bluuebunny/crossref_metadata_2025 huggingface dataset:
Radioactive heat production variations in the Faroe–Shetland Basin: key new heat production, geological and geochronological data for regional and local basin modelling
Authors: Finlay Alexander J. , Wray David S. , Comfort Guy , Moore Julian K.
Published: August 2023

This study presents the results of a joint Chemostrat–APT study that aimed to produce a suite of radioactive heat production data for basement rocks in the Faroe Shetland Basin to enable more accurate basin modelling to be undertaken. To enable regional studies to be undertaken, the basement has been split into four zones based on similarities. Zone A is formed of high grade metamorphic basement from the Rockall trough (quads 154 & 164) SW of the Laxfordian front. Zone B comprises granodioritic, tonalitic and dioritic Neoarchean aged (2700–2830 Ma) high grade metamorphic basement from the SW of the Rona Ridge and Basin (wells 202/08-1, 204/15-2, 205/161, 205/21-1A, 206/7a-2, 206/08-2, 206/09-2 and 206/12-1) and NE of the Laxfordian front. Zone C contains Neoarchean aged high grade metamorphic basement of a predominantly granitic and quartz rich granitoid composition from the NE of the Rona Ridge (wells 207/01-3, 207/02-1, 208/23-1 and 208/26-1). Zone D differs from the rest of the material in this study in that it is Caledonian (
c.
460 Ma) granitic plutonic basement from Quads 209 (Ereland volcanic centre). Radioactive heat production values were derived from potassium, thorium and uranium data produced from the analysis of eighty-four basement samples by ICP-OES and ICP-MS analysis. Each mapped basement zone was then assigned a mean radioactive heat production value for use in future basin modelling studies; Zone A = 0.21 µWm
3
, Zone B, 0.64 µWm
3
, zone C = 0.88 µWm
3
and zone D = 2.1 µWm
3
.

Supplementary material:
Tables containing full mineralogical (SI 1) and U-Pb geochronological analytical (SI 2) data at
https://doi.org/10.6084/m9.figshare.c.6771540

Thematic collection:
This article is part of the New learning from exploration and development in the UKCS Atlantic Margin collection available at:
https://www.lyellcollection.org/topic/collections/new-learning-from-exploration-and-development-in-the-ukcs-atlantic-margin
Self-Adaptive Clothing Mapping Based Virtual Try-on
Authors: Shen Chengji , Liu Zhenjiang , Gao Xin , Feng Zunlei , Song Mingli
Published: August 2023

VTON (Virtual Try-ON), as an innovative visual application in e-commerce scenarios with great commercial value, has been widely studied in recent years. Due to its better robustness and realistic effect, deformation-synthesize-based VTON has become the dominant approach in this field. Existing clothing deformation techniques optimize the mapping relations between the original clothing image and the ground truth (GT) image of the worn clothing. However, there are color differences between the original and GT clothing images caused by lighting, warping, and occlusion. The color differences may lead to misaligned clothing mapping by only minimizing the cost of pixel value difference. Another drawback is that taking the parsing prediction as GT will bring alignment remnant, rooting in the processing order of parsing and deformation. Aiming above two drawbacks, we put forward SAME-VTON (Self-Adaptive clothing Mapping basEd Virtual Try-ON) for achieving realistic virtual try-on results. The core of SAME-VTON is the self-adaptive clothing mapping technique, composed of two parts: a color-adaptive clothing mapping module and a parsing-adaptive prediction process. In the color-adaptive clothing mapping module, we map each pixel of the target clothing with a combination of multiple pixel values from the original clothing image, which considers both the position and color changes. Furthermore, different combination weights are learned to increase the diversity of color mapping. In the parsing-adaptive prediction process, the color-adaptive clothing mapping module is adopted to deform clothing first, then the human parsing result is predicted under the reference of the deformed clothing, which can avoid alignment remnant. Extensive experiments demonstrate that the proposed SAME-VTON with the self-adaptive clothing mapping technique can achieve optimal mapping in the case of large color differences and obtain superior results compared with existing deformation-synthesize-based VTON.
Recognizing
k
-Leaf Powers in Polynomial Time, for Constant
k
Authors: Lafond Manuel
Published: August 2023

