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BackgroundAlthough breakthroughs have been achieved in gastric cancer (GC) therapy with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), the acquisition of high response rate remains a huge challenge for clinicians. It is imperative to identify novel biomarkers for predicting response to immunotherapy and explore alternative therapeutic strategy for GC.MethodsThe transcriptomic profiles and clinical information of GC patients from The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) database was used to screen differentially expressed lncRNAs between the tumor specimens and the paracancerous tissues. The TargetScan, miRDB and miRcode database were then utilized to construct competing endogenous RNA (ceRNA) networks and identify pivotal lncRNAs. An independent dataset from GEO (GSE70880) and 23 pairs of GC specimens of our cohort were subsequently performed for external validity. The relationship between clinical variables and gene expression were evaluated by Kruskal–wallis test and Wilcoxon signed-rank. The prognostic value of the candidate genes was assessed using Kaplan-Meier analysis and Cox regression models. CIBERSORT and Gene set enrichment analysis (GSEA) were used to determine immune cell infiltration. Gastric adenocarcinoma AGS cells and human embryonic kidney 293T (HEK293T) cells with knockdown of LINC01094 were generated by siRNA transfection, followed by detecting the alteration of the target miRNA and PD-L1/PD-L2 by RT-qPCR. Besides, the interaction between lncRNA and the miRNA–PD-L1/PD-L2 axis were verified by dual luciferase reporter assay.ResultsTwenty-two intersecting lncRNAs were identified to be PD-L1/PD-L2-related lncRNAs and LINC01094–miR-17-5p–PD-L1/PD-L2 was constructed as a potential ceRNA network. LINC01094 was increased in tumor specimens than adjacent normal samples and was positively associated with advanced tumor stages and EBV and MSI status. Furthermore, LINC01094 expression was an independent risk factor for poor overall survival (OS) in GC patients. CD8+ T cell exhaustion-related genes were enriched in high-LINC01094 tissues and high-PD-L2 group. A strong positive association of LINC01094 expression was established with M2 macrophages, IL-10+ TAM, as well as PD-L1 and PD-L2 levels, therefore a LINC01094–miR-17-5p–IL-10 network was proposed in macrophages. Using the exoRBase database, LINC01094 was assumed in blood exosomes of GC patients The results of knockdown experiments and luciferase reporter assays revealed that LINC01094 interacted with miR-17-5p and served as a miRNA sponge to regulate the expression of PD-L1 and PD-L2.ConclusionLINC01094 dually regulates the expression of PD-L1 and PD-L2 and shapes the immunosuppressive tumor microenvironment via sponging miR-17-5p. LINC01094 may serve as a potential prognostic predictor and therapeutic target in GC.

Rye (Secale cereale L., 2n=2x=14, RR) is a significant genetic resource for improving common wheat because of its resistance to multiple diseases and abiotic-stress tolerant traits. The 1RS chromosome from the German cultivated rye variety Petkus is critical in wheat breeding. However, its weakened disease resistance highlights the need to identify new resources. In the present study, a novel derived line called D27 was developed from common wheat and Mexico Rye. Cytological observations characterized the karyotype of D27 as 2n=42=21 II. Genomic in situ hybridization indicated that a pair of whole-arm translocated Mexico Rye chromosomes were inherited typically in the mitotic and meiosis stages of D27. Experiments using fluorescence in situ hybridization (FISH) and gliadin electrophoresis showed that D27 lacked wheat 1DS chromosomes. They were replaced by 1RS chromosomes of Mexico Rye, supported by wheat simple-sequence repeat markers, rye sequence characterized amplified region markers, and wheat 40K SNP array analysis. The wheat 1DS chromosomes could not be detected by molecular markers and wheat SNP array, but the presence of rye 1RS chromosomes was confirmed. Agronomic trait assessments indicated that D27 had a higher tiller number and enhanced stripe rust and powdery mildew resistance. In addition, dough properties analysis showed that replacing 1DS led to higher viscosity and lower dough elasticity in D27, which was beneficial for cake making. In conclusion, the novel cytogenetically stable common wheat–Mexico Rye T1DL·1RS translocation line D27 offers excellent potential as outstanding germplasm in wheat breeding programs focusing on disease resistance and yield improvement. Additionally, it can be valuable for researching the rye 1RS chromosome’s genetic diversity.

