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BackgroundAlthough immunotherapy can induce durable anti-tumor response in multiple cancers, immune checkpoint blockade (ICB) therapy resistance in ovarian cancer and melanoma remains problematic. Here, we report that tumor cell-intrinsic mTORC1 regulates ICB response through mTORC1 defining subunit Raptor (Rptor) by modulating interferon-gamma (IFNg) resistance and tumor-initiating cell (TIC) virulence.MethodsWe knocked down two distinct mTORC1 signaling components: Rptor (Rptorlo, aids in mTORC1 assembly) and Lamtor1 (Ltor1lo, docks mTORC1 on lysosomes) in murine ovarian cancer ID8agg and melanoma B16 cells. PD-L1 was CRISPR knocked out in B16 and human ovarian cancer line ES2. Mice with tumors were treated with a-PD-L1± a-CD8 antibody. TICs were estimated by flow-cytometry.1ResultsRptorlo B16 and ID8agg, but not Ltor1lo B16 tumors grew slower and were a-PD-L1 responsive unlike control (ctrl) in WT mice. We noted that ctrl and Rptorlo B16 and ID8agg cells expressed similar surface PD-L1 in vitro. Thus, Rptor suppresses a-PD-L1 response in ICB-resistant tumors. Tumor immune analysis revealed increased CD8+ T cell% and a trend to increased IFNg+CD8+ T cells in a-PD-L1 treated Rptorlo, but not ctrl B16. Rptorlo a-PD-L1 efficacy was lost with a-CD8 and in IFNg knockout mice. In vitro, IFNg suppressed Rptorlo ID8agg proliferation, unlike ctrl. These data suggested that lack of Rptor makes tumors ICB responsive, possibly by making tumors IFNg-sensitive and increasing IFNg+CD8+ T cells. Further, tumor and draining lymph node (DLN) TCF1+PD-1+ T cell stem cells (critical for aPD-L1/PD-1 success2 3) were significantly higher in a-PD-L1 treated Rptorlo tumors. Thus, tumor Rptor status could regulate tumor microenvironment and distal DLN immune landscape on a-PD-L1 treatment.We previously published that mTORC1 promotes PD-L1-dependent tumor proliferation, TIC virulence1 4 PD-L1KO B16 and ES2 cells expressed similar total Rptor protein. However, lower levels of Rptor were loaded in mTOR complex in absence of PD-L1, as assessed by a-mTOR immunoprecipitation, suggesting that pro-tumorigenic Rptor functions were downstream of, and dependent on PD-L1. Successful Rptorlo aPD-L1 treatment reduced TIC in vivo, an effect reversed in absence of CD8+ T cells or host IFNg. Inhibiting ID8agg mTORC1 with rapamycin reduced stemness genes oct4, nanog expression by QPCR. Further, ID8agg Rptorlo TIC formed significantly smaller tumors versus ctrl TIC in immune-compromised NSG mice, confirming their reduced virulence. Rptor, but not Ltor1, expression inversely correlated with tumor CD8+ infiltrate in IMvigor210 trial, and strongly with TIC gene signature in ovarian cancer patients.5 6ConclusionsTumor-cell intrinsic Rptor modulates ICB resistance, IFNg responsiveness, immune microenvironment, and TIC virulence.AcknowledgementsN/ATrial RegistrationN/AReferencesGupta HB, et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1,Article number:16030.Im SJ, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 2016;537:417–421.Dammeijer F, et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell 2020;38:685–700.Clark CA, et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 2016;76:6964–6974.Smith BA, et al. A human adult stem cell signature marks aggressive variants across epithelial cancers. Cell Rep 2018;24:3353–3366.Hoffman-Censits JH, et al. IMvigor 210, a phase II trial of atezolizumab (MPDL3280A) in platinum-treated locally advanced or metastatic urothelial carcinoma (mUC). J Clin Oncol 2016;34, no.2_suppl:355–355.

IntroductionNatural cycle (NC) and hormone replacement treatment (HT) are frequently used endometrial preparation protocols prior to frozen-thawed embryo transfer in ovulatory women. It is not clear which protocol results in a higher live birth rate. It has been suggested that there is an increased risk in maternal and perinatal morbidity following HT protocol due to the lack of corpus luteum. The objective of this trial is to compare the clinical outcomes of NC and HT protocols in frozen embryo transfer.Methods and analysisCOMPETE is an open-label, single-centre, randomised controlled trial targeting to recruit 888 women, with 444 women each in two arms (1:1 treatment ratio). Women undergoing in vitro fertilisation scheduled for a frozen embryo transfer and have a regular menstrual cycle are eligible. Exclusion criteria include ovulation disorders and intrauterine adhesions. The primary outcome is live birth resulting from the first frozen embryo transfer after randomisation. Secondary outcomes include biochemical pregnancy, clinical pregnancy, multiple pregnancy, ongoing pregnancy, miscarriage, endometrial thickness, cycle cancellation, gestational diabetes mellitus, hypertensive disorders of pregnancy, antepartum haemorrhage, preterm birth, birth weight, large for gestational age, congenital anomaly and perinatal mortality. The data analysis will be following the intention-to-treat principle.Ethics and disseminationThis study has been approved by the Institutional Review Board of Northwest women’s and children’s hospital (2020008). Written informed consent will be obtained from each participant before randomisation. The results of the trial will be presented via publications.Trial registration numberChiCTR2000040640.