A graph
G
is a
k
-leaf power if there exists a tree
T
whose leaf set is
V
(
G
), and such that
uv
∈
E
(
G
) if and only if the distance between
u
and
v
in
T
is at most
k
(and
u
≠
v
). The graph classes of
k
-leaf powers have several applications in computational biology, but recognizing them has remained a challenging algorithmic problem for the past two decades. The best known result is that 6-leaf powers can be recognized in polynomial time. In this article, we present an algorithm that decides whether a graph
G
is a
k
-leaf power in time
O
(
n

f(k)

for some function
f
that depends only on
k
(but has the growth rate of a power tower function).

Our techniques are based on the fact that either a
k
-leaf power has a corresponding tree of low maximum degree, in which case finding it is easy, or every corresponding tree has large maximum degree. In the latter case, large-degree vertices in the tree imply that
G
has redundant substructures which can be pruned from the graph. In addition to solving a long-standing open problem, it is our hope that the structural results presented in this work can lead to further results on
k
-leaf powers and related classes.
Smooth and Spiky: The Importance of Variability in Marine Climate Change Ecology
Authors: Witman Jon D. , Pershing Andrew J. , Bruno John F.
Published: August 2023

Greenhouse gas emissions are warming the ocean with profound consequences at all levels of organization, from organismal rates to ecosystem processes. The proximate driver is an interplay between anthropogenic warming (the trend) and natural fluctuations in local temperature. These two properties cause anomalously warm events such as marine heatwaves to occur with increasing frequency and magnitude. Because warming and variance are not uniform, there is a large degree of geographic variation in temporal temperature variability. We review the underappreciated interaction between trend and variance in the ocean and how it modulates ecological responses to ocean warming. For example, organisms in more thermally variable environments are often more acclimatized and/or adapted to temperature extremes and are thus less sensitive to anthropogenic heatwaves. Considering both trend and variability highlights the importance of processes like legacy effects and extinction debt that influence the rate of community transformation.
Looking Back for the Future: The Ecology of Terrestrial Communities Through the Lens of Conservation Paleobiology
Authors: Kemp Melissa E. , Boville Alexandra E. , Carneiro Celine M. , Jacisin John J. , Law Chris J. , Ledesma David T. , Meza Antonio , Shields-Estrada Analisa , Xu Tianyi
Published: August 2023

Terrestrial ecosystems encompass a vast and vital component of Earth's biodiversity and ecosystem services. The effect of increased anthropogenic dominance on terrestrial communities defines major challenges for ecosystem conservation, including habitat destruction and fragmentation, climate change, species invasions and extinctions, and disease spread. Here, we integrate fossil, historical, and present-day organismal and ecological data to investigate how conservation paleobiology provides deep-time perspectives on terrestrial organisms, populations, communities, and ecosystems impacted by anthropogenic processes. We relate research tools to conservation outputs and highlight gaps that currently limit conservation paleobiology from reaching its full impact on conservation practice and management. In doing so, we also highlight how the colonial legacies of conservation biology and paleobiology confound our understanding of present-day biodiversity, ecosystem processes, and conservation outlooks, and we make recommendations for more inclusive and ethical practices moving forward.
Transcription–Replication Conflicts as a Source of Genome Instability
Authors: Goehring Liana , Huang Tony T. , Smith Duncan J.
Published: August 2023

Transcription and replication both require large macromolecular complexes to act on a DNA template, yet these machineries cannot simultaneously act on the same DNA sequence. Conflicts between the replication and transcription machineries (transcription–replication conflicts, or TRCs) are widespread in both prokaryotes and eukaryotes and have the capacity to both cause DNA damage and compromise complete, faithful replication of the genome. This review will highlight recent studies investigating the genomic locations of TRCs and the mechanisms by which they may be prevented, mitigated, or resolved. We address work from both model organisms and mammalian systems but predominantly focus on multicellular eukaryotes owing to the additional complexities inherent in the coordination of replication and transcription in the context of cell type–specific gene expression and higher-order chromatin organization.
Catalyst Layer Resistance and Utilization in PEM Electrolysis
Authors: Padgett Elliot , Bender Guido , Haug Andrew , Lewinski Krzysztof , Sun Fuxia , Yu Haoran , Cullen David A. , Steinbach Andrew J. , Alia Shaun M.
Published: August 2023

