Proteogenomics of Non-smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression.

Lung cancer in East Asia is characterized by a high percentage of never-smokers, early onset and predominant EGFR mutations. To illuminate the molecular phenotype of this demographically distinct disease, we performed a deep comprehensive proteogenomic study on a prospectively collected cohort in Taiwan, representing early stage, predominantly female, non-smoking lung adenocarcinoma. Integrated genomic, proteomic, and phosphoproteomic analysis delineated the demographically distinct molecular attributes and hallmarks of tumor progression. Mutational signature analysis revealed age- and gender-related mutagenesis mechanisms, characterized by high prevalence of APOBEC mutational signature in younger females and over-representation of environmental carcinogen-like mutational signatures in older females. A proteomics-informed classification distinguished the clinical characteristics of early stage patients with EGFR mutations. Furthermore, integrated protein network analysis revealed the cellular remodeling underpinning clinical trajectories and nominated candidate biomarkers for patient stratification and therapeutic intervention. This multi-omic molecular architecture may help develop strategies for management of early stage never-smoker lung adenocarcinoma.

Chronic Viral Hepatitis B and C Outweigh MASLD in the Associated Risk of Cirrhosis and HCC.

BACKGROUND & AIMS: The impact of metabolic dysfunction-associated steatotic liver disease (MASLD) on the development of cirrhosis and hepatocellular carcinoma (HCC) by chronic hepatitis B (CHB) or C infection and antiviral treatment statuses is not well-known. METHODS: A total of 336,866 adults aged ≥30 years were prospectively enrolled in a health screening program between 1997-2013. MASLD was identified by abdominal ultrasonography and cardiometabolic profiles. Data linkage was performed using 3 nationwide databases-National Health Insurance, Cancer Registry, and Death Certification System-to obtain information on antiviral treatment, vital status, and newly diagnosed cirrhosis and HCC. Follow-up was conducted until December 31, 2019. RESULTS: In the total population, 122,669 (36.4%) had MASLD. Over a mean follow-up of 15 years, 5562 new cases of cirrhosis and 2273 new cases of HCC were diagnosed. Although MASLD significantly increased the cumulative risks of cirrhosis or HCC (P < .0001), the associated risk was more pronounced when comparing CHB or C infection with the presence of MASLD. Stratifying the participants based on their MASLD and CHB or C statuses, hazard ratios (HRadj) with 95% confidence intervals for HCC were 8.81 (7.83-9.92) for non-steatotic liver disease (SLD) with CHB or C, 1.52 (1.32-1.74) for MASLD without CHB or C, and 8.86 (7.76-10.12) for MASLD with CHB or C, compared with non-SLD without CHB or C (all P < .0001). Among CHB or C patients who received antivirals during follow-up, MASLD was associated with increased risks of cirrhosis and HCC, with HRadj of 1.23 (1.01-1.49) and 1.32 (1.05-1.65), respectively. CONCLUSIONS: These findings underscore the need to prioritize treatment of chronic viral hepatitis before addressing MASLD.

Reduced symmetric dimethylation stabilizes vimentin and promotes metastasis in MTAP-deficient lung cancer.

The aggressive nature and poor prognosis of lung cancer led us to explore the mechanisms driving disease progression. Utilizing our invasive cell-based model, we identified methylthioadenosine phosphorylase (MTAP) and confirmed its suppressive effects on tumorigenesis and metastasis. Patients with low MTAP expression display worse overall and progression-free survival. Mechanistically, accumulation of methylthioadenosine substrate in MTAP-deficient cells reduce the level of protein arginine methyltransferase 5 (PRMT5)-mediated symmetric dimethylarginine (sDMA) modification on proteins. We identify vimentin as a dimethyl-protein whose dimethylation levels drop in response to MTAP deficiency. The sDMA modification on vimentin reduces its protein abundance but trivially affects its filamentous structure. In MTAP-deficient cells, lower sDMA modification prevents ubiquitination-mediated vimentin degradation, thereby stabilizing vimentin and contributing to cell invasion. MTAP and PRMT5 negatively correlate with vimentin in lung cancer samples. Taken together, we propose a mechanism for metastasis involving vimentin post-translational regulation.

Higher tumor mutational burden is associated with inferior outcomes among pediatric patients with neuroblastoma.