Fluorescent carbon dots (CDs) have attracted considerable interest due to their superior optical properties and facile preparation. In this work, O-phenylenediamine and melamine were used as precursors for the one-step hydrothermal synthesis of novel orange emissive CDs (O-CDs) in an aqueous solution. The fluorescence intensity (580 nm) of the O-CDs exhibited a good linear relationship with Ag

Background: The optimal means to prepare the endometrial preparation for PCOS patients is a topic of ongoing controversy. Our objective was to compare the clinical outcomes of frozen-thawed embryo transfer (FET) with and without pretreatment gonadotropin-releasing hormone agonist (GnRHa) in polycystic ovary syndrome (PCOS) patients. Methods: In this retrospective cohort study, we evaluated 1638 consecutive cycles between June 2014 and December 2017 in the Assisted Reproduction Center of Northwest Women’s and Children’s Hospital. The patients who underwent FET were assigned to two groups as follows: hormone replacement treatment (HRT) group, comprising 1115 cycles; HRT with GnRHa pretreatment (GnRHa + HRT), comprising 523 cycles. Patients using GnRHa + HRT (n=519) were matched with 519 patients using HRT. Results: The live birth rate was higher in the GnRHa + HRT group compared with the HRT group with no significant difference (60.4% vs 55.5%, p=0.062). The clinical pregnancy rate (72.74% vs 75.33%), miscarriage rate (14.26% vs 13.96%) and ectopic pregnancy rate (0.36% vs 0.38%) were similar between the two groups. The preterm birth rate in HRT was lower than GnRHa + HRT (14.08% vs 20.08%). There were no significant interactions in any of the subgroups (p>0.05 for all comparisons). In the unadjusted model and adjusted model, the live birth rate was comparable between GnRHa + HRT and HRT group (OR 1.22, 95%CI, 0.99-1.51, p=0.062; aOR 1.56, 95%CI, 1.001-2.41, p=0.048). Similar results were obtained after propensity score matching in the entire cohort. Conclusions: GnRHa pretreatment could not improve the live birth rate in women with PCOS.

Glutathione and 2-aminopyridine are used as carbon sources to prepare carbon dots (CDs) by a one-step hydrothermal reaction. The results show that the average particle diameter of CDs is 8.64 nm with uniform size distribution and the fluorescence quantum yield is 13.62%. We further demonstrate that novel CDs possess highly selective sensing of Fe

To compare the clinical outcome of fresh embryo transfer with frozen-thawed embryo transfer in subsequent cycle of GnRH antagonist protocol. Totally, 1430 women were enrolled from the cases of our Assisted Reproduction Center from January 2015 to January 2019 for this retrospective cohort study. The inclusion criteria of the subjects included women with ages under 40 years, 3–10 oocytes retrieved, good embryo quality according to gardener score, GnRH antagonist protocol, underwent first cycle of fresh embryo transfer or freeze-all strategy and transferred in subsequent cycle. However, the patients with endometriosis, PGD/PGS cycles, history of recurrent pregnancy loss and uterine pathology were excluded. 495 women of group I underwent fresh embryo transfer in first cycle and 935 patients of group II received frozen-thawed transfer in subsequent cycle. The primary outcome was clinical pregnancy rate. A logistic regression analysis was performed to determine the variables that could be independently associated with clinical pregnancy rate. Models were adjusted for covariates including patients’ age, fertilization type, infertility type, infertility duration, the number of oocytes retrieved, the number of embryos transferred and type of embryo transferred. Clinical pregnancy rate was significantly higher in frozen-thawed embryo transfer than in fresh embryo transfer (63.70% vs. 54.50%, p

The genus Hyloconis included four species when it was erected by Kumata in 1963 based on Japanese specimens. Noreika (1994) subsequently transferred Lithocolletis improvisella Ermolaev, 1986 to Hyloconis. Since then no further study has been carried out on this genus in the world. In the present paper, we record this genus in China for the first time and describe two new species, with amendment of generic characters based on the study of the Chinese material. Type specimens are deposited in the Insect Collection, College of Life Sciences, Nankai University (NKUM), Tianjin, and the Zoological Museum, Department of Bioscience and Biotechnology, Changzhi College (ZMCZC), Changzhi, Shanxi, China.

Spirituality has long served as a source of solace for many grievers following a loss. For other mourners, whose bereavement experience has been significantly challenged by struggles in their relationship with God and/or their faith community, the opposite is true. Complicated spiritual grief (CSG) is a spiritual crisis following the loss of a loved one. To assess CSG in samples of bereaved adults, a simple-to-use, multidimensional measure of spiritual crisis following loss called the Inventory of Complicated Spiritual Grief (ICSG) was previously developed and validated. However, subsequent research providing greater clarity about the construct of CSG supported the need to revise and update the ICSG. The goal of the present study was to establish the psychometric validity of a revised measure of CSG, called the Inventory of Complicated Spiritual Grief 2.0 (ICSG 2.0), with a large, diverse cohort of bereaved Christian adults (

This study examines the role of several key features of professional development (PD) in bringing about changes in teachers’ mathematical knowledge for teaching. Artifacts (e.g., PD tasks, materials, and agendas) of the PD activities completed by 542 teachers in 21 different Mathematics and Science Partnership programs were coded based on the core features of PD identified in earlier literature. Multilevel analyses examined whether the programs’ focus on specific components of teacher knowledge (e.g., knowledge of mathematics teaching) and specific strategies for implementing the PD content (e.g., examining students’ work and solving mathematics problems) were related to gains in teachers’ mathematical knowledge. The results showed that a focus on curricular content knowledge and examining students’ work were significantly related to teachers’ learning. Implications for research and teacher education are discussed.