Improving utilization, performance, and stability of low iridium (Ir)-loaded anodes is a key goal to enable widespread adoption of polymer electrolyte membrane water electrolysis (PEMWE) for clean hydrogen production. A potential limitation is high ionic or electronic resistance of the anode catalyst layer, which leads to poor catalyst utilization, increased voltage losses, and high local overpotentials that can accelerate degradation. While catalyst layer resistance is relatively well-understood in fuel cells and other porous electrode systems, characterization of these effects is not as well established in PEMWE research. Here we present in-situ methods for measuring catalyst layer resistance in electrolysis cells using a non-faradaic H2/H2O condition as well as methods for calculating the associated voltage losses. These methods are applied to anode catalyst layers based on IrO2 nanoparticles as well as dispersed nano-structured thin film (NSTF) Ir catalysts. Trends with anode catalyst loading and interactions between the porous transport layer and catalyst layer are investigated for IrO2 anodes. Post-mortem microscopic analysis of durability-tested anodes is also presented, showing uneven degradation of the catalyst layer caused by catalyst layer resistance.
A Promotion Role of MIR31 in the Process of Vocal Fold Wound Healing
Authors: Wang Haizhou , Xu Wen
Published: August 2023

The role of MIR31 in the wound healing process, specifically in vocal fold wound healing (VFWH), remains uncertain despite its potential to facilitate the process. In this study, we first constructed a literature-based pathway to examine both the positive and negative effects of MIR31 on wound healing. We then conducted animal experiments on 20 rats to investigate MIR31 expression at different time points (1, 4, and 8 weeks) after vocal fold injury. Co-expression analysis and pathway analysis were performed to explore the potential function of MIR31 in VFWH. The literature-based pathway suggested that MIR31 could both impede and promote the wound healing process by regulating 14 and 47 wound healing upstream regulators, respectively. However, the rat experiment indicated that MIR31 expression significantly increased after vocal fold injury (

p
<
5.65
×

10

−
5

) but decreased in the late stage of VFWH compared with the early and middle stages (

p
<
5.40
×

10

−
3

. Strong co-expression was observed between MIR31 and 17 VFWH-significant genes (Pearson correlation coefficient ∈ (0.63, 0.83)), primarily involved in collagen production. Overall, our findings suggest that MIR31 plays a critical role in VFWH, particularly in collagen synthesis and other biological processes, which warrant further investigation.
Time-Dependent Reliability Analysis of RC Bridges Considering Shrinkage, Creep, Resistance Degradation, and Vehicle Load Flows
Authors: Fan Xueping , Zhou Heng , Liu Yuefei
Published: August 2023

Due to concrete shrinkage, concrete creep, resistance degradation, and vehicle load flows, the long-term performance of reinforced concrete bridges exhibits time-varying characteristics. The vehicle-borne process is a nonstationary random process, which interacts with concrete shrinkage, concrete creep, and resistance degradation to cause constant changes in bridge internal force and deformation, further, bridge dynamic reliability occurs. This study presented a reasonable method for calculating the time-varying reliability of simply supported girder bridges under the effects of traffic loads and shrinkage creep. Stochastic truck-load models were simulated based on site-specific weigh-in-motion measurements, then the internal forces of the bridge were calculated when the mean value of vehicle-mounted effects increases by 1% per year. Considering the resistance degradation and load effect increase, the reliability of the RC bridge in serviceability limit state and capacity-carrying ultimate state were analyzed using first-passage probability method and Monte Carlo method, respectively. The accuracy of the proposed method was verified by comparison. The evaluation results show that the failure probability including shrinkage and creep has increased significantly; creep is affected by the bridge span and the number of main girders, and the reliability assessment results are safer for bridges with smaller spans.
The Efficacy and Safety of Teprotumumab in Thyroid Eye Disease: Evidence from Randomized Controlled Trials
Authors: Lin Fei , Yao Qiu’e , Yu Bin , Deng Zehui , Qiu Jingyue , He Rong
Published: August 2023