INTRODUCTION: Neuroblastoma is a pediatric malignancy with heterogeneous clinical outcomes. Our aim was to identify prognostic genetic markers for patients with neuroblastoma, who were treated with the Taiwan Pediatric Oncology Group (TPOG) neuroblastoma N2002 protocol, to improve risk stratification and inform treatment. METHODS: Our analysis was based on 53 primary neuroblastoma specimens, diagnosed pre-chemotherapy, and 11 paired tumor relapse specimens. Deep sequencing of 113 target genes was performed using a custom panel. Multiplex ligation-dependent probe amplification was performed to identify clinical outcomes related to copy-number variations. RESULTS: We identified 128 variations associated with survival, with the number of variations being higher in the relapse than that in the diagnostic specimen (p = .03). The risk of event and mortality was higher among patients with a tumor mutational burden ≥10 than that in patients with a lower burden (p < .0001). Multivariate analysis identified tumor mutational burden, MYCN amplification, and chromosome 3p deletion as significant prognostic factors, independent of age at diagnosis, sex, and tumor stage. The 5-year event-free survival and overall survival rate was lower among patients with high tumor burden than in patients with low tumor burden. Furthermore, there was no survival of patients with an ALK F1147L variation at 5 years after diagnosis. CONCLUSIONS: Genome sequencing to determine the tumor mutational burden and ALK variations can improve the risk classification of neuroblastoma and inform treatment.

Patients with first-episode psychosis in northern Taiwan: neurocognitive performance and niacin response profile in comparison with schizophrenia patients of different familial loadings and relationship with clinical features.

BACKGROUND: Examining patients with first-episode psychosis (FEP) provides opportunities to better understand the mechanism underlying these illnesses. By incorporating quantitative measures in FEP patients, we aimed to (1) determine the baseline distribution of clinical features; (2) examine the impairment magnitude of the quantitative measures by comparing with external controls and then the counterparts of schizophrenia patients of different familial loadings; and (3) evaluate whether these quantitative measures were associated with the baseline clinical features. METHODS: Patients with FEP were recruited from one medical center, two regional psychiatric centers, and two private clinics in northern Taiwan with clinical features rated using the Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale. Quantitative measurements included the Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), niacin response abnormality (NRA), and minor physical anomalies and craniofacial features (MPAs). To evaluate the relative performance of the quantitative measures in our FEP patients, four external comparison groups from previous studies were used, including three independent healthy controls for the CPT, WCST, and NRA, respectively, and one group of treatment-resistant schizophrenia patients for the MPAs. Additionally, patients from simplex families and patients from multiplex families were used to assess the magnitude of FEP patients' impairment on the CPT, WCST, and NRA. RESULTS: Among the 80 patients with FEP recruited in this study (58% female, mean age = 25.6 years, mean duration of untreated psychosis = 132 days), the clinical severity was mild to moderate (mean PANSS score = 67.3; mean PSP score = 61.8). Patients exhibited both neurocognitive and niacin response impairments (mean Z-scores: -1.24 for NRA, - 1.06 for undegraded d', - 0.70 for degraded d', - 0.32 for categories achieved, and 0.44 for perseverative errors) but did not show MPAs indicative of treatment resistance. Among these quantitative measures, three of the four neurocognitive indices were correlated with the baseline clinical features, whereas NRA did not show such correlation. CONCLUSIONS: This FEP study of Taiwanese patients revealed the presence of neurocognitive performance and niacin response and their different relationships with clinical features, rendering this sample useful for future follow-up and incorporation of multiomics investigation.

Doping Shortens the Metal/Metal Distance and Promotes OH Coverage in Non-Noble Acidic Oxygen Evolution Reaction Catalysts.

Acidic water electrolysis enables the production of hydrogen for use as a chemical and as a fuel. The acidic environment hinders water electrolysis on non-noble catalysts, a result of the sluggish kinetics associated with the adsorbate evolution mechanism, reliant as it is on four concerted proton-electron transfer steps. Enabling a faster mechanism with non-noble catalysts will help to further advance acidic water electrolysis. Here, we report evidence that doping Ba cations into a Co3O4 framework to form Co3-xBaxO4 promotes the oxide path mechanism and simultaneously improves activity in acidic electrolytes. Co3-xBaxO4 catalysts reported herein exhibit an overpotential of 278 mV at 10 mA/cm2 in 0.5 M H2SO4 electrolyte and are stable over 110 h of continuous water oxidation operation. We find that the incorporation of Ba cations shortens the Co-Co distance and promotes OH adsorption, findings we link to improved water oxidation in acidic electrolyte.