Objective To examine the association between maternal education level and live birth after in vitro fertilization (IVF). Design Retrospective cohort study. Setting Public fertility center in China. Population 41546 women who underwent the first cycle of fresh or frozen-thawed embryo transfer between 2014 and 2019. Methods The women were divided into four educational categories according to the level of education received (elementary school graduate or less, middle school graduate, high school graduate, college graduate or higher). Main outcome measures Live birth rates. Results Patients were grouped by maternal educational level: elementary school graduate or less (n=1590), middle school graduate (n=10996), high school graduate (n=8354), and college graduate or higher (n=20606). The live birth rate, miscarriage rate, and clinical pregnancy rate in elementary school graduate or less were lower compared to other groups. In multivariate logistic regression analysis, we fail to demonstrate a statistically significant relationship between educational level and live birth in middle school graduate (adjusted odds ratio [AOR] 0.96; 95% confidence interval [CI], 0.84-1.09), high school graduate (AOR 1.01; 95% CI, 0.87-1.14) or college graduate or higher (AOR 1.01; 95% CI, 0.88-1.14) patients compared with the elementary school graduate or less reference group after adjusting for female age, infertility duration, BMI, EM thickness, no. of oocyte retrieved, infertility type, protocol in the fresh cycle, fertilization type, time of transfer and no. of embryo transferred. Conclusion No statistically significant relationship was identified between educational level and live birth in patients undergoing fresh or frozen embryo transfer.

BackgroundTumor PD-L1 canonically signals to PD-1 on immune cells to evade immune destruction.1 We reported that tumor PD-L1 also mediates diverse pathologic intracellular signals,2 3 including promoting the ATM/Chk2 DNA damage response, and that genetically PD-L1 deficient tumors are sensitized to Chk1 inhibitor therapy.4 DNA damage increases cytosolic DNA, which induces immunogenic STING signals through inflammatory type I interferon and cytokine production.5MethodsWe conducted a high-throughput drug screen that identified the β-lactam cephalosporin antibiotic cefepime as a pharmacologic tumor PD-L1 depleting agent. In vitro tests of β-lactam antibiotics used 80 μM and the Chk1 inhibitors rabusertib and prexasertib were used at indicated concentrations. Cell lines were RT4 human bladder cancer, ID8agg murine ovarian cancer, and B16 mouse melanoma. Viability was by MTT and proteins by immunoblot. We challenged NSG mice (n = 5 per group) with RT4 (SQ) and treated with cefepime (200 mg/kg), rabusertib (2.5 mg/kg), vehicle, or combination daily.ResultsCefepime at pharmacologically relevant concentrations depletes tumor PD-L1 and phenocopies genetic tumor PD-L1 depletion by decreasing Chk2 protein and increasing DNA damage (γH2AX) (figure 1). Chk2 is depleted by cefepime in CTRL cells, but not in PD-L1KO or PD-L1 overexpressing cells, and sensitizes PD-L1+ tumor cells to Chk1 inhibitors in vitro in a PD-L1-dependent manner (figures 1 and 2). Combining cefepime with rabusertib in vivo significantly prolonged severely immunodeficient NSG mice survival in RT4 challenge versus cefepime alone while rabusertib alone was not effective (figure 3). Antimicrobial mechanisms, reported to influence tumor treatment responses,6 are unlikely in NSG mice. To test β-lactam contributions to cefepime efficacy, we found that ceftazidime, a structurally related cephalosporin, also depletes tumor PD-L1 and Chk2 protein and sensitizes tumors to rabusertib in a PD-L1 dependent manner (figures 4 and 5). Structurally-unrelated β-lactam antibiotics did not sensitize tumors to rabusertib. Both cefepime and ceftazidime activate tumor STING, suggesting they could augment immunotherapies by increasing tumor immunogenicity (figure 6).ConclusionsAs genetic PD-L1 depletion is not yet clinically feasible, we provide pharmacologic means to deplete tumor PD-L1 to improve clinical treatment efficacy as a rapidly translated approach. Cefepime is the prototype agent, but ceftazidime is structurally similar with significant activity, suggesting important structure activity relationships to explore. Pharmacologic tumor PD-L1 depletion could augment other standard of care approaches, including immunotherapy, and deserves further investigation.ReferencesDong H, Strome SE, Salomao DR, Tamura H, Fumiya H, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002;8:793–800.Clark CA, Gupta HB, Gangadhara S, Pandeswara S, Lao S, Yuan B, et al. Tumor-Intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in Ovarian Cancer and Melanoma. Cancer Res 2016;76(23):6964–6974.3. Gupta HB, Clark CA, Yuan B, Sareddy G, Pandeswara S, Padron AS, et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1.Kornepati AV, Zhang D, Hambright HG, Kari SC, Deng Y, Clark CA, et al. Cell-intrinsic programmed death ligand-1 (PD-L1) inhibits cytotoxic chemo, promotes DNA damage repair, and enhances ATM/ATR signaling following exposure to DNA damaging agents in bladder, melanoma, and ovarian cancer cells. J Immunol 2019;202(1):195.17.Gehrke N, Mertens C, Zillinger T, Wenzel J, Bald T, Zahn S, et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 2013;39(3):482–495.Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018;359(6371):97–103.Ethics ApprovalThis protocol was approved by the UTHSCSA IACUC.Abstract 755 Figure 1Cefepime depletes tumor PD-L1 and Chk2 and induces γH2AXAbstract 755 Figure 2Cefepime sensitizes tumors to Chk1 inhibitors in a PD-L1 dependent mannerAbstract 755 Figure 3Cefepime combined with Chk1 inhibitors in vivo prolongs NSG mouse survivalAbstract 755 Figure 4Ceftazidime depletes tumor PD-L1 and Chk2Abstract 755 Figure 5Ceftazidime, but not other B-lactam antibiotics, sensitizes RT4 to Chk1 inhibitors in a PD-L1 dependent mannerAbstract 755 Figure 6Cefepime and ceftazidime induce STING and p-TBK1

