bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 6340: Preclinical development of a monoclonal antibody targeting CD24 as cancer immunotherapy
Authors: Tian Wenzhi , Li Song , Chen Dianze , Liu Dandan , Guo Huiqin , Yang Chunmei , Zhang Li , Zhang Wei , Tu Xiaoping , Peng Liang , Zhao Gui , Zhang Ruliang , Zhang Fan , Gan Frank X.
Published: June 2023

CD24 is a novel immune checkpoint that suppresses activation of macrophages, natural killer (NK) cells, T cells and B cells by binding to inhibitory receptor Siglec-10. CD24 is highly expressed on cancers of genitourinary (GU) and gastrointestinal (GI) systems, breast, and lung. High expression of CD24 is also known to be associated with poor prognosis for many types of cancers including breast, lung, GU and GI systems, bone, skin and brain. Mouse models of breast and lung cancer in literature revealed that CD24 attenuation in vivo leads to tumor inhibition and prolonged survival. To address the limited (~25%) overall response rate (ORR) of approved PD-1/PD-L1 antibodies for solid tumors, we developed IMM47, an IgG1 antibody that differentially targets phagocytosis and cytotoxicity onto CD24-expressing cancer cells. At doses between 3 mg/kg to 10mg/kg, IMM47 significantly reduced tumor volume in a MC38 mouse model of colon cancer. Mice treated with 10mg/kg IMM47 produced tumor-specific immune response that prevented growth of re-inoculation of colon cancer cells. Further mechanism of action studies showed that IMM47 selectively and differentially increased M1 spleen macrophages quantity to 7-10 folds higher in that induced by PBS control. In contrast, IMM47 only increased M2 spleen macrophages to less than 1.5 folds higher than induced by PBS control. Expression of MHC II in M1 macrophages was also increased in IMM47-treated mice, suggesting significant activation and antigen presentation by macrophages. Our data has also confirmed that IMM47 specifically binds to and induces ADCC (antibody-dependent cellular cytotoxicity),ADCP (antibody-dependent cellular phagocytosis), and CDC (complement-dependent cytotoxicity) against a variety of cancer cells. Taken together, our data show that targeting CD24 on tumor cells using our IMM47 antibody may serve as potent immunotherapy for multiple cancer indications.

Citation Format: Wenzhi Tian, Song Li, Dianze Chen, Dandan Liu, Huiqin Guo, Chunmei Yang, Li Zhang, Wei Zhang, Xiaoping Tu, Liang Peng, Gui Zhao, Ruliang Zhang, Fan Zhang, Frank X. Gan. Preclinical development of a monoclonal antibody targeting CD24 as cancer immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6340.
Abstract 6344: Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines
Authors: Dogbey Dennis Makafui , Masuku Sizalobuhle , Barth Stefan
Published: June 2023

Introduction: The high prevalence of cervical cancer remains a global challenge particularly in developing countries where its therapy is principally by chemoradiation marked by severe toxicities. Antibody-based therapy targeting specific overexpressed surface antigen has proven as a promising strategy. Tumor-associated calcium signal transducer 2 (Trop2), also known as epithelial glycoprotein-1 antigen, is a membrane protein found in epithelial tissues involved in cellular signalling, migration, proliferation, and differentiation in normal cells. Its overexpression is validated in several tumor types including basal, squamous and adenocarcinomas of the cervix, breast, colon, and gastrointestinal tracts. Due to its differential overexpression, Trop2 is a viable therapeutic marker whereby a recombinant immunotoxin composed of a single chain variable antibody fragment (scFv) armed with Pseudomonas exotoxin A (Anti-Trop2-ETA) may be delivered for targeted killing of such tumors.

Methods: Plasmids encoding Anti-Trop2-ETA were designed in silico by fusion of anti-Trop2 single chain variable fragment (scFv) antibody to the N-terminus of Pseudomonas exotoxin A and then cloned into an pMT backbone. Expression was performed in BL21 E. Coli cells under osmotic stress and then Anti-Trop2-ETA was purified by IMAC via an N-terminus encoded polyhistidine tag. Purified fractions were structurally characterized by SDS PAGE gel and immunoblotting to confirm the presence of the Anti-Trop2-ETA protein to be used for treatment of tumor cell lines. Trop2 expression cervical cancer and breast tumor cell lines were confirmed, and cells were treated with Anti-Trop2-ETA.

Results: Dose dependent killing by Anti-Trop2-ETA was observed in the Trop2 expressing tumor cell lines. IC50 values were significantly lower for Trop2 expressing cells as compared to control cells lacking Trop2 expression.

Conclusion: Here, we demonstrated antigen specific killing of Trop2 overexpressing tumor cells in vitro. Targeted deployment of recombinant immunotoxin to specifically engage and kill Trop2 positive cells is a potential approach for cancer therapeutics. As such, the ability of the rIT to specifically target and kill Trop2 expressing tumors is an important initial finding towards the possibility of antigen-dependent elimination of Trop2 expressing cancer cells. Ongoing evaluations are aimed at antigen dependent biological activity as well as pharmacokinetics of the rIT in tumor bearing in vivo models.