The China initiative Accelerator-Driven subcritical System (CiADS) project aims to design and build the world’s first accelerator-driven subcritical system demonstration facility. The facility will attain 2.5 MW thermal power in 2026 to realize accelerator-target-reactor coupling experiments. As the first approved accelerator-driven subcritical system facility, the CiADS driver linac will adopt cutting-edge accelerator technologies to achieve the challenging goals of high beam power and high reliability. The accelerator will operate in cw mode to produce a 500 MeV, 5 mA proton beam. To meet the extremely high demands on beam availability, the linac design lays strong emphasis on beam loss control and increased fault tolerance via a novel fault-compensation method. The accelerator complex consists of a room temperature front-end section, a main linac that employs superconducting accelerator technologies, and a high-energy beam transport line. The beam-loss-oriented beam dynamics design of the driver linac complex is presented in the paper.

Abstract Background Physical activity is related to health-related quality of life, but little evidence from multiple waves of panel data in Asian countries area available. This study aims to explore the impacts of different degree of regular exercise on the trajectories of physical and mental dimensions of health-related quality of life (HRQOL) for community-dwelling Taiwanese adults during 2006–2014. Methods Data were derived from the “Landseed Integrated Outreaching Neighborhood Screening (LIONS)” study, with 6182 adults enrolled at the baseline and subsequently followed up to three times till 2014. Linear mixed-effects modeling approach was employed to evaluate the growth curve models of HRQOL (with 16,281 observations) by linear & quadratic time effects, regular exercise (5-level moderate-intensity physical activity), and major influential factors of HRQOL. Results Regular exercise showed significantly positive dose-response effects on physical HRQOL (β =1.27~2.54), and regular exercise of 150 min or more showed positive effects on mental HRQOL (β = 1.55~2.03). Besides, irregular exercise could also improve both physical and mental HRQOL (β = 1.27 & β = 0.87). However, such effects were not significant over time (at time slope) on HRQOL. In addition, physical and mental HRQOL improved across time (β = 1.01 and 1.49, respectively), but the time quadratic effect would significantly offset a little bit on physical dimension (β = − 0.22). Moreover, being female, increasing age, living alone, or poorer health status were related to lower physical HRQOL; and being younger, living alone, or poorer health status were associated with lower mental HRQOL. Conclusions The positive dose-response relationship between regular exercise and HRQOL or its domains was demonstrated for community-dwelling Taiwanese adults. Thus, a regular exercise habit (better ≧150 min per week) is advised for community-based healthcare professionals and the government to incorporate into health promotion strategies and plans.

Abstract Background Spironolactone can improve endothelial dysfunction in the setting of heart failure and diabetes models. However, its beneficial effect in the cardiovascular system is not clear in the setting of non-diabetic renal failure. We conducted this study to investigate whether spironolactone can ameliorate endothelial dysfunction in a 5/6 nephrectomy model, and to determine the underlying mechanism. Methods Twenty-four Sprague-Dawley rats were divided into four groups. A renal failure model was created using the 5/6 nephrectomy method. The four groups included: Sham-operation group (Group1), chronic kidney disease (CKD; Group2), CKD + ALT-711 (advanced glycation end products [AGEs] breaker; Group 3), and CKD + spironolactone group (Group4). Acetylcholine (Ach)-mediated vasodilatation responses were compared between the four groups. To investigate the underlying mechanism, we cultured human aortic endothelial cells (HAECs) for in-vitro assays. Differences between two groups were determined with the paired student’s t test. Differences between three or more groups were determined through one-way analysis of variance (ANOVA) with post-hoc analysis with LSD method. Results Compared with Group 1, Group 2 has a significantly impaired Ach-mediated vasodilatation response. Group 3 and 4 exhibited improved vasoreactivity responses. To determine the underlying mechanism, we performed an in-vitro study using cultured HAECs. We noted significant sirtuin-3 (SIRT3) protein downregulation, reduced phosphorylation of endothelial nitric oxide synthase at serine 1177 (p-eNOS), and increased intracellular oxidative stress in cultured HAECs treated with AGEs (200 μg/mL). These effects were counter-regulated when cultured HAECs were pretreated with spironolactone (10 μM). Furthermore, the increased p-eNOS production by spironolactone was abrogated when the HAECs were pretreated with tenolvin (1 μM), a SIRT3 inhibitor. Conclusions Spironolactone could ameliorate endothelial dysfunction in a 5/6 nephrectomy renal failure model through AGEs/Receptor for AGEs (RAGEs) axis inhibition, SIRT3 upregulation, and nicotinamide adenine dinucleotide phosphate oxidase-2 (NOX-2) and its associated intracellular oxidative stress attenuation.

