Publications by authors named "Shuqing Chen"

146 Publications

A novel genomic classification system of gastric cancer via integrating multidimensional genomic characteristics.

Gastric Cancer 2021 Jun 6. Epub 2021 Jun 6.

Department of Surgical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China.

Background: Gastric cancer (GC) is one of the leading causes of cancer deaths with high heterogeneity. There is currently a paucity of clinically applicable molecular classification system to guide precise medicine.

Methods: A total of 70 Chinese patients with GC were included in this study and whole-exome sequencing was performed. Unsupervised clustering was undertaken to identify genomic subgroups, based on mutational signature, copy number variation, neoantigen, clonality, and essential genomic alterations. Subgroups were characterized by clinicopathological factors, molecular features, and prognosis.

Results: We identified 32 significantly mutated genes (SMGs), including TP53, ARID1A, PIK3CA, CDH1, and RHOA. Of these, PREX2, PIEZO1, and FSIP2 have not been previously reported in GC. Using a novel genome-based classification method that integrated multidimensional genomic features, we categorized GC into four subtypes with distinct clinical phenotypes and prognosis. Subtype 1, which was predominantly Lauren intestinal type, harbored recurrent TP53 mutation and ERBB2 amplification, high tumor mutation burden (TMB)/tumor neoantigen burden (TNB), and intratumoral heterogeneity, with a liver metastasis tendency. Subtype 2 tended to occur at an elder age, accompanying with frequent TP53 and SYNE1 mutations, high TMB/TNB, and was associated with poor prognosis. Subtype 3 and subtype 4 included patients with mainly diffuse/mixed type tumors, high frequency of peritoneal metastasis, and genomical stability, whereas subtype 4 was associated with a favorable prognosis.

Conclusions: By integrating multidimensional genomic characteristics, we proposed a novel genomic classification system of GC associated with clinical phenotypes and provided a new insight to facilitate genome-guided risk stratification and disease management.
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http://dx.doi.org/10.1007/s10120-021-01201-9DOI Listing
June 2021

All-Dielectric Metasurface-Based Beam Splitter with Arbitrary Splitting Ratio.

Nanomaterials (Basel) 2021 Apr 28;11(5). Epub 2021 Apr 28.

International Collaborative Laboratory of 2D Materials for Optoelectronics Science & Technology of Ministry of Education, Engineering Technology Research Center for 2D Material Information Function Devices and Systems of Guangdong Province, Institute of Microscale Optoelectronics, Shenzhen University, Shenzhen 518060, China.

The development of optical systems is heading to multi-branch circuit design and miniaturization. A beam splitter is a common device for dividing an incident beam into two separate beams. Conventional beam splitters are constructed using coated prisms or glass plate. Their bulky size, right-angled output direction, and fixed splitting ratio greatly limit the design of optical arrangement and also hinder the system integration. Here, an all-dielectric metasurface composed of symmetric nano-rings as a beam splitter are designed by Finite-Difference Time-Domain method. By changing the inner and outer radiuses of the nano-rings, the wavefront phase of the emergence beam can be adjusted to form a phase gradient, and the incident beam of arbitrary polarization is divided into two beams according to the designed transmittance and angle. The initial phase of the emergence beam can be changed by adjusting the refractive index of the substrate or adding the silicon film to the substrate, and the splitting ratio can be adjusted from 0.5:1 to 1:1. The simulation demonstrates that the metasurface-based beam splitter is independent of polarization and the power efficiency is over 92% with a compact area of 33.6 μm × 33.6 μm. This compact metasurface-based beam splitter has promising potential for enabling new types of compact optical systems and advancing metasurface-based functional integrated photonic applications.
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http://dx.doi.org/10.3390/nano11051137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8146930PMC
April 2021

CanDriS: posterior profiling of cancer-driving sites based on two-component evolutionary model.

Brief Bioinform 2021 Apr 20. Epub 2021 Apr 20.

Department of Genetics, Development and Cell Biology, Iowa State University, Ames, 12 Iowa 50011, USA.

Current cancer genomics databases have accumulated millions of somatic mutations that remain to be further explored. Due to the over-excess mutations unrelated to cancer, the great challenge is to identify somatic mutations that are cancer-driven. Under the notion that carcinogenesis is a form of somatic-cell evolution, we developed a two-component mixture model: while the ground component corresponds to passenger mutations, the rapidly evolving component corresponds to driver mutations. Then, we implemented an empirical Bayesian procedure to calculate the posterior probability of a site being cancer-driven. Based on these, we developed a software CanDriS (Cancer Driver Sites) to profile the potential cancer-driving sites for thousands of tumor samples from the Cancer Genome Atlas and International Cancer Genome Consortium across tumor types and pan-cancer level. As a result, we identified that approximately 1% of the sites have posterior probabilities larger than 0.90 and listed potential cancer-wide and cancer-specific driver mutations. By comprehensively profiling all potential cancer-driving sites, CanDriS greatly enhances our ability to refine our knowledge of the genetic basis of cancer and might guide clinical medication in the upcoming era of precision medicine. The results were displayed in a database CandrisDB (http://biopharm.zju.edu.cn/candrisdb/).
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http://dx.doi.org/10.1093/bib/bbab131DOI Listing
April 2021

Investigation of a Progressive Relaxation Training Intervention on Precompetition Anxiety and Sports Performance Among Collegiate Student Athletes.