Citation Format: Dennis Makafui Dogbey, Sizalobuhle Masuku, Stefan Barth. Recombinant Immunotoxin exhibited targeted killing of Trop2 overexpressing tumour cells lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6344.
Abstract 6346: Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy
Authors: Ke Hang , Zhang Faming , Li Jialin , Peng Feiyu , Chen Cen , Li Henry Qixiang
Published: June 2023

OX40, tumor necrosis factor receptor superfamily member 4, is an immune co-stimulatory receptor, together with its ligand OX40L, forming OX40-OX40L trimer-trimer complex between the surface of T-cells (OX40) and APCs/NKs (OX40L). OX40 expresses constitutively on Treg as well as on conventional Teff, particularly within TME. OX40/OX40L interactions directly triggers conventional T cell activation via NF-kB1 pathway and inhibits bcl-x and survivin to prevent apoptosis; and it also downregulates FoxP3/CTLA4, thus Treg function. OX40 agonistic antibodies have also been shown to activate tumor immunity and increase anti-tumor activity in preclinical models. Here we report that we identified/constructed a novel OX40-agonistic humanized IgG1 monoclonal antibody (mAb), HX011, with high affinity through hybridoma technology. HX011 was subsequently confirmed of the similar binding properties and functions as the original mouse mAb clone, 9C12: 1) binding to human OX40 (EC50 ~0.012 nM; 2) similar function binding in the reporter assay (EC50 ~6.6 nM); but 3) has little blockade of the OX40L binding to OX40. In another word, HX011 is similar to BMS-986178 for the first two assays, but contrastingly different for the third assay. Non-competing with OX40L may actually maximize T-cell activation, a potential advantage over a competing antibody. In vivo pharmacology modeling of HX011 in the humanized syngeneic CRC model, MC38, where syngeneic C57BL/6 mouse mice were knocked in with huOX40 (“HuGEMM-OX40”), demonstrated strong anti-tumor activity (TGI ~100% at 1 mg/kg, twice weekly). HX011 is being further investigated as a potential new immunotherapy for the treatment of cancers.

Citation Format: Hang Ke, Faming Zhang, Jialin Li, Feiyu Peng, Cen Chen, Henry Qixiang Li. Discovery of HX011, a novel OX40 mAb, for potential cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6346.
Abstract 6348: ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer
Authors: Park Heegeon , Lee Saehyung , Park Hayeon , Hong Sunghyun , Kim Jaemun , Hong Sungyoul , Park Ji-hyun , Shin Young Kee , Choi Jun Young , Kim Na Young
Published: June 2023

ABN202 is an antibody-cytokine fusion protein consisting of interferon-β mutein (ABN102) molecularly fused to a anti-EGFR monoclonal antibody that recognizes the EGFR expressed on various types of cancer cells. In previous studies, we developed ABN102, a bio-better version of recombinant human interferon-β with hyperglycosylation via site-directed mutagenesis to improve stability, productivity, and pharmacokinetics properties. An addition of glycosylation at the N25 residue of ABN102 is expected to reduce the peripheral toxicity of ABN202, as it can shield the IFNAR2 binding interface. In this study, the binding ability and biological activity of ABN202 was evaluated in vitro models. ABN202 downregulates the EGFR protein expression and reduces EGFR phosphorylation by degrading target proteins via internalization in the EGFR-positive NSCLC cell line. In addition, we also determined the direct and indirect anti-cancer activity of ABN202 in preclinical models. Taken together, we suggest that ABN202 has potent anti-cancer activities, via direct cytotoxicity in EGFR-positive tumors and indirectly activating immune cells through Type I IFN signaling. we conclude ABN202 is a promising drug candidate for patients with EGFR-positive NSCLC.

Citation Format: Heegeon Park, Saehyung Lee, Hayeon Park, Sunghyun Hong, Jaemun Kim, Sungyoul Hong, Ji-hyun Park, Young Kee Shin, Jun Young Choi, Na Young Kim. ABN202 (αEGFR-interferon-β mutein), a potent antibody-cytokine fusion protein for the treatment of EGFR-positive non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6348.
Abstract 6366: NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity
Authors: Zhang Yu , Dong Jinyu , Wang Binbin , Ni Jie , Wang Dong , Shao Liegang , Xiong Meiguang , Wang Ting , McAllister Florencia , Dong Xin
Published: June 2023

Antibody-based Immune checkpoint inhibitor (ICI) therapies targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) or programmed death receptor-1 (PD-1) have significantly improved clinical outcomes in cancer treatment. Nonetheless, a large portion of the population has limited benefit from these ICI treatments due to lack of efficacy, resistance and intolerance. T-cell immunoglobulin and mucin domain containing-3 (TIM-3) has been proposed as a target for cancer immunotherapy. It is an inhibitory receptor modulating immune tolerance, and its expression has been broadly reported to be closely correlated to T cell exhaustion and pessimistic prognosis. Besides negatively modulating T cell status, TIM-3 is also expressed on natural killer (NK) cells, dendritic cells (DCs), macrophages and regulates immune responses bridging innate immunity and adaptive immunity. NB002 is a novel humanized Fc-engineered IgG1κ antibody, developed via NeologicsBio’s integrated target validation & antibody screening Tier-A platform. It has been characterized in a serial of function and efficacy studies and completed IND-enabling preclinical development. NB002 binds to human TIM3 with high affinity in the low nanomolar range and antagonize the TIM-3 pathway effectively in reporter cell and primary cell assays. NB002 increased the secretion of IFN-γ by activated PBMC cells and enhanced activation and killing activity of NK cells. Moreover, it exhibited a distinctive activity of restoring myeloid cells and enhancing antigen presentation and processing during anti-tumor immune responses, and superior efficacy in multiple humanized mouse models of cancer as monotherapy regimen. Importantly, X-ray crystallography demonstrated that NB002 recognized a unique epitope on TIM-3 and was confirmed by epitope binning assay and structural alignment. These data could potentially explain novel features of NB002, restoring both acquired and innate immunity which could lead cold tumor to hot tumor.In summary, these data showed that NB002 is a potent anti-TIM-3 antibody with pre-clinical properties. A phase 1 study is planned and patients with advanced metastatic solid tumors will be recruited.