Objective: Air pollution has been widely recognized to pose a threat to health. Urban outdoor air pollution was listed as the 14th biggest risk factor for global deaths in 2004 in the Global Health Risks report published by the World Health Organization in 2009. Many past studies have indicated that exposure to environmental contaminants promotes changes in the internal mechanisms of diseases, including the infection of various systems in the body, hormonal changes, and vascular proliferation. These changes may be related to the severity of endometrial hyperplasia. Therefore, this study used the air quality monitoring data of the Environmental Protection Administration (EPA) to examine the effects of air pollutant concentration on patients with endometrial hyperplasia. Materials and methods: This population-based nationwide study used data for 2002–2013 from the National Health Insurance Research Database of Taiwan. Patients who developed endometrial hyperplasia before 2002 were excluded. In total, 14,883 patients with endometrial hyperplasia were tracked. The exposure levels and air quality index (AQI) values in this study were based on the taiwan air quality monitoring network data collected by the EPA from 2000 to 2013. The data were further divided into the good air quality group (AQI ≤ 50) and poor air quality group (AQI > 50). The study used linear regression model to estimate the correlation linking air pollutant concentration with endometrial hyperplasia. Results: The results indicated that, in comparison to endometrial hyperplasia patients who were exposed to air with good quality, those exposed to air with poor quality had a higher average age (p

Abstract The chemokine receptor CXCR4 mediates cell anchorage in the bone marrow (BM) microenvironment and is overexpressed in 25–30% of patients with acute myeloid leukemia (AML). Here we have shown that a new CXCR4 receptor antagonist IgG1 antibody (PF-06747143) binds strongly to AML cell lines and to AML primary cells inhibiting their chemotaxis in response to CXCL12. PF-06747143 also induced cytotoxicity in AML cells via Fc-effector function. To characterize the effects of PF-06747143 on leukemia progression, we used two different patient-derived xenograft (PDX) models: Patient 17CXCR4-low and P15CXCR4-high models, characterized by relatively low and high CXCR4 expression, respectively. Weekly administration of PF-06747143 to leukemic mice significantly reduced leukemia development in both models. Secondary transplantation of BM cells from PF-06747143-treated or IgG1 control-treated animals showed that leukemic progenitors were also targeted by PF-06747143. Administration of a single dose of PF-06747143 to PDX models induced rapid malignant cell mobilization into the peripheral blood (PB). These findings support evaluation of this antibody in AML therapy, with particular appeal to patients resistant to chemotherapy and to unfit patients, unable to tolerate intensive chemotherapy.

Abstract: The chemokine receptor CXCR4 is highly expressed and associated with poor prognosis in multiple malignancies. Upon engagement by its ligand, CXCL12, CXCR4 triggers intracellular signaling pathways that control trafficking of cells to tissues where the ligand is expressed, such as the bone marrow (BM). In hematologic cancers, CXCR4-driven homing of malignant cells to the BM protective niche is a key mechanism driving disease and therapy resistance. We developed a humanized CXCR4 immunoglobulin G1 (IgG1) antibody (Ab), PF-06747143, which binds to CXCR4 and inhibits CXCL12-mediated signaling pathways, as well as cell migration. In in vivo preclinical studies, PF-06747143 monotherapy rapidly and transiently mobilized cells from the BM into the peripheral blood. In addition, PF-06747143 effectively induced tumor cell death via its Fc constant region–mediated effector function. This Fc-mediated cell killing mechanism not only enhanced antitumor efficacy, but also played a role in reducing the duration of cell mobilization, when compared with an IgG4 version of the Ab, which does not have Fc-effector function. PF-06747143 treatment showed strong antitumor effect in multiple hematologic tumor models including non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and multiple myeloma (MM). Importantly, PF-06747143 synergized with standard-of-care agents in a chemoresistant AML patient-derived xenograft model and in an MM model. These findings suggest that PF-06747143 is a potential best-in-class anti-CXCR4 antagonist for the treatment of hematologic malignancies, including in the resistant setting. PF-06747143 is currently in phase 1 clinical trial evaluation (registered at www.clinicaltrials.gov as #NCT02954653).

