bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dose–response relationship between cigarette smoking and site-specific cancer risk: protocol for a systematic review with an original design combining umbrella and traditional reviews
Authors: Lugo Alessandra , Bosetti Cristina , Peveri Giulia , Rota Matteo , Bagnardi Vincenzo , Gallus Silvano 
Published: May 2024

IntroductionOnly a limited number of meta-analyses providing risk curve functions of dose–response relationships between various smoking-related variables and cancer-specific risk are available.Methods and analysisTo identify all relevant original publications on the issue, we will conduct a series of comprehensive systematic reviews based on three subsequent literature searches: (1) an umbrella review, to identify meta-analyses, pooled analyses and systematic reviews published before 28 April 2017 on the association between cigarette smoking and the risk of 28 (namely all) malignant neoplasms; (2) for each cancer site, an updated review of original publications on the association between cigarette smoking and cancer risk, starting from the last available comprehensive review identified through the umbrella review; and (3) a review of all original articles on the association between cigarette smoking and site-specific cancer risk included in the publications identified through the umbrella review and the updated reviews. The primary outcomes of interest will be (1) the excess incidence/mortality of various cancers for smokers compared with never smokers; and (2) the dose–response curves describing the association between smoking intensity, duration and time since stopping and incidence/mortality for various cancers. For each cancer site, we will perform a meta-analysis by pooling study-specific estimates for smoking status. We will also estimate the dose–response curves for other smoking-related variables through random-effects meta-regression models based on a non-linear dose–response relationship framework.Ethics and disseminationEthics approval is not required for this study. Main results will be published in peer-reviewed journals and will also be included in a publicly available website. We will provide therefore the most complete and updated estimates on the association between various measures of cigarette smoking and site-specific cancer risk. This will allow us to obtain precise estimates on the cancer burden attributable to cigarette smoking.Trial registration numberThis protocol was registered in the International Prospective Register of Systematic Reviews (CRD42017063991).
The RELIEF feasibility trial: topical lidocaine patches in older adults with rib fractures
Authors: Clout Madeleine , Turner Nicholas , Clement Clare , Braude Philip , Benger Jonathan , Gagg James , Gendall Emma , Holloway Simon , Ingram Jenny , Kandiyali Rebecca , Lewis Amanda , Maskell Nick A , Shipway David , Smith Jason E , Taylor Jodi , Darweish Medniuk Alia , Carlton Edward 
Published: May 2024

BackgroundLidocaine patches, applied over rib fractures, may reduce pulmonary complications in older patients. Known barriers to recruiting older patients in emergency settings necessitate a feasibility trial. We aimed to establish whether a definitive randomised controlled trial (RCT) evaluating lidocaine patches in older patients with rib fracture(s) was feasible.MethodsThis was a multicentre, parallel-group, open-label, feasibility RCT in seven hospitals in England and Scotland. Patients aged ≥65 years, presenting to ED with traumatic rib fracture(s) requiring hospital admission were randomised to receive up to 3×700 mg lidocaine patches (Ralvo), first applied in ED and then once daily for 72 hours in addition to standard care, or standard care alone. Feasibility outcomes were recruitment, retention and adherence. Clinical end points (pulmonary complications, pain and frailty-specific outcomes) and patient questionnaires were collected to determine feasibility of data collection and inform health economic scoping. Interviews and focus groups with trial participants and clinicians/research staff explored the understanding and acceptability of trial processes.ResultsBetween October 23, 2021 and October 7, 2022, 206 patients were eligible, of whom 100 (median age 83 years; IQR 74–88) were randomised; 48 to lidocaine patches and 52 to standard care. Pulmonary complications at 30 days were determined in 86% of participants and 83% of expected 30-day questionnaires were returned. Pulmonary complications occurred in 48% of the lidocaine group and 59% in standard care. Pain and some frailty-specific outcomes were not feasible to collect. Staff reported challenges in patient compliance, unfamiliarity with research measures and overwhelming the patients with research procedures.ConclusionRecruitment of older patients with rib fracture(s) in an emergency setting for the evaluation of lidocaine patches is feasible. Refinement of data collection, with a focus on the collection of pain, frailty-specific outcomes and intervention delivery are needed before progression to a definitive trial.Trial registration numberISRCTN14813929.
Agreement between audiometric hearing loss and self-reported hearing difficulty on the Revised Hearing Handicap Inventory differs by demographic factors
Authors: Dillard Lauren K , Matthews Lois J , Dubno Judy R 
Published: May 2024