Hydrogen sulfide (H

Background Ovarian cancer (OC) responds poorly to immunotherapies. Regulatory T cells (Treg) engage IL-2 by high-affinity CD25 for differentiation and function,1 and anti-tumor effector T cells (Teff) use intermediate affinity CD122. We studied IL-2 complexes (IL-2c) that selectively activate CD122 (Teff) over CD25 (Tregs). Methods Orthotopic ID8agg-luc mouse OC burden was measured by in vivo imaging. Tumor, ascites and draining lymph nodes (TDLN) were analyzed by flow and tSNE. IL-2c was complexed using 1.5 µg/mouse IL-2 and 7.5 µg/mouse aIL-2 (clone JES6-5H4) before i.p. injection every other day x 4 starting at day 7. antiPD-L1 was given at 100ug/mouse every 3 days x 4 starting from Day 11. FIR mice2 were used to sort live Tregs. Results IL-2c but not antiPD-L1 potently inhibits ID8agg (figure 1). IL-2c decreased ascites Treg functional markers (e.g., CD25, granzymeB) while upregulating the same markers on Teffs (figure 2). IL-2c inhibited Treg suppression in ascites while TDLN Tregs were unaffected (figure 3). tSNE showed great similarity of TDLN Tregs treated with isotype and IL-2c while ascites Tregs after IL-2c showed a fragile phenotype (e.g., increased PD-1, T-bet, and IFNgamma with maintained FoxP3 expression [figure 4]) which is known to contribute to better response to cancer immunotherapy.3 4 We observed a complete reduction of tumor bioluminescence with IL-2c and antiPD-L1 combo treatment in nearly all subjects significantly exceeding effect of IL-2c alone (figure 5). A CD8+CXCR5+TCF-1+ T cell stem cell (TCSC) population reportedly improves immune checkpoint blockade efficacy.5 6 Since CD122 is regulated by TCF-1,7 we explored the effect of IL-2c on these TCSC. IL-2c significantly induced a CD8+TCF-1+ TCSC population in ID8agg tumors (figure 6), possibly through a positive feedback loop by further enhancing CD122 expression on TCF-1+, but not TCF-1- cells (figure 7). tSNE analysis of detailed immune phenotype of IL-2c induced TCSC revealed that these TCSC differed from those induced by antiPD-L1. In ID8agg, antiPD-L1-induced TCSC are mostly CXCR5+ and PD1+, consistent with previous reports in other cancers3 4 while IL-2c-induced TCSC were PD1- (figure 8), expressed CCR2 and CXCR3, and produced TNFalpha (figure 9). Conclusions We define two novel IL-2c effects: inducing Treg fragility therefore reducing immunosuppression while promoting TCSC that could enhance effective anti-tumor immunity. Current work tests if effects are related and help efficacy, and mechanisms for IL-2c Treg effects. We also show that elicited TCSC differ by treatment and tumor, requiring additional investigations. Acknowledgements This work is supported by CPRIT Research Training Award (RP 170345), Ovarian Cancer Research Alliance Ann and Sol Schreiber Mentored Investigator Award to YD and R01 CA205965to TC. Ethics Approval All mice studies were approved by UT Health San Antonio Institutional Animal Care and Use Committee (IACUC). Approval number 20150093AR, 20140001AR, 20170035AR, 20140039AR, 20140027AR, 20090128AR, 20120071AR, 20180021AR. References Malek TR: The biology of interleukin-2. Annu Rev Immunol 2008, 26:453–479. Fantini MC, Dominitzki S, Rizzo A, Neurath MF, Becker C: In vitro generation of CD4+ CD25+ regulatory cells from murine naive T cells. Nat Protoc 2007, 2(7):1789–1794. Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, Horne W, Moskovitz JM, Kolls JK, Sander C, et al: Interferon-gamma Drives Treg Fragility to Promote Anti-tumor Immunity. Cell 2017, 169(6):1130–1141e1111. Overacre-Delgoffe AE, Vignali DAA: Treg Fragility: A Prerequisite for Effective Antitumor Immunity? Cancer Immunol Res 2018, 6(8):882–887. Brummelman J, Mazza EMC, Alvisi G, Colombo FS, Grilli A, Mikulak J, Mavilio D, Alloisio M, Ferrari F, Lopci E, et al: High-dimensional single cell analysis identifies stem-like cytotoxic CD8(+) T cells infiltrating human tumors. J Exp Med 2018. Sade-Feldman M, Yizhak K, Bjorgaard SL, Ray JP, de Boer CG, Jenkins RW, Lieb DJ, Chen JH, Frederick DT, Barzily-Rokni M, et al: Defining T Cell States Associated with Response to Checkpoint Immunotherapy in Melanoma. Cell 2018, 175(4):998–1013 e1020. Jeevan-Raj B, Gehrig J, Charmoy M, Chennupati V, Grandclement C, Angelino P, Delorenzi M, Held W: The Transcription Factor Tcf1 Contributes to Normal NK Cell Development and Function by Limiting the Expression of Granzymes. Cell Rep 2017, 20(3):613–626.

