bluuebunny/crossref_metadata_2025_split huggingface dataset:
The value of long-term angiographic follow-up following Pipeline embolization of intracranial aneurysms
Authors: Lauzier David C , Cler Samuel J , Chatterjee Arindam R , Osbun Joshua W , Moran Christopher J , Kansagra Akash P 
Published: July 2021

BackgroundFlow diversion of intracranial aneurysms with the Pipeline Embolization Device (PED) is commonly performed, but the value of long-term angiographic follow-up has not been rigorously evaluated. Here we examine the prevalence of actionable findings of aneurysm recurrence and development of in-stent stenosis in a cohort of patients that underwent long-term angiographic follow-up at multiple time points.MethodsAngiographic data from eligible patients were retrospectively assessed for aneurysm occlusion, in-stent stenosis, and aneurysm regrowth or recurrence. Patients were included in this study if they underwent angiographic imaging at 6 months post-treatment and at least one later time point.Results100% (132/132) of aneurysms occluded at 6 months remained occluded at final follow-up. 85.7% (6/7), 56.3% (27/48), and 25% (6/24) of aneurysms with entry remnant, subtotal filling, and total filling, respectively, at 6 months were completely occluded at final follow-up. 98.7% (147/149) of PED constructs that demonstrated no stenosis at 6 months demonstrated no stenosis at final angiography, while 44.4% (8/18) of PED constructs demonstrating in-stent stenosis at 6 months had resolution of stenosis on final angiography.ConclusionsAmong patients who undergo treatment of intracranial aneurysms with PED, the value of long-term angiography in patients demonstrating complete aneurysm occlusion and no in-stent stenosis on 6 month post-treatment angiography is low.
The clinical indications for testing women for Mycoplasma genitalium
Authors: Latimer Rosie L , Vodstrcil Lenka A , Plummer Erica L , Doyle Michelle , Murray Gerald L , Fairley Christopher K , Bodiyabadu Kaveesha , Read Tim R H , Kaiser Marti , Mokany Elisa , Guy Rebecca , Chow Eric P F , Bradshaw Catriona 
Published: July 2021

BackgroundWhile the contribution of Mycoplasma genitalium (MG) to symptoms in men is well described, less is known about its association with common genital symptoms in women. We aimed to determine the prevalence of MG and macrolide resistance, and its association with common genital symptoms in women attending a sexual health service, to inform indications for testing and clinical practice.MethodsWe undertook a cross-sectional study of symptomatic and asymptomatic women attending Melbourne Sexual Health Centre (MSHC), between April 2017 and April 2019. Women were tested for MG and macrolide resistance, Chlamydia trachomatis (CT), Neisseria gonorrhoeae, Trichomonas vaginalis, bacterial vaginosis and vulvovaginal candidiasis. Women completed a questionnaire on symptoms, and symptomatic women underwent examination. The prevalence of MG (and macrolide resistance) and other genital infections was calculated with 95% CIs, and associations between these outcomes and specific genital symptoms were examined using logistic regression.ResultsOf 1318 women, 83 (6%, 95% CI: 5% to 8%) had MG, of which 39 (48%, 95% CI: 36% to 59%) had macrolide-resistant MG; 103 (8%, 95% CI: 6% to 9%) women had CT. MG prevalence was similar in asymptomatic (10 of 195; 5%) and symptomatic (73 of 1108; 7%) women, p=0.506. MG was associated with mucopurulent cervicitis on examination (adjusted OR=4.38, 95% CI: 1.69 to 11.33, p=0.002), but was not associated with other specific genital symptoms or signs.ConclusionsMG was as common as CT among women attending MSHC. MG was not associated with genital symptoms, but like CT, was significantly associated with cervicitis. These data provide evidence that routine testing for MG in women with common genital symptoms is not indicated. The presence of macrolide resistance in 48% of women supports use of resistance-guided therapy.
Reconstruction of the three-dimensional beat pattern underlying swimming behaviors of sperm
Authors: Gong A. , Rode S. , Gompper G. , Kaupp U. B. , Elgeti J. , Friedrich B. M. , Alvarez L. 
Published: July 2021

Abstract
The eukaryotic flagellum propels sperm cells and simultaneously detects physical and chemical cues that modulate the waveform of the flagellar beat. Most previous studies have characterized the flagellar beat and swimming trajectories in two space dimensions (2D) at a water/glass interface. Here, using refined holographic imaging methods, we report high-quality recordings of three-dimensional (3D) flagellar bending waves. As predicted by theory, we observed that an asymmetric and planar flagellar beat results in a circular swimming path, whereas a symmetric and non-planar flagellar beat results in a twisted-ribbon swimming path. During swimming in 3D, human sperm flagella exhibit torsion waves characterized by maxima at the low curvature regions of the flagellar wave. We suggest that these torsion waves are common in nature and that they are an intrinsic property of beating axonemes. We discuss how 3D beat patterns result in twisted-ribbon swimming paths. This study provides new insight into the axoneme dynamics, the 3D flagellar beat, and the resulting swimming behavior.

