bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B067: CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells
Authors: Kumar Rajendra , Mendonca Janet , Yang Yuhan , Shetty Abhishek , Wilson Lillian , Boyapati Kavya , Topiwala Deven , Soundappan Keerti , Panagopoulos Eleni , Carducci Michael , Kachhap Sushant 
Published: June 2023

Abstract
Background: Advanced metastatic prostate cancer is the second leading cause of death in men in the United States. Androgen deprivation therapy has been used as a front-line therapy; however, despite initial success, it fails subsequently and results in the development of castration-resistant prostate cancer. Due to these unmet therapeutic needs, there is an urgency to identify novel targets to develop next-generation therapeutics. Chromosome region maintenance 1 (CRM1) is one of the seven members of mammalian export proteins that function to export the proteins using nuclear export signal (NES). Several tumors, including prostate cancer, overexpress CRM1 to efflux tumor suppressor proteins to the cytoplasm and exhibit dysregulated nuclear export. CRM1-mediated export can lead to functional inactivation of p53, cyclinD1, p16, p21, and p27. Essential DNA repair proteins such as Rad51 and BRCA1 exhibit leucine-containing hydrophobic residues rich in NES and are known to be shuttled by CRM1. Based on this, we hypothesize that CRM1 inhibition may affect the expression, kinetics, localization, and stability of DNA repair network proteins. Methods: Androgen receptor-positive and negative prostate cancer cells were treated with Selinexor. The dose of the drug and duration was dependent on the endpoint measurement. Cell death was monitored using MTT assay and western blot measurement of cleaved PARP. Total RNA and cell lysate were collected to measure the relative levels of BRCA-1, RAD51, p53, and other members of the DNA repair pathway (HR and NHEJ). DNA damage was estimated using the number of micronuclei and immunofluorescence staining for γ-H2AX and COMET assay. Results: Selinexor treatment in prostate cancer cells affects the functioning of the DNA repair network and can be combined with inhibitors of DNA repair proteins.
Citation Format: Rajendra Kumar, Janet Mendonca, Yuhan Yang, Abhishek Shetty, Lillian Wilson, Kavya Boyapati, Deven Topiwala, Keerti Soundappan, Eleni Panagopoulos, Michael Carducci, Sushant Kachhap. CRM1 inhibitor selinexor induces DNA damage repair-related vulnerability in prostate cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B067.
Abstract IA003: Evolution of AR gene structure during prostate cancer progression
Authors: Dehm Scott M 
Published: June 2023

Abstract
Castration-resistant prostate cancer (CRPC) emerges when endocrine therapies are no longer effective at suppressing activity of the androgen receptor (AR) transcription factor. Our laboratory has implemented DNA sequencing approaches to identify genomic mechanisms contributing to CRPC in prostate cancer cell lines, patient-derived xenografts (PDXs), and clinical specimens. These approaches have revealed AR as one of the most frequently-rearranged genes in CRPC. However the patterns of AR gene rearrangements observed between patients and even between anatomically distinct metastases within a single patient are remarkably complex and heterogeneous. To address this complexity, we analyzed a cohort of prostate cancer specimens using linked-read DNA-sequencing. This approach found that a subset of clinical CRPC metastases had accumulated complex AR rearrangements in conjunction with very high AR copy number, a phenomenon that also occurred in PDX models grown under selective pressure of castration. Using orthogonal approaches of optical genome mapping and fluorescence in situ hybridization, we found that AR residing on extrachromosomal circular DNA (eccDNA) was an underlying mechanism. This study identifies eccDNA as an engine for accumulation of AR gene copy number and structural complexity during CRPC progression.
Citation Format: Scott M Dehm. Evolution of AR gene structure during prostate cancer progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA003.
Abstract IA004: Metabolic mechanisms of prostate cancer progression that feed nuclear receptors
Authors: Sharifi Nima 
Published: June 2023