Citation Format: Yu Zhang, Jinyu Dong, Binbin Wang, Jie Ni, Dong Wang, Liegang Shao, Meiguang Xiong, Ting Wang, Florencia McAllister, Xin Dong. NB002, a novel therapeutic antibody targeting unique epitope on TIM-3 presenting potent antitumor activity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6366.
Abstract 6368: Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced tumors
Authors: Zhu Bing , Dai Tongcheng , Liu Ruifeng , Suarez Alfonso , Liban Tyler , Zhang Bin , Karow Margaret , Sheng Jackie , Sheng Zelin , Lv Binhua
Published: June 2023

ZG005 is a humanized anti-PD-1/TIGIT bispecific antibody that effectively blocks the binding between PD-1 and TIGIT, on immune cells, with their specific ligands PD-L1 and PVR, on tumors. As a dual blockade of PD-1/TIGIT immune checkpoints, ZG005 exhibits sustained occupancy to both targets and inhibits their pathways specifically and simultaneously, leading to synergistic effects and boosting the ability of the immune system in killing tumor cells. With high binding affinities, ZG005 elicits the activation of T cells and NK cells resulting in increased release of cytokines and the depletion of Tregs, independent of ADCC activities. ZG005 utilizes the IgG4 isotype to avoid the potential negative impact of effector function and target-crosslinking that has been reported for anti-TIGIT therapeutics using IgG1 isotype. In vivo animal studies indicate that ZG005 has potent and dose-dependent anti-tumor efficacies in syngeneic models using CT26 and MC38 colon tumors in humanized PD-1/TIGIT dKIs mice. In these models, the whole blood and TIL analyses confirmed increases in CD8+ and NK cells but reduction of Treg cell levels after ZG005 treatments. The combination of ZG005 with chemotherapeutic-reagents, cisplatin and donafenib, enhanced their anti-tumor efficacies. Toxicity and safety pharmacology studies with weekly repeat doses for four weeks in cynomolgus monkeys, indicate that ZG005 is well tolerated. Over the dose range 20-180 mg/kg, there were no obvious toxic or adverse effects, and the HNSTD and NOAEL values were 180 mg/kg and 60 mg/kg, respectively. PK/TK analyses indicate a prolonged ZG005 receptor occupancy over 80%, consistent with in vitro binding results that are attribute to the S228P mutation in the IgG4 hinge region to prevent Fab exchange and enhance stability. The IND application of ZG005 has been approved by both FDA and NMPA, and the molecule is currently in phase I clinical trials for advanced solid tumors at escalated dosing of 0.3~20 mg/kg, Q3W, via i.v. administration.

Citation Format: Bing Zhu, Tongcheng Dai, Ruifeng Liu, Alfonso Suarez, Tyler Liban, Bin Zhang, Margaret Karow, Jackie Sheng, Zelin Sheng, Binhua Lv. Preclinical pharmacology and safety studies of ZG005: an anti-PD-1/TIGIT bispecific mAb in a phase I clinical trial for advanced tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6368.
Abstract 6431: Targeting Rab7-mediated STING degradation to amplify therapeutic STING agonism in TNBC
Authors: Zhang Yuqing , Ritter Jessica L. , Thai Tran C. , Dillon Deborah A. , Barbie David A. , Barbie Thanh U.
Published: June 2023

STING (Stimulator of interferon genes), encoded by TMEM173, is a critical regulator of the innate immune response to cytoplasmic double stranded DNA in cancer and is actively being pursued as a target for cancer immunotherapy. STING agonist analogues of 2’-3’cGAMP, the cyclic dinucleotide that directly activates STING downstream of cyclic-GAMP synthase, have entered phase 1 clinical trials for triple negative breast cancers (TNBC). Recently, we have identified tumor cell Phosphatase and tensin homolog (PTEN) inactivation as a precision-based context in which to apply STING agonists. Mechanistically, PTEN null TNBCs maintain Ras-related protein Rab-7a (Rab7) in an inactive state and therefore trafficking of STING to the lysosome is impaired and cells are rendered hypersensitive to STING agonism. Tissue microarray analysis reveals high STING expression in PTEN null TNBCs. Consistently, PTEN null TNBC cell lines were hyper-responsive to STING agonists with increased downstream production of IRF3 targets including CXCL10. In contrast, PTEN wild-type cells exhibit low STING expression and modest sensitivity to STING agonism. As such, although a significant proportion of TNBCs are PTEN null, we sought to broaden these findings to PTEN wild-type TNBCs by genetically and pharmacologically mimicking the PTEN null state by Rab7 knockout and use of a novel selective Rab7 inhibitor, CID1067700. Indeed, using the PTEN wild-type TNBC cell line, MDA-MB-231, we found that PTEN deletion robustly increased STING protein expression. Rab7 CRISPR-Cas9 knockout or treatment of MDA-MB-231 cells with CID1067700 and the STING agonist (ADU-S100) impaired trafficking of STING for lysosomal degradation, upregulated T cell chemokines, and enhanced growth inhibition. Next, to model the potential in vivo implications for immune cell recruitment and function, we used a 3D microfluidic T-cell migration assay. We found that the enhanced CXCL10 levels resulting from addition of CID1067700 to MDA-MB-231 cells led to T-cell recruitment to the tumor spheroids. Taken together, our study identifies PTEN null status as a specific genomic context in TNBC that has exquisite sensitivity to STING agonist therapy and combination with Rab7 inhibition could amplify therapeutic STING agonism in PTEN wild-type TNBCs.