Propensity score methods are popular and effective statistical techniques for reducing selection bias in observational data to increase the validity of causal inference based on observational studies in behavioral and social science research. Some methodologists and statisticians have raised concerns about the rationale and applicability of propensity score methods. In this review, we addressed these concerns by reviewing the development history and the assumptions of propensity score methods, followed by the fundamental techniques of and available software packages for propensity score methods. We especially discussed the issues in and debates about the use of propensity score methods. This review provides beneficial information about propensity score methods from the historical point of view and helps researchers to select appropriate propensity score methods for their observational studies.

BackgroundProgrammed cell death ligand-1 (PD-L1) overexpression in tumor cells inhibits T cells activity and delivers pathologic intracellular signals that can reduce cancer treatment responses in pre-clinicalmodels.1 2MethodsTo reduce tumor intracellular PD-L1-mediated pathology, we performed a drug screen that identified chlorambucil as a tumor cell PD-L1 depletion drug.ResultsChlorambucil depletes basal tumor PD-L1 expression through the ubiquitination proteasome pathway. In the tumor microenvironment, high chlorambucil doses treated orthotopic B16 melanoma and ID8agg ovarian cancer. Chlorambucil treatment efficacy was lost or reduced in PD-L1lo ID8agg and PD-L1KO B16 tumors, corroborated with in vitro data. These data suggest that chlorambucil anti-tumor activity of CAMB requires tumor PD-L1 expression, confirmed in PD-L1KO host challenge with CTRL tumor, which chlorambucil treated effectively. Chlorambucil rendered αPD-L1 resistant CTRL ID8agg and PD-L1lo B16 tumors αPD-L1 sensitive, preliminarily possibly due to tumor STING activation, and associated with enhanced tumor NK cell infiltration and central memory T cell generation. Chlorambucil also phenocopied genetic PD-L1KO by reducing tumor cell mTORC1 signals and stem cell content,3 suggesting additional treatment potential.ConclusionsChlorambucil could be a useful strategy to reprogram tumor PD-L1 signals and boost immune-based therapies especially for anti-PD-L1-resistant tumors.ReferencesClark CA et al. Tumor-intrinsic PD-L1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res 2016;76:6964–6974.Juneja VR et al. PD-L1 on tumor cells is sufficient for immune evasion in immunogenic tumors and inhibits CD8 T cell cytotoxicity. J Exp Med 2017;214:895–904.Gupta HB et al. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer. Signal Transduct Target Ther 2016;1:2095–9907.Ethics ApprovalWe received approval from the UT Health San Antonio Institutional Animal Care and Use Committee (IACUC) for each procedure that used mice. We conducted each experiment per the standards required by the UT Health San Antonio Department of Laboratory Animal Resources.

Fluorescent carbon dots (CDs) have attracted considerable interest due to their superior optical properties and facile preparation. In this work, O-phenylenediamine and melamine were used as precursors for the one-step hydrothermal synthesis of novel orange emissive CDs (O-CDs) in an aqueous solution. The fluorescence intensity (580 nm) of the O-CDs exhibited a good linear relationship with Ag+ in the range of 0.0–50.0 μM with the detection limit of 0.289 μM. Moreover, the O-CDs were successfully used to determine Ag+ in biological samples (Hela cells) because of their low cytotoxicity, and good biocompatibility. Besides, the O-CDs-doped solid-phase detection materials (test paper and hydrogel) were employed to monitor Ag+ qualitatively and quantitatively, indicated that the O-CDs had a great capacity for the detection of Ag+ in biological and environmental areas. Based on their extraordinary fluorescence property, the O-CDs could also be used as security ink. Overall, based on their excellent fluorescent performance, the CDs in this study have significant potential for practical application toward solid-phase sensing and security ink.

Hydrogen sulfide (H2S) played crucial roles in biological processes and daily life, and the abnormal level of H2S was associated with many physiological processes. In this paper, we designed and developed a dicyanomethylene-4H-chromene (DCM)-based near-infrared (NIR) fluorescent probe DCM-NO guided by theoretical calculation. The probe displayed excellent selectivity towards H2S with a fast response time (3 min) and low detection limit (fluorescence 25.3 nM/absorption 6.61 nM) in Hela cells and real water samples. Furthermore, the probe-doped solid sensing materials (test strips and nanofibrous films) exhibited specific visualization of H2S under ambient light or hand-held UV lamp, providing great potential for on-site and real-time application in environmental and biological systems.

