bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A37: Evaluation of eDHFR/iTag PET reporter gene immunogenicity and application in GPC3 CAR T cells
Authors: Sellmyer Mark A , Lee Iris K , Kuszpit Kyle , Roy Jyoti , Alfaro Alex , Ory Virginie , Cheng Lily , Sutton Daniel , Bosco Emily , Fazenbaker Christine , Novarra Shabazz , Gilbreth Ryan , Tschernia Nick , Berry Deborah , Chen Xiaoru , Wu Yuling , Wong Ryan
Published: December 2022

Genetically engineered medicines such as chimeric antigen receptor (CAR) T cells have great potential to be the next pillar of medical therapy beyond chemo- and traditional biologic therapies. To develop genetic medicines, new methods to understand their pharmacokinetics (PK) in humans are crucial. It is not feasible to perform traditional PK analysis for “living drugs”, because the genes themselves (in the form of DNA or RNA), are not typically responsible for the therapeutic effect. Rather, the protein products of the genes or the cells harboring the engineered genes are the actuators, and thus cannot be measured using standard HPLC or ligand binding immunoassays for PK analysis. We used a positron emission tomography (PET) reporter gene or “imaging tag” based on the intracellular bacterial enzyme dihydrofolate reductase (eDHFR) that can be paired with radiolabeled versions of trimethoprim (TMP). In this work, we evaluate the potential for immunogenicity using primary human cells and assays geared to assess low affinity and rare T cell clones that may react to eDHFR. We used overlapping pools of 15-mer eDHFR peptides and found that across 9 patients, there was little reactivity compared to EBV and CMV peptide controls. Further, the relative strength of reactivity to the eDHFR peptides was less than that of the viral peptides. Next, we showed that eDHFR iTag harboring CAR T cells were functionally comparable to unlabeled CAR T cells in vitro, and demonstrated strong, selective [18F]-TMP uptake in the eDHFR-expressing CAR T cells. Finally, using a glypican 3 (GPC3) CAR T rodent model, we performed a feasibility study to non-invasively track proliferation in antigen-harboring xenograft tumors over time with ex vivo correlation to anti-CD3 immunohistochemistry. These data demonstrate the potential for non-invasive monitoring of CAR T cells using PET imaging and translational applicability of DHFR/TMP radiotracers.

Citation Format: Mark A Sellmyer, Iris K Lee, Kyle Kuszpit, Jyoti Roy, Alex Alfaro, Virginie Ory, Lily Cheng, Daniel Sutton, Emily Bosco, Christine Fazenbaker, Shabazz Novarra, Ryan Gilbreth, Nick Tschernia, Deborah Berry, Xiaoru Chen, Yuling Wu, Ryan Wong. Evaluation of eDHFR/iTag PET reporter gene immunogenicity and application in GPC3 CAR T cells [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A37.
Abstract A49: Proof of principle that loss of mismatch repair protein reduces tumor burden in mouse model of gastric cancer
Authors: Huber Anne , Dijkstra Christine , Whitehall Vicki , Ernst Matthias , Eissmann Moritz
Published: December 2022

Gastric cancer (GC) remains the third leading cause of cancer-related death worldwide. Unfortunately, only a subset of GC patients, characterized by tumors with high microsatellite instability (MSI), responds to immune checkpoint (ICI) therapy. In the context of GC, the mechanisms of how MSI improves ICI therapy responses remain poorly understood. Here we are undertaking a proof of principle study to demonstrate in novel GC mouse models that loss of mismatch repair protein MLH1 confers MSI phenotype and impairs tumor growth via altered anti-tumor immune responses. To study the functional and mechanistic effects of loss of MLH1 protein, we established MLH1-deficient (Kras-, Pi3kca-, Tp53-mutant) murine tumor organoids via CRISPR/Cas9 technology. These organoids were subcutaneously allografted into immunocompetent C57BL/6 mice to study tumor progression, immune surveillance, and responses to immunotherapy in vivo. MSI testing confirmed that MLH1-proficient parental organoids are MSI low, whereas MLH1-deficient organoids are MSI high. Low passage MLH1-deficient organoid tumors grew similarly to MLH1-proficient tumors. However, after culturing of organoids in vitro for a prolonged time prior to injection to allow accumulation of mutations, subcutaneous allograft MLH1-deficient tumors were considerably smaller compared to MLH1-proficient tumors. MLH1-deficient tumors showed a significantly higher number of CD8+ T cells. Additionally, MLH1-deficient tumors were similar in size to MLH1-proficient tumors when allografted into Rag1-/- mice. Interestingly, CD8- and CD4-depleting experiments showed an involvement of CD4+ T cells in the impairment of MLH1-deficient tumor growth. Treatment with anti-PD-1, but not anti-CTLA-4, reduced tumor mass further. We are currently investigating the underlying mechanism for the impaired growth of MLH1-deficient organoid allograft tumors via tumor mutational burden analysis and neoantigen testing. Taken together, we provide evidence that loss of MLH1 leads to high MSI in gastric tumors, reduces tumor growth after prolonged in vitro culture and increases response to anti-PD-1 therapy. Our findings encourage further studies to investigate the mechanisms of impaired tumor growth after MLH1 loss in GC and may provide insights leading to improve ICI therapy responses for GC patients.