Citation Format: Yuqing Zhang, Jessica L. Ritter, Tran C. Thai, Deborah A. Dillon, David A. Barbie, Thanh U. Barbie. Targeting Rab7-mediated STING degradation to amplify therapeutic STING agonism in TNBC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6431.
Abstract 6440: Targeting TCTP reverses the multi-malignant phenotypes of immune-refractory tumor cells
Authors: Lee Hyo-Jung , Kim Tae Woo
Published: June 2023

Cancer immunotherapy, particularly T cell-mediated therapy such as immune checkpoint blockade (ICB) and adoptive T cell transfer (ACT), has emerged as a potentially powerful approach to cancer treatment. However, immunotherapeutic resistance limits its clinical success by disrupting one or more steps of the cancer immunity cycle. In addition, multi-malignant phenotypes of immune-refractory tumor cells are also one of the major causes result poor prognosis of patients. Therefore, identifying the immune-resistance and multi-malignant factor, which not only can be targeted by clinically available medicines it can also be a prognostic marker, is needed ideally. Here, we identified TCTP as a novel factor conferring multi-malignant phenotypes of immune-refractory tumor cells. We discovered a crucial role of TCTP at the crossroads between multi-malignant tumor cells and the anti-cancer immunity system by demonstrating that TCTPhigh tumor cells enriched by immune selection pressure drive immune-refractory phenotypes. Importantly, the levels of TCTP within the tumors significantly correlated with the clinical outcome of anti-PD-L1 therapy, which demonstrate TCTP as a prognostic marker in the case of clinical trials. Furthermore, targeting TCTP by clinical available drug enhanced the response to T cell-mediated therapy including ICB and ACT. Thus, our findings emphasize that TCTP could be a both a valid target a prognostic marker providing a framework for patient selection to apply combined therapy of T cell-mediated therapy with TCTP-targeting agents.

Citation Format: Hyo-Jung Lee, Tae Woo Kim. Targeting TCTP reverses the multi-malignant phenotypes of immune-refractory tumor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6440.
Abstract 6459: Developed and persistent dyslipidemia is associated with increased risk of gastric cancer in a prospective study
Authors: Huang Dan , Shin Woo-Kyoung , la Torre Katherine De , Min Sukhong , Shin Aesun , Lee Jong-Koo , Kim Hyung-Ho , Kang Daehee
Published: June 2023

Background: Increasing evidence suggests that metabolic disorders are a risk factor for gastric cancer. However, there is a lack of evidence on whether changes and persistence of metabolic disorders affect the subsequent gastric cancer occurrence. Therefore, this study aimed to evaluate the effects of changes or persistence in metabolic syndrome and its components' status on the incidence of gastric cancer among Korean population.

Methods: This study comprised 59,671 individuals from the Health Examinees Study who had baseline surveys from 2004 to 2012 and repeated measurements from 2012 to 2016; and were followed up until 2018. Metabolic syndrome and its components were defined according to the National Cholesterol Education Program Adult Treatment Panel III and modified based on Korean population criteria. Participants were categorized into free, developed, recovered, and persistent metabolic syndrome and its components. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for gastric cancer incidence using multivariable cox proportional hazard models with age as a time scale.

Results: During the mean follow-up of 9.4 years, 312 subjects were newly diagnosed with gastric cancer. Compared with the metabolic syndrome-free group, the persistent group had a higher incidence of gastric cancer (HR 1.37, 95% CI 1.02-1.84). Among individual components, the developed-high triglycerides group had the highest gastric cancer incidence (HR 1.52, 95% CI 1.12-2.05), followed by the persistent group (HR 1.40, 95% CI 1.04-1.90) compared to the free group. The low HDL-cholesterol persistent group (HR 1.45, 95% CI 1.08-1.93) showed a higher incidence than in the free group. In the subgroup analysis, we found association between high triglycerides developed and gastric cancer in men, while for women, the associations were significant between high triglycerides and low HDL-cholesterol persistent groups and gastric cancer incidence.

Conclusions: In this prospective cohort study, we found that developed or persistent dyslipidemia, assessed as abnormal triglycerides and low HDL-cholesterol, were associated with an increased incidence of gastric cancer. These findings suggest that effective management of dyslipidemia may reduce gastric cancer risk.

