidates for the observed behavior were identified, i.e., buckling of the TMD on the substrate and loss of gate control due to the source geometry and the high-k dielectric between the metal gate and the metal source electrode.

An Assessment of Cataract Severity Based on Antioxidant Status and Ascorbic Acid Levels in Aqueous Humor.

Cataract is the leading cause of blindness throughout the world. Currently, the cataract severity evaluation is based on the subjective LOCS III guideline. To ameliorate the evaluation system and develop an objective and quantitative analysis, we investigated the relationships among aqueous humor total antioxidant capacity (AqTAC), ascorbic acid (AqAA) concentration, and cataract severity. In this study, we enrolled 130 cataract patients who underwent phacoemulsification between April 2019 and March 2020. The AqTAC and AqAA were measured by our own developed TAC assay and commercially available kit. Cataract severity was recorded by nuclear opalescence (NO) and cortical cataract (CC) degree according to LOCS III. Cumulative dissipated energy (CDE) during phacoemulsification was recorded to verify the severity of the cataract. As a result, we found a moderate correlation between AqTAC and CDE (p < 0.001). In addition, we found AqTAC independently associated with the CDE when analyzed by multivariate linear regression (p < 0.001). AqTAC also negatively correlated to cataract severity when measured by NO and CC (p = 0.012 in NO grade 3 vs. grade 1; p = 0.012 in CC grade 2 vs. grade 1; p < 0.001 in CC grade 3 vs. grade 1). We further found AqAA provided 71.9 ± 13.5% of AqTAC, and showed a high correlation (rho = 0.79, p < 0.001). In conclusion, we found a significant correlation between AqTAC/AqAA and cataract severity measured by CDE. The correlation was superior to the correlation between LOCS III and CDE. Aqueous humor TAC owns the potential to assess cataracts in an objective and quantitative way.

Machine Learning to Predict the Progression of Bone Mass Loss Associated with Personal Characteristics and a Metabolic Syndrome Scoring Index.

A relationship exists between metabolic syndrome (MetS) and human bone health; however, whether the combination of demographic, lifestyle, and socioeconomic factors that are associated with MetS development also simultaneously affects bone density remains unclear. Using a machine learning approach, the current study aimed to estimate the usefulness of predicting bone mass loss using these potentially related factors. The present study included a sample of 23,497 adults who routinely visited a health screening center at a large health center at least once during each of three 3-year stages (i.e., 2006-2008, 2009-2011, and 2012-2014). The demographic, socioeconomic, lifestyle characteristics, body mass index (BMI), and MetS scoring index recorded during the first 3-year stage were used to predict the subsequent occurrence of osteopenia using a non-concurrence design. A concurrent prediction was also performed using the features recorded from the same 3-year stage as the predicted outcome. Machine learning algorithms, including logistic regression (LR), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost), were applied to build predictive models using a unique feature set. The area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, precision, and F1 score were used to evaluate the predictive performances of the models. The XGBoost model presented the best predictive performance among the non-concurrence models. This study suggests that the ensemble learning model with a MetS severity score can be used to predict the progression of osteopenia. The inclusion of an individual's features into a predictive model over time is suggested for future studies.

Whole-body MRI-based multivariate prediction model in the assessment of bone metastasis in prostate cancer.

PURPOSE: A whole-body MRI (WB-MRI) including T1, short time inversion recovery (STIR), diffusion-weighted imaging (high b value) was applied in our center for the detection of bone metastasis in prostate cancer (PCa) patients. We intended to assess the diagnostic performance of this examination. METHODS: 547 cases of PCa patients with higher risk of metastasis were referred to bone scintigraphy with SPECT/CT (BS + SPECT/CT) and whole-body MRI in Shanghai Changhai Hospital. Best valuable comparator (BVC) was applied for the final diagnosis of metastasis. A panel of radiologists interpreted the results. Decision curve analysis (DCA) and receiver operating characteristic curve (ROC) analysis were applied. RESULTS: Bone metastasis was diagnosed in 110 cases, and others were non-metastatic by BVC. The area under the receiver operating characteristic curve (AUC) was higher in WB-MRI (0.778) than BS + SPECT/CT (0.634, p < 0.001). A WB-MRI-based prediction model was established with AUC of 0.877. Internal validation showed that the predictive model was well-calibrated. The DCA demonstrated that the model had higher net benefit than the BS + SPECT/CT-based model. CONCLUSION: WB-MRI is more effective in identifying metastasis in PCa patients than BS + SPECT/CT. The prediction model combined WB-MRI with clinical parameters may be a promising approach to the assessment of metastasis.