Citation Format: Anne Huber, Christine Dijkstra, Vicki Whitehall, Matthias Ernst, Moritz Eissmann. Proof of principle that loss of mismatch repair protein reduces tumor burden in mouse model of gastric cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A49.
Abstract A58: Increased systemic activated CD4+ T cells and non-classical monocytes are associated with improved immunotherapy response and progression-free survival in non-small cell lung cancer patients
Authors: Figueiredo Amanda B , Ferreira Stephanie M Iasbeke , Evangelista Guilherme FB , Santos Iasmim P , Kuil Larissa M , Cavalcanti Clara M , Morais Kátia LP , Galdino Nayane AL , Lopes Ananda D , Freitas Helano C , Gross Jefferson L , Pinto Clóvis A Lopes , Chojniak Rubens , de Lima Vladmir C Cordeiro , Gollob Kenneth J
Published: December 2022

The development of immune checkpoint inhibitors initiated a new era of anti-cancer therapies with very promising results. Although effective for many patients, others are primarily refractory to this treatment. Identifying systemic immune cell subpopulations associated with treatment success or failure can reveal mechanisms behind therapeutic failure and offer potential predictive markers of clinical use. Here, for the first time, we performed a prospective non-interventional study and evaluated the pretreatment systemic immunological status of 33 patients with stage IV non-small cell lung cancer treated with anti-PD-1 combined with chemotherapy by flow cytometry. Treatment outcome was evaluated 9 weeks after treatment to define patients as Responders and Non-responders. Patients were reevaluated 6 months after therapy. Responders presented a higher frequency of activated CD4+ CD69+ T lymphocytes and non-classical monocytes before treatment began, which acted as predictive biomarkers for response measured at nine weeks. Conversely, CTLA-4+CD4+ T lymphocytes were more frequent in Non-responders and may contribute to an immunosuppressive milieu impairing the control of the tumor. Patients with durable responses (³ 6 months) also had higher frequency of activated CD4+ T lymphocytes before treatment started, compared with non-responders. In contrast, non-classical monocytes did not predict a durable response. However, patients with a higher frequency of both immune populations had longer median progression free survival. Our results suggest that higher frequency of peripheral activated CD4+CD69+, CD4+CTLA-4+ T cells may be useful biomarkers of therapeutic success or failure in NSCLC and point to mechanisms underlying therapeutic outcome. Studies are underway to further characterize the functional potential and activation status these systemic immune subpopulations.

Citation Format: Amanda B Figueiredo, Stephanie M Iasbeke Ferreira, Guilherme FB Evangelista, Iasmim P Santos, Larissa M Kuil, Clara M Cavalcanti, Kátia LP Morais, Nayane AL Galdino, Ananda D Lopes, Helano C Freitas, Jefferson L Gross, Clóvis A Lopes Pinto, Rubens Chojniak, Vladmir C Cordeiro de Lima, Kenneth J Gollob. Increased systemic activated CD4+ T cells and non-classical monocytes are associated with improved immunotherapy response and progression-free survival in non-small cell lung cancer patients [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A58.
Abstract B12: T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy
Authors: Hansen Aida S. , Jensen Lea S. , Ryttersgaard Kristoffer G. , Krapp Christian , Just Jesper , Joensson Kasper L. , Etzerodt Anders , Deleuran Bent W. , Jakobsen Martin R.
Published: December 2022

Despite recent years advancement reported for cancer immunotherapies within multiple cancer types, we still see a large group of patients failing to respond to treatment. Activation of the innate immune pathway controlled by STimulator of INterferon Genes (STING) has been considered as an attractive target for boosting cancer immunotherapy. Extracellular vesicles (EVs) are key players in shaping immune responses and are proposed to provide a danger signal for antigen-presenting cells. Here, we hypothesize that CD4+ T-cell derived EVs (T-EVs) enhance innate immune cells function, such as macrophages, by priming the STING signaling pathway. We purified T-EVs from aCD3/aCD28 stimulated CD4+ T cells by differential ultracentrifugation, and primed macrophages with these prior to stimulation with STING agonists. Subsequent activation was measured by induction of type I Interferons and phosphorylation of signaling molecules within the STING pathway. We further explored the in vivo efficacy of combining T-EVs priming and STING agonists in tumor bearing mice models. We found that T-EVs sensitizes macrophages to respond more potently to STING activation. Importantly, this was independent on both surface-associated and intravesicular DNA. The priming of STING signaling was largely induced by IFNγ and TNFα carried by the T-EVs. We further showed that the T-EVs enhances the efficacy of STING agonist stimulation, by controlling tumor growth in syngeneic MC38 tumor models. Our work support that T-EVs can disrupt the immune suppressive tumor microenvironment by reprogramming macrophages to a pro-inflammatory phenotype, and priming them for a robust immune response towards STING activation.