Abstract Background The CXCR4-CXCL12 axis plays an important role in the chronic lymphocytic leukemia (CLL)-microenvironment interaction. Overexpression of CXCR4 has been reported in different hematological malignancies including CLL. Binding of the pro-survival chemokine CXCL12 with its cognate receptor CXCR4 induces cell migration. CXCL12/CXCR4 signaling axis promotes cell survival and proliferation and may contribute to the tropism of leukemia cells towards lymphoid tissues and bone marrow. Therefore, we hypothesized that targeting CXCR4 with an IgG1 antibody, PF-06747143, may constitute an effective therapeutic approach for CLL. Methods Patient-derived primary CLL-B cells were assessed for cytotoxicity in an in vitro model of CLL microenvironment. PF-06747143 was analyzed for cell death induction and for its potential to interfere with the chemokine CXCL12-induced mechanisms, including migration and F-actin polymerization. PF-06747143 in vivo efficacy was determined in a CLL murine xenograft tumor model. Results PF-06747143, a novel-humanized IgG1 CXCR4 antagonist antibody, induced cell death of patient-derived primary CLL-B cells, in presence or absence of stromal cells. Moreover, cell death induction by the antibody was independent of CLL high-risk prognostic markers. The cell death mechanism was dependent on CXCR4 expression, required antibody bivalency, involved reactive oxygen species production, and did not require caspase activation, all characteristics reminiscent of programmed cell death (PCD). PF-06747143 also induced potent B-CLL cytotoxicity via Fc-driven antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity activity (CDC). PF-06747143 had significant combinatorial effect with standard of care (SOC) agents in B-CLL treatment, including rituximab, fludarabine (F-ara-A), ibrutinib, and bendamustine. In a CLL xenograft model, PF-06747143 decreased tumor burden and improved survival as a monotherapy, and in combination with bendamustine. Conclusions We show evidence that PF-06747143 has biological activity in CLL primary cells, supporting a rationale for evaluation of PF-06747143 for the treatment of CLL patients.

Skin autofluorescence (AF) has been validated as a tool for estimating tissue advanced glycation end products (AGEs) accumulation and predicting long-term cardiovascular outcomes. However, whether measurements of skin AF could predict renal function decline remains controversial. From April, 2014 to April, 2015, we enrolled 245 subjects with at least two conventional risk factors for coronary artery disease (CAD). All were measured for body height and weight, blood pressure, plasma creatinine level, and skin AF at the start of the study. Baseline demographics and laboratory tests data were obtained by chart reviews and patient interviews. Serial plasma creatinine levels were followed regularly every 6-12 months for 2 years. In a stepwise multivariate linear regression analysis, skin AF, was an independent factor for predicting the relative renal function decline rate after adjustment of multiple covariates (ß = -0.036±0.016; p = 0.03). Subgroups analysis revealed that skin AF was a significant factor for relative renal function decline rate in subgroups of age < 65 years (ß = -0.068±0.024; p = 0.02), male sex (ß = -0.053±0.016; p< 0.01), body mass index≧25 Kg/m2(ß = -0.042±0.021; p = 0.04), and estimated glomerular filtration rate ≥ 60 ml/min/1.73m2(ß = -0.043±0.020; p = 0.04). However, only an interaction between skin AF and age attained significance (p for interaction = 0.04). Skin AF is a useful predictor for renal function decline in patients at increased risk of CAD.