Front Psychol 2020 17;11:617541. Epub 2021 Mar 17.

School of Physical Education & Sports Science, South China Normal University, Guangzhou, China.

This study aims to investigate whether simple and convenient progressive relaxation training (PRT) is effective in enhancing collegiate student athletes' mental health and sports performance. An experimental group of 14 (6 female) and a control group of 10 (5 female) collegiate student athletes were recruited from among track and field athletes who were preparing for provincial competition. The experimental group was exposed to a PRT intervention in 30-min sessions conducted twice per week for a duration of one month. At baseline, the Competitive State Anxiety Inventory-2 (CSAI-2), State-Trait Anxiety Inventory (STAI), and Eysenck Personality Questionnaire-Revised Short Scale for Chinese (EPQ-RSC) were completed, while only the CSAI-2 was reassessed at one, two, and three weeks after initiation of the intervention. Additionally, within half a day after completing all one's individual competition events, the CSAI-2 was again assessed in the two groups recalling their memory of their precompetition state anxiety. Then, the differences in the three dimensions of the CSAI-2 between the two groups at the five time points introduced above were compared. This study also explored whether PRT affected sports performance, defined by the athletes reaching their best records or not, by logistic regressive analysis. This study found significant between-group differences in the self-confidence dimension score at the second and third time points. Through logistic regression analysis, a positive effect of PRT was found for the enhancement of sports performance. In sum, PRT showed positive effects on precompetition state self-confidence and enhanced sports performance among collegiate student athletes.
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http://dx.doi.org/10.3389/fpsyg.2020.617541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009973PMC
March 2021

Corrigendum: COVIEdb: A Database for Potential Immune Epitopes of Coronaviruses.

Front Pharmacol 2020 8;11:646111. Epub 2021 Feb 8.

Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

[This corrects the article DOI: 10.3389/fphar.2020.572249.].
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http://dx.doi.org/10.3389/fphar.2020.646111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898895PMC
February 2021

COVIEdb: A Database for Potential Immune Epitopes of Coronaviruses.

Front Pharmacol 2020 2;11:572249. Epub 2020 Sep 2.

College of Pharmaceutical Sciences, Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, Zhejiang University, Hangzhou, China.

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http://dx.doi.org/10.3389/fphar.2020.572249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898897PMC
September 2020

Deep action learning enables robust 3D segmentation of body organs in various CT and MRI images.

Sci Rep 2021 Feb 8;11(1):3311. Epub 2021 Feb 8.

Pattern Recognition Lab, Friedrich-Alexander University, Erlangen-Nürnberg, Germany.

In this study, we propose a novel point cloud based 3D registration and segmentation framework using reinforcement learning. An artificial agent, implemented as a distinct actor based on value networks, is trained to predict the optimal piece-wise linear transformation of a point cloud for the joint tasks of registration and segmentation. The actor network estimates a set of plausible actions and the value network aims to select the optimal action for the current observation. Point-wise features that comprise spatial positions (and surface normal vectors in the case of structured meshes), and their corresponding image features, are used to encode the observation and represent the underlying 3D volume. The actor and value networks are applied iteratively to estimate a sequence of transformations that enable accurate delineation of object boundaries. The proposed approach was extensively evaluated in both segmentation and registration tasks using a variety of challenging clinical datasets. Our method has fewer trainable parameters and lower computational complexity compared to the 3D U-Net, and it is independent of the volume resolution. We show that the proposed method is applicable to mono- and multi-modal segmentation tasks, achieving significant improvements over the state-of-the-art for the latter. The flexibility of the proposed framework is further demonstrated for a multi-modal registration application. As we learn to predict actions rather than a target, the proposed method is more robust compared to the 3D U-Net when dealing with previously unseen datasets, acquired using different protocols or modalities. As a result, the proposed method provides a promising multi-purpose segmentation and registration framework, particular in the context of image-guided interventions.
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http://dx.doi.org/10.1038/s41598-021-82370-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870874PMC
February 2021

Bola3 Regulates Beige Adipocyte Thermogenesis Maintaining Mitochondrial Homeostasis and Lipolysis.

Front Endocrinol (Lausanne) 2020 11;11:592154. Epub 2021 Jan 11.

Department of Endocrinology and Metabolism, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.

Mitochondrial iron-sulfur (Fe-S) cluster is an important cofactor for the maturation of Fe-S proteins, which are ubiquitously involved in energy metabolism; however, factors facilitating this process in beige fat have not been established. Here, we identified BolA family member 3 (Bola3), as one of 17 mitochondrial Fe-S cluster assembly genes, was the most significant induced gene in the browning program of white adipose tissue. Using lentiviral-delivered shRNA , we determined that Bola3 deficiency inhibited thermogenesis activity without affecting lipogenesis in differentiated beige adipocytes. The inhibition effect of Bola3 knockdown might be through impairing mitochondrial homeostasis and lipolysis. This was evidenced by the decreased expression of mitochondria related genes and respiratory chain complexes, attenuated mitochondrial formation, reduced mitochondrial maximal respiration and inhibited isoproterenol-stimulated lipolysis. Furthermore, BOLA3 mRNA levels were higher in human deep neck brown fat than in the paired subcutaneous white fat, and were positively correlated with thermogenesis related genes (UCP1, CIDEA, PRDM16, PPARG, COX7A1, and LIPE) expression in human omental adipose depots. This study demonstrates that Bola3 is associated with adipose tissue oxidative capacity both in mice and human, and it plays an indispensable role in beige adipocyte thermogenesis maintaining mitochondrial homeostasis and adrenergic signaling-induced lipolysis.
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http://dx.doi.org/10.3389/fendo.2020.592154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829353PMC
June 2021

[Preparation of an anti-cotinine monoclonal antibody and its application in immunological detection].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2020 Dec;49(6):765-771

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Objective: To prepare monoclonal antibody against cotinine (COT) and to establish immunoassay for detecting COT in human urinary samples.