In this study, we conducted a meta-analysis to assess the efficacy and safety of teprotumumab in treating thyroid eye disease. We searched the Cochrane Library, PubMed, and Embase databases from inception to May 25, 2022, and included all randomized controlled trials. Odds ratios (ORs) were calculated using fixed- or random-effect models. A total of three studies involving 341 patients were identified. Overall, the analysis revealed that teprotumumab demonstrated superior integrated proptosis response compared to placebo in both the intention-to-treat (ITT) population (OR = 17.81, 95% CI = [10.32, 30.76], I2 = 50%) and per-protocol population (OR = 24.53, 95% CI = [12.96, 46.45], I2 = 14%). Furthermore, patients receiving teprotumumab showed significant improvement in overall response (OR = 8.35, 95% CI = [4.74, 14.71], I2 = 79%), diplopia response (OR = 5.53, 95% CI = [3.24, 9.44], I2 = 0%), and achieving a clinical activity score (CAS) of 0 or 1 (OR = 6.26, 95% CI = [3.87, 10.12], I2 = 0%). Moreover, patients treated with teprotumumab experienced greater improvements in proptosis (MD = −2.49, 95% CI = [−2.54, −2.45], I2 = 98%) and Graves’ ophthalmopathy-specific quality of life (GO-QOL, MD = 11.48, 95% CI = [11.03, 11.93], I2 = 95%). However, it is important to note that patients receiving teprotumumab had a higher risk of adverse events, including serious adverse events, gastrointestinal adverse reactions, and muscle spasms. In summary, teprotumumab demonstrated greater improvement in proptosis response, proptosis, diplopia response, overall response, GO-QOL, and CAS. Nonetheless, it should be considered that its use is associated with a higher risk of adverse events.
Structural Condition Assessment and Temperature Effect Analysis of Cable–Pylon Anchorage Zone Using Long-Term SHM Data
Authors: Ye Hanhui , Chen Zhijian
Published: August 2023

To study the temperature effect in the anchorage zone of a long-span cable-stayed bridge, a wavelet multiresolution analysis and layered stripping method were used in this paper. Based on long-term structural health monitoring data, the signals were decomposed and reconstructed at multiple time scales, confirming temperature to be the main factor causing the stress change in the anchorage zone. The results of structural condition during operation showed that the general compressive stress level of the anchorage zone was low. However, the tensile stress level of the sidewall was high, which led to a severe concrete cracking. Excluding the influence of the seasonal temperature, the compressive stress increased slightly, the horizontal tensile stress in the upstream inner pylon wall increased, and the crack width increased gradually. By analysing the daily temperature effect on the upstream and downstream pylon walls, the regression model proposed in this study can be used to predict the daily temperature effect at any time in the diurnal cycle. The accuracy of the model is reliable within 6 days, but for the location of severe cracks, the monitoring data should be updated in real time to ensure the precision.
Generative Deep Learning for Visual Animation in Landscapes Design
Authors: Ardhianto Peter , Santosa Yonathan Purbo , Moniaga Christian , Utami Maya Putri , Dewi Christine , Christanto Henoch Juli , Chen Abbott Po Shun
Published: August 2023

The biggest challenge for architecture designers is the time required for the design process. Especially landscape architects who have different work limits from architects in general. In contrast to architects in general, who are assisted in producing design plans by building standards, building requirements, and space programs that adapt to the type of project being undertaken. At the same time, some design jobs demand high-productivity landscape animation presentation in a short time. The long process involved in designing animation often makes it difficult for designers to produce optimal work. This study proposes generative zooming animation with artificial intelligence support to shorten the designer’s work process and energy optimization. Deep learning with Vector Quantized Generative Adversarial Network and Contrastive Language-Image Pre-Training was used to generate alternative landscape designs from text prompt-based and compile them in animation. Our experiment shows that one frame can be generated roughly in 3.636 ± 0.089 s, which is significantly faster than the conventional method to create animation. Moreover, our method is able to achieve a good-quality image, which scored 3.2904 using inception score evaluation. The effectiveness of deep learning in visual landscape and animation creation can help designers speed up the design process. Furthermore, working time efficiency without compromising design quality will increase designer productivity and economic growth.
Stratifin Promotes Hepatocellular Carcinoma Progression by Modulating the Wnt/β-Catenin Pathway
Authors: Ye Shan-Ping , Yu Hong-Xin , Lu Wei-Jie , Wang Jun-Fu , Li Tai-Yuan , Shi Jun , Cheng Xiao-Ye
Published: August 2023