Citation Format: Aida S. Hansen, Lea S. Jensen, Kristoffer G. Ryttersgaard, Christian Krapp, Jesper Just, Kasper L. Joensson, Anders Etzerodt, Bent W. Deleuran, Martin R. Jakobsen. T-cell derived extracellular vesicles prime macrophages for improved STING based cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B12.
Abstract B17: Data-driven discovery of targets for immune-metabolic antitumor drugs identifies Estrogen Related Receptor Alpha
Authors: Sahu Avinash
Published: December 2022

Drugs that kill tumors through multiple mechanisms have the potential for broad clinical benefits. Here, we first developed an in silico multi-omics approach (BipotentR) to find cancer-cell-specific regulators that simultaneously modulate tumor immunity and another oncogenic pathway, and use it to identify 38 candidate immune-metabolic regulators. We show the tumor activity of these regulators stratify melanoma patients by their response to anti-PD1 using machine learning and deep neural approaches, which we benchmarked against current biomarkers. The topmost identified regulator, ESRRA (Estrogen Related Receptor Alpha), is activated in immunotherapy-resistant tumors of many types. Its inhibition killed tumors by suppressing energy metabolism and activating two immune mechanisms: (i) cytokine induction, causing proinflammatory macrophage polarization (ii) antigen-presentation stimulation, recruiting CD8+ T cells into tumors. We also demonstrate a wide utility of BipotentR by applying it to angiogenesis and growth-suppressor pathways. BipotentR, available at http://bipotentr.dfci.harvard.edu/, provides a resource for evaluating patient response and discovering drug targets that act simultaneously through multiple mechanisms.

Citation Format: Avinash Sahu. Data-driven discovery of targets for immune-metabolic antitumor drugs identifies Estrogen Related Receptor Alpha [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B17.
Abstract B28: Targeting TBK1 to overcome resistance to cancer immunotherapy
Authors: Sun Yi , Revach Or-yam , Anderson Seth , Manguso Robert T. , Jenkins Russell W
Published: December 2022

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking. We identified the innate immune kinase TANK-binding kinase 1 (TBK1) as a candidate immune evasion gene in a pooled genetic screen. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNF𝛂/IFN𝛄). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumor models, with concordant findings in matched patient-derived organotypic tumor spheroids (PDOTS) and matched patient-derived organoids (PDOs). Tumor cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNF𝛂/IFN𝛄 in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.

Citation Format: Yi Sun, Or-yam Revach, Seth Anderson, Robert T. Manguso, Russell W Jenkins. Targeting TBK1 to overcome resistance to cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B28.
Abstract B40: Co-targeting autophagy, macrophages and vasculature in glioma tumors triggers tumor immunity
Authors: Chryplewicz Agnieszka , Scotton Julie , Tichet Mélanie , Hanahan Douglas
Published: December 2022

Glioblastoma (GBM) is the most common primary tumor arising in the central nervous system (CNS). The currently approved standard of care has transient clinical benefit as GBM tends to be exceedingly aggressive. Despite pronounced efforts to identify novel therapies, curative options for GBM do not exist, and the survival rate of diagnosed patients is very low. Therefore, there is an urgent need for new treatment strategies. One approach would be to co-target and thereby disrupt distinct hallmarks of cancer, aiming to elicit sustained therapeutic responses. We have assessed this concept by combining a tricyclic antidepressant -imipramine - with drugs targeting VEGF-A ligand or VEGF-Receptor in mice bearing de novo GBM. All monotherapies were ineffective. In notable contradistinction, we found that combinatorial regimens significantly increased survival benefit and regressed established tumors. Investigation of the basis for the therapeutic efficacy revealed that combining the VEGF pathway inhibitor with imipramine accentuated autophagy while modifying the angiogenic tumor vasculature to be more normal-like with induction of high endothelial venules. In addition, imipramine downregulated an M2-like phenotype of tumor-associated macrophages via histamine receptor and reprogramed them to express chemokines attracting otherwise rare CD8 T cells, which demonstrably contributed to the observed efficacy. As such, these hallmark co-targeting combinations reprogram the GBM microenvironment from immunosuppressive to pro-inflammatory, thereby rendering it immunogenic and sensitizing the tumors to immune checkpoint blockade, as evidenced by enhanced responses when an anti-PD-L1 therapy was included in the mix. The results to be presented will elaborate on a provocative new therapeutic approach for glioblastoma that has the prospect of motivating clinical evaluation in this daunting form of human cancer.

Citation Format: Agnieszka Chryplewicz, Julie Scotton, Mélanie Tichet, Douglas Hanahan. Co-targeting autophagy, macrophages and vasculature in glioma tumors triggers tumor immunity [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B40.
Abstract B46: Immune characterization of C57BL/6J syngeneic breast cancer mouse models for application in immunotherapy development
Authors: Magna Melinda , Lippman Marc E , Hudson Barry I
Published: December 2022

