Publications by authors named "Liya Wang"

275 Publications

Role of the nervous system in cancers: a review.

Cell Death Discov 2021 Apr 12;7(1):76. Epub 2021 Apr 12.

Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.

Nerves are important pathological elements of the microenvironment of tumors, including those in pancreatic, colon and rectal, prostate, head and neck, and breast cancers. Recent studies have associated perineural invasion with tumor progression and poor outcomes. In turn, tumors drive the reprogramming of neurons to recruit new nerve fibers. Therefore, the crosstalk between nerves and tumors is the hot topic and trend in current cancer investigations. Herein, we reviewed recent studies presenting direct supporting evidences for a better understanding of nerve-tumor interactions.
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http://dx.doi.org/10.1038/s41420-021-00450-yDOI Listing
April 2021

Data Integration to Improve Real-world Health Outcomes Research for Non-Small Cell Lung Cancer in the United States: Descriptive and Qualitative Exploration.

JMIR Cancer 2021 Apr 12;7(2):e23161. Epub 2021 Apr 12.

Eli Lilly and Company, Indianapolis, IN, United States.

Background: The integration of data from disparate sources could help alleviate data insufficiency in real-world studies and compensate for the inadequacies of single data sources and short-duration, small sample size studies while improving the utility of data for research.

Objective: This study aims to describe and evaluate a process of integrating data from several complementary sources to conduct health outcomes research in patients with non-small cell lung cancer (NSCLC). The integrated data set is also used to describe patient demographics, clinical characteristics, treatment patterns, and mortality rates.

Methods: This retrospective cohort study integrated data from 4 sources: administrative claims from the HealthCore Integrated Research Database, clinical data from a Cancer Care Quality Program (CCQP), clinical data from abstracted medical records (MRs), and mortality data from the US Social Security Administration. Patients with lung cancer who initiated second-line (2L) therapy between November 01, 2015, and April 13, 2018, were identified in the claims and CCQP data. Eligible patients were 18 years or older and received atezolizumab, docetaxel, erlotinib, nivolumab, pembrolizumab, pemetrexed, or ramucirumab in the 2L setting. The main analysis cohort included patients with claims data and data from at least one additional data source (CCQP or MR). Patients without integrated data (claims only) were reported separately. Descriptive and univariate statistics were reported.

Results: Data integration resulted in a main analysis cohort of 2195 patients with NSCLC; 2106 patients had CCQP and 407 patients had MR data. The claims-only cohort included 931 eligible patients. For the main analysis cohort, the mean age was 62.1 (SD 9.27) years, 48.56% (1066/2195) were female, the median length of follow-up was 6.8 months, and for 37.77% (829/2195), death was observed. For the claims-only cohort, the mean age was 66.6 (SD 12.69) years, 52.1% (485/931) were female, the median length of follow-up was 8.6 months, and for 29.3% (273/931), death was observed. The most frequent 2L treatment was immunotherapy (1094/2195, 49.84%), followed by platinum-based regimens (472/2195, 21.50%) and single-agent chemotherapy (441/2195, 20.09%); mean duration of 2L therapy was 5.6 (SD 4.9, median 4) months. We describe challenges and learnings from the data integration process, and the benefits of the integrated data set, which includes a richer set of clinical and outcome data to supplement the utilization metrics available in administrative claims.

Conclusions: The management of patients with NSCLC requires care from a multidisciplinary team, leading to a lack of a single aggregated data source in real-world settings. The availability of integrated clinical data from MRs, health plan claims, and other sources of clinical care may improve the ability to assess emerging treatments.
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http://dx.doi.org/10.2196/23161DOI Listing
April 2021

Spectral Wavelet-feature Analysis and Classification Assisted Denoising for enhancing magnetic resonance spectroscopy.

NMR Biomed 2021 Mar 9:e4497. Epub 2021 Mar 9.

Department of Radiology and Imaging Sciences, Emory University School of Medicine, Atlanta, Georgia, USA.

Magnetic resonance spectroscopy (MRS) is capable of revealing important biochemical and metabolic information of tissues noninvasively. However, the low concentrations of metabolites often lead to poor signal-to-noise ratio (SNR) and a long acquisition time. Therefore, the applications of MRS in detection and quantitative measurements of metabolites in vivo remain limited. Reducing or even eliminating noise can improve SNR sufficiently to obtain high quality spectra in addition to increasing the number of signal averaging (NSA) or the field strength, both of which are limited in clinical applications. We present a Spectral Wavelet-feature ANalysis and Classification Assisted Denoising (SWANCAD) approach to differentiate signal and noise peaks in magnetic resonance spectra based on their respective wavelet features, followed by removing the identified noise components to improve SNR. The performance of this new denoising approach was evaluated by measuring and comparing SNRs and quantified metabolite levels of low NSA spectra (e.g. NSA = 8) before and after denoising using the SWANCAD approach or by conventional spectral fitting and denoising methods, such as LCModel and wavelet threshold methods, as well as the high NSA spectra (e.g. NSA = 192) recorded in the same sampling volumes. The results demonstrated that SWANCAD offers a more effective way to detect the signals and improve SNR by removing noise from the noisy spectra collected with low NSA or in the subminute scan time (e.g. NSA = 8 or 16 s). The potential applications of SWANCAD include using low NSA to accelerate MRS acquisition while maintaining adequate spectroscopic information for detection and quantification of the metabolites of interest when a limited time is available for an MRS examination in the clinical setting.
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http://dx.doi.org/10.1002/nbm.4497DOI Listing
March 2021

Decreased miR-149 expression in sperm is correlated with the quality of early embryonic development in conventional in vitro fertilization.

Reprod Toxicol 2021 Apr 18;101:28-32. Epub 2021 Feb 18.

Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China; Key Laboratory of Reproductive Genetics, Ministry of Education, Hangzhou, China. Electronic address:

miRNAs play a critical role in the regulation of highly orchestrated gene expression profiles during spermatogenesis and early human embryonic development. However, there is much less information available on the effects of sperm-borne miRNAs on human embryonic development than on spermatogenesis. This study was designed to assess the relationship between two sperm-borne miRNAs (miR-34c and miR-149) and preimplantation embryo development in conventional in vitro fertilization treatment. A positive correlation was seen between a decreased level of miR-149 and a higher percentage of good-quality embryos on day 3 in conventional in vitro fertilization treatment (P < 0.0001), but no correlation was seen between miR-34c and a higher percentage of good-quality embryos (P = 0.1084). Receiver-operating characteristic curve analysis and logistic regression analysis showed that sperm-borne miR-149 with decreased expression was significantly associated with a high rate of good-quality embryos (area under the curve 0.781) (odds ratio: 0.078, 95 % confidence interval: 0.024-0.259, P < 0.0001). Our results demonstrate that the expression profile of miR-149 with significantly decreased expression could be used as a first indication of early embryonic development and may provide novel insight into the biological background of idiopathic infertile males.
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http://dx.doi.org/10.1016/j.reprotox.2021.02.005DOI Listing
April 2021

Single-cell RNA sequencing of developing maize ears facilitates functional analysis and trait candidate gene discovery.

Dev Cell 2021 Feb 4;56(4):557-568.e6. Epub 2021 Jan 4.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. Electronic address:

Crop productivity depends on activity of meristems that produce optimized plant architectures, including that of the maize ear. A comprehensive understanding of development requires insight into the full diversity of cell types and developmental domains and the gene networks required to specify them. Until now, these were identified primarily by morphology and insights from classical genetics, which are limited by genetic redundancy and pleiotropy. Here, we investigated the transcriptional profiles of 12,525 single cells from developing maize ears. The resulting developmental atlas provides a single-cell RNA sequencing (scRNA-seq) map of an inflorescence. We validated our results by mRNA in situ hybridization and by fluorescence-activated cell sorting (FACS) RNA-seq, and we show how these data may facilitate genetic studies by predicting genetic redundancy, integrating transcriptional networks, and identifying candidate genes associated with crop yield traits.
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http://dx.doi.org/10.1016/j.devcel.2020.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904613PMC
February 2021

The emerging role of small non-coding RNA in renal cell carcinoma.

Transl Oncol 2021 Jan 6;14(1):100974. Epub 2020 Dec 6.

Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou 310016, China. Electronic address:

Noncoding RNAs are transcribed in the most regions of the human genome, divided into small noncoding RNAs (less than 200 nt) and long noncoding RNAs (more than 200 nt) according to their size. Compelling evidences suggest that small noncoding RNAs play critical roles in tumorigenesis and tumor progression, especially in renal cell carcinoma. MiRNA, the most famous small noncoding RNA, has been comprehensively explored for its fundamental role in cancer. And several miRNA-based therapeutic strategies have been applied to several ongoing clinical trials. However, piRNAs and tsRNAs, have not received as much research attention, because of several technological limitations. Nevertheless, some studies have revealed the presence of aberration of piRNAs and tsRNAs in renal cell carcinoma, highlighting a potentially novel mechanism for tumor onset and progression. In this review, we provide an overview of three classes of small noncoding RNA: miRNAs, piRNAs and tsRNAs, that have been reported dysregulation in renal cell carcinoma and have the potential for advancing diagnosis, prognosis and therapeutic applications of this disease.
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http://dx.doi.org/10.1016/j.tranon.2020.100974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719974PMC
January 2021

Preimplantation Genetic Testing for a Chinese Family With X-Linked Lymphoproliferative Syndrome Type 1.

Front Genet 2020 4;11:550507. Epub 2020 Nov 4.

The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Background: X-linked lymphoproliferative disease (XLP) is a rare primary immunodeficiency disorder. We performed experiments based on two strategies of preimplantation genetic testing (PGT) for a family with XLP caused by a mutation in (c.191G > A).

Methods: First, a single-cell polymerase chain reaction (PCR) protocol was established using single lymphocytes. A nested PCR experiment was performed with direct sequencing after whole genome amplification of single cells to assess the accuracy of the genetic diagnosis. Embryos obtained after intracytoplasmic sperm injection were biopsied on day 3 and detected using the established single-cell PCR protocol. In the second PGT cycle, targeted next generation sequencing (NGS) was performed and the single nucleotide polymorphism (SNP) markers flanking were selected to determine the disease-carrying haplotype phase in each embryo.

Result: In the first PGT cycle, six embryos were biopsied. Discounting an embryo from a single failed PCR experiment, five embryos were identified, including three unaffected and two hemizygous. After PCR, one normal embryo was transferred when it was developing into an early blastocyst. Although the ultrasound images indicated a viable singleton pregnancy, the implantation was on the cesarean scar. Therefore, an artificial abortion was performed. In the haplotyping cycle, six embryos were identified to have inherited a haplotype without pathogenic mutations. After the embryo implantation process failed twice, a successful singleton pregnancy was established, and subsequently, a healthy female child was born.

Conclusion: Targeted NGS with haplotyping analysis circumvents the laborious process of multiplex PCR and is more likely to ensure diagnostic accuracy. However, when a genetic recombination occurs close to the site of mutation, confirmed identification using selected SNP markers can be challenging.
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http://dx.doi.org/10.3389/fgene.2020.550507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7672036PMC
November 2020

Oncometabolite L-2-hydroxyglurate directly induces vasculogenic mimicry through PHLDB2 in renal cell carcinoma.

Int J Cancer 2021 Apr 15;148(7):1743-1755. Epub 2021 Jan 15.

Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Metabolism reprograming is a hallmark of cancer and plays an important role in tumor progression. The aberrant metabolism in renal cell carcinoma (RCC) leads to accumulation of the oncometabolite L-2-hydroxyglurate (L-2HG). L-2HG has been reported to inhibit the activity of some α-ketoglutarate-dependent dioxygenases such as TET enzymes, which mediate epigenetic alteration, including DNA and histone demethylation. However, the detailed functions of L-2HG in renal cell carcinoma have not been investigated thoroughly. In our study, we found that L-2HG was significantly elevated in tumor tissues compared to adjacent tissues. Furthermore, we demonstrated that L-2HG promoted vasculogenic mimicry (VM) in renal cancer cell lines through reducing the expression of PHLDB2. A mechanism study revealed that activation of the ERK1/2 pathway was involved in L-2HG-induced VM formation. In conclusion, these findings highlighted the pathogenic link between L-2HG and VM and suggested a novel therapeutic target for RCC.
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http://dx.doi.org/10.1002/ijc.33435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986127PMC
April 2021

Differential effects of size-specific particulate matter on lower respiratory infections in children: A multi-city time-series analysis in Sichuan, China.