Methods: BALB/c mice were immunized with synthesized cotinine-bovine serum albumin (COT-BSA) to screen monoclonal antibody with technique of cell fusion. The monoclonal antibody was used for the indirect competitive enzyme-linked immunosorbent assay (ic-ELISA) and colloidal gold immunochromatographic strip assay for the detection of COT in human urine.

Results: The monoclonal antibody against COT was identified by ic-ELISA with a 50%inhibitive concentration (IC) value of 21 ng/mL; and it was also identified by colloidal gold immunochromatographic strip assay with a cut-off value of 100 ng/mL. For ic-ELISA, the range of detection was 0-100 ng/mL with a minimal limit of 0.1 ng/mL; the recovery of assay was 99.41%-117.98%, and the intra-assay and inter-assay coefficient variations were not higher than 15.31%and 15.07%, respectively. For colloidal gold immunochromatographic strip assay, the accuracy of stability and repeatability both were 100%.

Conclusions: The ic-ELISA and colloidal gold immunochromatographic strip assay using the prepared monoclonal antibody against COT have been proved to be reliable for the rapid detection of COT in human urines, which may be used for monitoring of environmental tobacco smoke.
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http://dx.doi.org/10.3785/j.issn.1008-9292.2020.12.12DOI Listing
December 2020

Factors Associated with Lymph Node Count in Mucosal Squamous Cell Carcinoma Neck Dissection.

Laryngoscope 2021 Jan 4. Epub 2021 Jan 4.

Department of Otolaryngology Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, U.S.A.

Objective/hypothesis: Decreased lymph node count (LNC) from neck dissection (ND) for mucosal head and neck squamous cell carcinoma (HNSCC) patients is correlated with decreased survival. Advanced age and low BMI due to undernutrition from dysphagia from advanced T-stage tumors are common in patients with HNSCC. We studied the relationship between these two well-described causes for immune dysfunction and LNC in patients undergoing neck dissection.

Study Design: We conducted a retrospective review at a single tertiary care institution of patients with HNSCC that underwent neck dissection from 2006 to 2017.

Methods: Stepwise linear and logistic regression analyses were performed on 247 subjects to identify independent significant factors associated with 1) the LNC per neck level dissected; 2) advanced T-stage. One-way ANOVA was utilized to demonstrate differences between the p16 positive and negative subgroups.

Results: Low BMI (<23 vs. ≥23) (P = .03), extra nodal extension (ENE) (P = .0178), and advanced age (P = .005) were associated with decreased LNC per neck level dissected on multivariable analysis. Higher T-stage (P = .0005) was correlated with low BMI (<23) after controlling for the effects of tobacco, smoking, sex, ECE, and p16 status. p16+ patients, on average had higher BMI, were younger and produced a higher nodal yield (P < .0001, .007, and .035).

Conclusions: Patient intrinsic factors known to correlate with decreased immune function and worse outcomes, including p16 negative status, advanced age, and low BMI from undernutrition and ENE are associated with low nodal yield in neck dissections. LNC may be a metric for anti-tumor immune function that correlates with prognosis and T-stage.

Level Of Evidence: 3 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29353DOI Listing
January 2021

Cylindrical vector beam multiplexing for radio-over-fiber communication with dielectric metasurfaces.

Opt Express 2020 Dec;28(26):38666-38681

Radio-over-fiber (ROF) technology, loading microwave signal on light beams, has attracted considerable attention in wireless access network for its superiority in processing high-frequency microwave signals. Multiplexing for achieving high-capacity density, however, remains elusive in ROF communication because the optical microwave occupies large bandwidth. Here, we introduce a cylindrical vector beam (CVB) multiplexing for ROF communication with dielectric Pancharatnam-Berry phase-based metasurfaces (PBMs). CVBs, a structured light beam possessing spatially nonuniform polarization distribution and carrying vector mode, provide an additional multiplexing dimension for optical communication with the advantages of weak scintillation in free-space and low mode injure in few-mode-fiber. Exploiting the spin-orbit interaction of the PB phase, we construct PBMs to manipulate CVBs, which show broadband working wavelengths ranging from C- to L-band. After 3 m free-space propagation, two multiplexed CVBs carrying 100 GHz microwave are successfully demultiplexed, and the 100 GHz ROF communication with 12 Gbit/s QPSK-OFDM signals is realized. The crosstalk of the multiplexed CVBs is less than -15.13 dB, and the bit-error-rates (BERs) are below 3.26 × 10. With 5 km few-mode-fiber transmission, the CVBs are also demultiplexed with the BERs of 6.51 × 10. These results indicate that CVB is not only capable of free-space transmission but also available for few-mode-fiber transmission, which might pave new avenues for the multiplexing of ROF communications.
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http://dx.doi.org/10.1364/OE.406300DOI Listing
December 2020

TCR-mimic antibody-drug conjugates targeting intracellular tumor-specific mutant antigen KRAS G12V mutation.