Clinical impact of minimal residual disease and genetic subtypes on the prognosis of childhood acute lymphoblastic leukemia.

BACKGROUND: This study analyzed data from two consecutive protocols for children newly diagnosed with acute lymphoblastic leukemia (ALL) to determine the clinical impact of minimal/measurable residual disease (MRD) and recently identified tumor genetic subtypes. METHODS: Genetic subtypes were determined by sequential approaches including DNA indexing, reverse transcriptase-polymerase chain reaction, multiplex ligation-dependent probe amplification, and RNA-sequencing. MRD was assessed by flow cytometry. The Taiwan Pediatric Oncology Group TPOG-ALL-2013 study enrolled patients who received MRD-directed therapy. RESULTS: The 5-year event-free survival (EFS) and overall survival rates in the 2013 cohort were 77.8% and 86.9% compared to those of the 2002 cohort, which were 62.4% and 76.5%. Among patients treated with MRD-guided therapy, those with ETV6-RUNX1 fusion and high hyperdiploidy had the highest 5-year EFS (91.4% and 89.6%, respectively). The addition of dasatinib improved outcomes in patients with BCR-ABL1 ALL. Recently identified subtypes like DUX4-rearranged, ZNF384-rearranged, MEF2D-rearranged, and PAX5alt subtypes were frequently positive for MRD after remission induction, and these patients consequently received intensified chemotherapy. Treatment intensification according to the MRD improved the outcomes of patients presenting DUX4 rearrangements. In high-risk or very-high-risk subtypes, the TPOG-ALL-2013 regimen did not confer significant improvements compared to TPOG-ALL-2002, and the outcomes of BCR-ABL1-like, MEF2D-rearranged, and KMT2A-rearranged ALL subtypes (in addition to those of T-cell ALL) were not sufficiently good. Novel agents or approaches are needed to improve the outcomes for these patients. CONCLUSIONS: The TPOG-ALL-2013 study yielded outcomes superior to those of patients treated in the preceding TPOG-ALL-2002 study. This study provides important data to inform the design of future clinical trials in Taiwan. PLAIN LANGUAGE SUMMARY: MRD-directed therapy improved the outcomes for pediatric ALL, especially standard-risk patients. Genomic analyses and MRD might be used together for risk-directed therapy of childhood ALL. Our work provides important data to inform the design of future clinical trials in Taiwan.

Regulation of dendritic cell maturation in osimertinib-treated lung adenocarcinoma patients.

Osimertinib (OSI), a third-generation tyrosine kinase inhibitor (TKI), efficiently benefits lung adenocarcinoma (LUAD) patients with epidermal growth factor receptor (EGFR) mutations. However, combined OSI and immune checkpoint inhibitor in EGFR-mutant patients increases the incidence of interstitial lung disease (ILD), although the mechanism is unknown. Here, we investigated the interaction between dendritic cells (DCs), a potential critical player in ILD, and OSI. Seventeen LUAD patients received TKI therapy, and only the OSI therapy group (N = 10) showed a significant increase in CD40 and CD83 on immature DCs (iDCs), and an elevated trend for both markers on mature DCs (mDCs) during short- and long-term OSI therapy. Our results indicated that OSI therapy may potentially activate DC functions, which might increase the potential immune toxicity when combined with onco-immunotherapy.

Diagnostic accuracy of algorithms to define incident and second hip fractures: A Taiwan validation study.

BACKGROUND: Previous epidemiological researchers have used various algorithms to identify a second hip fracture; however, there has been no validation of these algorithms to date. This study aimed to verify existing algorithms for identifying second hip fracture under the International Classification of Diseases diagnostic coding systems. Furthermore, we examined the validity of two newly proposed algorithms that integrated the concept of periprosthetic fractures and laterality of the ICD-10 coding system. METHODS: Claims data of patients hospitalized for hip fracture from National Taiwan University Hospitals between 2007 and 2020 were retrieved. Hip fracture was confirmed by 2 orthopaedic surgeons with medical records and imaging data as gold standards. The validity of 9 existing and 2 newly proposed algorithms for identifying second hip fracture was evaluated. RESULTS: The positive predictive value (PPV) range between 84% and 90% in existing algorithms for identifying second hip fractures. Noteworthy, the longer time interval for discrimination resulted in slightly increased PPV (from 87% to 90%), while decreased sensitivity noticeably (from 87% to 72%). When considering the information about periprosthetic fracture, the PPV increased to 91% without diminished sensitivity. The PPV of the newly proposed ICD-10-specific algorithm was 100%. CONCLUSION: Algorithms integrated clinical insights of periprosthetic fractures and laterality concept of ICD-10 coding system provided satisfactory validity and help precisely define second hip fracture in future database research.