Environ Res 2021 02 9;193:110581. Epub 2020 Dec 9.

School of Computer Science and Engineering, University of Electronic Science and Technology of China, Chengdu, China; Big Data Research Center, University of Electronic Science and Technology of China, Chengdu, China. Electronic address:

Evidence on the short-term effects of size-specific particulate matter with aerodynamic diameter ≤2.5 μm (PM), ≤10 μm (PM), and their difference (PM) on children's Lower Respiratory Infections (LRI) is scare. This study aimed to estimate the differential effects of three size-specific PM on hospitalizations of children aged <18 years for pneumonia and bronchitis in 18 cities of southwestern China. The city-specific association was firstly estimated using the over-dispersed generalized additive model and then combined to obtain the regional average association. Further, to evaluate the robustness of the key findings, subgroup analyses and co-pollutant models were constructed. PM-related risks of LRI differed by PM fractions and cause-specific LRI. A 10 μg/m increment in PM_lag03, PM_lag06, and PM_lag06 was associated with a 0.79% (95% CI: 0.29%, 1.29%), 0.77% (95% CI: 0.13%, 1.41%), and 2.33% (95% CI: 1.23%, 3.44%) increase in children's LRI hospitalizations, respectively. After adjustment for gaseous pollutants, adverse effects of the three types of size-specific PM on pneumonia hospitalizations were stable, ranging from 0.29% (95% CI: 0.05%, 0.54%) for PM-2.50% (95% CI: 1.38%, 3.64%) for PM. Additionally, PM-related risk of bronchitis hospitalizations remained stable after adjustment for gaseous pollutants. Associations of pneumonia with PM and PM in infants, bronchitis with PM in children aged 6-17 years, pneumonia and bronchitis with PM, PM, and PM in children aged 1-5 years were all statistical significant. Specifically, the effects of PM on LRI hospitalizations increased by age, with the highest effect of 1.72% (95%CI: 1.01%, 2.43%) in children aged 6-17 years. Our study provided evidence for short-term effects of different PM fractions on children LRI hospitalizations in Southwestern China, which will be useful for making and promoting policies on air quality standards in order to protect children's health.
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http://dx.doi.org/10.1016/j.envres.2020.110581DOI Listing
February 2021

Predictors of successful discontinuation from renal replacement therapy during AKI: A meta-analysis.

Semin Dial 2021 Mar 19;34(2):137-146. Epub 2020 Nov 19.

Department of Nephrology, West China Hospital, Sichuan University, Chengdu, China.

The predictors of weaning time of renal replacement therapy (RRT) remain controversial for special patients suffering from acute kidney injury (AKI). The present work aims to perform a meta-analysis to evaluate proper predictors of RRT weaning in AKI patients. We systematically searched EMBASE, PubMed, and Cochrane Central Register of Controlled trials for literatures between 1984 and June 2019. Studies evaluating predictors of weaning success of RRT in patients of AKI were included. Random-effects model or fixed-effects model meta-analyses were performed to compute a standard mean difference (SMD). Newcastle-Ottawa Scale was employed to assess the risk of bias. We included 10 observational trials including 1453 patients. Twelve predictors including urine output, serum creatinine, serum urea, mean arterial pressure, central venous pressure, lactate, serum potassium, serum bicarbonate, pH value, SOFA score, urinary urea, and urinary creatinine were identified, showing urine output (p = 0.0000), serum creatinine (p = 0.008), serum potassium (p = 0.02), serum bicarbonate (p = 0.01), pH value (p = 0.03), urinary urea (p = 0.002), and urinary creatinine (p = 0.02) were significantly associated with weaning success. With the limited evidence, we speculate that urine output, serum creatinine, serum potassium, serum bicarbonate, pH value, urinary urea, and urinary creatinine might be associated with successful weaning.
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http://dx.doi.org/10.1111/sdi.12936DOI Listing
March 2021

Mechanical properties of 2D blue phosphorus and temperature effect.

Nanotechnology 2021 Feb;32(8):085702

Faculty of Civil Engineering and Mechanics, Jiangsu University, #301 Xuefu Rd, Zhenjiang, 212013, People's Republic of China.

Blue phosphorus is an emerging 2D material that exhibits finite electronic band gap and may find promising applications in advanced semiconducting devices. Comparing to its allotrope, black phosphorus, mechanical properties of blue phosphorus have not been explored in detail. Here we report molecular dynamics simulations of mechanical responses of blue phosphorus under uniaxial tensile, biaxial tensile and shear loadings. It is found that blue phosphorus shows less anisotropic effect as compared to black phosphorus, the room temperature Young's modulus is about 122.3 GPa and 121.6 GPa along armchair and zigzag directions, respectively, shear modulus is about 27.1 GPa and 28.6 GPa, respectively, along armchair and zigzag directions. Temperature effect on mechanical responses is also systematically studied within a range of 5-400 K. It is found that temperature reduces both Young's modulus and fracture strain and fracture strength of blue phosphorus, owing to the interplay between thermal energy and strain energy applied to the models. Brittle fracture mode is found in blue phosphorus in all loading conditions, with varied crack nucleation and propagation modes. The role of strain rate on the mechanical properties is examined and found to systematically modify the ultimate stress and ultimate strain of BlueP. Structural details including bond length and bond angle variations to external strain are analyzed to gain deeper insights into the underlying mechanisms.
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http://dx.doi.org/10.1088/1361-6528/abc98fDOI Listing
February 2021

Malignant Ovarian Tumors During Pregnancy: A Multicenter Retrospective Analysis.