Asian J Pharm Sci 2020 Nov 5;15(6):777-785. Epub 2020 Mar 5.

College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.

Limited clinical application of antibody-drug conjugates (ADCs) targeting tumor associated antigens (TAAs) is usually caused by on-target off-tumor side effect. Tumor-specific mutant antigens (TSMAs) only expressed in tumor cells which are ideal targets for ADCs. In addition, intracellular somatic mutant proteins can be presented on the cell surface by human leukocyte antigen class I (HLA I)molecules forming tumor-specific peptide/HLA I complexes. KRAS G12V mutation frequently occurred in varied cancer and was verified as a promising target for cancer therapy. In this study, we generated two TCR-mimic antibody-drug conjugates (TCRm-ADCs), 2E8-MMAE and 2A5-MMAE, targeting KRAS G12V/HLA-A*0201 complex, which mediated specific antitumor activity and without obvious toxicity. Our findings are the first time validate the strategy of TCRm-ADCs targeting intracellular TSMAs, which improves the safety of antibody-based drugs and provides novel strategy for precision medicine in cancer therapy.
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http://dx.doi.org/10.1016/j.ajps.2020.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7750800PMC
November 2020

Automatic dementia screening and scoring by applying deep learning on clock-drawing tests.

Sci Rep 2020 11 30;10(1):20854. Epub 2020 Nov 30.

Pattern Recognition Lab, Computer Science, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058, Erlangen, Germany.

Dementia is one of the most common neurological syndromes in the world. Usually, diagnoses are made based on paper-and-pencil tests and scored depending on personal judgments of experts. This technique can introduce errors and has high inter-rater variability. To overcome these issues, we present an automatic assessment of the widely used paper-based clock-drawing test by means of deep neural networks. Our study includes a comparison of three modern architectures: VGG16, ResNet-152, and DenseNet-121. The dataset consisted of 1315 individuals. To deal with the limited amount of data, which also included several dementia types, we used optimization strategies for training the neural network. The outcome of our work is a standardized and digital estimation of the dementia screening result and severity level for an individual. We achieved accuracies of 96.65% for screening and up to 98.54% for scoring, overcoming the reported state-of-the-art as well as human accuracies. Due to the digital format, the paper-based test can be simply scanned by using a mobile device and then be evaluated also in areas where there is a staff shortage or where no clinical experts are available.
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http://dx.doi.org/10.1038/s41598-020-74710-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704614PMC
November 2020

Editorial Comment on "Enhanced Recovery After Surgery (ERAS) in Head and Neck Oncologic Surgery: A Case-Matched Analysis of Perioperative and Pain Outcomes".

Ann Surg Oncol 2021 Feb 11;28(2):604-605. Epub 2020 Nov 11.

Department of Otolaryngology-Head and Neck Surgery, University of Texas Southwestern Medical Center, Dallas, TX, USA.

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http://dx.doi.org/10.1245/s10434-020-09337-1DOI Listing
February 2021

Threshold conditions of electric field enhancement and energy confinement in the low-index core of nanoscale waveguides.

Appl Opt 2020 Oct;59(30):9415-9423

Threshold conditions to realize electric field enhancement and energy confinement in the low-refractive-index core of nanoscale waveguides are studied by solving the field function. When the incident lightwave meets the relation of special thresholds, we observe the enhanced electric field and a concentrated light energy in the core. The electric field enhancement and the confined light power are highly dependent on the light wavelength. When the core width is 30 nm, for a wavelength of 1.55 µm, we achieve a power confinement factor above 40%. As the basis for a growing number of potential applications, the threshold conditions discovered in this work will find significant applications in many fields, such as optical sensors and optical communication components.
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http://dx.doi.org/10.1364/AO.400081DOI Listing
October 2020

Dysfunction of dimorphic sperm impairs male fertility in the silkworm.

Cell Discov 2020 8;6:60. Epub 2020 Sep 8.

Key Laboratory of Insect Developmental and Evolutionary Biology, Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, 200032 Shanghai, China.

Sperm, which have a vital role in sexual reproduction in the animal kingdom, can display heteromorphism in some species. The regulation of sperm dichotomy remains a longstanding puzzle even though the phenomenon has been widely documented for over a century. Here we use as a model to study a form of sperm dimorphism (eupyrene and apyrene sperm), which is nearly universal among Lepidoptera. We demonstrate that () is crucial for apyrene sperm development, and that () is required for eupyrene sperm development. BmSXL is distributed in the nuclei and cytoplasm of somatic cyst cells in a mesh-like pattern and in the cytoplasm of germ cells enclosed in spermatocysts and sperm bundles. Cytological analyses of dimorphic sperm in mutants (∆) showed deficient apyrene sperm with abnormal nuclei, as well as loss of motility associated with malformed mitochondrial derivatives. We define the crucial function of apyrene sperm in the process of fertilization as assisting the migration of eupyrene spermatozoa from bursa copulatrix to spermatheca. By contrast, deficiency (∆) caused eupyrene sperm abnormalities and impaired the release of eupyrene sperm bundles during spermiation. Although apyrene or eupyrene sperm defects impaired fertility of the mutated males, double copulation of a wild-type female with ∆ and ∆ males could rescue the sterility phenotypes induced by single copulation with either gene-deficient male. Our findings demonstrate the crucial functions of and in the development of sperm dimorphism and the indispensable roles of nonfertile apyrene sperm in fertilization.
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http://dx.doi.org/10.1038/s41421-020-00194-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477584PMC
September 2020

Idarucizumab Reverses Dabigatran Anticoagulant Activity in Healthy Chinese Volunteers: A Pharmacokinetics, Pharmacodynamics, and Safety Study.