Abnormal stratifin (SFN) expression is closely related to the progression of several human cancers, but the potential roles of SFN in hepatocellular carcinoma (HCC) remain largely unknown. In this study, we found that SFN was upregulated in HCC cell lines and tissues and was positively associated with tumor size, poor differentiation, Tumor Node Metastasis (TNM) stage, and vascular invasion. In addition, high expression levels of SFN were associated with poor overall survival and disease-free survival. Biologically, downregulation of SFN suppressed tumor cell proliferation, epithelial–mesenchymal transition (EMT), invasion, and migration in vitro and tumor growth in vivo. However, overexpression of SFN promoted cell proliferation, EMT, invasion, and migration in vitro and tumor growth in vivo. Mechanistically, overexpression of SFN activated the Wnt/β-catenin pathway by promoting Glycogen synthase kinase-3 beta (GSK-3β) phosphorylation, decreasing β-catenin phosphorylation, promoting β-catenin transport into the nucleus, and enhancing the expression of c-Myc, whereas depletion of SFN inhibited the Wnt/β-catenin pathway. In addition, TOPFlash/FOPFlash reporter assays showed that overexpression or downregulation of SFN obviously increased or decreased, respectively, the activity of the Wnt/β-catenin pathway. Our results indicated that SFN plays an important role in HCC, possibly providing a prognostic factor and therapeutic target for HCC.
Data from Elevated Mast Cell Abundance is Associated with Enrichment of CCR2+ Cytotoxic T cells and Favorable Prognosis in Lung Adenocarcinoma
Authors: Fan Fanfan , Gao Jian , Zhao Yue , Wang Jun , Meng Lu , Ma Jiaqiang , Li Teng , Han Han , Lai Jinglei , Gao Zhendong , Li Xiongfei , Guo Ran , Cao Zhiwei , Zhang Yang , Zhang Xiaoming , Chen Haiquan
Published: August 2023

Abstract
Mast cells constitute indispensable immunoregulatory sentinel cells in the tumor microenvironment. A better understanding of the regulation and functions of mast cells in lung adenocarcinoma (LUAD) could uncover therapeutic approaches to reprogram the immunosuppressive tumor microenvironment. Here, we performed flow cytometry and single-cell RNA sequencing of patient LUAD samples to comprehensively characterize LUAD infiltrating mast cells. Mast cells exhibited functional heterogeneity and were enriched in LUAD with ground-glass opacity features (gLUAD). The mast cells in gLUAD exhibited proinflammatory and chemotactic properties while those in radiologically solid LUAD (sLUAD) were associated with tumor angiogenesis. Mast cells were an important source of CCL2 and correlated with the recruitment of CCR2+ cytotoxic T lymphocytes (CTLs), a specific subcluster of pre-exhausted T cells with tissue-resident memory phenotype and enhanced cytotoxicity. Increased infiltration of mast cells and CCR2+ CTLs and their colocalization showed a strong association with favorable prognosis after surgery but were not associated with improved survival after chemotherapy. Collectively, these findings reveal a key role of mast cells in LUAD and their potential crosstalk with CTLs, suggesting that targeting mast cells may be an immunotherapeutic strategy for LUAD.
Data from A Phase 1, Multicenter, Open-Label, First-in-Human Study of DS-6157a in Patients With Advanced Gastrointestinal Stromal Tumor
Authors: George Suzanne , Heinrich Michael C. , Somaiah Neeta , Oppelt Peter , McLeod Robert , Nishioka Satoshi , Kundu Madan G. , Qian Xiaozhong , Kumar Prasanna , Laadem Abderrahmane , Lau Yvonne , Tran Brittany P. , Fallon Maura , Dosunmu Ololade , Shi Julia , Naito Yoichi
Published: August 2023