Background: Breast cancer is the second leading cause of cancer-related mortality in women worldwide. While immunotherapy has shown success in various solid tumors, it has been largely ineffective in breast cancer. Critical to establishing effective immunotherapies in breast cancer is the development and better characterization of the tumor immunology of immunocompetent syngeneic models. Here, we describe the molecular and in-depth immunological characterization of three C57BL/6J syngeneic breast cancer mouse models: AT3, Py8119 and E0771 cells. Methods: AT3, Py8119, and E0771 cells were obtained from commercial sources. 5x105 cells were implanted orthotopically in 8 weeks old C57BL/6J female mice. Tumors were isolated from mice and breast cancer subtype classification was performed by immunohistochemical (IHC) staining of estrogen receptor alpha (ERα), progesterone receptor (PR) and Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2/HER2). T cell and myeloid cell infiltration patterns of the tumors were determined by CD3 and CD11b IHC staining respectively. Immunophenotyping of splenic immune cell populations and tumor-infiltrating immune cells was performed with multicolor flow cytometry in all three models. Results: Based on the IHC analysis of the orthotopic murine tumors, E0771 and Py8119 tumors fit the histopathological criteria of triple-negative breast cancer models, while AT3 tumors appear to be a model of the HER2-enriched breast cancer subtype. We show significant differences between the AT3, Py8119 and E0771 models regarding the accumulation of myeloid cells (mMDSC, gMDSC, macrophages, dendritic cells) in the tumor and spleen. Furthermore, analysis of tumor-infiltrating CD4 and CD8 T lymphocytes showed high expression levels of PD-1 in all three models, and varying levels of expression of other immune checkpoint molecules (CTLA4, TIM3, LAG3 and PD-L1) that were model specific. Furthermore, flow cytometry analysis also revealed high levels of PD-L1 expression on all three tumor cell types. Conclusion: In summary, we determined the breast cancer molecular subtype, and described the splenic and intratumoral immune landscape of the AT3, Py8119 and E0771 orthotopic C57BL/6J syngeneic breast cancer mouse models. These data will aid the better design of future tumor immunological studies and provide essential knowledge about these preclinical breast cancer models for use in immunotherapy development.

Citation Format: Melinda Magna, Marc E Lippman, Barry I Hudson. Immune characterization of C57BL/6J syngeneic breast cancer mouse models for application in immunotherapy development [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr B46.
Abstract IA11: Immune selection and predictability of cancer evolution
Authors: Luksza Marta
Published: December 2022

Immune editing of neoantigens is crucial for the success of immunotherapies, but it is still unknown to what extent the immune system naturally edits evolving tumors and what is the fitness cost associated with the presence of neoantigens. Here we develop a biophysically grounded neoantigen quality model, which quantifies the immunogenicity of tumor neoantigens. We use the model to define the fitness of tumor clones as a combination of negative selection due to immune recognition and positive selection due to oncogenic mutations. We investigate how pancreatic cancers – a lowly mutated, poorly immunogenic cancer, largely presumed to not be subject to immunoediting – evolve over 10 years. Our patient cohort includes a set of long-term survivors, who are characterized by high levels of immune infiltration of their primary tumors. With the fitness model, we show that long-term survivors evolve new clones of markedly lower immune fitness cost, to indicate clones with high-quality neoantigens are negatively selected. Importantly, the fitness model predicts the clonal composition of recurrent tumors of the patients. Thus, we submit longitudinal evidence that the human immune system naturally edits neoantigens. Furthermore, we present a model that describes how tumor cell populations evolve under immune pressure over time, with implications for cancer biology and therapy.

Citation Format: Marta Luksza. Immune selection and predictability of cancer evolution [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr IA11.
In utero Treatment of Congenital High Airway Obstruction Syndrome via Fetal Laryngoscopy and EXIT Procedure
Authors: Sabra Rana , Gheorghe Ciprian P. , Monson Martha A. , Masri Jinnen , Chmait Ramen H.
Published: December 2022

Introduction: Congenital high airway obstruction syndrome (CHAOS) is a rare condition that can progress to fetal hydrops and demise in utero or at birth unless interventions are undertaken to alleviate the tracheal obstruction. While the ex-utero intrapartum treatment (EXIT) procedure for airway stabilization is technically feasible, abnormal pulmonary development as a result of the antenatal obstructive process may result in severe postnatal respiratory complications. Case Presentation: We describe a case of CHAOS with secondary hydrops treated in utero at 24 0/7 weeks’ gestation by fetoscopic tracheal decompression via laser perforation of the airway obstruction. Interval imaging after the fetoscopic operation demonstrated resolution of the fetal hydrops. Tracheostomy for airway stabilization was performed at the time of the EXIT procedure near term (36 0/7 weeks). The patient underwent tracheal reconstruction and decannulation at 3 years of life. Discussion/Conclusion: The primary goal of fetoscopic airway evaluation and intervention is not necessarily to perform definitive stabilization of the airway but rather to achieve sufficient decompression of the trachea to reverse fetal hydrops and salvage pulmonary development. In utero fetoscopic treatment may allow for prolongation of the pregnancy with delivery at or near term via EXIT procedure for definitive neonatal airway stabilization.
Shorter Version of the Brain Assessment Is Suitable for Longitudinal Public Cognitive Evaluations
Authors: Satoh Masayuki , Tabei Ken-ichi , Abe Makiko , Kamikawa Chiaki , Fujita Saiko , Ota Yoshinori
Published: December 2022