BackgroundNew standardised measures of self-reported hearing difficulty can be validated against audiometric hearing loss. This study reports the influence of demographic factors (age, sex, race and socioeconomic position (SEP)) on the agreement between audiometric hearing loss and self-reported hearing difficulty.MethodsParticipants were 1558 adults (56.9% female; 20.0% racial minority; mean age 63.7 (SD 14.1) years) from the Medical University of South Carolina Longitudinal Cohort Study of Age-Related Hearing Loss (1988–current). Audiometric hearing loss was defined as the average of pure-tone thresholds at frequencies 0.5, 1.0, 2.0 and 4.0 kHz >25 dB HL in the worse ear. Self-reported hearing difficulty was defined as ≥6 points on the Revised Hearing Handicap Inventory (RHHI) or RHHI screening version (RHHI-S). We report agreement between audiometric hearing loss and the RHHI(-S), defined by sensitivity, specificity, accuracy, positive predictive value, negative predictive value and observedminuspredicted prevalence. Estimates were stratified to age group, sex, race and SEP proxy.ResultsThe prevalence of audiometric hearing loss and self-reported hearing difficulty were 49.0% and 48.8%, respectively. Accuracy was highest among participants aged <60 (77.6%) versus 60–70 (71.4%) and 70+ (71.9%) years, for white (74.6%) versus minority (68.0%) participants and was similar by sex and SEP proxy. Generally, agreement of audiometric hearing loss and RHHI(-S) self-reported hearing difficulty differed by age, sex and race.ConclusionsRelationships of audiometric hearing loss and self-reported hearing difficulty vary by demographic factors. These relationships were similar for the full (RHHI) and screening (RHHI-S) versions of this tool.
Nigrostriatal blood-brain barrier opening in Parkinson’s disease
Authors: Gasca-Salas Carmen , Pineda-Pardo José A , Del Álamo Marta , Jiménez Tamara , Trompeta Clara , Toltsis Gabriella , Garcia-Cañamaque Lina , Fernández-Rodríguez Beatriz , Matarazzo Michele , Plaza de las Heras Isabel , Natera-Villalba Elena , Martínez-Fernández Raúl , Duque Alicia , Ruiz de Aguiar Santiago , Blesa Javier , Rachmilevich Itay , Obeso José A 
Published: May 2024

BackgroundThe nigrostriatal system is especially vulnerable to neurodegeneration in Parkinson’s disease (PD) and the blood-brain barrier (BBB) is a limiting factor for delivery of therapeutic agents to the brain. This pilot study aimed to demonstrate safety, feasibility and tissue penetration (by 18F-Choline-positron emission tomography (PET)) of MR-guided focused ultrasound (MRgFUS) simultaneous BBB opening (BBB-O) in the substantia nigra (SN) and putamen in PD.MethodsThree patients underwent MRgFUS for midbrain and putamen BBB-O. Patients were evaluated clinically and underwent brain MRI with gadolinium (baseline, 24 hours, 14 days and 3 months postprocedure). In two patients, BBB-O was repeated after 2–3 weeks, and 18F-Choline-PET was performed immediately after.ResultsThe right SN and putamen were simultaneously opened unilaterally in 3 patients once and the left SN in 1 patient in a different session. No severe clinical or neuroimaging adverse events developed in any patient. 18F-Choline-PET uptake was enhanced in the targeted SN and putamen regions.ConclusionBBB-O of the nigrostriatal system is a feasible and well-tolerated approach in patients with PD. 18F-Choline-PET uptake indicates penetration into the parenchyma after BBB-O, which suggests that the opening is functionally effective. This minimally invasive technique could facilitate delivery of putative neurorestorative molecules to brain regions vulnerable to neurodegeneration.
Holographic inflation, primordial black holes and early structure formation
Authors: Banks Tom , Fischler Willy 
Published: May 2024