Keywords: Gastric cancer, Dyslipidemia, Metabolic syndrome, Prospective cohort

Citation Format: Dan Huang, Woo-Kyoung Shin, Katherine De la Torre, Sukhong Min, Aesun Shin, Jong-Koo Lee, Hyung-Ho Kim, Daehee Kang. Developed and persistent dyslipidemia is associated with increased risk of gastric cancer in a prospective study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6459.
Abstract 663: Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells
Authors: Hamaidia Malik , Jamakhani Majeed , Jacques Jean-Rock , Fontaine Alexis , Scherpereel Arnaud , Wasielewski Eric , Renaud Louis , Heinen Vincent , Duysinx Bernard , Willems Luc
Published: June 2023

Tumor-associated macrophages (TAM) are particularly abundant (i.e. 27% ± 9%) in the microenvironment of malignant pleural mesothelioma (MPM). These macrophages do not correspond to classical (M1) and alternatively-activated (M2) phenotypes but, instead, are shaped by local inflammatory mediators released in the pleura. We previously showed that, besides classical functions exerted by macrophages (i.e. phagocytosis, cytokine expression and antigen presentation), murine RAW264.7 cells are directly cytotoxic to MPM tumors (Hamaidia et al, JCI Insight 4:e128474). Upon direct cell-to-cell contact, RAW264.7 macrophages kill mesothelioma cells by a mechanism of oxeiptosis involving the enhancer of zeste homolog 2 (EZH2) methyltransferase. We have now investigated this immune-editing activity in human mesothelioma. We show that M1-activated primary macrophages are more cytotoxic for M14K cells than M2. The killing activity of M1 macrophages is dependent on NADPH oxidase activity and peroxynitrite levels. Mesothelioma cells and M2 macrophages interact through an inhibitory synapse characterized by engagement of the PD-1 receptor. Consistently, the immune-editing activity of M2 macrophages is partially restored in presence of neutralizing anti-PD1 antibody. Primary human macrophages cultured in presence of pleural effusions of MPM patients are less cytotoxic than M1 and are unable to inhibit tumor growth in mice. Macrophages differentiated in pleural effusions display a broad spectrum of cytotoxic activities (i.e. from complete inactivity to rates similar to those of M2). Luminex profiling of pleural fluids has identified a series of key mediators associated with the cytotoxic phenotype. The best correlation is obtained with resistin (RETN, FIZZ3, ADSF). Recombinant human resistin improves the killing activity of pleural effusion macrophages in cell culture. Gene transduction of RETN in RAW264.7 impairs growth of AB12 tumors in BALB/c mice. In conclusion, we have shown that resistin is the main factor that mediates immunoediting activity exerted by primary human macrophages towards mesothelioma cells, opening new prospects for therapeutic intervention.

Citation Format: Malik Hamaidia, Majeed Jamakhani, Jean-Rock Jacques, Alexis Fontaine, Arnaud Scherpereel, Eric Wasielewski, Louis Renaud, Vincent Heinen, Bernard Duysinx, Luc Willems. Resistin mediates the immunoediting activity exerted by primary human macrophages towards mesothelioma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 663.
EFEKTIVITAS STATIN TERHADAP PENCEGAHAN AWITAN DAN PROGRESI AGE RELATED MACULAR DEGENERATION: SEBUAH TINJAUAN SISTEMATIS
Authors: Santosa Rizki Adi , Yuna Uray Nabila , Virgana Rova
Published: June 2023

Pendahuluan : Age Related Macular Degeneration (AMD) merupakan salah satu penyebab gangguan penglihatan yang hingga saat ini belum memiliki terapi definitif. Golongan statin memiliki efek pleiotropi yang diduga berpotensi sebagai salah satu terapi untuk AMD. Studi ini berupa tinjauan sistematis yang bertujuan untuk menilai efektivitas pemberian statin terhadap pencegahan awitan dan progresi AMD. Metode : Dilakukan pencarian artikel yang terbit antara bulan Januari 2011 hingga Desember 2020 pada beberapa database; PubMed, CENTRAL, sciencedirect, Latin American and Caribbean Health Sciences Literature Database (LILACS), metaRegister of Controlled Trials (mRCT), WHO International Clinical Trials Registry Platform (ICTRP) dan clinicaltrials.gov. Kata kunci yang digunakan dalam pencarian; “hydroxymethylglutaryl-CoA reductase inhibitor”, “statin”, "HMG-CoA reductase inhibitor", "3-hydroxy-3-methylglutaryl co-enzyme A reductase", “macular degeneration", "age-related macular degeneration”, "age-related eye disease”, "advanced age-related macular degeneration”, “maculopathy”, “retinal degeneration”, "retinal disease”, dan "neovascular age-related macular degeneration”. Setelah artikel tersaring, dilakukan telaah kritis dengan menggunakan The Joanna Briggs Institute (JBI) Critical Appraisal Tools. Adanya perbedaan pendapat dan ketidaksepakatan antara penulis diselesaikan dengan diskusi. Hasil : Didapatkan 4 studi dari proses seleksi, berupa 1 RCT, 1 studi case-control, 1 studi cohort, dan 1 studi cross-sectional. Terdapat variasi pada variabel yang dinilai, metode intervensi, dan metode penilaian luaran yang dilakukan pada studi-studi tersebut. Potensi efek protektif statin terhadap progresivitas AMD yang signifikan secara statistik hanya ditemukan pada 1 studi (OR= 0,43 (95% CI 0,18, 0,99), P= 0,047). Simpulan : Tidak ditemukan cukup bukti efektivitas pemberian statin terhadap pencegahan awitan dan progresi AMD.
LENSA KONTAK SEBAGAI TATALAKSANA MYOPIC SURPRISE PASCAOPERASI KATARAK
Authors: Tanto Raissa Metasari , Sirait Susanti Natalya
Published: June 2023