Introduction: We have developed an online cognitive test (Brain Assessment [BA]) which exhibits moderate correlations with established neuropsychological tests. We made a short version of the BA that requires only 10 min and investigated correlations with the original version. Participants and Methods: Three hundred and twenty-three subjects (26–82 years old, mean age 41.9 years) were recruited via the internet and performed the original version of the BA online, and, for the analyses of the original and short version, the results of the whole and of the first 2 min were utilized, respectively. Correlations were evaluated between both versions, and 144 subjects agreed to be interviewed about BA utilization. Results: Correlations between the short and original versions of the BA were strong (memory of numbers, r = 0.72: total, r = 0.73) or moderate (memory of words, r = 0.66; visuospatial, r = 0.42; working memory, r = 0.53; judgment, r = 0.54). We found a strong negative correlation between the “memory of words” subtest and age (short version, r = −0.85; original version, r = −0.88). Regarding the interview, most wanted to be assessed by the short version every year. In the case of a concerning score, they would then want to be examined by the original version of the BA and/or more specific neuropsychological tests. Discussion: We found that the short and the original versions of the BA exhibited strong correlations, and the correlation coefficients between age and subtest scores were almost the same between the two versions. Conclusion: The short version of the BA will be useful to perform cognitive assessments in the clinic.
Same Diagnosis but Different Story! A Tale of Two Primary Lymphomas of the Calvaria
Authors: Champeaux-Depond Charles , Bernat Anne-Laure , Polivka Marc
Published: December 2022

We present 2 cases of isolated tumour of the calvaria that underwent a different management but, unexpectedly, the same very rare diagnosis of primary diffuse large B-cell lymphoma of the cranial vault. Unfortunately, the outcome was the opposite due to numerous factors. We discuss herein the radiological diagnosis and surgical options in the light of the literature.
Subsequent Pregnancy Outcomes after Open in utero Spina Bifida Repair
Authors: Zepf Julia , Vonzun Ladina , Krähenmann Franziska , Strübing Nele , Moehrlen Ueli , Meuli Martin , Mazzone Luca , Moehrlen Theres , Ochsenbein-Kölble Nicole
Published: December 2022

Introduction: Fetal spina bifida (SB) repair is a distinct therapeutic option in selected cases. Since this procedure may not only be associated with short-term obstetrical complications, the aim of this study was to assess the outcomes of subsequent pregnancies after open fetal SB repair. Methods: 138 patients having had open fetal SB repair at our center received a questionnaire regarding the occurrence, course, and outcome of subsequent pregnancies. Additionally, medical records were reviewed. All subsequent pregnancies with complete outcome data that progressed beyond 20 gestational weeks (GW) were included for further analysis. Results: 70% of all women answered the questionnaire. Out of this cohort, 35 subsequent pregnancies were reported in 29% of women. The rate of early pregnancy loss including elective terminations was 14%. All 29 pregnancies processing >20 GW ended in live births without preterm births <34th GW. Mean gestational age at delivery was 37.3 ± 1.4 GW. Uterine rupture occurred in two cases (7%) and uterine thinning/dehiscence was present in six cases (21%). No maternal transfusions were required. Conclusion: When counseling women undergoing open fetal SB repair, one should consider possible risks for subsequent pregnancies, especially the one of uterine dehiscence and rupture that is similar compared to numbers reported after classical cesarean deliveries.
High On-Treatment Platelet Reactivity: Aspirin versus Clopidogrel
Authors: M’Pembele René , Ahlbrecht Samantha , Helten Carolin , Mourikis Philipp , Naguib David , Zako Saif , Trojovsky Kajetan , Huhn Ragnar , Petzold Tobias , Hohlfeld Thomas , Zeus Tobias , Kelm Malte , Dannenberg Lisa , Polzin Amin
Published: December 2022

Background: Antithrombotic regimen in patients on oral anticoagulation (OAC) post-percutaneous coronary intervention (PCI) is challenging. At least, one antiplatelet agent in combination with OAC is recommended after PCI for 6–12 months. Clopidogrel is used most frequently in this setting. However, data comparing P2Y12 inhibition with clopidogrel versus cyclooxygenase inhibition by acetylsalicylic acid (ASA, aspirin) is missing. It is well known that the antiplatelet effects of ASA and clopidogrel are frequently impaired (high on-treatment platelet reactivity [HTPR]). In this pilot investigation, we compared the antiplatelet effects of clopidogrel versus ASA. Methods: In this retrospective single-center database analysis, we investigated platelet reactivity by light transmission aggregometry in patients under different antiplatelet regimes. Results were presented as maximum of aggregation (MoA). HTPR to ASA and to clopidogrel were assessed. Results: 755 patients were enrolled. 677 were on ASA, 521 were on clopidogrel, and 198 had OAC. Overall mean age was 73 ± 13.4 years, and 458 (60.7%) were male. HTPR to ASA occurred in 94/677 patients (13.9%), and mean arachidonic acid-induced MoA was 14.15 ± 19.04%. HTPR to clopidogrel occurred in 241/521 patients (46.3%), and mean adenosine diphosphate-induced MoA was 50.06 ± 20.42%. HTPR to clopidogrel was significantly more frequent than HTPR to ASA; single antiplatelet therapy (SAPT)-mono ASA: 27/199 (13.6%) versus mono clopidogrel: 6/18 (33.3%); p = 0.037; SAPT with OAC-OAC with ASA: 8/35 (22.9%) versus OAC with clopidogrel: 27/60 (45%); p = 0.046. Same difference in HTPR contingency could be shown in subgroups of dual antiplatelet therapy and ASA + clopidogrel + OAC therapy. Conclusion: Impaired pharmacodynamic response to clopidogrel was more frequent as HTPR to ASA. Hence, ASA should be tested in combination with OAC post-PCI.
Análise cienciométrica da pesquisa sobre tracoma no Brasil, 2000–2020
Authors: Maciel Adjoane Maurício Silva , Ramos Júnior Alberto Novaes , Ferreira Anderson Fuentes , Almeida Nádia Maria Girão Saraiva de , Gomes Vivian da Silva , Gómez Daniela Vaz Ferreira , Pires Neto Roberto da Justa
Published: December 2022