Abstract
The androgen axis is central to prostate cancer physiology and therapy. Androgens are gonadal and extragonadal in origin, both of which stimulate the androgen receptor (AR). The use of medical castration (ADT), adrenal androgen ablation (i.e., abiraterone) and potent AR antagonists (i.e., enzalutamide, apalutamide, darolutamide), has yielded complex clinical states of prostate cancer, including disease states that are resistant to multiple forms of hormonal therapy. One of the major questions that arises is whether men can be identified who will benefit from earlier intensive hormonal therapy. Another question is whether alternative hormonal treatment strategies can be used to address resistance to the current generation of hormonal therapies. We propose that identification of steroid metabolic dependencies is part of the answer to both of these questions. Approximately half of men with prostate cancer inherit an activating missense in the first and rate-limiting enzyme that converts extragonadal precursor steroids to dihydrotestosterone (DHT). The “adrenal-permissive” HSD3B1(1245C) allele encodes for a 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) enzyme that increases tumor DHT synthesis from adrenal DHEA. Heterozygous or homozygous HSD3B1(1245C) inheritance confers poor outcomes after ADT. Furthermore, men with HSD3B1(1245C) inheritance and castration-resistant prostate cancer (CRPC) treated with abiraterone or enzalutamide still have poorer outcomes. Together, these data suggest that directly targeting this metabolic lesion is necessary for optimal therapy in these men. We recently discovered that phosphorylation of the 3βHSD1 tyrosine 344 by the BMX kinase is necessary for androgen biosynthesis and CRPC in xenograft models. These findings have led to the launch of the Maverick clinical trial in the Prostate Cancer Clinical Trials Consortium (PCCTC) that combines abiraterone plus BMX inhibition with abivertinib in men with CRPC. In sum, this accumulating body of evidence suggests that steroid metabolic dependencies should be considered as an essential part of cancer metabolism, particularly in the context of developmental therapeutics for prostate cancer.
Citation Format: Nima Sharifi. Metabolic mechanisms of prostate cancer progression that feed nuclear receptors [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA004.
Abstract IA019: Tumor microenvironment modulation is critical for cellular immunotherapy efficacy
Authors: Dorff Tanya B , Blanchard M Suzette , Murad John , Adkins Lauren , Dhaploa Gaurav , Forman Stephen , Priceman Saul 
Published: June 2023

Abstract
Background: Chimeric antigen receptor (CAR)-engineered T cell therapies are being pursued for the treatment of prostate cancer, among other solid tumors. However the role of lymphodepletion was uncertain for application outside of heme malignancies. We studied the effect of chemotherapy preconditioning on the tumor immune microenvironment along with the impact on CAR-T cell activity. Methods: Immunocompetent mice bearing RM9 prostate tumors lentivirally transduced to express human prostate stem cell antigen (PSCA) and treated with PSCA targeted CAR T cells alone, or after 100 mg/kg cyclophosphamide (Cy). Tumors were evaluated for immune cell subsets infiltration in addition to clinical response. As part of a phase 1 dose escalation trial patients received 100 M PSCA-targeted CAR T cells, manufactured at City of Hope’s cGMP facility, alone or after Cy. CAR T persistence and cytokine levels were evaluated by flow cytometry and luminex, respectively. Results: CAR T cells alone had minimal anti-tumor effect in immune competent mice. Cy was associated with increased CD11c+ DCs and reduced CD206+ M2 macrophages in the tumors. With Cy pre-conditioning followed by infusion of PSCA-CAR T cells, over 40% of mice had complete response (CR) and rejected rechallenge of tumor. 10-fold greater T cell infiltration was noted in tumors after Cy preconditioning, with lesser increase and no anti-tumor effect noted with Cy + mock CAR T cells. In the phase 1 human trial greater CAR T cell expansion and cytokine induction were noted with Cy + PSCA-CAR T compared to PSCA-CAR T alone. Conclusion: Cy functions as a modifier of the prostate cancer tumor microenvironment, facilitating CAR T cell infiltration and expansion. This has resulted in greater activity of PSCA-CAR T cells both in murine models and preliminary human testing. Further study of manipulations to optimize the tumor immune microenvironment will likely be important to maximizing efficacy of cellular immunotherapy in prostate cancer.
Citation Format: Tanya B Dorff, M Suzette Blanchard, John Murad, Lauren Adkins, Gaurav Dhaploa, Stephen Forman, Saul Priceman. Tumor microenvironment modulation is critical for cellular immunotherapy efficacy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA019.
Abstract IA025: Pursuing novel treatment strategies for advanced prostate cancer
Authors: de Bono Johann 
Published: June 2023