Pendahuluan: Lensa kontak merupakan salah satu pilihan dalam penanganan kasus kelainan refraksi. Indikasi pemakaian lensa kontak meliputi anisometropia tinggi seperti pada kasus myopic surprise yang tidak dilakukan operasi tambahan. Tujuan: Untuk melaporkan pembahasan kasus lensa kontak sebagai tatalaksana myopic surprise pascaoperasi katarak. Laporan kasus: Seorang laki-laki berusia 60 tahun datang ke Pusat Mata Nasional Rumah Sakit Mata Cicendo dengan keluhan mata kanan masih terasa buram setelah menjalani operasi katarak. Tajam penglihatan mata kanan didapatkan 1/60 dan kiri 0.8. Tajam penglihatan terbaik mata kanan didapatkan 0.08 dengan pinhole dan 0.63 menggunakan koreksi S-10.00 D. Tajam penglihatan mata kiri 1.0 dengan pinhole. Pasien didiagnosis Miopia Gravior OD + Astigmatisma Mixtus OS + Anisometropia + Myopic Surprise OD + Pseudofakia ODS + Stafiloma posterior ODS + Vitrectomized eye OD. Tatalaksana dilakukan dengan menggunakan lensa kontak dengan mempertimbangkan preferensi pasien. Simpulan: Lensa kontak merupakan salah satu tatalaksana alternatif nonbedah pada kasus myopic surprise. Kata kunci: Anisometropia, Lensa kontak, Myopic Surprise
Visual Field Improvement After Pituitary Tumor Resection
Authors: Febriyanti Ericka , Kartika Antonia , Sari Rusti Hanindya , Ginting Dianita Veulina , Yollamanda Prettyla
Published: June 2023

Background: Optic neuropathy due to chiasmal compressive lesion can affect the visual acuity, color vision, and visual field in both eyes. The most common visual field defect of chiasmal compression is a bitemporal hemianopia. Restoration of visual function is possible following surgical decompression. Purpose: To report a case of visual field improvement after pituitary tumor resection. Case Presentation: A 53 years old woman came with a chief complaint of blurred vision on her left eye since 3 months. Patient visual acuity was 0.25F1 on the right eye and counting fingers at 1 meter on the left eye. Ophthalmologic examination revealed optic disc pallor on both eyes. HVF 30-2 results showed bitemporal hemianopia. Head MRI with contrast showed an pituitary macroadema, size 2.3 x 2.2 x 2.7 cm and pushing the optic chiasm superiorly. Patient diagnosed with bilateral papil atrophy and bitemporal hemianopia caused by pituitary macroadenoma. She underwent endoscopic transsphenoidal tumor resection by a neurosurgeon. Visual function showed an improvement after 6 months follow up. Colour vision and contrast sensitivity were increased in left eye. HVF 30-2 showed visual field improvement in both eyes, especially in right eye. Conclusion: Pituitary adenoma can lead to visual impairment. Preoperative factors such as retinal nerve fiber layer thickness, severity of the preoperative deficit, duration of visual symptoms, tumor size, extent of resection, and patient age may also serve as predictors of postoperative visual outcomes.
Comparative Effectiveness of Upper Limb Exercise Interventions in Individuals With Stroke: A Network Meta-Analysis
Authors: Tenberg Sarah , Mueller Steffen , Vogt Lutz , Roth Christian , Happ Kevin , Scherer Moritz , Behringer Michael , Niederer Daniel
Published: June 2023

BACKGROUND:

Although numerous effective exercise interventions can treat upper limb motor impairments after stroke, it remains unknown as to which are the most effective. The objective of the present study was to investigate the comparative effectiveness of various exercise interventions of the upper limb for individuals with an acute or subacute stroke.

METHODS:

For this systematic review with network meta-analysis, we searched PubMed/MEDLINE, Cochrane Library CENTRAL and Web of Science from database inception to September 2021 for randomized controlled trials examining individuals within 6 months of stroke onset, active upper limb exercise interventions, and any kind of control intervention. The primary outcome was upper limb motor function, secondary outcomes were activities of daily living and social participation, both assessed at post-intervention and follow-up. Nonspecific/multimodal active upper limb therapy was the standard comparator. Standardized mean differences, that is, Hedge’s g, were the effect size estimators. We calculated Frequentist-based network meta-analysis for the comparative effectiveness calculations using the R package netmeta. Main analyses were network plotting to display the geometry of the network and P-scores to summarize the intervention hierarchy. Results were derived from direct within-study and indirect between-study evidence comparisons. The Cochrane risk-of-bias tool II assessed all risk of bias domains.

RESULTS:

This review involved 145 randomized controlled trial on 6432 participants and 45 different treatment categories. The network meta-analysis analyzed 119 randomized controlled trials on 5553 participants and 41 different treatment categories. Electrical stimulation combined with task-specific training (standardized mean difference, 1.03 [95% CI, 0.51–1.55];
P
<0.0001, P-score=0.11), high-volume constraint-induced movement therapy (0.86 [0.4–1.32];
P
=0.0003, P-score=0.18), and strength training (0.65 [0.17–1.13];
P
=0.01, P-score=0.28) were the most effective interventions (each k=107).