Graphic abstract
α1-Acid Glycoprotein Enhances the Immunosuppressive and Protumor Functions of Tumor-Associated Macrophages
Authors: Matsusaka Kotaro , Fujiwara Yukio , Pan Cheng , Esumi Shigeyuki , Saito Yoichi , Bi Jing , Nakamura Yuka , Mukunoki Ayumi , Takeo Toru , Nakagata Naomi , Yoshii Daiki , Fukuda Ryo , Nagasaki Taisei , Tanaka Ryusei , Komori Hisakazu , Maeda Hitoshi , Watanabe Hiroshi , Tamada Koji , Komohara Yoshihiro , Maruyama Toru 
Published: July 2021

Abstract

Blood levels of acute-phase protein α1-acid glycoprotein (AGP, orosmucoid) increase in patients with cancer. Although AGP is produced from hepatocytes following stimulation by immune cell–derived cytokines under conditions of inflammation and tumorigenesis, the functions of AGP in tumorigenesis and tumor progression remain unknown. In the present study, we revealed that AGP contributes directly to tumor development by induction of programmed death ligand 1 (PD-L1) expression and IL6 production in macrophages. Stimulation of AGP induced PD-L1 expression in both human monocyte–derived macrophages through STAT1 activation, whereas AGP had no direct effect on PD-L1 expression in tumor cells. AGP also induced IL6 production from macrophages, which stimulated proliferation in tumor cells by IL6R-mediated activation of STAT3. Furthermore, administration of AGP to AGP KO mice phenocopied effects of tumor-associated macrophages (TAM) on tumor progression. AGP decreased IFNγ secretion from T cells and enhanced STAT3 activation in subcutaneous tumor tissues. In addition, AGP regulated PD-L1 expression and IL6 production in macrophages by binding with CD14, a coreceptor for Toll-like receptor 4 (TLR4), and inducing TLR4 signaling. These results provide the first evidence that AGP is directly involved in tumorigenesis by interacting with TAMs and that AGP might be a target molecule for anticancer therapy.

Significance:
AGP-mediated suppression of antitumor immunity contributes to tumor progression by inducing PD-L1 expression and IL6 production in TAMs.
Trends in Breast Cancer Survival by Race-Ethnicity in Florida, 1990–2015
Authors: Hines Robert B. , Johnson Asal M. , Lee Eunkyung , Erickson Stephanie , Rahman Saleh M.M. 
Published: July 2021

AbstractBackground:This study was conducted to evaluate trends in survival, by race-ethnicity, for women diagnosed with breast cancer in Florida over a 26-year period.Methods:This was a retrospective cohort study of women diagnosed with invasive breast cancer in Florida between 1990 and 2015. Data were obtained from the Florida Cancer Data System. Women in the study were categorized according to race (white/black) and Hispanic ethnicity (yes/no). Cumulative incidence estimates of 5- and 10-year breast cancer–related death with 95% confidence intervals (CI) were obtained by race-ethnicity, according to diagnosis year. Subdistribution hazard models were used to obtain subdistribution HRs (sHR) for the relative rate of breast cancer death accounting for competing causes.Results:Breast cancer mortality decreased for all racial-ethnic groups, and racial-ethnic minorities had greater absolute and relative improvement for nearly all metrics compared with non-Hispanic white (NHW) women. However, for the most recent time period (2010–2015), black women still experienced significant survival disparities with non-Hispanic black (NHB) women, having twice the rate of 5-year [sHR = 2.04; 95% confidence interval (CI), 1.91–2.19] and 10-year (sHR = 2.02; 95% CI, 1.89–2.16) breast cancer–related death. Adjustment for covariates substantially reduced the excess rate of breast cancer–related death for black women.Conclusions:Despite efforts to improve disparities in breast cancer outcomes for underserved women in Florida, black women continue to experience significant survival disparities.Impact:These results highlight the need for targeted approaches to eliminate disparities in breast cancer survival for black women.
Sex Hormone and Colorectal Cancer: The Knowns and Unknowns
Authors: Hang Dong , Shen Hongbing 
Published: July 2021