Cancer Manag Res 2020 29;12:10841-10848. Epub 2020 Oct 29.

Department of Gynecologic Oncology, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Municipal Key Clinical Specialty, Shanghai Key Laboratory of Embryo Original Disease, Shanghai, 200030, People's Republic of China.

Purpose: The aim of this study was to investigate the clinical characteristics and management of malignant ovarian tumors during pregnancy, as well as the feto-maternal outcomes and analyze the influential factors on the pregnancy outcomes.

Patients And Methods: Eighty-five patients with ovarian malignancies during pregnancy treated at 12 tertiary hospitals between 2009 and 2019 were analyzed in this study. The clinical features, histopathological characteristics, clinical management, and maternal and perinatal outcomes were retrospectively analyzed. The clinical features and managements were compared between abortion group and live birth group.

Results: The following diagnoses were made: 41 (48.24%) patients with borderline ovarian tumors, 18 (21.18%) patients with epithelial ovarian cancers, 17 (20.00%) patients with non-epithelial ovarian malignancies and 9 (10.59%) patients with metastatic ovarian tumors. Thirty-six (42.45%) patients underwent conservative surgical treatment. Thirty-four (40.00%) patients opted for fertility-sparing surgery, and fifteen (17.56%) patients received radical surgery. Chemotherapy was administered to 32.94% of the patients. The proportion of ovarian malignancies diagnosed in the first trimester in the abortion group was higher than that in the live birth group (<0.05). However, tumor diameter, reproductive history, stage and surgical indications showed no significant differences between groups. A total of 67 live babies were recorded in this study, including 19 premature babies and 1 full-term newborn who died of respiratory distress. All of the BOTs were diagnosed with stage I, among whom 38 (92.68%) patients exhibited disease-free survival. Twenty-eight ovarian cancers were in stage I-II and 26 of them had disease-free survival with the longest follow-up time of 10 years. Five of the sixteen patients in advanced stage (stage III-IV) died, four of whom had metastatic tumors.

Conclusion: Pregnant women with early-stage malignant ovarian tumors appear to have favorable outcomes. Conservative surgery is acceptable for early-stage borderline ovarian tumors during pregnancy. The gestational age of ovarian malignancy detection is key for pregnancy outcomes.
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http://dx.doi.org/10.2147/CMAR.S271806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605603PMC
October 2020

Deep anterior lamellar keratoplasty with cross-linked acellular porcine corneal stroma to manage fungal keratitis.

Xenotransplantation 2021 Mar 26;28(2):e12655. Epub 2020 Oct 26.

School of Ophthalmology and Optometry, Wenzhou Medical University, Zhejiang, China.

Purpose: To evaluate the effects of deep anterior lamellar keratoplasty (DALK) with cross-linked acellular porcine corneal stroma (APCS) and post-operative topical tacrolimus treatment in patients with fungal keratitis.

Methods: This multicenter prospective study involved 25 cases of fungal keratitis that were treated by DALK with cross-linked APCSs and post-operative topical tacrolimus from December 2013 to November 2014 at the Wenzhou Eye Hospital and the Henan provincial Eye Hospital. Signs of post-operative inflammation, corneal reepithelialization, corneal neovascularization, and graft rejection were assessed, and best corrected visual acuity (BCVA), intraocular pressure (IOP), and APCS graft transparency were monitored for the 12-month follow-up period.

Results: All 25 patients underwent DALK without Descemet's membrane perforation. Corneal epithelium recovered completely in 17 patients in the first week, and APCS grafts maintained transparency in 18 patients at 1-year follow-up. The mean BCVA significantly improved from 2.16 ± 0.32 (LogMAR) at baseline to 1.56 ± 0.70 at 1-week (P < .001), 0.95 ± 0.57 at 1-month (P < .001), and 0.70 ± 0.51 at 3-month follow-ups (P < .001). The BCVA kept stable at 6-month and 12-month follow-ups. Post-operative topical tacrolimus alleviated the ciliary injection, except in one case which acute stromal rejection occurred. One patient developed fungal reinfection and underwent penetrating keratoplasty. Graft rejection occurred in three patients. No case was noted with graft splitting, elevated IOP or tacrolimus intolerance.

Conclusions: DALK using cross-linked APCS combining topical tacrolimus treatment is safe and effective in managing fungal keratitis. It may ameliorate the shortage of corneal donation globally.
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http://dx.doi.org/10.1111/xen.12655DOI Listing
March 2021

Lymphomatoid papulosis subtype C: A case report and literature review.

Dermatol Ther 2021 Jan 3;34(1):e14452. Epub 2020 Nov 3.

Department of Dermatology, Clinical Medical College, Yangzhou University, Yangzhou, China.

Lymphomatoid papulosis (LyP) is a rare CD30 lymphoproliferative primary skin disease with a benign clinical course and malignant histopathology. LyP is classified into seven subtypes based on histopathology: subtypes A through F and LyP with 6p25.3 chromosome rearrangement. We present here, a case report of a 51-year-old man, afflicted with multiple papules and nodules on his left arm for over 3 months and diagnosed with LyP subtype C. The patient refused treatment, and his lesions faded with no visible rash on the left arm 14 months after diagnosis.
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http://dx.doi.org/10.1111/dth.14452DOI Listing
January 2021

Identification of a likely pathogenic structural variation in the gene by Bionano optical mapping.

NPJ Genom Med 2020 12;5:31. Epub 2020 Aug 12.

Women's Hospital, School of Medicine, Zhejiang University, 1, Xueshi Road, Hangzhou, Zhejiang 310006 People's Republic of China.