Oral Bioavailability Enhancement and Anti-Fatigue Assessment of the Andrographolide Loaded Solid Dispersion.

Andrographolide (AG), a major diterpene lactone isolated from Andrographis paniculata (Burm. f.) Nees (Acanthaceae), possesses a wide spectrum of biological activities. However, its poor water solubility and low bioavailability limit its clinical application. Therefore, this study aimed to develop a solid dispersion (SD) formulation to increase the aqueous solubility and dissolution rate of AG. Different drug-polymer ratios were used to prepare various SDs. The optimized formulation was characterized for differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffraction. The analysis indicated that the optimized SD enhanced AG solubility and dissolution rates by changing AG crystallinity to an amorphous state. The dissolution behaviors of the optimum SD composed of an AG-polyvinylpyrrolidone K30-Kolliphor EL ratio of 1:7:1 (w/w/w) resulted in the highest accumulated dissolution (approximately 80%). Pharmacokinetic studies revealed that Cmax/dose and the AUC/dose increased by 3.7-fold and 3.0-fold, respectively, compared with AG suspension. Furthermore, pretreatment using the optimized AG-SD significantly increased the swimming time to exhaustion by 1.7-fold and decreased the plasma ammonia level by 71.5%, compared with the vehicle group. In conclusion, the optimized AG-SD formulation appeared to effectively improve its dissolution rate and oral bioavailability. Moreover, the optimized AG-SD provides a promising treatment against physical fatigue.

Preliminary Assessment of Burn Depth by Paper-Based ELISA for the Detection of Angiogenin in Burn Blister Fluid-A Proof of Concept.

Rapid assessment of burn depth is important for burn wound management. Superficial partial-thickness burn (SPTB) wounds heal without scars, but deep partial-thickness burn (DPTB) wounds require a longer healing time and have a higher risk of scar formation. We previously found that DPTB blister fluid displayed a higher angiogenin level than SPTB blister fluid by conventional ELISA. In this study, we developed a paper-based ELISA (P-ELISA) technique for rapid assessment of angiogenin concentration in burn blister fluid. We collected six samples of SPTB blister fluid, six samples of DPTB blister fluid, and seven normal healthy serum samples for analysis. We again chose ELISA to measure and compare angiogenin levels across all of our samples, but we developed a P-ELISA tool and compared sample results from that tool to the results from conventional ELISA. As with conventional ELISA, DPTB blister fluid displayed higher angiogenin levels than SPTB in P-ELISA. Furthermore, our P-ELISA results showed a moderate correlation with conventional ELISA results. This new diagnostic technique facilitates rapid and convenient assessment of burn depth by evaluating a key molecule in burn blister fluid. It presents a novel and easy-to-learn approach that may be suitable for clinically determining burn depth with diagnostic precision.

Utilization willingness of institutional care between disabled and non-disabled seniors: evidence from Jiangsu, China.