AbstractSex hormones have been suggested as a contributor to gender disparity in incidence and mortality of colorectal cancer, but previous observational studies on endogenous sex hormones and colorectal cancer risk have led to contradictory results. Leveraging the large-scale UK biobank resource, Dimou and colleagues performed both observational and Mendelian randomization (MR) analyses to investigate the association of serum testosterone and sex hormone binding globulin concentrations with the risk of colorectal cancer. Although the findings provide little evidence for independent roles of the hormones in colorectal cancer, further interrogation of possible mediating effects of sex hormones on the causal pathways of colorectal cancer could deepen our understanding of colorectal cancer etiology and improve tailored prevention. While MR analysis is useful for inferring causality in observational studies, the current null results should be interpreted with caution because of insufficient statistical power and predefined assumptions of linearity. Moreover, given the widespread use of testosterone supplementation in older men to restore age-related decline of endogenous concentrations, large and long-term randomized controlled trials are required to clarify the effect of testosterone on colorectal cancer risk, which would provide critical evidence for health decision making.See related article by Dimou et al., p. 1336
Deciphering Intratumoral Molecular Heterogeneity in Clear Cell Renal Cell Carcinoma with a Radiogenomics Platform
Authors: Udayakumar Durga , Zhang Ze , Xi Yin , Dwivedi Durgesh K. , Fulkerson Michael , Haldeman Sydney , McKenzie Tiffani , Yousuf Qurratulain , Joyce Allison , Hajibeigi Asghar , Notgrass Hollis , de Leon Alberto Diaz , Yuan Qing , Lewis Matthew A. , Madhuranthakam Ananth J. , Sibley Robert C. , Elias Roy , Guo Junyu , Christie Alana , McKay Renée M. , Cadeddu Jeffrey A. , Bagrodia Aditya , Margulis Vitaly , Brugarolas James , Wang Tao , Kapur Payal , Pedrosa Ivan 
Published: July 2021

Abstract

Purpose:
Intratumoral heterogeneity (ITH) challenges the molecular characterization of clear cell renal cell carcinoma (ccRCC) and is a confounding factor for therapy selection. Most approaches to evaluate ITH are limited by two-dimensional ex vivo tissue analyses. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can noninvasively assess the spatial landscape of entire tumors in their natural milieu. To assess the potential of DCE-MRI, we developed a vertically integrated radiogenomics colocalization approach for multi-region tissue acquisition and analyses. We investigated the potential of spatial imaging features to predict molecular subtypes using histopathologic and transcriptome correlatives.

Experimental Design:
We report the results of a prospective study of 49 patients with ccRCC who underwent DCE-MRI prior to nephrectomy. Surgical specimens were sectioned to match the MRI acquisition plane. RNA sequencing data from multi-region tumor sampling (80 samples) were correlated with percent enhancement on DCE-MRI in spatially colocalized regions of the tumor. Independently, we evaluated clinical applicability of our findings in 19 patients with metastatic RCC (39 metastases) treated with first-line antiangiogenic drugs or checkpoint inhibitors.

Results:
DCE-MRI identified tumor features associated with angiogenesis and inflammation, which differed within and across tumors, and likely contribute to the efficacy of antiangiogenic drugs and immunotherapies. Our vertically integrated analyses show that angiogenesis and inflammation frequently coexist and spatially anti-correlate in the same tumor. Furthermore, MRI contrast enhancement identifies phenotypes with better response to antiangiogenic therapy among patients with metastatic RCC.

Conclusions:
These findings have important implications for decision models based on biopsy samples and highlight the potential of more comprehensive imaging-based approaches.
Abstract 1117: Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi's): A library-based approach
Authors: Sootome Hiroshi , Kato Suzuko , Kato Masanori , Hirai Hiroshi 
Published: July 2021