Adv Ther 2020 09 20;37(9):3916-3928. Epub 2020 Jul 20.

Department of Pharmacy, Peking University First Hospital, Beijing, China.

Introduction: Idarucizumab is a humanized monoclonal antibody fragment that specifically binds to dabigatran with high affinity and reverses its anticoagulant effect. This study investigated the pharmacokinetics (PK) and pharmacodynamics (PD) of idarucizumab in healthy Chinese subjects at steady state of dabigatran and explored the effect of idarucizumab on PK and PD of dabigatran.

Methods: Twelve subjects received dabigatran etexilate treatment alone (220 mg twice daily, b.i.d., oral). After a washout period, the 12 subjects again received dabigatran etexilate (220 mg b.i.d., oral) and idarucizumab (2.5 + 2.5 g, intravenous) 2 h after the last administration of dabigatran etexilate.

Results: The geometric mean (gMean) values of area under the plasma concentration-time curve (AUC) and maximum concentration (C) were 44,200 nmol h/L and 30,900 nmol/L, respectively. An amount of 35.3 μmol of idarucizumab, corresponding to 33.8% of the total dose, was excreted by urine over 72 h. The area under the effect (AUEC) in the presence and absence of idarucizumab was close to zero for all coagulation parameters, diluted thrombin time (dTT), ecarin clotting time (ECT), activated partial thromboplastin time (aPTT), and thrombin time (TT), which indicated the reversal of dabigatran anticoagulation by idarucizumab. There were no serious adverse events reported in this study. No subject tested positive for anti-idarucizumab antibodies.

Conclusion: Idarucizumab was well tolerated and no subject tested positive for anti-idarucizumab antibodies in this study. PK and PD of idarucizumab in healthy Chinese subjects at a steady state of dabigatran were comparable with those in Japanese and Caucasian subjects.

Clinical Registration: ClinicalTrials.gov Identifier No. NCT03086356.
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http://dx.doi.org/10.1007/s12325-020-01439-2DOI Listing
September 2020

Regulation of olfactory-based sex behaviors in the silkworm by genes in the sex-determination cascade.

PLoS Genet 2020 06 10;16(6):e1008622. Epub 2020 Jun 10.

Key Laboratory of Insect Developmental and Evolutionary Biology, Center for Excellence in Molecular Plant Sciences, Shanghai Institute of Plant Physiology and Ecology, Chinese Academy of Sciences, Shanghai, China.

Insect courtship and mating depend on integration of olfactory, visual, and tactile cues. Compared to other insects, Bombyx mori, the domesticated silkworm, has relatively simple sexual behaviors as it cannot fly. Here by using CRISPR/Cas9 and electrophysiological techniques we found that courtship and mating behaviors are regulated in male silk moths by mutating genes in the sex determination cascade belonging to two conserved pathways. Loss of Bmdsx gene expression significantly reduced the peripheral perception of the major pheromone component bombykol by reducing expression of the product of the BmOR1 gene which completely blocked courtship in adult males. Interestingly, we found that mating behavior was regulated independently by another sexual differentiation gene, Bmfru. Loss of Bmfru completely blocked mating, but males displayed normal courtship behavior. Lack of Bmfru expression significantly reduced the perception of the minor pheromone component bombykal due to the down regulation of BmOR3 expression; further, functional analysis revealed that loss of the product of BmOR3 played a key role in terminating male mating behavior. Our results suggest that Bmdsx and Bmfru are at the base of the two primary pathways that regulate olfactory-based sexual behavior.
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http://dx.doi.org/10.1371/journal.pgen.1008622DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307793PMC
June 2020

A Pan-cancer Clinical Study of Personalized Neoantigen Vaccine Monotherapy in Treating Patients with Various Types of Advanced Solid Tumors.

Clin Cancer Res 2020 09 21;26(17):4511-4520. Epub 2020 May 21.

Hangzhou Neoantigen Therapeutics Co., Ltd., Hangzhou, Zhejiang, China.

Purpose: Because of their high tumor specificity and immunogenicity, neoantigens have been considered as ultimate targets for cancer immunotherapy. Neoantigen-based vaccines have demonstrated promising efficacy for several cancer types. To further investigate the antitumor potentials for other types of solid tumors, we designed a peptide-based neoantigen vaccine, iNeo-Vac-P01, and conducted a single-arm, open-labeled, investigator-initiated clinical trial (NCT03662815).

Patients And Methods: Personalized neoantigen vaccines were designed and manufactured according to our bioinformatics analysis results from the whole-exome sequencing of tumor and peripheral blood cell DNAs. Patients were scheduled to be vaccinated subcutaneously with adjuvant on days 1, 4, 8, 15, and 22 (prime phase), and days 78 and 162 (boost phase). Additional immunizations were administrated every 2-3 months as per patient's potential benefit. The safety and efficacy were assessed through adverse events (AE), progression-free survival (PFS), overall survival (OS), and other parameters.