Abstract
While there have been major advances in understanding of prostate cancer biology, and outcomes including survival and quality of life for men suffering from advanced prostate cancer, the development of novel treatment strategies for aggressive prostate cancer remains an unmet medical need. Studies have shown that advanced prostate cancer has considerable inter- and intra-patient heterogeneity and biomarkers supporting disease molecular stratification are also urgently required to further improve outcomes. This presentation will focus on rational, biomarker driven, novel approaches to improve prostate cancer treatment and will discuss novel targets such as B7-H3, and the targeting of tumour-stroma paracrine interactions.
Citation Format: Johann de Bono. Pursuing novel treatment strategies for advanced prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA025.
Abstract PR008: Molecular determinants of prostate cancer lineage plasticity
Authors: Wadosky Kristine , Ku Sheng-Yu , Wang Yanqing , Zhang Xiaojing , Wang Jie , Wang Jianmin , Beltran Himisha , Goodrich David W. 
Published: June 2023

Abstract
Androgen deprivation therapy (ADT) has been an effective treatment for advanced prostate cancer (PCa) for decades because PCa retains the lineage specific dependence of normal prostate tissue on androgen receptor (AR) signaling. Unfortunately, nearly all patients will progress through ADT with castrate resistant prostate cancer (CRPC). CRPC is typically associated with reactivation of AR signaling despite ADT. However with widespread clinical deployment of potent AR signaling inhibitors, an increasing fraction of CRPCs (~20) are now observed to lose AR signaling activity and show gene expression patterns consistent with alternative lineage states. These lineage variants share clonal origin with the pre-existing adenocarcinoma, so some PCa cells have sufficient plasticity to reprogram to an AR independent lineage state like neuroendocrine prostate cancer (NEPC) that is recalcitrant to available therapies. The molecular determinants of prostate cancer lineage plasticity are incompletely defined, and this knowledge gap has hindered development of diagnostic and therapeutic approaches necessary to identify and treat prostate cancer lineage plasticity. We present results from experiments testing the contribution of EZH2 and NOTCH signaling to prostate cancer lineage plasticity and NEPC reprogramming. EZH2 expression is elevated in advanced PCa, particularly NEPC, suggesting it drives lineage reprogramming. However, using genetically engineered mice and organoids we find that EZH2 is not required for NEPC reprogramming that occurs in some PCa cells in the absence of the RB1 and TP53 tumor suppressor genes. EZH2 deficiency does alter multi-lineage prostate cancer plasticity, biasing development towards lineage variants observed clinically including amphicrine and double negative prostate cancer. In contrast, data from clinical specimens indicates NOTCH signaling activity declines in NEPC compared to AR+ CRPC. NOTCH signaling suppresses NEPC development in both organoids and genetically engineered mice, and loss of NOTCH signaling is required to maintain the NEPC lineage state. Constitutive NOTCH signaling biases PCa development towards unique lineage variants including AR positive metastatic PCa with luminal differentiation. These results identify EZH2 and NOTCH signaling as molecular determinants of PCa lineage plasticity and NEPC reprogramming with implications for ongoing efforts to target these molecules for PCa therapy.
Citation Format: Kristine Wadosky, Sheng-Yu Ku, Yanqing Wang, Xiaojing Zhang, Jie Wang, Jianmin Wang, Himisha Beltran, David W. Goodrich. Molecular determinants of prostate cancer lineage plasticity [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR008.
Efficacy and Safety of Adjunctive and Primary Use of the TightRail Mechanical Cutting Sheath for Lead Extraction
Authors: Sampognaro James R. , Karatela Maham , Lewis Robert K. , Black-Maier Eric , Pokorney Sean D. , Hegland Donald D. , Piccini Jonathan P. 
Published: June 2023

Background:
Rotational cutting tools are increasingly used in transvenous lead extraction. There are limited data on their safety and efficacy, particularly when used adjunctively for stalled progression. The aim of this study was to evaluate the utilization, safety, and effectiveness of mechanical rotational cutting tools for transvenous lead extraction.