Abstract
Background: The emergence of secondary FGFR kinase domain (KD) mutations with FGFRi's leads to drug resistance and disease progression. The frequency of resistance mutations with individual FGFRi's is unknown. Using an unbiased library-based approach, we examined the development of acquired resistance with the irreversible FGFRi futibatinib and the ATP-competitive FGFRi's erdafitinib (ERD) and pemigatinib (PEM).
Methods: Mutant (mt) libraries were generated with random mutagenesis in two FGFR2 KD regions: #1 (amino acids [aa] 540-569), and #2 (aa 640-669). Library were transfected as TEL-fusions into Ba/F3 cells, resulting in FGFR2-dependent cell growth. Transfected cells were treated with FGFRi's at concentrations suppressing parental cell line growth. Surviving drug-resistant clones were counted, isolated, and sequenced to identify the KD mutation. The inhibitory activity of FGFRi's against resistant clones was assessed using phospho-FGFR2 ELISA.
Results: Treatment of the library-transfected Ba/F3-TEL-FGFR2 KD cells with PEM, ERD, and futibatinib resulted in an average (n=2) of 93, 27, and 13 resistant clones in region #1 and 28, 21 and 1 resistant in region #2, respectively. Sequencing (table) identified, among others, the following aa mutations: N549, E565, and K641 (regulatory triad), V564 (gatekeeper region) and K659 (activation loop), also seen in patients who developed resistance to Debio1347, infigratinib, and PEM. Among FGFR mts shown (table), futibatinib inhibited 8/10, and ERD, 5/10 mts at IC50 values comparable to wild type (wt) FGFR; however, PEM activity against all FGFR mts was attenuated by ≥5-fold vs wt.
Conclusions: Resistance mutations identified with this unbiased library-based in vitro approach were consistent with those observed in the clinic. Acquired drug resistance mutations were less frequent with futibatinib than with ATP-competitive FGFRi's. Futibatinib demonstrated the most robust inhibition of drug resistant mts.
FGFR mutationKD regionFutibatinib IC50 (nM)Erdafitinib IC50 (nM)Pemigatinib IC50 (nM)Wild-type (parent)-2.12.51.5N549DRegulatory triad4.225.5153.2N549KRegulatory triad16.732.0246.2V562L-6.32.97.7V564IGatekeeper8.32.762.4V564LGatekeeper91.956.5502.3E565ARegulatory triad6.82.911.8E565GRegulatory triad3.93.09.0K641IRegulatory triad3.855.829.6K641RRegulatory triad4.73.210.3K659MActivation loop9.546.633.8
Citation Format: Hiroshi Sootome, Suzuko Kato, Masanori Kato, Hiroshi Hirai. Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi's): A library-based approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1117.
Abstract 1229: Novel Arf1-targeting ã-dipeptides counteract triple negative breast cancer by inducing autophagic death
Authors: He Leilei , Chavanieu Alain , Vo-Hoang Yen , Teng Yong 
Published: July 2021

Abstract
ADP-ribosylation factor 1 (Arf1) is a crucial regulator in vesicle-mediated membrane trafficking and involved in the activation of signaling molecules. However, the molecular mechanisms underlying Arf1-dependent cancer development and progression are far from understood. We report here that Arf1 is the most amplified gene in Arf gene family in breast cancer, and knocking it down leads to an induction of autophagy via the AMPK pathway. To effectively target Arf1, we rationally designed and synthesized constrained ATC-based (4-amino-(methyl)-1,3-thiazole-5-carboxylic acid) γ-dipeptides, which can block Arf1 activation more efficiently than other commercially available Arf1 inhibitors through targeting the Arf1-GDP/ARNO complex at the Golgi. The anticancer effects of these γ-dipeptides were evaluated in triple native breast cancer MDA-MB-231 cells and their bone-seeking and lung-seeking sublines, showing reduced cell viability along with significant increased autophagy following treatment in both 2D and 3D cell cultures. Among these new inhibitors, the γ-dipeptide 10b displayed strongest cytotoxicity. The orthotopic NSC mouse model for breast cancer further showed the γ-dipeptides 10b exhibited a superior anticancer effects by inducing autophagic cell death in breast tumor, with no significant systemic toxicity. These findings reveal that Arf1-targeting γ-dipeptides developed by our collaborative team may represent a promising targeted therapeutic to improve treatment of breast cancer.
Citation Format: Leilei He, Alain Chavanieu, Yen Vo-Hoang, Yong Teng. Novel Arf1-targeting ã-dipeptides counteract triple negative breast cancer by inducing autophagic death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1229.
Abstract 126: HUB Organoids: bringing the 'patient in the lab' for preclinical and clinical development
Authors: Mullenders Jasper , Buijs Annemarie , Fielmich Lars-Eric , Sluimer Jasper , Sun Jane , Vries Robert G. , Boj Sylvia F. 
Published: July 2021