Integration of immunohistochemistry, RNA sequencing, and multiplex ligation-dependent probe amplification for molecular classification of pediatric medulloblastoma.

BACKGROUND: Medulloblastoma (MB) is commonly classified into four molecular groups, that is, WNT, SHH, group 3, and group 4, for prognostic and therapeutic purposes. METHODS: Here we applied immunohistochemistry (IHC) and RNA sequencing (RNA-seq) for the molecular classification of MB, and utilized multiplex ligation-dependent probe amplification (MLPA) to determine chromosomal alterations and specific gene amplifications. RESULTS: We retrospectively enrolled 37 pediatric MB patients. Twenty-three had genomic material available for gene/RNA analysis. For IHC, ß-catenin, GAB1, and YAP were the biomarkers to segregate MB into three subgroups, WNT (1/23), SHH (5/23), and non-WNT/non-SHH (17/23). However, four cases (17.3%) were found to be misclassified after analysis by RNA-seq. The result of MLPA revealed two group 3 tumors carrying MYC amplification, and three SHH tumors harboring MYCN amplification. While IHC provided rapid subgroup stratification, it might result in incorrect subgrouping. Thus, validation of the IHC result with genomic data analysis by RNA-seq or other tools would be preferred. In addition, MLPA can detect important genetic alterations and is helpful for the identifications of high-risk patients. CONCLUSIONS: Our study revealed that integration of these diagnostic tools can provide a precise and timely classification of MB, optimizing an individualized, risk-directed postoperative adjuvant therapy for these patients. This workflow can be applied in a countrywide fashion to guide future clinical trials for patients with MB.

Air Pollution Is Associated with Cognitive Deterioration of Alzheimer's Disease.

INTRODUCTION: Dementia is one of the major causes of disability and dependency among older people worldwide. Alz-heimer's disease (AD), the most common cause of dementia among the elderly, has great impact on the health-care system of developed nations. Several risk factors are suggestive of an increased risk of AD, including APOE-ε4, male, age, diabetes mellitus, hypertension, and low social engagement. However, data on risk factors of AD progression are limited. Air pollution is revealed to be associated with increasing dementia incidence, but the relationship between air pollution and clinical AD cognitive deterioration is unclear. METHODS: We conducted a case-control and city-to-city study to compare the progression of AD patients in different level of air-polluted cities. Clinical data of a total of 704 AD patients were retrospectively collected, 584 residences in Kaohsiung and 120 residences in Pingtung between 2002 and 2018. An annual interview was performed with each patient, and the Clinical Dementia Rating score (0 [normal] to 3 [severe stage]) was used to evaluate their cognitive deterioration. Air pollution data of Kaohsiung and Pingtung city for 2002-2018 were retrieved from Taiwan Environmental Protection Administration. Annual Pollutant Standards Index (PSI) and concentrations of particulate matter (PM10), sulfur dioxide (SO2), ozone (O3), nitrogen dioxide (NO2), and carbon monoxide (CO) were obtained. RESULTS: The PSI was higher in Kaohsiung and compared with Pingtung patients, Kaohsiung patients were exposed to higher average annual concentrations of CO, NO2, PM10, and SO2. AD patients living in Kaohsiung suffered from faster cognitive deterioration in comparison with Pingtung patients (log-rank test: p = 0.016). When using multivariate Cox proportional hazards regression analysis, higher levels of CO, NO2, PM10, and SO2 exposure were associated with increased risk of AD cognitive deterioration. Among all these air pollutants, high SO2 exposure has the greatest impact while O3 has a neutral effect on AD cognitive deterioration. CONCLUSIONS: Air pollution is an environment-related risk factor that can be controlled and is associated with cognitive deterioration of AD. This finding could contribute to the implementation of public intervention strategies of AD.

Risk factors for reconstruction plate exposure after surgery in oral cancer patients. A retrospective cohort study.