Results: Of the 22 patients enrolled with advanced malignancies, 20 had no or mild AEs, while 2 had grade 3 or 4 acute allergic reactions only after their sixth boost vaccination. The disease control rate was 71.4%. The median PFS was 4.6 months, whereas the median OS was not reached (12-month OS = 55.1%). Around 80% of individual peptides or peptide pools elicited measurable specific immune response. In addition, our findings revealed several potential biomarkers for the prediction of better response.

Conclusions: iNeo-Vac-P01 as monotherapy is feasible and safe for patients with advanced solid tumors. It could elicit T-cell-mediated immune response targeting tumor neoantigens, and might have promising antitumor efficacy..
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2881DOI Listing
September 2020

Shared neoantigens: ideal targets for off-the-shelf cancer immunotherapy.

Pharmacogenomics 2020 06 19;21(9):637-645. Epub 2020 May 19.

Institute of Drug Metabolism & Pharmaceutical Analysis & Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.

Neoantigen, as an important member of tumor-specific antigens, has attracted a great deal of attention as a target for immunotherapy. Neoantigens are potential targets for personalized vaccines and adoptive cell transfer therapies. However, most of the neoantigen-targeted immunotherapies in the process are customized and costly. So, we are inclined to find shared neoantigens suitable for more patients. With the help of existing neoantigen prediction algorithms, we found that the most frequent shared neoantigens occurred in more than 1% of patients for 17 tumor types and the ten most frequent shared neoantigens covered approximately 50% of pancreatic cancer patients, providing a potential list of targets for off-the-shelf immunotherapy.
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http://dx.doi.org/10.2217/pgs-2019-0184DOI Listing
June 2020

Exploring Patients' Intentions for Continuous Usage of mHealth Services: Elaboration-Likelihood Perspective Study.

JMIR Mhealth Uhealth 2020 04 6;8(4):e17258. Epub 2020 Apr 6.

Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

Background: With the increasingly rapid development of Web 2.0 technologies, the application of mobile health (mHealth) care in the field of health management has become popular. Accordingly, patients are able to access consulting services and effective health information online without temporal and geographical constraints. The elaboration-likelihood model (ELM) is a dual-process persuasion theory that describes the change of attitudes and behavior.

Objective: In this study, we drew on the ELM to investigate patients' continuous usage intentions regarding mHealth services. In addition, we further examined which route-central or peripheral-has a stronger impact on a patient's usage of health care management.

Methods: To meet these objectives, five hypotheses were developed and empirically validated using a field survey to test the direct and indirect effects, via attitude, of the two routes on continuous usage intention.

Results: We found that patients' perceived mHealth information quality and perceived mHealth system quality had a positive effect on their personal attitudes. The results revealed that social media influence had a positive effect on a patient's attitude toward mHealth services. In particular, our findings suggest that a patient's health consciousness has a positive effect on the relationship between social media influence and attitude.

Conclusions: This study contributes to the mHealth services literature by introducing the ELM as a referent theory for research, as well as by specifying the moderating role of health consciousness. For practitioners, this study introduces influence processes as policy tools that managers can employ to motivate the uptake of mHealth services within their organizations.
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http://dx.doi.org/10.2196/17258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171561PMC
April 2020

Anti-tumor immune response varies among individuals: A gene expression profiling of mouse melanoma.

Int Immunopharmacol 2020 Mar 20;80:106211. Epub 2020 Jan 20.

Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou 310058, China. Electronic address:

Melanoma is amongst the most aggressive malignant tumors. The purpose of this study is to detect the tumor microenvironment systematically using multi-omics analyses and to propose strategies for precision medicine. Multiple factors of tumor microenvironment contribute to the drug resistance and immune surveillance failure. Here we analyzed genome mutations and characterized the immune state of tumor microenvironments in mouse melanoma by whole exome sequencing (WES) and RNA sequencing (RNA-Seq) approaches. Somatic mutation analysis revealed 35.1% novel mutations in mouse tumors when compared with B16F10 cell line, provided a basis for multi-site sequencing for accurate neoantigen selection. Mutation cluster, gene expression comparison, and gene ontology (GO) analyses by R packages proved DNA repair damage, inflammation, slower cell division, and metabolic change in tumor microenvironment. Further analyses of T-cell receptor (TCR) sequences, immune signaling pathway activation, tumor infiltrated immune cells and chemokine expression revealed extensive difference of antitumor immune response among individuals. Our study revealed the characteristics of tumor microenvironment with mouse melanoma model, suggested the need of comprehensive genome mutations and personal immune state analyses for cancer precision medicine.
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http://dx.doi.org/10.1016/j.intimp.2020.106211DOI Listing
March 2020

Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.

Onco Targets Ther 2019 30;12:11597-11608. Epub 2019 Dec 30.

Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, People's Republic of China.

Background: The aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy. For example, trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target HER2-positive tumour cells. Despite their advances in clinical applications, emerging resistance to these two HER2-targeting antibodies has hindered their further application. Somatic mutations in HER2 receptor have been identified as one of the major reasons for resistance to anti-HER2 antibodies.