CONCLUSIONS:

Electrical stimulation combined with task-specific training (low evidence), high-volume constraint-induced movement therapy (moderate evidence), and strength training (low evidence) were the most effective interventions in improving upper limb motor function in individuals with a stroke. As the results were sensitive against a high risk of bias, likewise, these interventions should receive more attention in research and practice. Due to the heterogeneous use, electrical stimulation in combination with task-specific training should be further investigated in well-designed studies alongside other successful interventions (eg, constraint-induced movement therapy).

REGISTRATION:

URL:
https://www.crd.york.ac.uk/prospero/
; Unique identifier: CRD42021284064.
Taming Nature and Gaining Authority—Rabbinic Decrees Reconsidered
Authors: Manekin-Bamberger Avigail
Published: June 2023

The root gzr, in nominal and verbal forms, is prominent in rabbinic literature and is usually translated ‘legislation’ or ‘decree’. However, attention to the numerous rabbinic accounts in which rabbis employ this root demonstrates that it was not merely a term used for human legislation. Rather, in rabbinic Amoraic narratives, the root gzr was often used by the rabbis to gain control over their surroundings and subdue the natural and supernatural, in both Palestine and Babylonia. Comparing these narratives to contemporary Jewish magical texts highlights the uniqueness of this rabbinic decree. Therefore, translating gzr in rabbinic literature strictly as a legal decree obscures important components of the self-presentation of the rabbis, especially the way they conceived of and represented the power of their rulings. Finally, I suggest that a careful reading of legal-magical decrees may teach us about the place of the rabbis in a world in which miracle workers, magical practitioners, and the rabbis themselves competed over the power to defeat demonic forces of evil.
A Previously Overlooked Manuscript of Fragment Targum (EVR II A 371, National Library of Russia, St. Petersburg)
Authors: Patmore Hector M.
Published: June 2023

The Fragment Targums contain selections of verses from the Pentateuch and form a distinct textual family within the Palestinian Targum tradition. To date, our understanding of their textual tradition has been based on nine manuscripts (excluding those copied from printed texts). This article introduces another manuscript of Fragment Targum that has been previously overlooked. The article describes the manuscript’s content, provides a preliminary characterisation of the text’s relationship to the other extant witnesses of the Fragment Targums and the other Pentateuchal Targums, and considers some possible implications of this new witness for our understanding of the origins, purpose, and transmission history of the Fragment Targums.
Combating illegal wildlife trade and conserving biodiversity in Bangladesh through legal provisions
Authors: Islam Md. Ziaul , Zheng Xinxin
Published: June 2023

Despite numerous domestic legislations, international treaties, agreements, conventions, and protocols to curb wildlife crimes, Bangladesh’s illegal wildlife trade (IWT) crime rate has increased significantly in recent years. The provision of the Wildlife (Conservation and Security) Act 2012 sets the highest seven and lowest two years punishment for killing tigers and elephants, a maximum of two years, and a minimum of six months imprisonment for killing birds. Nevertheless, the country has only 17% forest land; in this small area, wildlife crime increased 28 times in 2020, and nearly 4,000 live wild animals have been rescued, while more than 300 cases have been registered in the last ten years. We suggest that ineffective legal enforcement is the main reason for the illegal transaction of wild species through insecure border areas. Hence, successfully controlling the IWT problem in Bangladesh requires reducing the demand for wild animals, stopping the route of supplies, and combating global transnational wildlife crime.
A new species of Contarinia (Diptera: Cecidomyiidae) from flower galls on the relict tree Zelkova abelicea (Ulmaceae) endemic to Crete (Greece)
Authors: FAZAN LAURENCE , DORCHIN NETTA , GIRIENS SOPHIE , PASTA SALVATORE , GARFÌ GIUSEPPE , REMOUNDOU ILEKTRA , PETRAKIS PANOS V. , KOZLOWSKI GREGOR
Published: June 2023

Contarinia ampelitsiae n. sp. Dorchin & Fazan is described as a newly discovered gall-midge species (Diptera: Cecidoymiidae) forming galls in flowers of Zelkova abelicea (Ulmaceae), a tree species endemic to the Mediterranean island of Crete (Greece). Larvae develop within modified filaments of male flowers, contrary to many Contarinia species that develop freely in flowers or in simple flower galls. The species has one generation per year, and its galls are sometimes found in great numbers on individual trees, thus affecting both fruit quantity and weight. This is the first report of a gall midge from Zelkova and the first record of Contarinia from Ulmaceae. Based on its host-plant association and on the barcoding section of the mtCOI gene, this species has no obvious relatives within Contarinia.
Religious life in schooled society? A global study of the relationship between schooling and religiosity in 76 countries
Authors: Kavadias Leandros , Spruyt Bram , Kuppens Toon
Published: June 2023