Abstract
Preclinical disease models are essential for the development of novel therapies and help better understand the molecular processes. In recent years, the groundbreaking technology to generate patient specific in vitro cultures based on adult stem-cell (ASC) organoids, has gained widespread interest for the development of new therapies and as a predictive diagnostic tool. ASC-derived organoids can be generated at high efficiency from both healthy and diseased tissue (resections as well as biopsies) including most carcinomas. These patient-derived cultures can be expanded for prolonged periods of time while maintaining many properties of the tissue they were derived from.
At Hubrecht Organoid Technology (HUB), we have created comprehensive ‘organoid living biobanks' from tumors of different origin like colon, lung, breast, pancreas and ovary. These biobanks have been characterized at the genetic and transcriptional level. These analyses have shown that our ‘organoid living biobanks' capture disease heterogeneity at the genetic and molecular level.
Because HUB Organoids can be expanded long term, drug screening is feasible in these models. HUB has developed procedures for (high-throughput) compound screening in organoids including small molecules and biologics. In this setting, HUB Organoids have been used to identify novel targets, identify lead compounds and stratify potential responders based on their genetic or molecular profile.
In addition, HUB Organoids can serve as a patient avatar in clinical development or diagnostics. In this setting, HUB Organoids could add a functional test for therapy response in a patient centered setting providing a unique tool for personalized medicine.
Citation Format: Jasper Mullenders, Annemarie Buijs, Lars-Eric Fielmich, Jasper Sluimer, Jane Sun, Robert G. Vries, Sylvia F. Boj. HUB Organoids: bringing the 'patient in the lab' for preclinical and clinical development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 126.
Abstract 1275: Potent ENPP1 inhibitors activating STING pathway in tumor microenvironment
Authors: Peng Zhiyuan , Guo Kun , Li Ying-Ying , Kong Deming , Yang Jinfu , (Shelley) Qin Xiaoli , Hao Xiaolin 
Published: July 2021

Abstract
Cyclic GMP-AMP synthase (cGAS) recognizes and binds double-stranded DNA (dsDNA) in the cytosol to generate 2′3′-cGAMP, a cyclic dinucleotide and an activator of STING-dependent innate immunity. Emerging studies revealed that tumor derived 2′3′-cGAMP could act as an immune transmitter and directly trigger anti-tumor immunity. Up to date, Ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1/NPP1), a membrane-bound nucleotide hydrolase, was discovered as the predominant enzyme hydrolyzing 2'3'cGAMP. The breakdown of 2'3' cGAMP by ENPP1 may dampen STING-dependent anti-tumor innate immune response. Employing genomic approach, we found that ENPP1 expression varies dramatically among different tumor tissues. Interestingly, ENPP1 expression in breast cancer tissues is overall double the level in normal breast tissues. These results made ENPP1 an attractive cancer immunotherapy target, to enhance STING-dependent innate immunity in tumor microenvironment.We have discovered a novel class of potent ENPP1 inhibitors with pico-molar IC50 in rhENPP1 enzymatic assay. In a cell-based enzymatic assay, compound ZXP-8202 showed an EC50 of 20 nM. To further assess its efficacy on STING-dependent interferon production, 2'3'-cGAMP was added to the culture medium of a high ENPP1-expressing cell line MDA-MB-231 in the absence and presence of ZXP-8202. IFNB1 production in THP1 monocyte was induced when THP-1 cells were incubated with the conditioned medium from MDA-MB-231 cells. In this IFNB1 assay, ZXP-8202 had an EC50 of 10nM. To confirm the ZXP-8202 potency in this culture system reflecting cellular ENPP1 activity, MDA-MB-231 was also treated with 2'3'-cGAMP(PS)2(Rp/Sp), a potent activator of STING but resistant to ENPP1 hydrolysis. The presence of ZXP-8202 showed no effect on 2'3'-cGAMP(PS)2(Rp/Sp) stimulated IFNB1 production in THP-1 cells when cultured in conditioned medium. These results demonstrated ZXP-8202 as a potent ENPP1 inhibitor, blocking 2'3-cGAMP hydrolysis by ENPP1, subsequently activating STING pathway. ZXP-8202 was dosed in CT26 syngeneic mouse model for 14 days and achieved about 70% tumor growth inhibition. No body weight loss was observed at this efficacious dose during treatment. The studies on further characterization of ENPP1 inhibitors and their mechanism of actions are ongoing and the results will be reported in due course.
Citation Format: Zhiyuan Peng, Kun Guo, Ying-Ying Li, Deming Kong, Jinfu Yang, Xiaoli (Shelley) Qin, Xiaolin Hao. Potent ENPP1 inhibitors activating STING pathway in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1275.