OBJECTIVES: The aim of this study was to elaborate risk factors for reconstruction plate exposure after wide excision in oral cancer patients, and to find out the most effective treatment. MATERIALS AND METHODS: We include patients who underwent ablative surgery for oral cancer and reconstruction plate fixation from the year 2010 to 2016, separate them into two groups according to whether the hardware was exposed, compare risk factors including age, tumor site, staging, comorbidities, and previous treatment between the two groups. The treatment course and outcome were also recorded. RESULTS: In total, 75 patients received reconstruction plate fixation after ablative surgery. Bone plate exposure was found in 26 cases (34.6%). The size of the bone defect and the thickness of soft tissue covering the plate were significant risk factors for plate exposure. In 21 patients (72.4%), the bone plate was removed. Conservative treatment was not effective. Removal of bone plate and debridement in one single surgery had a success rate of 81%. CONCLUSION: In this study, skin thickness less than 1.5 mm over the reconstruction plate and bone defect size larger than 8.4 cm were the two significant risk factors for bone plate exposure. Although a standardized treatment algorithm is lacking, surgical debridement with removal of the bone plate result in complete soft tissue healing in most patients and should be the treatment of choice. CLINICAL RELEVANCE: Patients with larger bone defect and thinner covering soft tissue bear more risk for exposure. The most effective treatment is to remove the hardware.

Evaluation of Calibration Equations by Using Regression Analysis: An Example of Chemical Analysis.

A calibration curve is used to express the relationship between the response of the measuring technique and the standard concentration of the target analyst. The calibration equation verifies the response of a chemical instrument to the known properties of materials and is established using regression analysis. An adequate calibration equation ensures the performance of these instruments. Most studies use linear and polynomial equations. This study uses data sets from previous studies. Four types of calibration equations are proposed: linear, higher-order polynomial, exponential rise to maximum and power equations. A constant variance test was performed to assess the suitability of calibration equations for this dataset. Suspected outliers in the data sets are verified. The standard error of the estimate errors, s, was used as criteria to determine the fitting performance. The Prediction Sum of Squares (PRESS) statistic is used to compare the prediction ability. Residual plots are used as quantitative criteria. Suspected outliers in the data sets are checked. The results of this study show that linear and higher order polynomial equations do not allow accurate calibration equations for many data sets. Nonlinear equations are suited to most of the data sets. Different forms of calibration equations are proposed. The logarithmic transformation of the response is used to stabilize non-constant variance in the response data. When outliers are removed, this calibration equation's fit and prediction ability is significantly increased. The adequate calibration equations with the data sets obtained with the same equipment and laboratory indicated that the adequate calibration equations differed. No universe calibration equation could be found for these data sets. The method for this study can be used for other chemical instruments to establish an adequate calibration equation and ensure the best performance.

Exploring the Mechanism of Adjuvant Treatment of Glioblastoma Using Temozolomide and Metformin.

Glioblastoma is the most frequent and lethal primary central nervous system tumor in adults, accounting for around 15% of intracranial neoplasms and 40-50% of all primary malignant brain tumors, with an annual incidence of 3-6 cases per 100,000 population. Despite maximum treatment, patients only have a median survival time of 15 months. Metformin is a biguanide drug utilized as the first-line medication in treating type 2 diabetes. Recently, researchers have noticed that metformin can contribute to antineoplastic activity. The objective of this study is to investigate the mechanism of metformin as a potential adjuvant treatment drug in glioblastoma. Glioblastoma cell lines U87MG, LNZ308, and LN229 were treated with metformin, and several cellular functions and metabolic states were evaluated. First, the proliferation capability was investigated using the MTS assay and BrdU assay, while cell apoptosis was evaluated using the annexin V assay. Next, a wound-healing assay and mesenchymal biomarkers (N-cadherin, vimentin, and Twist) were used to detect the cell migration ability and epithelial-mesenchymal transition (EMT) status of tumor cells. Gene set enrichment analysis (GSEA) was applied to the transcriptome of the metformin-treated glioblastoma cell line. Then, DCFH-DA and MitoSOX Red dyes were used to quantify reactive oxygen species (ROS) in the cytosol and mitochondria. JC-1 dye and Western blotting analysis were used to evaluate mitochondrial membrane potential and biogenesis. In addition, the combinatory effect of temozolomide (TMZ) with metformin treatment was assessed by combination index analysis. Metformin could decrease cell viability, proliferation, and migration, increase cell apoptosis, and disrupt EMT in all three glioblastoma cell lines. The GSEA study highlighted increased ROS and hypoxia in the metformin-treated glioblastoma cells. Metformin increased ROS production, impaired mitochondrial membrane potential, and reduced mitochondrial biogenesis. The combined treatment of metformin and TMZ had U87 as synergistic, LNZ308 as antagonistic, and LN229 as additive. Metformin alone or combined with TMZ could suppress mitochondrial transcription factor A, Twist, and O6-methylguanine-DNA methyltransferase (MGMT) proteins in TMZ-resistant LN229 cells. In conclusion, our study showed that metformin decreased metabolic activity, proliferation, migration, mitochondrial biogenesis, and mitochondrial membrane potential and increased apoptosis and ROS in some glioblastoma cells. The sensitivity of the TMZ-resistant glioblastoma cell line to metformin might be mediated via the suppression of mitochondrial biogenesis, EMT, and MGMT expression. Our work provides new insights into the choice of adjuvant agents in TMZ-resistant GBM therapy.