Methods:
Patients undergoing transvenous lead extraction at a single tertiary center (April 2015 to January 2021, n=586) were included in this retrospective analysis. The study characterized the 251 patients (42.8%) whose cases involved the TightRail mechanical cutting tool.

Results:

Among 251 patients, 526 leads were extracted and TightRail was used for 70.5%. The TightRail was used adjunctively with the laser for 65.2% of leads, 97.8% of the time as the second tool after stalled progression. Using a multivariable logistic regression model, we found that active-fixation leads (odds ratio, 2.78 [95% CI, 1.62–4.78];
P
=0.0002), dual-coil leads (odds ratio, 3.39 [95% CI, 1.87–6.16];
P<0
.0001), and lead dwell time (odds ratio, 1.16 [95% CI for 1-year increase, 1.11–1.21];
P<0
.0001) were factors independently associated with adjunctive TightRail use. Stalled progression requiring TightRail occurred most often in the innominate vein and superior vena cava (59.3%). The clinical success rate was 96.8%, and the rate of major adverse events was 2.8%. Only 1 major adverse event was observed during TightRail use.

Conclusions:
Rotational cutting with TightRail was used in 42.8% of transvenous lead extractions, predominantly in an adjunctive manner after stalled laser progression in the innominate vein and superior vena cava, and more frequently for dual-coil and leads with longer dwell times. Adjunctive TightRail use carries a low risk of major complications.
Association Between Omega‐3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose–Response Meta‐Analysis of Randomized Controlled Trials
Authors: Wang Tianjiao , Zhang Xin , Zhou Na , Shen Yuxuan , Li Biao , Chen Bingshu E. , Li Xinzhi 
Published: June 2023

Background
Previous results provide supportive but not conclusive evidence for the use of omega‐3 fatty acids to reduce blood lipids and prevent events of atherosclerotic cardiovascular disease, but the strength and shape of dose–response relationships remain elusive.

Methods and Results
This study included 90 randomized controlled trials, reported an overall sample size of 72 598 participants, and examined the association between omega‐3 fatty acid (docosahexaenoic acid, eicosapentaenoic acid, or both) intake and blood lipid changes. Random‐effects 1‐stage cubic spline regression models were used to study the mean dose–response association between daily omega‐3 fatty acid intake and changes in blood lipids. Nonlinear associations were found in general and in most subgroups, depicted as J‐shaped dose–response curves for low‐/high‐density lipoprotein cholesterol. However, we found evidence of an approximately linear dose–response relationship for triglyceride and non‐high‐density lipoprotein cholesterol among the general population and more evidently in populations with hyperlipidemia and overweight/obesity who were given medium to high doses (>2 g/d).

Conclusions
This dose–response meta‐analysis demonstrates that combined intake of omega‐3 fatty acids near linearly lowers triglyceride and non‐high‐density lipoprotein cholesterol. Triglyceride‐lowering effects might provide supportive evidence for omega‐3 fatty acid intake to prevent cardiovascular events.
Comparison of Boston Criteria v2.0/v1.5 for Cerebral Amyloid Angiopathy to Predict Recurrent Intracerebral Hemorrhage
Authors: Fandler-Höfler Simon , Gattringer Thomas , Enzinger Christian , Werring David J. 
Published: June 2023

BACKGROUND:
Intracerebral hemorrhage (ICH) caused by cerebral amyloid angiopathy (CAA) has a high recurrence risk. The Boston criteria, while not designed to predict recurrence, are commonly used for in vivo diagnosis of CAA and have recently been revised to the version 2.0 (v2.0), introducing nonhemorrhagic white matter features. We investigated whether the new v2.0 criteria change ICH recurrence risk in patients with probable CAA.

METHODS:
We assessed ICH recurrence risk in consecutive patients with ICH and available brain magnetic resonance imaging. Patients with macrovascular or structural causes were excluded. Recurrent ICH was determined using electronic health records and confirmed by neuroimaging. We compared ICH recurrence risk for Boston criteria v2.0 versus v1.5 for probable CAA using survival analysis.