Evidence has accumulated that there are SuperMassive Black Holes (SMBHs) in the centers of most galaxies, and that these were formed in the very early universe by some as yet unknown process. In particular, there is evidence [J. Silk, M. C. Begelman, C. Norman, A. Nusser and R. F. G. Wyse, Astrophys. J. Lett. 961 (2024) L39, https://doi.org/10.3847/2041-8213/ad1bf0 , arXiv:2401.02482 [astroph. GA]; A. Bogdan et al., Nature Astron. 8 (2024) 126, https://doi.org/10.1038/s41550-023-02111-9 , arXiv:2305.15458 [astro-ph.GA]; S. Y. Guo, M. Khlopov, X. Liu, L. Wu, Y. Wu and B. Zhu, arXiv:2306.17022 [hep-ph]] that at least some galaxies formed as early as [Formula: see text] years after the big bang host SMBHs. We suggest that the holographic model of inflation, whose dark matter candidates are primordial black holes carrying a discrete gauge charge, which originated as a small subset of the inflationary horizon volumes in the very early universe, can provide the seeds for this early structure formation. Aspects of the model pointed out long ago suggested an early era of structure formation, with structures dominated by dark matter. The additional assumption that the dark matter consists of discretely charged black holes implies black hole dominance of early structures, which seems to be implied by JWST data.
Abstract A003: Characterization of circulating tumor cells from patients with metastatic bladder cancer
Authors: Niu Zeqi , Kozminski Molly , Day Kathleen C. , Broses Luke , Henderson Marian L. , Merajver Sophia , Udager Aaron , Palmbos Phillip L. , Nagrath Sunitha , Day Mark L. 
Published: May 2024

Abstract
Assessing the molecular profile of bladder tumors from patients with metastatic disease is crucial for implementing personalized treatment. Current standards are based on highly invasive biopsies. Alternatively, liquid biopsies of tumor cells, proteins, and nucleic acids allows longitudinal profiling in a less invasive manner. Circulating tumor cells (CTCs) isolated from blood are a key analyte of liquid biopsy. In this study, we developed a protein and transcriptomic co-analysis workflow for bladder cancer CTCs utilizing the graphene oxide (GO) microfluidic chip conjugated with antibodies against both EpCAM and EGFR to isolate CTCs from blood of patients with metastatic bladder cancer. Following CTC capture, protein and mRNA were analyzed using immunofluorescent staining and ion-torrent whole transcriptome sequencing. This is the first time that whole transcriptome sequencing was used in a downstream application for the GO microfluidic platform. We found that elevated CTC counts were significantly associated with patient disease status at the time of blood draw and that greater than 2 CTCs per mL were associated with shorter overall survival. Invasive markers, including EGFR, HER-2, CD31, and ADAM15, were detected in subpopulations of CTCs. Targeted whole transcriptome sequencing showed distinct expression profiles from patients with metastatic burden at the time of blood draw. In these patients, we found significant upregulation of several metastasis-related and chemotherapy-resistant genes demonstrating the capability of identifying tumor-related RNA signatures from circulating CTCs using immune-affinity GO chip-based assays. In addition, this workflow highlights the prognostic potential of CTCs in metastatic bladder cancer patients.
Citation Format: Zeqi Niu, Molly Kozminski, Kathleen C. Day, Luke Broses, Marian L. Henderson, Sophia Merajver, Aaron Udager, Phillip L. Palmbos, Sunitha Nagrath, Mark L. Day. Characterization of circulating tumor cells from patients with metastatic bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A003.
Abstract A012: Kmt2c/d loss primes urothelium for tumorigenesis and redistributes Menin to bivalent promoters
Authors: Wang Naitao , Pachai Mohini , Li Dan , Lee Cindy , Warda Sarah , Khudoynazarova Makhzuna , Cho Woo Hyun , Xie Guojia , Kuo Fengshen , Shah Sagar , Yao Li , Qian Cheng , Wong Elissa , Yan Juan , Tomas Fanny , Hu Wenhuo , Gao Sizhi , Smith Alison , Han Ming , Gao Dong , Ge Kai , Yu Haiyuan , Chandarlapaty Sarat , Iyer Gopakumar , Rosenberg Jonathan , Solit David , AI-Ahmadie Hikmat , Chi Ping , Chen Yu 
Published: May 2024