OBJETIVO: Analisar o perfil cienciométrico das pesquisas sobre tracoma no Brasil. MÉTODOS: Pesquisa bibliográfica de publicações sobre tracoma no Brasil indexadas pela base de dados da Scopus, a partir de critérios específicos no período de 2000 a 2020. Foram extraídos e analisados dados sobre autoria, país de origem, instituições e descritores, com análises de tendências temporais. As redes bibliográficas foram construídas via software de visualização cienciométrica VOSviewer® 1.6.16. RESULTADOS: Do total de 42 publicações analisadas sobre tracoma no Brasil, observou-se média anual de dois artigos, com incremento de aproximadamente 50% no período. Verificou-se média de três autores por documento e os inquéritos escolares foram a categoria de assunto mais comum. Os artigos publicados provêm majoritariamente de instituições brasileiras (95,2%), principalmente das sediadas nas regiões Sudeste e Norte. Dez autores mais produtivos estão mencionados nas primeiras autorias em 26,2% (11/42) e as instituições predominantes estão afiliadas ao estado de São Paulo. O termo Trachoma (n = 18) apresenta maior recorrência como descritor. CONCLUSÃO: Esta primeira análise cienciométrica sobre tracoma no Brasil evidencia limitado número de pesquisas sobre essa doença. Há discreto incremento da produção científica, apesar da concentração da origem em áreas geográficas com menor endemicidade da doença. Maiores investimentos são necessários para o melhor entendimento e controle dessa doença tropical negligenciada. A análise da produção bibliográfica tem papel relevante para fortalecimento do desenvolvimento de pesquisas e planejamento estratégico de programas para o controle de tracoma e doenças tropicais negligenciadas em geral.
Tradução e adaptação transcultural da Composite Abuse Scale para o português brasileiro
Authors: Rocha Raiza Wallace Guimaraes da , Oliveira Daniel Canavese de , Liebel Vitor Adriano , Pallu Patricia Helena Rubens , Hegarty Kelsey Lee , Signorelli Marcos Claudio
Published: December 2022

OBJETIVO: Realizar a tradução e adaptação transcultural do inglês para o português brasileiro da Composite Abuse Scale, instrumento que identifica e quantifica a violência por parceiro íntimo. MÉTODOS: Este estudo baseia-se na execução rigorosa de seu protocolo, previamente publicado, e que consiste em dez etapas: (a) análise conceitual; (b) tradução duplo-cega; (c) comparação e primeira versão reconciliada das duas traduções; (d) retrotradução; (e) revisão da retrotradução feita pela desenvolvedora e segunda versão reconciliada; (f) revisão por comitê de especialistas (n = 6); (g) comparação das revisões por especialistas e terceira versão reconciliada; (h) entrevistas cognitivas com mulheres da Casa da Mulher Brasileira de Curitiba (n = 15); (i) avaliações das percepções das usuárias e reconciliação final; e (j) apresentação da versão final do questionário à desenvolvedora. RESULTADOS: A execução das 10 etapas do protocolo permitiu as equivalências idiomática, semântica, conceitual e experiencial da Composite Abuse Scale, incorporando sugestões e críticas dos diferentes participantes do processo, que incluíram desde a desenvolvedora, tradutores profissionais, pesquisadores especializados no tema, mulheres em situação de violência por parceiro íntimo e profissionais que as atendem. Especialistas e entrevistas cognitivas com mulheres foram fundamentais para garantir equivalências e facilitar a compreensão, incluindo: (1) adaptação do termo “relacionamento íntimo” para “relacionamento afetivo ou conjugal”; (2) substituição de ênclises por próclises em 20 itens; (3) adoção de linguagem de gênero neutro, permitindo sua utilização em relacionamentos hetero, bi e homoafetivos; (4) materialização de um instrumento de rigor científico e autoaplicável, que pode auxiliar as mulheres a visibilizarem as situações de abuso em seus relacionamentos. CONCLUSÕES: O processo de tradução e adaptação transcultural da Composite Abuse Scale resultou na Composite Abuse Scale Versão Português brasileiro, instrumento autoaplicável com 30 itens, capaz de identificar e quantificar a violência por parceiro íntimo, sua frequência, severidade e tipologias (violências física, emocional, assédio e grave combinada).
Buddhist Homiletics on Gambling (*Saddharmaparikathā, Ch. 12)
Authors: Szántó Péter-Dániel
Published: December 2022