BACKGROUND: Due to rapidly growing number of old adults and diminishing supportive functions of family in China, the issue of willingness to use institutional care is of high priority, especially for disabled seniors. The objective of this study is to compare the willingness of institutional care and its determinants between disabled and non-disabled seniors in China. METHODS: 2493 seniors (60+) were randomly selected from a cross-sectional study conducted in three urban districts and three rural counties in Jiangsu Province. Binary logistic regression model was employed to examine differences towards the preference for institutional care between two subgroups, and to identify factors associated with willingness of institutional care between disabled and non-disabled seniors. RESULTS: Of 2493 respondents, 402 (16.1%) were disabled seniors. Overall, 14.2% of the participants had willingness for institutional care in Jiangsu, China. The willingness for institutional care among non-disabled seniors (OR = 0.513; 95%CI 0.387-9.680) was significantly lower than that among disabled ones. The preference for institutional care of both disabled and non-disabled seniors was associated with household income. The willingness of institutional care was also related to age, education and living arrangement among disabled seniors. Meanwhile, non-disabled seniors who had non-communicable diseases were found to be more likely to choose elder care in institution. CONCLUSIONS: Our findings indicated that the willingness for institutional care among disabled seniors was significantly higher than that among non-disabled ones. Household income was determinant of utilization willingness for institutionalization both in disabled and non-disable seniors. Different policies should be made or modified for disabled and non-disabled seniors separately.

Recent advances in microbial production of mannitol: utilization of low-cost substrates, strain development and regulation strategies.

Mannitol has been widely used in fine chemicals, pharmaceutical industries, as well as functional foods due to its excellent characteristics, such as antioxidant protecting, regulation of osmotic pressure and non-metabolizable feature. Mannitol can be naturally produced by microorganisms. Compared with chemical manufacturing, microbial production of mannitol provides high yield and convenience in products separation; however the fermentative process has not been widely adopted yet. A major obstacle to microbial production of mannitol under industrial-scale lies in the low economical efficiency, owing to the high cost of fermentation medium, leakage of fructose, low mannitol productivity. In this review, recent advances in improving the economical efficiency of microbial production of mannitol were reviewed, including utilization of low-cost substrates, strain development for high mannitol yield and process regulation strategies for high productivity.

Paper-based ELISA to rapidly detect Escherichia coli.

Escherichia coli is a generic indicator of fecal contamination, and certain serotypes cause food- and water-borne illness such as O157:H7. In the clinic, detection of bacteriuria, which is often due to E. coli, is critical before certain surgical procedures or in cases of nosocomial infection to prevent further adverse events such as postoperative infection or sepsis. In low- and middle-income countries, where insufficient equipment and facilities preclude modern methods of detection, a simple, low-cost diagnostic device to detect E. coli in water and in the clinic will have significant impact. We have developed a simple paper-based colorimetric platform to detect E. coli contamination in 5h. On this platform, the mean color intensity for samples with 10(5)cells/mL is 0.118±0.002 (n=4), and 0.0145±0.003 (P<0.01⁎⁎) for uncontaminated samples. This technique is less time-consuming, easier to perform, and less expensive than conventional methods. Thus, paper-based ELISA is an innovative point-of-care diagnostic tool to rapidly detect E. coli, and possibly other pathogens when customized as appropriate, especially in areas that lack advanced clinical equipment.

Glycan-based diagnostic devices: current progress, challenges and perspectives.

Diagnosis is an essential launching point for accurate medical treatment, and rapid and accurate diagnostic approaches have become the increasingly vital goal inspiring developments in a variety of analytical methods. With increasing attention in the area of glycosciences, the roles that carbohydrates play in many diseases have been elucidated, and the use of carbohydrates as disease biomarkers has become an emerging diagnostics strategy. This review article does not intend to comprehensively include all carbohydrate-related diagnostics studies. We do, however, wish to describe carbohydrate recognition and the design of sensitive detecting devices, especially those developed recently, so that readers might better grasp the principles behind such devices and relevant detection strategies, particularly those favoring inexpensive, rapid, and point-of-care (POC) approaches.

Cost-effectiveness analysis of carrier and prenatal genetic testing for X-linked hemophilia.