Childhood acute lymphoblastic leukemia mercaptopurine intolerance is associated with NUDT15 variants.

BACKGROUND: Mercaptopurine-induced neutropenia can interrupt chemotherapy and expose patients to infection during childhood acute lymphoblastic leukemia (ALL) treatment. Previously, six candidate gene variants associated with mercaptopurine intolerance were reported. Herein, we investigated the association between the mean tolerable dose of mercaptopurine and these genetic variants in Taiwanese patients. METHODS: In total, 294 children with ALL were treated at the National Taiwan University Hospital from April 1997 to December 2017. Germline variants were analyzed for NUDT15, SUCLA2, TPMT, ITPA, PACSIN2, and MRP4. Mean daily tolerable doses of mercaptopurine in the continuation phase of treatment were correlated with these genetic variants. RESULTS: Mercaptopurine intolerance was significantly associated with polymorphisms in NUDT15 (P value < 0.0001). Patients with SUCLA2 variants received lower mercaptopurine doses (P value = 0.0119). The mean mercaptopurine doses did not differ among patients with TPMT, ITPA, MRP4, and PACSIN2 polymorphisms (P value = 0.9461, 0.5818, and 0.7951, respectively). After multivariable linear regression analysis, only NUDT15 variants retained their clinically significant correlation with mercaptopurine intolerance (P value < 0.0001). CONCLUSION: In this cohort, the major genetic determinant of mercaptopurine intolerance was NUDT15 in Taiwanese patients. IMPACT: NUDT15 causes mercaptopurine intolerance in children with ALL. The NUDT15 variant is a stronger predictor of mercaptopurine intolerance than TPMT in a Taiwanese cohort. This finding is similar with studies performed on Asian populations rather than Caucasians. Pre-emptive genotyping of the patients' NUDT15 before administering mercaptopurine may be more helpful than genotyping TPMT in Asians.

Verification of the Efficacy of New Diagnostic Criteria for Retropharyngeal Nodes in a Cohort of Nasopharyngeal Carcinoma Patients.

Purpose: A multistage approach to diagnose lateral retropharyngeal nodes (LRPNs) of nasopharyngeal carcinoma (NPC) had been proposed and warranted for validation. Methods: Between 2012 and 2017, the patients with newly diagnosed NPC were enrolled. The responsive nodes or those that progressed during follow-up were positive. The criteria for the multistage approach delimited LRPNs with a minimal axial diameter (MIAD) ≥ 6.1 mm were assessed as positive and if the mean standard uptake value ≥ 2.6, or if the maximal coronal diameter ≥ 25 mm and maximal axial diameter ≥ 8 mm with nodes MIAD < 6.1 mm were also considered as positive. The outcomes were compared with the MIAD cutoff value ≥ 6 mm (traditional method). A chi-squared test was used to compare two areas under the curve of the receiver operating characteristic curves. Results: A total of 67 eligible NPC cases and 155 LRPNs (72 positive and 83 negative) were analyzed. The accuracy, specificity, and sensitivity of the traditional method were 0.91, 0.93, and 0.89, respectively. The values for the multistage approach all reached 0.94. The area under the curve was significantly greater for the multistage approach compared with the traditional method (p = 0.023). Conclusion: The results support the advantage of the multistage approach.

Security Privacy and Policy for Cryptographic Based Electronic Medical Information System.