Abstract
Urothelial carcinoma arises from a “field” of precancerous but histologically normal urothelium. The KMT2C/D-KDM6A complexes known to bind and activate enhancers are frequently mutated in urothelial carcinoma and in histologically normal urothelium. Here, using a genetically engineered mouse model, we demonstrate that knockout of Kmt2c and/or Kmt2d induced a histologically normal, pre-tumorigenic state characterized by impaired differentiation from basal state and by augmented responses to growth and inflammatory stimuli. This sensitized the urothelium to transformation by known oncogenic drivers in urothelial carcinoma. Mechanistically, Kmt2d localized to both active enhancers and a small group of CpG-poor promoters and Kmt2c/d knockout led to diminished H3K4me1, H3K27ac and nascent RNA transcription at these sites, which together led to downregulation of the urothelial differentiation program. We further observed that Menin distributed extensively to Kmt2d localized enhancers and Kmt2c/d knockout led to redistribution of Menin to CpG-high and particularly bivalent promoters, resulting in transcriptional de-repression of bivalent genes. Blockade of Kmt2a/b-Menin interaction partially rescued the transcriptional changes that induced by Kmt2c/d deletion. Therapeutically, Kmt2c/d knockout maintained a basal state that upregulated EGFR signaling and conferred vulnerability to EGFR inhibitors. Together, our data posits that functional loss of Kmt2c/d licenses a molecular “field effect” priming histologically normal urothelium for oncogenic transformation and leading to therapeutic vulnerabilities to EGFR signaling pathway inhibition.
Citation Format: Naitao Wang, Mohini Pachai, Dan Li, Cindy Lee, Sarah Warda, Makhzuna Khudoynazarova, Woo Hyun Cho, Guojia Xie, Fengshen Kuo, Sagar Shah, Li Yao, Cheng Qian, Elissa Wong, Juan Yan, Fanny Tomas, Wenhuo Hu, Sizhi Gao, Alison Smith, Ming Han, Dong Gao, Kai Ge, Haiyuan Yu, Sarat Chandarlapaty, Gopakumar Iyer, Jonathan Rosenberg, David Solit, Hikmat AI-Ahmadie, Ping Chi, Yu Chen. Kmt2c/d loss primes urothelium for tumorigenesis and redistributes Menin to bivalent promoters [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A012.
Abstract A015: Novel genetic driver for the genesis of muscle invasion in bladder cancer
Authors: Mohanvelu Sreenidhi , Subramanian Poorvi , Salim Sabir , Somasundaram Dinesh Babu , Aravindan Sheeja , Aravindan Natarajan 
Published: May 2024

Abstract
Non-muscle invasive bladder cancer (NMIBC) is a heterogeneous type of urothelial carcinoma with a substantial risk (&gt;50%) of tumor progression and muscle invasion. Our sequential studies uniquely unveiled the availability of Retinal Degeneration Protein 3 (RD3) in human adult/fetal tissues and recognized its functional significance in tumor evolution. Herein, we investigated the relevance of RD3 in coordinating de novo MIBC from NMIBC. Compared to the low-grade tumor, RD3 is significantly lost (mRNA, qPCR; protein, ELISA) in grade III and IV patient derived NMIBC cells. In a cohort of (n=55) NMIBC patients, RD3-loss associated with increased tumor invasive potential (complete loss in highly invasive T4), metastasis (vs. primary tumors), therapy pressure (insignificant levels in progressive disease that defies therapy), disease recurrence, and death (custom archived TMA with automated RD3 IHC).Crucially, we observed a significant low-is-worse association to overall survival (p=7.30E-03, hazard ratio (HR) of 5.161), relapse-free survival (p=4.464E-02, HR = 2.328), and progression-free survival (p=7.00E-0.4, HR = 3.264). Further, radio-resistant cells exposed to fractionated irradiation (FIR, 2Gy/Day for 5 days) to a total dose of 10 or 20Gy displayed a dose dependent loss of RD3 recognizing an ongoing acquisition of RD3-loss with therapy pressure. More interestingly, Grade I or III bystander cells (BSE) co-cultured with FIR-exposed cells displayed anew acquisition of RD3-loss and displayed tumor grade-dependent increase (vs. mock-irradiated) in NFkB transcriptional activity (EMSA) and the activation of NFkB trans-activated pro-survival molecules (QPCR profiling of 89 NFkB targets). Together, these results clearly depict that RD3 regulates NMIBC disease pathogenesis, dissemination, acquired loss of RD3 with therapy pressure and further implies its role in the evolution of de novo MIBC from NMIBC. Funding: DOD CA-210339, OCAST-HR19-045, NIH-P20GM103639, NIH-NCI-P30CA225520 and TSET-R23-03.
Citation Format: Sreenidhi Mohanvelu, Poorvi Subramanian, Sabir Salim, Dinesh Babu Somasundaram, Sheeja Aravindan, Natarajan Aravindan. Novel genetic driver for the genesis of muscle invasion in bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A015.
Abstract A026: PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway
Authors: Wang Xue , Hunter Tony 
Published: May 2024