The thesis that schooling inevitably leads to secularization continues to be debated. Indeed, while education has become a central and authoritative institution across the world, religiosity seems to persist. An alternative hypothesis proposes that recognizing the cultural aspects of the growth of “schooled societies” may reveal unexpected compatibilities between education and religiosity. However, research that both empirically integrates these aspects and examines their relationship with religiosity from a global perspective remains scarce. Against this background, this article first constructs a macro-level indicator that taps into cross-national variation in the different dimensions of “schooled societies.” Subsequently, we examine its relationship with the subjective importance of religion in people’s lives and individual-level educational differences in religiosity. Results based on data from 94,011 respondents across 76 countries show that in societies that are more “schooled,” people generally tend to be less religious. Moreover, the development of a schooled society moderates the relationship between educational attainment and religiosity. In societies that show more characteristics of a schooled society, especially less educated people are likely to remain religious. Finally, we found that our new indicator for the schooled society explained more variance than other, less fine-grained indicators of this concept. This illustrates the added value of a more comprehensive indicator for the role of schooling as an institution. In the conclusion, we use our findings to outline a research agenda.
Huge Nasopalatine Duct Cyst Treated by Transnasal Endoscopic Marsupialization: A Case Report and Literature Review
Authors: Kim Su-Jong , Moon Jee Won , Lee Heung-Man
Published: June 2023

Nasopalatine duct cyst (NPDC) is the most common nonodontogenic cyst originating from the epithelial remnants of the incisive canal in the maxilla. NPDC is treated with complete enucleation via a sublabial or transpalatal approach, and recently tranasnasal endoscopic marsupialization has been gradually used. However, in large and extensive cases, it is difficult to remove the cyst completely, and there is a high risk of postoperative complications, including oronasal fistula. Therefore, tranasnasal endoscopic marsupialization is recommended as an effective treatment modality. Herein, we report a case of a 49-year-old man with a very large NPDC with a maximum diameter of 58 mm. NPDC was successfully managed by transnasal endoscopic marsupialization under general anesthesia without any major problems. No postoperative complications or recurrence occurred until 12 months postoperatively. Transnasal endoscopic marsupialization for large NPDC is minimally invasive and useful.
The golden calf of Bethel and Judah’s mimetic desire of Israel
Authors: Hong Koog P.
Published: June 2023

Based on René Girard’s mimetic theory, this article reexamines the vilification of Jeroboam’s cultus in 1 Kgs. 12.25–33 as an attempt to depict Bethel and the Northern Kingdom as the monstrous double of Jerusalem and Judah. Mimetic rivalry and mutual desire often impose a grotesque mixture of the emotional residues of mimetic crisis—be they anxiety, fury, or fear—on rivals’ faces. Although the text attempts to highlight differences between Bethel and Jerusalem, mimetic theory suggests that the rivals’ mutual blame conceals their fundamental similarities. The text paints Jeroboam’s golden calf as a monstrous double of Jerusalem’s cherubim, but the monstrous depiction of the calf as a pagan idol also conceals Judah’s own insecurity and mimetic desire of Israel. As the “inferior” party, Judah imitated Israel and eventually supplanted her older sibling, and this sense of insecurity is reflected in the accusations against her rival.
Impact Analysis of Driver Takeover Under a Connected Environment: A Study of the External Effects on Vehicle Conversions
Authors: Hua Xuedong , Yu Weijie , Xiang Yun , Zhao De , Wang Wei
Published: June 2023

The moment we face cooperative adaptive cruise control (CACC), driver takeover, that is, drivers actively take over vehicles to avoid unknown risks, is a necessary concern in reality, especially with the distrust or low acceptance of automated driving technology in the early stage of CACC development. However, the impact of driver takeover on traffic flow has not been accurately presented, as researchers only focused on the taken-over vehicle and neglected the external effects on surrounding vehicles. Departing from the literature, this study provides a novel external perspective for the impact analysis of driver takeover under a connected environment, that is, it considers the resulting communication heterogeneity and specifies multi-class conversions in the entire traffic flow. To be specific, we subdivide the dynamic process of driver takeover into 10 vehicle conversions considering vehicle degradation and platoon reorganization, then analyze their contributions to traffic stability, emissions, and fuel consumption. What is also innovative is that two forms of driver takeover are first developed in this study, which is determined by whether drivers continue opening the communication device after the takeover. On this basis, this study indicates that driver takeover has the potential to cause greater heterogeneity of the traffic flow in contrast to that in the literature and proposes theoretical models for the changed traffic flow configuration and traffic stability after the takeover. Finally, numerical experiments verify the theoretical results with discussions on multiple factors, for example, vehicle proportion, platoon length, and driving behaviors. The findings extend the external effects of driver takeover on multi-class vehicle conversions in heterogeneity traffic flow and provide a more realistic basis for the evaluation of driver takeover.
Single diamond grit scratching of unidirectional Cf/SiC composite: Mechanical responses and fracture mechanism
Authors: Wang Qingxia , Wen Jiazhou , Wu Chongjun , Luo Chao , Lin Zhijian , Liang Steven Y
Published: June 2023

Cf/SiC composite is a typical heterogeneous brittle composite material, its precision machining has always been affected by the complicated removal mechanism. This paper conducted a single diamond grit scratching experiment on the unidirectional Cf/SiC composite to investigate the material’s mechanical response under different loads and scratching depths. The scratching force and acoustic emission signals were measured to reveal the removal characteristics. The scratching removal behavior of SiC matrix and carbon fibers in the two-phase component of unidirectional Cf/SiC composites was analyzed based on the fracture size and fiber fracture morphology. The results show that the parallel scratching process could produce a better strength resistance with mild rupture features of fiber extrusion fracture and shear removal. While the perpendicular scratching process is generally resulting in crack propagation along the fiber direction with interface failure and bending fracture failure along the moving direction.