The paper focuses on the 12th chapter of the *Saddharmaparikathā, a Buddhist homileticians’ guidebook containing sample sermons, dealing with the topic of gambling (dyūta). I edit, translate, and discuss the chapter with an introduction that includes a short overview of gambling in Sanskrit literature at large. The anonymous author is dismissive of gambling in all its forms, whether it is practised for material gain, for mere pleasure, and even if studied as an art. In spite of its exiguity, his discussion of the topic is, as far as we are aware, the most comprehensive in classical Buddhist literature.
Interaction between marine protists and bacteria results in magnetotaxis and iron recycling
Authors: Mandal Fatik Baran
Published: December 2022

Marine protists are eukaryotic trophic linkers that play a crucial role in iron recycling. Some marine protists have the ability of magnetotaxis, which they gain by consuming their ectosymbiotic bacteria. They graze and internalize the magnetotactic bacteria along with their magnetosome chains. Through egestion, marine protists avoid iron toxicity. Colloidal iron digestion by protists produces bioavailable iron for other marine organisms, passing to phytoplankton and mesozooplankton through the mesotrophic system. Indeed, ectosymbiotic bacteria and their protistan host form a microbial holobiont acting as an ecological unit. Some of the genetic mechanisms influencing the biosynthesis of magnetite in both prokaryotes and eukaryotes appear to be common. The recorded history of the magnetoreception ability of some marine protists goes back to the study by F.F. Torres de Araujo in 1986. After research over 35 years or more, it is safe to record that magnetotaxis in marine protists is yet to be fully understood, and might be similar to that of free-living magnetotactic bacteria. However, the attainment of magnetotaxis by protistan grazers through bacterivory and its role in iron recycling in the marine ecosystem is very interesting. The present article aims to provide an account of such interesting facts.
Creatio ex Creatione a Natura Amoris
Authors: Orr Brian J.
Published: December 2022

Creatio ex nihilo is the dominant creation theory in the Christian tradition. Relational theologian Thomas Jay Oord proposes an alternative creation theory, in which God everlastingly creates from what he previously created. Key reasons why Oord argues creatio ex nihilo should be rejected are that it has Gnostic roots, is not explicitly taught in Scripture, and is illogical. This article critically assesses Oord’s arguments against creatio ex nihilo, contending that his conclusions are misguided due to a Biblicist tendency in his reading of the text and the inaccurate definition of creatio ex nihilo he argues against. With the biblical and historical data, a definition of creatio ex nihilo representative of the Christian tradition is articulated. This essay then demonstrates how creatio ex nihilo is superior to Oord’s alternative theory.
Monte Carlo Simulations for Evaluating the Accuracy of Geostationary Lightning Mapper Detection Efficiency and False Alarm Rate Retrievals
Authors: Virts Katrina S. , Koshak William J.
Published: December 2022

Performance assessments of the Geostationary Lightning Mapper (GLM) are conducted via comparisons with independent observations from both satellite-based sensors and ground-based lightning detection (reference) networks. A key limitation of this evaluation is that the performance of the reference networks is both imperfect and imperfectly known, such that the true performance of GLM can only be estimated. Key GLM performance metrics such as detection efficiency (DE) and false alarm rate (FAR) retrieved through comparison with reference networks are affected by those networks’ own DE, FAR, and spatiotemporal accuracy, as well as the flash matching criteria applied in the analysis. This study presents a Monte Carlo simulation–based inversion technique that is used to quantify how accurately the reference networks can assess GLM performance, as well as suggest the optimal matching criteria for estimating GLM performance. This is accomplished by running simulations that clarify the specific effect of reference network quality (i.e., DE, FAR, spatiotemporal accuracy, and the geographical patterns of these attributes) on the retrieved GLM performance metrics. Baseline reference network statistics are derived from the Earth Networks Global Lightning Network (ENGLN) and the Global Lightning Dataset (GLD360). Geographic simulations indicate that the retrieved GLM DE is underestimated, with absolute errors ranging from 11% to 32%, while the retrieved GLM FAR is overestimated, with absolute errors of approximately 16% to 44%. GLM performance is most severely underestimated in the South Pacific. These results help quantify and bound the actual performance of GLM and the attendant uncertainties when comparing GLM to imperfect reference networks.
Mental Health Screening in Pediatric Primary Care: Factors Associated With Screening Completion and Elevated Scores
Authors: Habayeb Serene , Onofaro Kayla C. , Hawila Nour , Druskin Lindsay R. , Godoy Leandra , Long Melissa
Published: December 2022

This study aimed to examine predictors of complete and elevated youth mental health screens. Parents of 4- to 11-year-old children completed the Strengths and Difficulties Questionnaire (SDQ) during a routine, universal mental health screening initiative in primary care. Bivariate logistic regressions were run to examine associations between independent (visit age, sex, race/ethnicity, language, insurance, and guardian) and dependent variables (screening completion and elevated SDQ score). Parents of younger and Spanish-speaking (vs English-speaking) children were less likely to have a complete SDQ screen. Among those with complete SDQ screens, older children, male children, those with public or no insurance, and those who had a mother (vs father) complete the screener were more likely to have an elevated score. Understanding patterns of screening completion rates and predictors of elevated screens provides valuable information to improve resource mapping and planning. Findings can inform mental health screening implementation and optimization within primary care.
Recommendations to improve use and reporting of statistics in animal experiments
Authors: Rowe Anthony
Published: December 2022