With the development of the internet, applications have become complicated, and the relevant technology has diversified. Compared with medical applications, the significance of information technology has been expanding to include clinical auxiliary functions of medical information. This includes electronic medical records, electronic prescriptions, medical information systems, etc. Although research on the data processing structure and format of various related systems is becoming mature, the integration is insufficient. An integrated medical information system with security policy and privacy protection, which combines e-patient records, e-prescriptions, modified smart cards, and fingerprint identification systems, and applies proxy signature and group signature, is proposed in this study. This system effectively applies and saves medical resources-satisfying the mobility of medical records, presenting the function, and security of medicine collection, and avoiding medical conflicts and profiteering to further acquire the maximum effectiveness with the least resources. In this way, this medical information system may be developed into a comprehensive function that eliminates the transmission of manual documents and maintains the safety of patient medical information. It can improve the quality of medical care and indispensable infrastructure for medical management.

TP53 alterations in relapsed childhood acute lymphoblastic leukemia.

TP53 alterations are frequent relapse-acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation-dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B-cell and T-cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back-tracking matched diagnostic samples. TP53 alterations were associated with lower 5-year event-free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty-five patients received hematopoietic stem-cell transplantations post-relapse. Patients with TP53 alterations (14/45) had inferior 5-year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.

A high-resolution HLA imputation system for the Taiwanese population: a study of the Taiwan Biobank.

An imputation algorithm for human leukocyte antigen (HLA) is helpful for exploring novel disease associations. However, population-specific HLA imputation references are essential for achieving high imputation accuracy. In this study, a subset of 1012 individuals from the Taiwan Biobank (TWB) who underwent both whole-genome SNP array and NGS-based HLA typing were used to establish Taiwanese HLA imputation references. The HIBAG package was used to generate the imputation references for eight HLA loci at a two- and three-field resolution. Internal validation was carried out to evaluate the call threshold and accuracy for each HLA gene. HLA class II genes found to be associated with rheumatoid arthritis (RA) were validated in this study by the imputed HLA alleles. Our Taiwanese population-specific references achieved average HLA imputation accuracies of 98.11% for two-field and 98.08% for three-field resolution. The frequency distribution of imputed HLA alleles among 23,972 TWB subjects were comparable with PCR-based HLA alleles in general Taiwanese reported in the allele frequency net database. We replicated four common HLA alleles (HLA-DRB1*03:01, DRB1*04:05, DQA1*03:03, and DQB1*04:01) significantly associated with RA. The population-specific references provide an informative tool to investigate the associations of HLA variants and human diseases in large-scale population-based studies.

HLA class I alleles are associated with clinic-based migraine and increased risks of chronic migraine and medication overuse.

OBJECTIVE: We aimed to evaluate associations of human leukocyte antigen variants with migraine or headache in hospital and population-based settings. METHODS: The case-control study population, aged 30-70, included 605 clinic-based migraine patients in a medical center and 8449 population-based participants in Taiwan Biobank (TWB). Clinic-based cases were ascertained by neurologists. Participants in Taiwan Biobank were interviewed by a structured questionnaire including headache and migraine history; among them, 2394 had headache or migraine history while 6055 were free of headache and served as controls. All subjects were genotyped by Axiom Genome-Wide Single Nucleotide Polymorphism Arrays and imputed for eight classical human leukocyte antigen genes. Human leukocyte antigen frequencies were compared between clinic-based and self-reported patients and controls. We utilized likelihood ratio tests to examine human leukocyte antigen-disease associations and logistic regressions to estimate the effect of human leukocyte antigen alleles on migraine. RESULTS: Human leukocyte antigen-B and C showed significant associations with clinic-based migraine (q-value < 0.05). Human leukocyte antigen-B*39:01, human leukocyte antigen-B*51:01, human leukocyte antigen-B*58:01 and human leukocyte antigen-C*03:02 were significantly associated with migraine, with age and sex-adjusted odds ratios (95% CIs) of 1.80 (1.28-2.53), 1.50 (1.15-1.97), 1.36 (1.14-1.62) and 1.36 (1.14-1.62), correspondingly. Clinic-based migraineurs carrying human leukocyte antigen-B*58:01 or human leukocyte antigen-C*03:02 had 1.63 (1.11-2.39) -fold likelihood to have chronic migraine with medication-overuse headache compared to episodic migraine. However, no human leukocyte antigen genes were associated with self-reported headache or migraine in the community. CONCLUSIONS: Human leukocyte antigen class I genetic variants are positively associated with risk of clinic-based migraine but not self-reported migraine or headache and may contribute to migraine chronification and medication overuse.