The development of therapeutic monoclonal antibodies through mouse immunization often originates drug candidates that are not cross-reactive to the mouse ortholog. In such cases, and particularly in oncology, drug efficacy studies are performed on human tumor xenografts or with "surrogate" anti-mouse ortholog antibodies if targeting tumor host cells. Safety assessment of drug candidate(s) is performed at a later development stage in healthy non-human primates. While the latter remains necessary before a drug advances into human subjects, it precludes evaluation of safety in disease conditions and drug de-risking during early development. Therefore, mouse models that allow concomitant evaluation of drug efficacy and safety are highly desirable. The C-X-C motif chemokine receptor 4 (CXCR4) is an attractive target for tumor-targeted and immuno-oncology therapeutics, with multiple mouse immunization-derived antibodies undergoing clinical trials. Given the pleiotropic role of CXCR4 in cancer biology, we anticipate continuous interest in this target, particularly in the testing of therapeutic combinations for immuno-oncology. Here, we describe the generation and validation of the first mouse knock-in of the whole coding region of human CXCR4. Homozygous human CXCR4 knock-in (hereafter designated as HuCXCR4KI) mice were viable and outwardly healthy, reproduced normally and nursed their young. The expression pattern of human CXCR4 in this model was similar to that of CXCR4 expression in normal human tissues. The human CXCR4 knock-in gene was expressed as a biologically active protein, thereby allowing normal animal development and adequate"homing" of leukocytes to the bone marrow. To further validate our model, we used an in vivo functional assay of leukocyte mobilization from bone marrow to peripheral blood by blocking CXCR4 signaling. Both an anti-human CXCR4 -specific blocking antibody and the small molecule CXCR4 inhibitor AMD3100 induced increased leukocyte counts in peripheral blood, whereas an anti-mouse CXCR4 -specific blocking antibody had no effect. This new mouse model is useful to evaluate efficacy and safety of anti-human CXCR4 -specific drugs as single agents or in combination therapies, particularly in the oncology, immuno-oncology, wound healing and chronic inflammation therapeutic areas.

[This corrects the article DOI: 10.1371/journal.pone.0176623.].

The family Sciaenidae, known as croakers or drums, is one of the largest perciform fish families. A recent multi-gene based study investigating the phylogeny and biogeography of global sciaenids revealed that the origin and early diversification of this family occurred in tropical America during the Late Oligocene-Early Miocene before undergoing range expansions to other seas including the Indo-West Pacific, where high species richness is observed. Despite this clarification of the overall evolutionary history of the family, knowledge of the taxonomy and phylogeny of sciaenid genera endemic to the Indo-West Pacific is still limited due to lack of a thorough survey of all taxa. In this study, we used DNA-based approaches to investigate the evolutionary relationships, to explore the species diversity, and to elucidate the taxonomic status of sciaenid species/genera within the Indo-West Pacific clade. Three datasets were herein built for the above objectives: the combined dataset (248 samples from 45 currently recognized species) from one nuclear gene (RAG1) and one mitochondrial gene (COI); the dataset with only RAG1 gene sequences (245 samples from 44 currently recognized species); and the dataset with only COI gene sequences (308 samples from 51 currently recognized species). The latter was primarily used for our biodiversity exploration with two different species delimitation methods (Automatic Barcode Gap Discovery, ABGD and Generalized Mixed Yule Coalescent, GMYC). The results were further evaluated with help of four supplementary criteria for species delimitation (genetic similarity, monophyly inferred from individual gene and combined data trees, geographic distribution, and morphology). Our final results confirmed the validity of 32 currently recognized species and identified several potential new species waiting for formal descriptions. We also reexamined the taxonomic status of the genera, Larimichthys, Nibea, Protonibea and Megalonibea, and suggested a revision of Nibea and proposed a new genus Pseudolarimichthys.

Delay in diagnosis may affect the survival of breast cancer patients. The purpose of this study was to investigate delayed diagnosis for breast cancer patients in Taiwan. Methods: This study was conducted via one-to-one interviews with structured questionnaires in hospital outpatient visit. Included were 600 breast cancer patients seeking medical care in two medical centers in central Taiwan. Results: Average delay in breast cancer diagnosis was 27.8 days. Service level of the patients' first visit and number of hospitals patients visited before obtaining a correct diagnosis were significantly associated with delay in diagnosis. Logistic regression analysis found that patients who had visited two, and three or more hospitals before getting a correct diagnosis had longer delays in diagnosis than patients who had visited one hospital (odds ratio = 2.23 and 9.26, 95% confidence interval 1.37–3.63 and 95% CI:3.87–22.15, respectively). Conclusion: Results of this study are anticipated to serve as a reference for the government and medical institutions to develop policies to reduce the number of hospitals visited before diagnosis for breast cancer patients, and ultimately to achieve the goal of early detection and treatment.