It is unknown whether seasonal variation influences the outcome of in vitro fertilization (IVF). Previous studies related to seasonal variation of IVF were all small sample size, and the results were conflicting. We performed a retrospective cohort study evaluating the relationship between seasonal variability and live birth rate in the year of 2014–2017. Patients were grouped into four seasons (Winter (December-February), Spring (March-May), Summer (June-August), and Autumn (September-November)) according to the day of oocyte pick-up (OPU). Multivariate logistic regression analysis was performed to evaluate association between seasonal variation and live birth. Models were adjusted for covariates including temperature, sunshine hour, infertility type, infertility duration, infertility factor and BMI. In total 38,476 women were enrolled, of which 25,097 underwent fresh cycles, 13,379 were frozen embryo transfer. Live birth rates of fresh embryo transfer were 50.36%, 53.14%, 51.94% and 51.33% for spring, summer, autumn and winter, respectively. Clinical pregnancy rate between the calendar months varied between 55.1% and 63.4% in fresh embryo transfer (ET) and between 58.8% and 65.1% in frozen embryo transfer (FET) (P-values 0.073 and 0.220). In the unadjusted model and adjust model, seasonal variation was not associated with live birth. In conclusion, there was no significant difference of seasonal variations in the outcome of IVF with fresh embryo transfer and frozen embryo transfer.

The authors present the development and validation of the Coping Assessment for Bereavement and Loss Experiences (CABLE), the first instrument designed to assess a range of potentially constructive...

A new genus with a new species, Lasiopsychops impunctatus gen. et sp. nov., and a new species, Electropsychops oligophlebius sp. nov., of silky lacewings in Psychopsidae are described from mid-Cretaceous Burmese amber. Lasiopsychops gen. nov. has typical characters of the extant Psychopsidae, i.e., broad triangular forewing, broad costal space, presence of the vena triplica and the paired ectoprocts and gonocoxites 9 of female genitalia, implying its close affinity with the extant lineages of Psychopsidae. The new findings of the Cretaceous psychopsids enhance our knowledge on the diversity and evolution of Psychopsidae during the Mesozoic.

To investigate the clinical efficacy of growth hormone (GH) in normal response patients with poor embryo quality in previous in vitro fertilization cycles. A total of 1562 infertile women w...

Microblog has become a popular social media because of its short text and timely release, and its impact on society has gradually increased. In order to study the behaviour of microblog users, this paper introduced two algorithms for microblog network community division, which were community discovery algorithm based on density peak clustering and community discovery algorithm based on similarity. Then the two algorithms were simulated using MATLAB software. The data used in the experiment included the artificial network generated by LFR tool and the following information data of different users collected by taking the API interface of the microblog of a student from Computer School of Jining Normal University as the starting point by crawlers. The results demonstrated that the normalised mutual information (NMI) and the density of the community structure obtained by the two algorithms decreased, and the conductivity increased with the expansion of the scale of microblog network, and the community structure obtained by the similarity-based algorithm had higher NMI and density and lower conductivity under the same scale of micrblog network. In conclusion, the similarity-based algorithm can divide microblog network better.

The purpose of this study is to assess the impact of a newly developed modules, Interactive Web-Based Visualization Tools for Gluing Undergraduate Fuel Cell Systems Courses system (IGLU), on learning motivations of engineering students using two samples (n1=144 and n2=135) from senior engineering classes. The multivariate analysis results revealed that the participants had a significant increase in their learning motivation after the treatment with the IGLU modules. This result was cross-validated with the two samples, in which the motivation mean posttest scores are significantly higher than the mean pretest scores, systematically (Sample 1: the mean score is increased by 2.09 [.32, 3.87] points, p = .021; Sample 2: the mean score is increased by 1.38 [.14, 2.61] points, p = .029). With the use of instructional technology prevailing in current university courses, the education initiative of the IGLU system and the assessment of its impact on student learning motivation provide us information to improve the modules to serve a more diverse student body. It will greatly help the development of engineering educational curriculum. With regards to the statistical inference, it is desirable to conduct further studies with a quasi-experiment control group design to assess the program effect focusing on student learning and its associations with student learning motivations and learning styles.

The ectopic pregnancy (EP) rate after in vitro fertilization-embryo transfer (IVF-ET) is higher than after spontaneous conception. The reason for the increased risk of EP is not clear. We aimed to determine the risk factors associated with EP in patients undergoing IVF-ET.This was a 1:4 matched case-control study that enrolled 225 EP patients and 900 matched intrauterine pregnancy patients from the ART center of Northwest Women's and Children's Hospital from January 2014 to April 2018. Conditional logistic regression was used to analyze the association between risk factors and EP, and a receiver-operating characteristic (ROC) curve was generated for the predictors of EP.Our findings showed that tubal factor (OR 1.61; 95% CI 1.12-2.31) and pelvic surgery other than cesarean section (OR 2.04; 95% CI 1.26-3.29) were associated with a higher risk of EP (p = 0.001). An endometrial thickness 12 mm prior to embryo transfer (OR 0.27; 95% CI 0.13-0.56) and the number of transferable embryos (OR 0.71; 95% CI 0.65-0.78) were protective factors against EP (p 0.001). The other factors did not have a significant effect on the probability of developing ectopic pregnancy. The area under the curve of the endometrial thickness and the number of transferable embryos for EP prediction were higher than those for tubal factor and pelvic surgery other than cesarean section.An endometrial thickness 12 mm is a strong protective factor against ectopic pregnancy. Attention should be paid to women with specific characteristics who have undergone IVF-ET.