Recent advances in Bionano optical mapping (BOM) provide a great insight into the determination of structural variants (SVs), but its utility in identification of clinical likely pathogenic variants needs to be further demonstrated and proved. In a family with two consecutive pregnancies affected with ventriculomegaly, a splicing likely pathogenic variant at the locus (NM_005559: c. 4663 + 1 G > C) inherited from the father was identified in the proband by whole-exome sequencing, and no other pathogenic variant associated with the clinical phenotypes was detected. SV analysis by BOM revealed an ~48 kb duplication at the locus in the maternal sample. Real-time quantitative PCR and Sanger sequencing further confirmed the duplication as c.859-153_4806 + 910dup. Based on these variants, we hypothesize that the fetuses have Poretti-Boltshauser syndrome (PBS) presenting with ventriculomegaly. With the ability to determine single nucleotide variants and SVs, the strategy adopted here might be useful to detect cases missed by current routine screening methods. In addition, our study may broaden the phenotypic spectrum of fetuses with PBS.
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http://dx.doi.org/10.1038/s41525-020-0138-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7538933PMC
August 2020

Impacts of age, diabetes, gender, and access type on costs associated with vascular access among Chinese patients on hemodialysis.

Int J Artif Organs 2020 Oct 4:391398820962112. Epub 2020 Oct 4.

Kidney Research Laboratory, Division of Nephrology, West China Hospital of Sichuan University, Chengdu, China.

Objectives: Examine the impacts of age, diabetes, gender, and access type on vascular access (VA) associated costs among Chinese hemodialysis (HD) patients.

Methods: We retrospectively included patients whose first permanent VA was created at the West China Hospital. Clinical characteristics, maturation, intervention, utilization, and exchange of every VA, as well as VA-related infection were collected. The study period for each patient was from HD initiation to the last follow-up. VA-related costs, including those for placement and intervention procedures, were calculated according to the standards set in 2019 for Chinese tertiary hospitals. U and Chi-square tests were conducted for comparisons between groups.

Results: A total of 358 Chinese HD patients experienced functionally 143 arteriovenous fistula (AVF), 22 arteriovenous graft (AVG), and 439 tunneled cuffed central venous catheter (tcCVC) during a median study period of 26 (IQR 13-44) months, of which 42.5% used more than one permanent VA. The median annual VA-related cost in the groups of age >75 years and ⩽75 years, diabetes and non-diabetes, male and female, was $525 and $397 ( = 0.016), $459 and $462 ( = 0.64), $476 and $445 ( = 0.94), respectively. The median monthly costs for AVF ($18), AVG ($289), and tcCVC ($37) were significantly different.

Conclusion: HD patients aged >75 years had significantly higher annual VA-related costs. However, the annual VA-related costs did not differ across the diabetes groups or the gender groups. AVF was the most cost-effective permanent VA type in China, partly due to the inexpensive materials used compared to AVG or tcCVC.
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http://dx.doi.org/10.1177/0391398820962112DOI Listing
October 2020

Healthcare utilization and total costs of care among patients with advanced metastatic gastric and esophageal cancer.

Future Oncol 2021 Jan 30;17(3):291-299. Epub 2020 Sep 30.

Charles A. Sammons Cancer Center at Baylor University Medical Center, Dallas, TX 75246, USA.

Study first-line (1L) treatment patterns and economic outcomes among patients with advanced metastatic gastric cancer (GC) and esophageal cancer (EC). Newly diagnosed patients with systemic GC and EC treatments were identified between 1 January 2011 and 31 July 2017; costs were presented as per patient per month (PPPM) basis. Study included 392 GC and 436 EC patients. Most frequently used 1L regimens were: 5-fluorouracil (5-FU) + oxaliplatin (22.5%) and epirubicin + cisplatin + 5-FU (ECF)/ECF modifications (21.9%) in patients with GC; and carboplatin + paclitaxel (29.6%) and 5-FU + oxaliplatin (11.5%) in EC patients. Mean all-cause costs were US$16,242 PPPM for GC, and $18,384 PPPM for EC during 1L treatment. GC and EC were resource intensive and costly. High costs and short treatment durations underscored a gap in care in 1L treatment.
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http://dx.doi.org/10.2217/fon-2020-0516DOI Listing
January 2021

Visceral Fat Area Is a Better Predictor Than Coronary Artery Calcification Score for Cardiovascular Outcomes and All-Cause Death in Patients on Hemodialysis.

J Ren Nutr 2020 Sep 24. Epub 2020 Sep 24.

Department of Nephrology, West China Hospital, Sichuan University, Chengdu, People's Republic of China; Disaster Medicine Center, Sichuan University, Chengdu, People's Republic of China; Institute for Disaster Management and Reconstruction, Sichuan University, Chengdu, People's Republic of China. Electronic address:

Objectives: The aim of this study is to compare the prognostic effects of visceral fat area (VFA) with coronary artery calcification score (CACs) in patients on maintenance hemodialysis.

Design And Methods: In the prospective study with no intervention, clinical characteristics and serum biochemical indexes at baseline for each patient were collected through the electronic medical records. Body composition assessment using bioelectrical impedance analysis, computed tomography examination with the Agatston scoring method, and echocardiographic measurements were performed at enrollment. Primary endpoints included cardiovascular events (CVEs), cardiovascular death (CVD), and all-cause death.

Results: A total of 97 Chinese patients aged 48 (35-62) years were enrolled from our Hemodialysis Center, of which 61.9% were male and 20.6% had diabetes. The median of VFA and CACs at baseline was 64.5 (43.5-88.7) cm and 0.9 (0-467.6), respectively. CVEs occurred in 20 (20.6%) patients during a median follow-up of 26.4 (13-27.7) months. The cardiovascular and all-cause mortality was 8.2% (8 patients) and 11.3% (11 patients), respectively. VFA was associated with CVEs (hazard ratio [HR] = 9.21 for VFA ≥71.3 cm vs. VFA <71.3 cm, P = .017), CVD (HR = 1.11 for 1 cm increase, P = .035), and all-cause mortality (HR = 1.08 for 1 cm increase, P = .011). Also, VFA was significantly correlated with cardiac structure parameters and the development of left ventricular hypertrophy (odds ratio = 1.02 for 1 cm increase, P = .03). Yet, CACs were not correlated with CVEs, CVD, or all-cause mortality.