Abstract
Bladder cancer, one of the most commonly diagnosed cancers worldwide, is associated with high morbidity, mortality, and a poor prognosis. The PIN1 phospho-dependent prolyl isomerase is frequently overexpressed in many human cancer types and affects tumor initiation and progression through disrupting the balance of oncoprotein and tumor suppressor protein signaling. However, the functional pSer/Thr.Pro protein substrates of PIN1 and its effects on downstream signaling in bladder carcinogenesis remain largely unknown. Phenotypically, we discovered that ablation of Pin1 in human/mouse bladder cancer cells and organoids formed from mouse primary urothelial cells resulted in decreased cell proliferation, stemness maintenance, cell invasion, migration, urothelium clearance capacity, and reduced free/total cholesterol levels in vitro. Re-expressing Pin1 in Pin1 knockout cells reversed the defects caused by lack of Pin1. Moreover, in vivo subcutaneous xenograft and allograft transplantation mouse models combined with an orthotopic implantation model were utilized to confirm a positive role for Pin1 in controlling tumor growth and potential metastasis. Therapeutically, a combination of the sulfopin PIN1 inhibitor and the simvastatin HMGCR inhibitor was shown to suppress cell proliferation in vitro and tumor growth in vivo synergistically. Mechanistically, we observed a negative enrichment of SREBP2-driven cholesterol metabolism pathways in PIN1 knockout cells via RNA-sequencing and used a suite of diverse molecular and biochemical approaches to show that PIN1 directly binds to JNK-dependent phosphorylated SREBP2 (Ser455) and vice versa. These results indicate that active cholesterol biosynthesis pathway in bladder cancer cells is regulated by PIN1-mediated isomerization and JNK-mediated phosphorylation of its key transcriptional factor SREBP2. These findings emphasize that PIN1 can act as a regulator and potential therapeutic target in bladder cancer.
Citation Format: Xue Wang, Tony Hunter. PIN1 isomerase promotes the initiation and progression of bladder cancer through SREBP2-mediated cholesterol biosynthesis pathway [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A026.
Abstract B009: Targeting bladder cancer-macrophage interactions by SPARC peptides
Authors: Diab Mariam , Said Neveen 
Published: May 2024

Abstract
Bladder cancer is one of the privileged cancers treated with two modalities of immune therapeutics: intravesical Bacille Calmette-Guérin (BCG) for non-muscle invasive disease and immune checkpoint inhibitors for advanced metastatic muscle invasive disease. However, recurrence, intolerance and adverse events are encountered in both modalities with limited second and third line treatment options. Clinical data indicated that pretreatment infiltration of bladder tumors with tumor associated macrophages (TAMs) is associated with BCG failure, resistance to standard of care chemo- and immune-therapy and poor disease outcome. Preclinical studies indicated that macrophage infiltration is the forerunner of carcinogen-induced preneoplastic bladder lesions and progresses throughout overt neoplastic and metastatic disease. Thus, TAMs represent a plausible therapeutic target for bladder cancer. Capitalizing on our earlier report that SPARC, as tumor suppressor of BCa, we developed peptides mapping the biologically active domains of SPARC and investigated their direct effect on tumor cell malignant phenotype. In tandem, we determined the effect of SPARC-peptides on macrophage differentiation, polarization, and anti-tumor effects. We identified a potent inhibitory effect of our peptides on a panel of bladder cancer cell survival and invasiveness in 2D and 3D cultures. Using macrophage cell lines as well as bone marrow-derived myeloid cells, we found these peptides induced an M1 phenotype in response to cytokine stimulation, with enhanced phagocytic activity and macrophage-induced tumor cell killing in vitro. Moreover, SPARC-peptides inhibited macrophage polarization to M2 phenotype. Our data strongly suggest that SPARC-peptides are promising therapeutic candidates for bladder cancer.
Citation Format: Mariam Diab, Neveen Said. Targeting bladder cancer-macrophage interactions by SPARC peptides [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B009.