Among the commonly used resampling methods of dealing with small-sample problems, the bootstrap enjoys the widest applications because it often outperforms its counterparts. However, the bootstrap still has limitations when its operations are contemplated. Therefore, the purpose of this study is to examine an alternative, new resampling method (called S-SMART) and compare the statistical performance of it with that of the bootstrap through an application of them to the most advanced modelling technique, SEM, as an example. The evaluation of the statistical performances of S-SMART and the bootstrap with respect to the standard errors of the parameter estimates was conducted through a Monte Carlo simulation study. This work, while potentially benefiting educational and behavioural research, conceivably would also provide methodological support for other research areas, such as bioinformatics, biology, geosciences, astronomy, and ecology, where large samples are hard to obtain.

This study assessed the needs of urban school leaders for special education preparation in a large public school district in the USA in order to assist the school administrators with improving their knowledge and skills for providing appropriate services to students with disabilities and their families to support inclusive education. The needs survey was created based on the Council for Exceptional Children (CEC 2009) standards for school administrators in the USA and the literature in special education. The validity and reliability of the instrument were verified. The needs assessment measures 10 aspects regarding special education knowledge and skills as indicated by 10 factors in the exploratory factor analysis. Quantitative data analyses on a sample of 289 participants revealed that there were significant differences in the needs of training in special education knowledge based on the school administrators’ backgrounds. The current research supports the call for the professional development and inclus...

We provide the first report on the leaf-mining Tischeriidae genus Paratischeria Diškus & Stonis from Asia. We describe Paratischeria jingdongensis Xu & Dai, sp. nov., a new species discovered in Yunnan, China, feeding on Dalbergia assamica Benth., Fabaceae and redescribe P. hestias (Meyrick, 1915), comb. nov., a hitherto very little known species from India, which has been recently discovered in northern Vietnam, feeding on Helicteres viscida Blume, Malvaceae. We also report on the Fabaceae family as a novel host-plant family of Tischeriidae. The described and redescribed Paratischeria species are illustrated with photographs of the leaf-mines, adults, genitalia, and habitats. We also provide maps of new Paratischeria findings, and, along with a diagnostic scheme to the genus, present some data on global distribution of Paratischeria occurring in tropical and subtropical regions on both sides of the Equator. In addition, we designate a new Paratischeria neotropicana species group and provide two more new taxonomic combinations: Paratischeria heteroterae (Frey & Boll, 1878) comb. nov. and P. capnota (Meyrick, 1915) comb. nov.

We provide the first report on the leaf-mining Tischeriidae genus Paratischeria DiškusStonis from Asia. We describe Paratischeria jingdongensis XuDai, sp. nov., a new species discovered in Yunnan, China, feeding on Dalbergia assamica Benth., Fabaceae and redescribe P. hestias (Meyrick, 1915), comb. nov., a hitherto very little known species from India, which has been recently discovered in northern Vietnam, feeding on Helicteres viscida Blume, Malvaceae. We also report on the Fabaceae family as a novel host-plant family of Tischeriidae. The described and redescribed Paratischeria species are illustrated with photographs of the leaf-mines, adults, genitalia, and habitats. We also provide maps of new Paratischeria findings, and, along with a diagnostic scheme to the genus, present some data on global distribution of Paratischeria occurring in tropical and subtropical regions on both sides of the Equator. In addition, we designate a new Paratischeria neotropicana species group and provide two more new taxonomic combinations: Paratischeria heteroterae (FreyBoll, 1878) comb. nov. and P. capnota (Meyrick, 1915) comb. nov.

This study investigated the effects of economic status and the educational expectations of significant others on early university aspirations and actual university attainment. The study analyzed two-wave longitudinal data collected from 1,595 Taiwanese students in their 9th grade in middle school and in their freshman year at universities. The results revealed that economic status affected neither university aspirations nor university attainment. Among the significant others studied, parental expectations fundamentally affected university aspirations and teacher expectations consistently affected university aspirations and attainment. After considering economic status and educational expectations, early university aspirations remained strongly related to actual university attainment. Future research directions and practical educational approaches are recommended based on the aforementioned results.

Although economic disadvantage is linked to poor relationship quality and increased individual distress, emerging literature supports couples and relationship education as effective at improving relationship quality for low-income couples. However, relationship education’s influence on individual distress for low-income couples has not yet been determined. We provided relationship education using the Prevention Relationship Enhancement Program curriculum to 96 low-to-moderate income married couples with children and examined changes in relationship quality and individual distress pre, post, and 3–6 months after intervention. We found significant improvements in relationship satisfaction and significant individual distress decreases. Implications are discussed.

Background Elective frozen-embryo transfer has been shown to result in a higher live-birth rate than fresh-embryo transfer among anovulatory women with the polycystic ovary syndrome. It is uncertain whether frozen-embryo transfer increases live-birth rates among ovulatory women with infertility. Methods In this multicenter, randomized trial, we randomly assigned 2157 women who were undergoing their first in vitro fertilization cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. Up to two cleavage-stage embryos were transferred in each participant. The primary outcome was a live birth after the first embryo transfer. Results The live-birth rate did not differ significantly between the frozen-embryo group and the fresh-embryo group (48.7% and 50.2%, respectively; relative risk, 0.97; 95% confidence interval [CI], 0.89 to 1.06; P=0.50). There were also no significant between-group differences in the rates of implantation, clinical pregnancy, o...

Evidence-based practices (EBPs) receive little attention in counselor education curricula despite the ethical obligation for counselor educators to teach EBPs to counseling students. This study investigates counselor educators’ attitudes toward EBPs along with perceived barriers to the inclusion of EBPs in counselor education curricula.