BACKGROUND/PURPOSE: Hemophilia involves a lifelong burden from the perspective of the patient and the entire healthcare system. Advances in genetic testing provide valuable information to hemophilia-affected families for family planning. The aim of this study was to analyze the cost-effectiveness of carrier and prenatal genetic testing in the health-economic framework in Taiwan. METHODS: A questionnaire was developed to assess the attitudes towards genetic testing for hemophilia. We modeled clinical outcomes of the proposed testing scheme by using the decision tree method. Incremental cost-effectiveness analysis was conducted, based on data from the National Health Insurance (NHI) database and a questionnaire survey. RESULTS: From the NHI database, 1111 hemophilic patients were identified and required an average medical expenditure of approximately New Taiwan (NT) $2.1 million per patient-year in 2009. By using the decision tree model, we estimated that 26 potential carriers need to be tested to prevent one case of hemophilia. At a screening rate of 79%, carrier and prenatal genetic testing would cost NT $85.9 million, which would be offset by an incremental saving of NT $203 million per year by preventing 96 cases of hemophilia. Assuming that the life expectancy for hemophilic patients is 70 years, genetic testing could further save NT $14.2 billion. Higher screening rates would increase the savings for healthcare resources. CONCLUSION: Carrier and prenatal genetic testing for hemophilia is a cost-effective investment in healthcare allocation. A case management system should be integrated in the current practice to facilitate patient care (e.g., collecting family pedigrees and providing genetic counseling).

Quantitative assessment of iron in heart and liver phantoms using dual-energy computed tomography.

The aim of the present study was to determine the correlation between dual-energy computed tomography (DECT) Hounsfield units (HU) and iron concentration, as well as the correlation between HU and magnetic resonance imaging (MRI)-derived R2* values, in phantoms of the heart and liver tissue. Phantoms were constructed containing pig heart or liver tissue and varying concentrations of iron (0.1, 5, 10, 15, 20 and 25 mg/ml). The phantoms were then examined by DECT and MRI. Linear regression analysis was used to determine the correlations between HU and iron concentration and HU and R2* values. The HU value of DECT increased with increasing iron concentrations in the liver and heart phantoms in a linear manner. The slope of the HU value change against iron concentration revealed that ΔH80-140 provided a better discernment of iron concentration as compared with ΔH100-140. The derived R2 values were all >0.9 for the associations of DECT and MRI measurements with iron concentrations. Therefore, DECT may be used for the determination of iron concentration in the liver and heart tissue, with the results correlating with those obtained with MRI.

Recent advances in low-cost microfluidic platforms for diagnostic applications.

The use of inexpensive materials and cost-effective manufacturing processes for mass production of microfluidic devices is very attractive and has spurred a variety of approaches. Such devices are particularly suited for diagnostic applications in limited resource settings. This review describes the recent and remarkable advances in the use of low-cost substrates for the development of microfluidic devices for diagnostics and clinical assays. Thus, a plethora of new and improved fabrication methods, designs, capabilities, detections, and applications of microfluidic devices fabricated with paper, plastic, and threads are covered.

Microfluidics expands the zebrafish potentials in pharmaceutically relevant screening.

The objective of this study is to enlarge the impact of microfluidics on the pharmaceutical industry by highlighting the reported scientific work on the synergistic relationship between zebrafish and microfluidics, and furthering that effort to shed light on how microfluidics can facilitate the use of zebrafish as a gene screening tool. Zebrafish is ranked the third most important animal model after rats and mice, according to a National Institutes of Health (NIH) announcement in 2003. It has become a staple for scientists to examine and subsequently begin to unravel the mystery of human diseases, and is increasingly used in toxicological studies for new drug development. The unique characteristics that this tiny fish possesses, including rapid growth rate, prodigious numbers of offspring, and eggs that develop outside the body, make it an invaluable genetic tool. Evidently, these advantages can be broadened with the addition of a properly designed microfluidic circuit. By means of the presented illustrations and demonstrated applications, the goal is to spark interest in the development of more novel microfluidic platform designs that can leverage the attributes of zebrafish and quickly come to commercial fruition.