Methods: We analysed the frequency of somatic mutations in various tumour types based on TCGA and COSMIC databases. Then, the effect of the most frequent mutation (S310F) on the interaction between pertuzumab and HER2 was analysed by molecular modelling analysis. The effect of the S310F mutation was further evaluated through multiple in vitro binding experiments and antitumour activity assays.

Results: We found through bioinformatics analysis that S310F, an activating mutation in the HER2 extracellular domain, was the most frequent mutation in HER2. The S310F mutation was shown to confer resistance of HER2-positive tumour cells to pertuzumab treatment. With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue S310. Further functional analyses revealed that the S310F mutation completely abolished pertuzumab binding to HER2 receptor and inhibited pertuzumab antitumour efficacy.

Conclusion: We demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.
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http://dx.doi.org/10.2147/OTT.S232912DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6941612PMC
December 2019

A potential role for the gene in repeat revascularization after first percutaneous coronary intervention.

Pharmacogenomics 2020 01 19;21(2):91-99. Epub 2019 Dec 19.

Department of Pharmacy, Peking University First Hospital, No. 6, Da Hong Luo Chang Street, Xicheng District, Beijing 100034, PR China.

Major drawbacks of percutaneous coronary intervention are the high occurrence of repeat revascularization due to restenosis and disease progression. The aim of this study was to find genetic indicators to predict the risk of repeat revascularization. From April 2015 to June 2016, 143 patients with percutaneous coronary intervention with genetic test results were enrolled. SNPs were measured by OmniZhongHua-8, and the SNPs in pathways genes related to known stenosis-related processes from the KEGG, BioCarta and Gene Cards databases were selected for analysis. Cell-extracellular matrix interactions were the pathways with the most significant SNP ( rs72819363) association with repeat revascularization. Compared with rs11859453G carriers, the adjusted odds ratio for A carriers was 0.25 and 0.33 at 18 and 30 months. We demonstrated a potential role of the cell-extracellular matrix interactions pathway and the possible biomarker in the development of coronary repeat revascularization.
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http://dx.doi.org/10.2217/pgs-2019-0118DOI Listing
January 2020

Automatic multi-organ segmentation in dual-energy CT (DECT) with dedicated 3D fully convolutional DECT networks.

Med Phys 2020 Feb 1;47(2):552-562. Epub 2020 Jan 1.

Pattern Recognition Lab, Universität Erlangen-Nürnberg, Erlangen, 91058, Germany.

Purpose: Dual-energy computed tomography (DECT) has shown great potential in many clinical applications. By incorporating the information from two different energy spectra, DECT provides higher contrast and reveals more material differences of tissues compared to conventional single-energy CT (SECT). Recent research shows that automatic multi-organ segmentation of DECT data can improve DECT clinical applications. However, most segmentation methods are designed for SECT, while DECT has been significantly less pronounced in research. Therefore, a novel approach is required that is able to take full advantage of the extra information provided by DECT.

Methods: In the scope of this work, we proposed four three-dimensional (3D) fully convolutional neural network algorithms for the automatic segmentation of DECT data. We incorporated the extra energy information differently and embedded the fusion of information in each of the network architectures.

Results: Quantitative evaluation using 45 thorax/abdomen DECT datasets acquired with a clinical dual-source CT system was investigated. The segmentation of six thoracic and abdominal organs (left and right lungs, liver, spleen, and left and right kidneys) were evaluated using a fivefold cross-validation strategy. In all of the tests, we achieved the best average Dice coefficients of 98% for the right lung, 98% for the left lung, 96% for the liver, 92% for the spleen, 95% for the right kidney, 93% for the left kidney, respectively. The network architectures exploit dual-energy spectra and outperform deep learning for SECT.

Conclusions: The results of the cross-validation show that our methods are feasible and promising. Successful tests on special clinical cases reveal that our methods have high adaptability in the practical application.
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http://dx.doi.org/10.1002/mp.13950DOI Listing
February 2020

Redox-neutral -C-H amination of pinacol arylborates palladium(ii)/norbornene catalysis for aniline synthesis.

Chem Sci 2019 Sep 23;10(36):8384-8389. Epub 2019 Jul 23.

Sauvage Center for Molecular Sciences , Engineering Research Center of Organosilicon Compounds & Materials (Ministry of Education) , College of Chemistry and Molecular Sciences , Wuhan University , Wuhan , 430072 , China.

A palladium(ii)/norbornene cooperative catalysis enabled redox-neutral -C-H amination of pinacol aryl- or heteroarylborates for the synthesis of structurally diverse anilines is reported. This method is scalable, robust (tolerance of air and moisture), phosphine ligand-free, and compatible with a wide range of functionalities. These practical features make this reaction amenable for industry. A plethora of synthetically very useful halogenated anilines, which often cannot be prepared other transition-metal-catalyzed aminations, are readily produced using this method. Particularly, the orthogonal reactivity between pinacol arylborates and aryl iodides is demonstrated. Preliminary deuterium-labeling studies reveal a redox-neutral -protonation mechanism of this process, which will surely inspire the future development of this field. Overall, the exceptionally broad scope (47 examples) and reliability of this procedure, together with the wide availability of pinacol arylborates, make this chemistry a valuable addition to the existing methods for aniline synthesis.
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http://dx.doi.org/10.1039/c9sc02759aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6839810PMC
September 2019

DeepHLApan: A Deep Learning Approach for Neoantigen Prediction Considering Both HLA-Peptide Binding and Immunogenicity.