Our Virtue Existential Career (VEC) model aims at complementing western modernism and postmodernism career theories with eastern philosophy. With dialectical philosophy and virtue-practice derived from the Classic of Changes, our VEC theoretical foundation incorporates merits from Holland typology, Minnesota Theory of Work Adjustment, Social Cognitive Career Theory, Meaning Therapy, Narrative Approach Career Counseling, and Happenstance Learning Theory. While modernism considers a matched job as an ideal career vision and prefers rational strategies (controlling and realizing) to achieve job security; postmodernism prefers adapting and appreciating strategies toward openness and appreciates multiple possible selves and occupations, our VEC model pursues a blending of security and openness via controlling-and-realizing and appreciating-and-adapting interwoven with each other in a dialectical and harmonious way. Our VEC counseling prototype aims at a secular goal of living on the earth with ways and harmony (安身以法以和) and an ultimate end to spiral up to the wisdom of living up to the way of heaven (天道) with mind and virtue (立命以心以德). A VEC counseling process of five major career strategies, metaphorical stories of qian and kun, and experiential activities are developed to deliver VEC concepts. The VEC model and prototype presented in this research is the product of an action research following Lewin’s (1946) top-to-down model. Situated structure analyses were conducted to further investigate the adequacy of this version of VEC model and prototype. Data from two groups (one for stranded college graduates and the other for growing college students) revealed empirical supports. Yang type of career praxes tend to induce actualization, which resulting in realistic goals and concrete action plans; yin type of career praxes tend to increase self-efficacy, which resulting in positive attitude toward current situatedness and future development. Acceptance and dialectic thinking often result from yin-yang-blending career praxes. Growing developers benefit from a strategy sequence of yang-yin-synthesized; stranded developers from a strategy sequence of yin-yang-synthesized. Our contributions and limitations are discussed in the context of developing indigenous career theories and practices for a globalized and ever-changing world.

The efficacy of an antibody-drug conjugate (ADC) is dependent on the properties of its linker-payload which must remain stable while in systemic circulation but undergo efficient processing upon internalization into target cells. Here, we examine the stability of a non-cleavable Amino-PEG6-based linker bearing the monomethyl auristatin D (MMAD) payload site-specifically conjugated at multiple positions on an antibody. Enzymatic conjugation with transglutaminase allows us to create a stable amide linkage that remains intact across all tested conjugation sites on the antibody, and provides us with an opportunity to examine the stability of the auristatin payload itself. We report a position-dependent degradation of the C terminus of MMAD in rodent plasma that has a detrimental effect on its potency. The MMAD cleavage can be eliminated by either modifying the C terminus of the toxin, or by selection of conjugation site. Both approaches result in improved stability and potency in vitro and in vivo. Furthermore, we show that the MMAD metabolism in mouse plasma is likely mediated by a serine-based hydrolase, appears much less pronounced in rat, and was not detected in cynomolgus monkey or human plasma. Clarifying these species differences and controlling toxin degradation to optimize ADC stability in rodents is essential to make the best ADC selection from preclinical models. The data presented here demonstrate that site selection and toxin susceptibility to mouse plasma degradation are important considerations in the design of non-cleavable ADCs, and further highlight the benefits of site-specific conjugation methods.

我們以網路動畫的方式製作了四個內容豐富的模擬實驗軟體，分別為：「檢索表的應用」、「水中的小生物」、「植物的呼吸作用」、「植物細胞觀察」等，屬於實質的模擬與步驟的模擬實驗教材，適合網路傳輸，可供國中學生反覆練習。經過國中學生和教師對製作技術和內容的滿意度調查，「檢索表的應用」並進行了學習成就檢測，評估結果顯示，這幾則具有創新意義的學習軟體，將豐富國中生物學的教學與學習，有效地增強實驗的學習成就。We report on the making of four simulated laboratory exercises software for the learning of biology for junior high school students. These software include the 1. use of dichotomous key, 2. microorganisms in water, 3. respiration of plant, and 4.observation of plant cells. Results of evaluation by teachers and students show that these software will help their teaching and learning of biology.