bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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

Abstract
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

Abstract
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

Abstract
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.
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

Abstract
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

Abstract
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

Abstract
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.
Renal glucose transporters play a role in removal of cadmium from kidney cells mediated by GMDTC – A novel metal chelator
Authors: Tang Xiaojiang , Xiao Bo , Zhao Qile , Hu Wei , McKenery Amber , Zhong Zhiyong 
Published: June 2023

Cadmium (Cd) is a toxic heavy metal, exposure to which leads to adverse health effects including chronic kidney damage. Tremendous efforts have been explored in identifying safe chelating agents for removing accumulated Cd from kidney, but with limited success owing to their associated side effects and the ineffectiveness in eliminating Cd. A newly developed chelating agent, sodium (S)-2-(dithiocarboxylato((2S,3 R,4R,5 R)-2,3,4,5,6-pentahydroxyhexyl) amino)-4(methylthio)butanoate (GMDTC), has been shown to effectively mobilize Cd from kidney. However, the mechanism(s) of removal are unclear, while it has been hypothesized that renal glucose transporters potentially play key roles mainly because GMDTC contains an open chain glucose moiety. To test this hypothesis, we utilized the CRISPR/Cas9 technology and human kidney tubule HK-2 cells, and constructed sodium-dependent glucose transporter 2 ( SGLT2) or glucose transporter 2 ( GLUT2) gene knockout cell lines. Our data showed that GMDTC’s ability in removing Cd from HK-2 cells was significantly reduced both in GLUT2 −/− or SGLT2 −/− cells, with a removal ratio reduced from 28.28% in the parental HK-2 cells to 7.37% in GLUT2 −/− cells and 14.6% in SGLT2 −/− cells. Similarly, knocking out the GLUT2 or SGLT2 led to a compromised protective effect of GMDTC in reducing cytotoxicity of HK-2 cells. This observation was further observed in animal studies, in which the inhibition of GLUT2 transporter by phloretin treatment resulted in reduced efficiency of GMDTC in removing Cd from the kidney. Altogether, our results show that GMDTC is safe and highly efficient in removing Cd from the cells, and this effect is mediated by renal glucose transporters.
Stem alignment with short tapered-wedge cementless stems affects bone mineral density continuously for at least 5 years after primary total hip arthroplasty
Authors: Masuda Sho , Iwakiri Kentaro , Ohta Yoichi , Minoda Yukihide , Kobayashi Akio , Nakamura Hiroaki 
Published: June 2023

Aim: This study aimed to assess the relationship between the three-dimensional (3D) alignment of short tapered-wedge cementless stems and bone mineral density (BMD) changes in patients followed up for 5 years after total hip arthroplasty (THA). Methods: We retrospectively analysed the hips of 52 patients who underwent THA using short tapered-wedge cementless stems at our institution from 2013 to 2016 with complete 5-year follow-up data. We evaluated the relationship between stem alignment, measured using a 3D-templating software, and BMD changes in the 7 Gruen zones. Results: After 1 year, significant negative correlations between varus insertion and a decrease in BMD in zone 7 and between flexed insertion and decreases in BMD in zones 3 and 4 were noted. After 5 years, significant negative correlations between varus insertion and a decrease in BMD in zone 7 and between flexed insertion and decreases in BMD zones 2, 3, and 4 were observed. With increased amounts of varus/flexion stem alignment, the amount of BMD loss decreased. There was no correlation between anteverted stem insertion and changes in BMD levels. Conclusions: Our data showed that stem alignment affects BMD based on 5-year follow-up data after surgery. Careful observation is necessary, especially when using short tapered-wedge cementless stems, as stem alignment may affect changes in BMD levels more than 5 years after surgery.
Prevalence of current smoking and association with meeting 24-h movement guidelines: Results from a national convenience sample of autistic adults
Authors: Laxton Paige , Healy Sean , Brewer Benjamin , Patterson Freda 
Published: June 2023

This study aimed to identify the prevalence of current smoking and examine the association between meeting combinations of the 24-h movement guidelines and current smoking in autistic adults. This cross-sectional study administered an electronic survey to a national sample of autistic adults in the United States. The study outcome was current smoking. Independent variables included the 24-h movement behaviors. Multivariable statistical modeling was used to assess the study aims. The study sample ( n = 259) had a mean age of 31.05 years (standard deviation = 7.70), 58.7% were male, 11.2% were fully independent, and 35.5% were current smokers. Current smokers met significantly fewer 24-h movement guidelines than non-smokers (mean = 1.52 (standard deviation = 0.73) vs mean= 1.93 (standard deviation = 0.88), respectively, t = 3.77, p < 0.01). Autistic adults with high levels of sedentary behavior were almost three times more likely (odds ratio = 2.784, 95% confidence interval = 1.490, 5.237) to be a current smoker than those who did not meet these guidelines. Autistic adults not meeting sleep and sedentary behavior recommendations had a 1.581 increased odds (odds ratio = 1.581 95% confidence interval = 1.25, 2.001) of being a smoker as compared to those meeting these recommendations. Current smoking was highly prevalent in this sample. Improving sleep health and reducing sedentary time may be viable intervention targets to help promote smoking cessation in autistic adults. Lay abstract Cigarette smoking is a leading risk behavior for cardiovascular disease; yet its prevalence and determinants are not clear in autistic adults. We examined the prevalence of current smoking and its association between meeting 24-h movement (i.e. sleep, physical activity, and sedentary behavior) guidelines in a self-selecting convenience sample of 259 autistic adults in the United States. We found that current smokers met fewer 24-h movement guidelines. Most significant, those who had insufficient sleep and those with high levels of sedentary behavior were more likely to be current smokers. Therefore, targeting these movement behaviors may be potential intervention targets for smoking cessation.