Conclusions: Increased VFA can be used as an independent predictor for CVEs, CVD, and all-cause mortality. The effect VFA exerts on cardiac reconstruction might be the underlying mechanism. Further studies are warranted for the management of VFA in the hemodialysis population.
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http://dx.doi.org/10.1053/j.jrn.2020.08.009DOI Listing
September 2020

Author Correction: Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

Nat Metab 2020 Aug;2(8):793

Research Program in Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s42255-020-0255-0DOI Listing
August 2020

BSAseq: an interactive and integrated web-based workflow for identification of causal mutations in bulked F2 populations.

Bioinformatics 2020 Aug 10. Epub 2020 Aug 10.

USDA-ARS Cropping Systems Research Laboratory, Lubbock, TX, USA.

Summary: With the advance of next-generation sequencing (NGS) technologies and reductions in the costs of these techniques, bulked segregant analysis (BSA) has become not only a powerful tool for mapping quantitative trait loci (QTL) but also a useful way to identify causal gene mutations underlying phenotypes of interest. However, due to the presence of background mutations and errors in sequencing, genotyping, and reference assembly, it is often difficult to distinguish true causal mutations from background mutations. In this study, we developed the BSAseq workflow, which includes an automated bioinformatics analysis pipeline with a probabilistic model for estimating the linked region (the region linked to the causal mutation) and an interactive Shiny web application for visualizing the results. We deeply sequenced a sorghum male-sterile parental line (ms8) to capture the majority of background mutations in our bulked F2 data. We applied the workflow to 11 bulked sorghum F2 populations and 1 rice F2 population and identified the true causal mutation in each population. The workflow is intuitive and straightforward, facilitating its adoption by users without bioinformatics analysis skills. We anticipate that the BSAseq workflow will be broadly applicable to the identification of causal mutations for many phenotypes of interest.

Availability: BSAseq is freely available on https://www.sciapps.org/page/bsa.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btaa709DOI Listing
August 2020

Coarse particles (PM) and cause-specific hospitalizations in southwestern China: Association, attributable risk and economic costs.

Environ Res 2020 11 31;190:110004. Epub 2020 Jul 31.

Health Information Center of Sichuan Province, Chengdu, China.

The short-term morbidity effects of the coarse particle (diameter in 2.5-10 μm, PM), as well as the corresponding morbidity burden and economic costs, remain understudied, especially in developing countries. This study aimed to examine the associations of PM with cause-specific hospitalizations in a multi-city setting in southwestern China and assess the attributable risk and economic costs. City-specific associations were firstly estimated using generalized additive models with quasi-poisson distribution to handle over-dispersion, and then combined to obtain the regional average association. City-specific and pooled concentration-response (C-R) associations of PM with cause-specific hospitalizations were also modeled. Subgroup analyses were performed by age, sex, season and region. The health and economic burden of hospitalizations for multiple outcomes due to PM were further evaluated. A total of 4,407,601 non-accidental hospitalizations were collected from 678 hospitals. The estimates of percentage change in hospitalizations per 10 μg/m³ increase in PM at lag01 was 0.68% (95%CI: 0.33%-1.03%) for non-accidental causes, 0.86% (95% CI: 0.36%-1.37%) for circulatory diseases, 1.52% (95% CI: 1.00%-2.05%) for respiratory diseases, 1.08% (95% CI: 0.47%-1.69%) for endocrine diseases, 0.66% (95% CI: 0.12%-1.21%) for nervous system diseases, and 0.84% (95% CI: 0.42%-1.25%) for genitourinary diseases, respectively. The C-R associations of PM with cause-specific hospitalizations suggested some evidence of nonlinearity, except for endocrine diseases. Meanwhile, the adverse effects were modified by age and season. Overall, about 0.70% (95% CI: 0.35%-1.06%) of non-accidental hospitalizations and 0.78% (95% CI: 0.38%-1.17%) of total hospitalization expenses could be attributed to PM. The largest morbidity burden and economic costs were observed in respiratory diseases. Our findings indicate that PM exposure may increase the risk of hospitalizations for multiple outcomes, and account for considerable morbidity and economic burden.
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http://dx.doi.org/10.1016/j.envres.2020.110004DOI Listing
November 2020

Associations of mitochondrial DNA copy number and deletion rate with early pregnancy loss.

Mitochondrion 2020 11 30;55:48-53. Epub 2020 Jul 30.

International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200030, China; Shanghai Key Laboratory of Embryo Original Diseases, Shanghai, China.

Early pregnancy loss (EPL) is a common event worldwide. Previous studies show that mitochondrial DNA (mtDNA) copy number (CN) is associated with semen parameters and preimplantation embryo viability, indicating the predictive potential of mtDNA CN for ongoing pregnancy outcomes. However, no relevant study has assessed the relationship between mtDNA CN and EPL. Thus, we aimed to determine whether mtDNA CN and mtDNA 4977-bp deletion rate (DR) in chorionic villous tissue are associated with EPL. Chorionic villous tissue total DNA was extracted from 75 EPL cases and 75 healthy controls. Chromosomal analysis was conducted using copy number variation (CNV) sequencing. The mtDNA CN and DR were measured in samples without pathogenic CNVs. The association between mtDNA CN or DR and EPL risk were estimated using logistic regression. The EPL group had a significantly different mtDNA CN (P < 0.001) and DR (P = 0.005) compared to the control group. Both biomarkers were independent risk factors for EPL (CN odds ratio 1.71, 95% confidence interval 1.17 to 2.49, P = 0.005; DR odds ratio 1.07, 95% confidence interval 1.02 to 1.12, P = 0.006). These results suggest that higher mtDNA CN and DR levels are strongly associated with EPL and represent independent risk factors for EPL. Further studies validating these findings and exploring the underlying biological mechanisms are warranted.
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http://dx.doi.org/10.1016/j.mito.2020.07.006DOI Listing
November 2020

Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

Nat Metab 2019 10 7;1(10):958-965. Epub 2019 Oct 7.

Research Program in Stem Cells and Metabolism, University of Helsinki, Helsinki, Finland.

Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown. Here, we show that cells from mutator mice display challenged nuclear genome maintenance similar to that observed in progeric cells with defects in nuclear DNA repair. Cells from mutator mice show slow nuclear DNA replication fork progression, cell cycle stalling and chronic DNA replication stress, leading to double-strand DNA breaks in proliferating progenitor or stem cells. The underlying mechanism involves increased mtDNA replication frequency, sequestering of nucleotides to mitochondria, depletion of total cellular nucleotide pools, decreased deoxynucleoside 5'-triphosphate (dNTP) availability for nuclear genome replication and compromised nuclear genome maintenance. Our data indicate that defects in mtDNA replication can challenge nuclear genome stability. We suggest that defects in nuclear genome maintenance, particularly in the stem cell compartment, represent a unified mechanism for mouse progerias. Therefore, through their destabilizing effects on the nuclear genome, mtDNA mutations are indirect contributors to organismal ageing, suggesting that the direct role of mtDNA mutations in driving ageing-like symptoms might need to be revisited.
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http://dx.doi.org/10.1038/s42255-019-0120-1DOI Listing
October 2019

Anticoagulant chitosan-kappa-carrageenan composite hydrogel sorbent for simultaneous endotoxin and bacteria cleansing in septic blood.

Carbohydr Polym 2020 Sep 25;243:116470. Epub 2020 May 25.

College of Polymer Science and Engineering, State Key Laboratory of Polymer Materials Engineering, Sichuan University, Chengdu, 610065, China. Electronic address:

Here, we describe a green approach to fabricate genipin crosslinked chitosan-kappa-carrageenan composite hydrogels (C-K hydrogels) aiming at reducing endotoxin level and bacteria burden in septic blood synchronously. The chemical compositions and morphologies of the developed C-K hydrogels were characterized by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy and scanning electron microscopy. The C-K hydrogels significantly inhibited adverse blood-material interactions such as hemolysis, complement activation, platelet activation and contact activation, and exhibited better anticoagulant properties than raw chitosan hydrogels. Most importantly, the optimized C-K hydrogels were competent to eliminate 63.3 % of endotoxin in septic blood with a maximum adsorption capacity of 95.0 EU/g during a 3-h simulative hemoperfusion procedure. Bacteria cleansing experiments further demonstrated that the optimized C-K hydrogels effectively decreased 46.0 % of E. coli and 68.7 % of S. aureus load, respectively. It is believed that the C-K hydrogels are promising hemoperfusion sorbents to treat severe septic patients.
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http://dx.doi.org/10.1016/j.carbpol.2020.116470DOI Listing
September 2020

Going even smaller: Engineering sub-5 nm nanoparticles for improved delivery, biocompatibility, and functionality.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2020 11 20;12(6):e1644. Epub 2020 May 20.

Department of Radiology and Imaging Sciences, Emory University, Atlanta, Georgia, USA.

The rapid development and advances in nanomaterials and nanotechnology in the past two decades have made profound impact in our approaches to individualized disease diagnosis and treatment. Nanomaterials, mostly in the range of 10-200 nm, developed for biomedical applications provide a wide range of platforms for building and engineering functionalized structures, devices, or systems to fulfill the specific diagnostic and therapeutic needs. Driven by achieving the ultimate goal of clinical translation, sub-5 nm nano-constructs, in particular inorganic nanoparticles such as gold, silver, silica, and iron oxide nanoparticles, have been developed in recent years to improve the biocompatibility, delivery and pharmacokinetics of imaging probes and drug delivery systems, as well as in vivo theranostic applications. The emerging studies have provided new findings that demonstrated the unique size-dependent physical properties, physiological behaviors and biological functions of the nanomaterials in the range of the sub-5 nm scale, including renal clearance, novel imaging contrast, and tissue distribution. This advanced review attempts to introduce the new strategies of rational design for engineering nanoparticles with the core sizes under 5 nm in consideration of the clinical and translational requirements. We will provide readers the update on recent discoveries of chemical, physical, and biological properties of some biocompatible sub-5 nm nanomaterials as well as their demonstrated imaging and theranostic applications, followed by sharing our perspectives on the future development of this class of nanomaterials. This article is categorized under: Diagnostic Tools > in vivo Nanodiagnostics and Imaging Implantable Materials and Surgical Technologies > Nanomaterials and Implants.
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http://dx.doi.org/10.1002/wnan.1644DOI Listing
November 2020

Reliability of Conclusions from Early Analyses of Real-World Data for Newly Approved Drugs in Advanced Gastric Cancer in the United States.

Pragmat Obs Res 2020 30;11:27-43. Epub 2020 Apr 30.

Medical Affairs, Eli Lilly and Company, Indianapolis, IN, USA.

Background: As real-world data resources expand and improve, there will increasingly be opportunities to study the effectiveness of interventions. There is a need to ensure that study designs explore potential sources of bias and either acknowledge or mitigate them, in order to improve the accuracy of findings. The objective of this study was to understand newly approved drug utilization patterns in real-world clinical settings over time.

Methods: This retrospective study included three sources of real-world data (claims, electronic health records, and recoded data from a quality care program) collected from patients diagnosed with gastric cancer who initiated therapy with either trastuzumab or ramucirumab. Linear regression was used to investigate trends in the use of these drugs for the care of patients with gastric cancer over time from Food and Drug Administration (FDA) approval.

Results: Eligible patients (n=1700) had consistent demographic and clinical characteristics over time. After regulatory approval, trastuzumab was used in later lines of therapy and then shifted to earlier lines (p=0.002), while ramucirumab utilization remained consistent over time after FDA approval (p=0.49). Ramucirumab augmentation, defined as the addition of the drug after initiation of a line of therapy, decreased over time (p=0.03), and trastuzumab augmentation remained consistent over time (p=0.58).

Conclusion: Since treatment effectiveness may change across lines of treatment, bias may arise if there are changes in the use of the drug (such as line migration) during the time period of analysis using real-world data.
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http://dx.doi.org/10.2147/POR.S241427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205419PMC
April 2020

Deep learning for detecting corona virus disease 2019 (COVID-19) on high-resolution computed tomography: a pilot study.