RESULTS:

Fifty-nine of 443 patients (13.3%) had recurrent ICH over a median follow-up of 5.7 years (2682 patient-years). Thirty-seven out of one hundred two patients (36.3%) with probable CAA according to the Boston criteria v2.0 had recurrent ICH compared with 36/82 patients (43.9%) according to the v1.5 criteria. Patients with probable CAA according to the Boston v1.5 criteria had a higher ICH recurrence rate (10.9 per 100 person-years [95% CI, 7.8–15.1]) compared with those diagnosed by the v2.0 criteria (8.5 per 100 person-years [95% CI, 6.1–11.7]). The 20 patients defined as probable CAA only by the v2.0 criteria had a very low recurrence rate (0.9 per 100 person-years [95% CI, 0.1–6.7]), lower than those diagnosed using the v1.5 criteria (
P
<0.001).

CONCLUSIONS:
Our findings suggest a wide spectrum of ICH recurrence risk in patients with probable CAA. Patients with ICH diagnosed with CAA based only on the nonhemorrhagic white matter markers introduced in the Boston v2.0 criteria had a much lower risk of recurrence than those diagnosed with the previous Boston criteria v1.5, comparable to that of patients with ICH not fulfilling any probable CAA criteria.
Is citizen satisfaction affected by the equivalent framing effect? A study based on situations involving poor government performance
Authors: Gao Xuede , Wang Qian , Shen Xiyun 
Published: June 2023

Although numerous studies have confirmed the existence and possible limitations of the equivalent framing effect in performance information evaluation, few studies have examined the conditions under which this framing effect works or does not work. This paper explores the equivalent framing effect of citizen satisfaction in the case of poor government performance by using two investigation experiments, and examines the boundary conditions of this effect in terms of performance information sources and trust in government. The results show that citizen satisfaction is higher when performance information is framed positively, rather than negatively. The findings demonstrate that the equivalent framing effect of citizen satisfaction is moderated by performance information sources and trust in government. This result indicates that equivalent framing effect has a certain fragility, showing heterogeneity with different sources of performance information and different levels of public trust in the government. Points for practitioners Truthfully reporting poor performance is the basic requirement for local governments. This study reminds government staff that, on the one hand, low performance is not a scourge, and small changes in poor performance reports may significantly change citizen satisfaction. On the other hand, it is not a panacea to improve citizen satisfaction simply by changing the presentation of performance information. The government should make more efforts to improve the public's confidence in performance information and the government.
Evaluation of qualitative and quantitative imaging features of hepatic hemangiomas with and without pseudo-washout sign on gadoxetic acid-enhanced MRI: a descriptive and comparative study
Authors: Aslan Serdar , Onder Ramazan Orkun , Sulun Emrah , Taşdemir Merve Nur 
Published: June 2023

Background Hepatic hemangiomas are the most common benign liver tumors. It is important to know the imaging features of hemangiomas on gadoxetic acid (GA)-enhanced magnetic resonance imaging (MRI). Purpose To evaluate the qualitative and quantitative imaging features of hemangiomas on GA-enhanced MRI, and to compare imaging features of hemangiomas with and without pseudo-washout sign (PWS). Material and Methods We retrospectively included 93 cases of hemangioma that underwent GA-enhanced MRI. The presence of an enhancement pattern in the arterial phase (AP) and PWSs in the transitional phase (TP) were evaluated. Signal-to-norm ratios (SINorm) of hemangiomas, liver parenchyma, and portal vein (PV) as well as contrast-to-norm ratio (CNorm) were assessed. Additionally, hemangiomas with and without PWSs were defined as two separate subgroups, and imaging features were compared. Results Of the 93 cases of hemangiomas, 49 (52.6%) had PWSs in the TP. The mean SINorms of hemangiomas showed the highest value in the AP ( P < 0.05). The mean CNorms showed positive values in the AP, and gradually decreased ( P < 0.05). Hemangiomas with PWSs were significantly rapidly enhanced and smaller in size ( P < 0.05), and the mean SINorms was lower in the TP ( P = 0.023). While the mean CNorms showed a significant difference in the AP between subgroups ( P < 0.001), the enhancement pattern was equal to that of the PV. Conclusion When evaluating GA-enhanced MRI, radiologists should utilize quantitative measures in addition to qualitative assessment and should be aware that SI matching with PV in all phases can be a distinguishing finding in the diagnosis of hemangioma.