Front Immunol 2019 1;10:2559. Epub 2019 Nov 1.

Institute of Drug Metabolism and Pharmaceutical Analysis and Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.

Neoantigens play important roles in cancer immunotherapy. Current methods used for neoantigen prediction focus on the binding between human leukocyte antigens (HLAs) and peptides, which is insufficient for high-confidence neoantigen prediction. In this study, we apply deep learning techniques to predict neoantigens considering both the possibility of HLA-peptide binding (binding model) and the potential immunogenicity (immunogenicity model) of the peptide-HLA complex (pHLA). The binding model achieves comparable performance with other well-acknowledged tools on the latest Immune Epitope Database (IEDB) benchmark datasets and an independent mass spectrometry (MS) dataset. The immunogenicity model could significantly improve the prediction precision of neoantigens. The further application of our method to the mutations with pre-existing T-cell responses indicating its feasibility in clinical application. DeepHLApan is freely available at https://github.com/jiujiezz/deephlapan and http://biopharm.zju.edu.cn/deephlapan.
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http://dx.doi.org/10.3389/fimmu.2019.02559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838785PMC
November 2020

Spatial phase and polarization retrieval of arbitrary circular symmetry singular light beams using orthogonal polarization separation.

Opt Express 2019 Sep;27(19):27282-27294

Circular symmetry singular light beams (CS-SLBs) possessing spatially variant field distributions have drawn extensive attention because of their unique optical properties. However, the extraction of spatial phase and polarization distributions is always a significant but difficult issue in CS-SLB applications. Here, we propose and experimentally investigate an orthogonal polarization separation (OPS) method to retrieve the spatial phase and polarization distributions of arbitrary CS-SLBs. Theoretically, the CS-SLB, including the vortex beam (VB), cylindrical vector beam (CVB), and cylindrical vector vortex beam (CVVB), can be decomposed into two orthogonal circularly polarized sub-VBs. Therefore, once the spatial phase distributions and initial phase difference of the two components are obtained, the phase and polarization distributions of the CS-SLB can be retrieved, and its type can also be identified. Based on this analysis relationship, we first separated the CS-SLB into two circularly polarized sub-VBs and designed an astigmatic phase iterative algorithm to restore their spatial phase information. After retrieving the phases of the two components, we have experimentally obtained the spatial phase and polarization distributions of three typical CS-SLBs, including VBs, CVBs, and CVVBs. These results demonstrate that this method provides a feasible way to retrieve the variant field distributions of CS-SLBs and may have great application prospects in optical imaging, optical communication, etc.
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http://dx.doi.org/10.1364/OE.27.027282DOI Listing
September 2019

Matrine enhances the efficacy of adriamycin chemotherapy in osteosarcoma cells by the STAT3 pathway.

Anticancer Drugs 2019 11;30(10):1006-1012

Departments of Chinese Medicine.

Matrine and adriamycin have been extensively considered to be effective in anticancer therapies. However, the role of matrine in the antitumor activity of adriamycin against human osteosarcoma (OS) remains elusive. The aim of this study was to investigate the effect of matrine in OS chemotherapy of adriamycin. In the study, we found that matrine promoted the inhibitory effect of adriamycin against OS cell proliferation and growth. Wound healing and transwell assays showed that the inhibitory effect of adriamycin against migration and invasion of OS cells was significantly enhanced by matrine. For the underlying mechanism investigation, we showed that adriamycin reduced the protein level of PCNA, MMP-9, phosphorylated STAT3, and survivin, which was further intensified by the application of matrine. These results show that matrine could promote the therapeutic efficacy of adriamycin against human OS.
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http://dx.doi.org/10.1097/CAD.0000000000000796DOI Listing
November 2019

Exploring the Impact of the Rational Antibiotic Use System on Hospital Performance: The Direct Effect and the Spillover Effect.

Int J Environ Res Public Health 2019 09 18;16(18). Epub 2019 Sep 18.

School of Management, Harbin Institute of Technology, Harbin 150000, China.

Irrational antibiotic usage not only causes an increase in antibiotic-borne diseases, but also inflicts pain on patients, as a result of inappropriate treatment. In order to resolve the hazards caused by irrational antibiotic usage, a kind of e-health service, the Rational Antibiotic Use System (RAUS), has been incorporated into the hospital information system. The RAUS provides doctors and patients with the functions of antibiotic usage monitoring, antibiotic information consultation and antibiotic prescription support. Though existing literature has already proved the usefulness of the RAUS on monitoring doctors' behavior, the effects on hospital performance from an organizational perspective has rarely been measured by empirical data. Therefore, our study has explored the effects of the RAUS on the performance of a large Chinese hospital, which has implemented the RAUS since March 2014. Through empirical research, we quantified the effects of the implementation of the RAUS on a hospital's performance from both the direct effects on the "drug income" and the spillover effect on the "treatment income". The results indicate a significant positive spillover effect on the treatment incomes of a hospital in its inpatient activities (seen as significant in the long term) and in its outpatient activities (seen as significant in both the short and long terms). In addition, this research provides certain theoretical and practical implications for the dilemma of e-health services application in irrational antibiotic usage.
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http://dx.doi.org/10.3390/ijerph16183463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766021PMC
September 2019