Ann Transl Med 2020 Apr;8(7):450

Department of Radiology, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, China.

Background: To evaluate the diagnostic efficacy of Densely Connected Convolutional Networks (DenseNet) for detection of COVID-19 features on high resolution computed tomography (HRCT).

Methods: The Ethic Committee of our institution approved the protocol of this study and waived the requirement for patient informed consent. Two hundreds and ninety-five patients were enrolled in this study (healthy person: 149; COVID-19 patients: 146), which were divided into three separate non-overlapping cohorts (training set, n=135, healthy person, n=69, patients, n=66; validation set, n=20, healthy person, n=10, patients, n=10; test set, n=140, healthy person, n=70, patients, n=70). The DenseNet was trained and tested to classify the images as having manifestation of COVID-19 or as healthy. A radiologist also blindly evaluated all the test images and rechecked the misdiagnosed cases by DenseNet. Receiver operating characteristic curves (ROC) and areas under the curve (AUCs) were used to assess the model performance. The sensitivity, specificity and accuracy of DenseNet model and radiologist were also calculated.

Results: The DenseNet algorithm model yielded an AUC of 0.99 (95% CI: 0.958-1.0) in the validation set and 0.98 (95% CI: 0.972-0.995) in the test set. The threshold value was selected as 0.8, while for validation and test sets, the accuracies were 95% and 92%, the sensitivities were 100% and 97%, the specificities were 90% and 87%, and the F1 values were 95% and 93%, respectively. The sensitivity of radiologist was 94%, the specificity was 96%, while the accuracy was 95%.

Conclusions: Deep learning (DL) with DenseNet can accurately classify COVID-19 on HRCT with an AUC of 0.98, which can reduce the miss diagnosis rate (combined with radiologists' evaluation) and radiologists' workload.
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http://dx.doi.org/10.21037/atm.2020.03.132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210135PMC
April 2020

Machine learning approaches to predict peak demand days of cardiovascular admissions considering environmental exposure.

BMC Med Inform Decis Mak 2020 05 1;20(1):83. Epub 2020 May 1.

Cardiology Division, West China Hospital, Sichuan University, Chengdu, China.

Background: Accumulating evidence has linked environmental exposure, such as ambient air pollution and meteorological factors, to the development and severity of cardiovascular diseases (CVDs), resulting in increased healthcare demand. Effective prediction of demand for healthcare services, particularly those associated with peak events of CVDs, can be useful in optimizing the allocation of medical resources. However, few studies have attempted to adopt machine learning approaches with excellent predictive abilities to forecast the healthcare demand for CVDs. This study aims to develop and compare several machine learning models in predicting the peak demand days of CVDs admissions using the hospital admissions data, air quality data and meteorological data in Chengdu, China from 2015 to 2017.

Methods: Six machine learning algorithms, including logistic regression (LR), support vector machine (SVM), artificial neural network (ANN), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM) were applied to build the predictive models with a unique feature set. The area under a receiver operating characteristic curve (AUC), logarithmic loss function, accuracy, sensitivity, specificity, precision, and F1 score were used to evaluate the predictive performances of the six models.

Results: The LightGBM model exhibited the highest AUC (0.940, 95% CI: 0.900-0.980), which was significantly higher than that of LR (0.842, 95% CI: 0.783-0.901), SVM (0.834, 95% CI: 0.774-0.894) and ANN (0.890, 95% CI: 0.836-0.944), but did not differ significantly from that of RF (0.926, 95% CI: 0.879-0.974) and XGBoost (0.930, 95% CI: 0.878-0.982). In addition, the LightGBM has the optimal logarithmic loss function (0.218), accuracy (91.3%), specificity (94.1%), precision (0.695), and F1 score (0.725). Feature importance identification indicated that the contribution rate of meteorological conditions and air pollutants for the prediction was 32 and 43%, respectively.

Conclusion: This study suggests that ensemble learning models, especially the LightGBM model, can be used to effectively predict the peak events of CVDs admissions, and therefore could be a very useful decision-making tool for medical resource management.
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http://dx.doi.org/10.1186/s12911-020-1101-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195717PMC
May 2020

Basic biochemical characterization of cytosolic enzymes in thymidine nucleotide synthesis in adult rat tissues: implications for tissue specific mitochondrial DNA depletion and deoxynucleoside-based therapy for TK2-deficiency.

BMC Mol Cell Biol 2020 Apr 28;21(1):33. Epub 2020 Apr 28.

Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, SE-750 07, Uppsala, Sweden.

Background: Deficiency in thymidine kinase 2 (TK2) or p53 inducible ribonucleotide reductase small subunit (p53R2) is associated with tissue specific mitochondrial DNA (mtDNA) depletion. To understand the mechanisms of the tissue specific mtDNA depletion we systematically studied key enzymes in dTMP synthesis in mitochondrial and cytosolic extracts prepared from adult rat tissues.

Results: In addition to mitochondrial TK2 a cytosolic isoform of TK2 was characterized, which showed similar substrate specificity to the mitochondrial TK2. Total TK activity was highest in spleen and lowest in skeletal muscle. Thymidylate synthase (TS) was detected in cytosols and its activity was high in spleen but low in other tissues. TS protein levels were high in heart, brain and skeletal muscle, which deviated from TS activity levels. The p53R2 proteins were at similar levels in all tissues except liver where it was ~ 6-fold lower. Our results strongly indicate that mitochondria in most tissues are capable of producing enough dTTP for mtDNA replication via mitochondrial TK2, but skeletal muscle mitochondria do not and are most likely dependent on both the salvage and de novo synthesis pathways.

Conclusion: These results provide important information concerning mechanisms for the tissue dependent variation of dTTP synthesis and explained why deficiency in TK2 or p53R2 leads to skeletal muscle dysfunctions. Furthermore, the presence of a putative cytosolic TK2-like enzyme may provide basic knowledge for the understanding of deoxynucleoside-based therapy for mitochondrial disorders.
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http://dx.doi.org/10.1186/s12860-020-00272-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189545PMC
April 2020