Flaws in experimental statistics are a major contributor to the poor reproducibility of animal experiments. Informed decisions about whether conclusions are justified requires clear reporting of experimental data and the statistical methods used to analyse them. When data are misinterpreted, manipulated or concealed to generate publications, it creates an illusion that chance observations are robust data which confirm the hypotheses presented. Attempts to reproduce and advance such observations can propagate large areas of irreproducible science. This hinders scientific progress, erodes public support for research, damages reputations and wastes resources. This review analyses and explains recommendations to improve use and reporting of statistics in animal experiments.
The Effects of Listening to Non-preferred or Self-Selected Music during Short-Term Maximal Exercise at Varied Times of Day
Authors: Bentouati Emna , Romdhani Mohamed , Khemila Syrine , Chtourou Hamdi , Souissi Nizar
Published: December 2022

In this investigation, we examined the effects of listening to non-preferred (neutral) or self-selected motivational music while warming-up for the Wingate test at varied times of day. Participants were 10 male physical education students who were randomly assigned in a counterbalanced order to perform the Wingate test after a 10-minute warm-up with (a) self-selected motivational music (WUMM), (b) non-preferred music (WUNPM) or (c) no music (WUWM) at morning (0700) or afternoon (1700) times of day. We measured their peak powers (PP) and mean powers (MP) during the Wingate test, and we measured their ratings of perceived exertion (RPE) immediately after each of the warm-up and Wingate performances. PP and MP were higher in the afternoon, compared to the morning for all conditions. Both WUNPM and WUMM conditions were associated with enhanced PP in the morning (WUNPM: p < 0.001, d = 1.82; WUMM: p < 0.001, d = 2.59) and in the afternoon (WUNPM: p < 0.001, d = 1.24; WUMM: p < 0.01, d = 1.76) compared to WUWM, with greater enhancements after WUMM (0700: p < 0.05, d = 0.77; 1700: p < 0.05, d = 0.81) than after WUNPM. After the Wingate test, participants reported lower RPE scores for the WUMM condition, compared to either the WUWM condition (0700: p < 0.001, d = 0.20; 1700: p < 0.001, d = 0.84) or the WUNPM condition (0700: p < 0.01, d = 0.10; 1700: p < 0.05, d = 0.79). Thus, a warm-up with self-selected motivational music improved muscle power and decreased perceived exertion at both time points, with greater improvements at the morning hour (0700).
The police journal Restorative Justice in roads policing
Authors: Lavanchy Andrew
Published: December 2022

With advocates for Restorative Justice arguing that punitive punishments through prosecution alone do little to prevent offending, it must be examined why restorative practices are not more frequently used to tackle road-related harm. In Roads Policing, the victim rarely has an opportunity to take part in the rehabilitation of an offender for their specific offence. Educational courses currently exist for offenders that cause low-level harm (or potential harm) on the roads, yet there appears to be no voice for the specific victim; instead, they must rely on an offender being deterred from future offending by general education or enforcement.
Stress distribution of the nonwoven fabric package during winding
Authors: Xia Tengteng , Li Yong , Li Jian , Li Lei , Chen Xiaochuan
Published: December 2022

During winding, the defects of wrinkles and buckling are prone to occur in the material package. This problem increases in larger packaging sizes, and it is related to the uneven distribution of internal stress. In order to study the internal stress distribution law of the wound package, it is necessary to analyze and discuss the mechanical behavior of the winding process. In this paper, a winding model based on thick-cylinder theory was established to deduce the internal stress distribution and change law of the wound package. Polypropylene melt-blown nonwoven fabric was used as the test material; it showed no deformation residue after the stretching test, which was the allowable stretching conditions of the nonwoven fabric from the low-strain stretching experiment. Based on the material mechanical properties, three tension control strategies (namely constant tension, constant torque, and taper tension winding) of the winding tension were analyzed and the variation law of winding stress was described. The internal stress of the ideal packaging was premised, which was determined as the winding tension control curve under even internal tension and can be called equal internal tension winding. The results showed that the properties of materials have a significant impact on packaging quality, and equal internal tension winding can effectively improve packaging quality and size. The research results can provide some reference for tension control in the winding process of nonwoven fabric or other textile materials.
Expanding anticipatory governance to legislatures: The emergence and global diffusion of legislature-based future institutions
Authors: Koskimaa Vesa , Raunio Tapio
Published: December 2022

Global challenges from climate change to the COVID-19 pandemic have raised legitimate questions about the ability of democratic decision-makers to prepare for such crises. Gradually, countries throughout the world have established state-level foresight mechanisms. Most operate under the executive branch, but increasingly such institutions have started to emerge also in legislatures, expanding anticipatory governance towards democratic publics. Drawing on a global survey, official documents and expert interviews, this article presents the first comprehensive analysis of the emergence and diffusion of legislature-based future institutions. We show that, despite the early emergence of a pacesetting institution, such committees have spread slowly and only very recently, and they still exist in only a few countries. For diffusion, the findings highlight the importance of the pacesetter, semi-formal networks of like-minded individuals and personalized agency. Most especially, the role of Members of Parliament (MPs) seems crucial, suggesting that expanding anticipatory governance to legislatures is largely in the hand of legislators.