Study question What factors does multivariate logistic regression show to be significantly associated with the likelihood of clinical pregnancy in vitrified-warmed embryo transfer (VET) cycles? Summary answer Assisted hatching (AH) and if the reason to freeze embryos was to avoid the risk of ovarian hyperstimulation syndrome (OHSS) were significantly positively associated with a greater likelihood of clinical pregnancy. What is known already Single factor analysis has shown AH, number of embryos transferred and the reason of freezing for OHSS to be positively and damaged blastomere to be negatively significantly associated with the chance of clinical pregnancy after VET. It remains unclear what factors would be significant after multivariate analysis. Study design, size, duration The study was a retrospective analysis of 2313 VET cycles from 1481 patients performed between January 2008 and April 2012. A multivariate logistic regression analysis was performed to identify the factors to affect clinical pregnancy outcome of VET. Participants/materials, setting, methods There were 22 candidate variables selected based on clinical experiences and the literature. With the thresholds of α entry = α removal= 0.05 for both variable entry and variable removal, eight variables were chosen to contribute the multivariable model by the bootstrap stepwise variable selection algorithm (n = 1000). Eight variables were age at controlled ovarian hyperstimulation (COH), reason for freezing, AH, endometrial thickness, damaged blastomere, number of embryos transferred, number of good-quality embryos, and blood presence on transfer catheter. A descriptive comparison of the relative importance was accomplished by the proportion of explained variation (PEV). Main results and the role of chance Among the reasons for freezing, the OHSS group showed a higher OR than the surplus embryo group when compared with other reasons for VET groups (OHSS versus Other, OR: 2.145; CI: 1.4-3.286; Surplus embryos versus Other, OR: 1.152; CI: 0.761-1.743) and high PEV (marginal 2.77%, P = 0.2911; partial 1.68%; CI of area under receptor operator characteristic curve (ROC): 0.5576-0.6000). AH also showed a high OR (OR: 2.105, CI: 1.554-2.85) and high PEV (marginal 1.97%; partial 1.02%; CI of area under ROC: 0.5344-0.5647). The number of good-quality embryos showed the highest marginal PEV and partial PEV (marginal 3.91%, partial 2.28%; CI of area under ROC: 0.5886-0.6343). Limitations, reasons for caution This was a retrospective multivariate analysis of the data obtained in 5 years from a single IVF center. Repeated cycles in the same woman were treated as independent observations, which could introduce bias. Results are based on clinical pregnancy and not live births. Prospective analysis of a larger data set from a multicenter study based on live births is necessary to confirm the findings. Wider implications of the findings Paying attention to the quality of embryos, the number of good embryos, AH and the reasons for freezing that are associated with clinical pregnancy after VET will assist the improvement of success rates.

Propensity score estimation plays a fundamental role in propensity score matching for reducing group selection bias in observational data. To increase the accuracy of propensity score estimation, the author developed a bootstrap propensity score. The commonly used propensity score matching methods: nearest neighbor matching, caliper matching, and Mahalanobis metric matching, are used for evaluating the quality of bias reduction results using propensity scores estimated with or without the bootstrap. The study reveals that the matching results with bootstrap propensity score are better than or comparable to those of matching without bootstrap procedures. With regard to the merit of the bootstrap method in reducing sampling errors and, therefore, improving the accuracy of propensity score estimation, the results of this study imply a great potential to use the bootstrap method in estimating propensity scores. This study provides a preliminary framework for further research in this area.

As a crucial component of propensity score methods for reducing selection bias, propensity score estimation can only account for observed covariates. The behaviors of sensitivity and robustness of propensity score estimation to the impact of unobserved covariates or uncontrolled confounders have not been fully understood. This chapter introduces a new technique to assess the sensitivity and robustness of propensity score estimation to the impact of uncontrolled confounders. The sensitivity is defined as a change from a propensity score that is estimated from a propensity score model including all observed covariates to a potential propensity score that would be estimated from the propensity score model adding an unobserved covariate. The robustness is subsequently defined as the probability of the sensitivity would cross a pre-specified threshold. To assess the robustness, a reference distribution of the sensitivity is derived by borrowing information from observed covariates and further approximated to one of Pearson distributions. This procedure of assessment is illustrated with empirical data on substance abuse prevention for high-risk youth.

This research study assessed the effectiveness of a three-dimensional mathematics game, DimensionM, through a pretest-posttest control group quasi-experimental design. Participants consisted of 437 eighth graders. The classrooms were randomly assigned either to the treatment group that utilized DimensionM as a supplement to regular classroom instructions or to the control group that received regular class instructions without any computer activities. The results of the analysis on the pretest-posttest data revealed that the DimensionM game increased mathematical knowledge acquisition in algebra and maintained student motivation to learn. The findings suggest that the implementation of DimensionM in mathematics education can greatly benefit middle school students learning algebra. Practitioner Notes What is already known about this topic Evaluations on the effectiveness of instructional games are known in the community of both practitioners and experienced researchers in educational research., What this paper adds This paper specifically added to the literature by evaluating the effectiveness of the novel instructional game, the DimensionM game, on increasing middle school student mathematical knowledge acquisition in algebra and maintaining student motivation to learn., Implications for practice and/or policy The study results suggested that the implementation of DimensionM in mathematics education can benefit middle school students' learning of algebra and can be helpful to maintain their motivation in learning. [ABSTRACT FROM AUTHOR]