Abstract
Purpose: To evaluate DS-6157a, an antibody-drug conjugate targeting G-protein coupled receptor 20 (GPR20), in gastrointestinal stromal tumors (GIST). Patients and methods: In this phase 1 multicenter, open-label, multiple-dose study, patients with previously-treated advanced GIST received intravenous DS-6157a on Day 1 of 21-day cycles, with a starting dose of 1.6 mg/kg. The primary objective evaluated the safety and tolerability of DS-6157a, while determining dose-limiting toxicity (DLT) and the maximum tolerated dose (MTD). Secondary objectives included plasma pharmacokinetics parameters, plasma antidrug antibodies (ADA), and efficacy. Results: A total of 34 patients enrolled. DS-6157a was well-tolerated, with DLTs in 4 patients (11.8%) at doses of 6.4 mg/kg, 9.6 mg/kg, and 12.8 mg/kg; the MTD was determined to be 6.4 mg/kg. Treatment-related adverse events (TEAE) grade ≥3 occurred in 17 patients (50.0%), including decreased platelet count (23.5%), anemia (20.6%), decreased neutrophil count (14.7%), and decreased white blood cell count (11.8%). Four patients (11.8%) experienced serious adverse events related to DS-6157a. Six patients died with 5 due to disease progression and 1 due to DS-6157a-related TEAE. Tumor shrinkage was observed in 7 patients (20.6%), and 1 patient (2.9%) achieved a partial response. Plasma concentrations and exposure of intact DS-6157a, DXd, and total anti-GPR20 antibody all demonstrated a dose-dependent profile. No treatment-emergent ADAs were observed. Conclusions: Targeting GPR20 with DS-6157a was tolerated in patients with advanced GIST with tumor shrinkage demonstrated in KIT/PDGFRA wild type GIST. However, the study did not proceed further due to lower efficacy outcomes than anticipated.
Data from Identifying mechanisms of resistance by circulating tumour DNA in EVOLVE, a Phase II Trial of Cediranib Plus Olaparib for Ovarian Cancer at time of PARP Inhibitor Progression
Authors: Lheureux Stephanie , Prokopec Stephenie D. , Oldfield Leslie E. , Gonzalez-Ochoa Eduardo , Bruce Jeff P. , Wong Derek , Danesh Arnavaz , Torti Dax , Torchia Jonathan , Fortuna Alexander , Singh Sharanjit , Irving Matthew , Marsh Kayla , Lam Bernard , Speers Vanessa , Yosifova Aleksandra , Oaknin Ana , Madariaga Ainhoa , Dhani Neesha C. , Bowering Valerie , Oza Amit M. , Pugh Trevor J.
Published: August 2023

Abstract
Purpose To evaluate the use of blood cell-free DNA (cfDNA) to identify emerging mechanisms of resistance to PARP inhibitors (PARPi) in high grade serous ovarian cancer (HGSOC). Patients and Methods We used targeted sequencing (TS) to analyse 78 longitudinal cfDNA samples collected from 30 patients with HGSOC enrolled in a phase II clinical trial evaluating cediranib (VEGF inhibitor) plus olaparib (PARPi) after progression on PARPi alone. cfDNA was collected at baseline, before treatment cycle 2, and at end of treatment. These were compared to whole exome sequencing (WES) of baseline tumour tissues. Results At baseline (time of initial PARPi progression), cfDNA tumour fractions were 0.2-67% (median 3.25%) and patients with high ctDNA levels (>15%) had a higher tumour burden (sum of target lesions; p = 0.043). Across all timepoints, cfDNA detected known from tumour WES with 74.4% sensitivity, and detected 3 of 5 expected BRCA1/2 reversion mutations. In addition, cfDNA identified 10 novel mutations not detected by WES, including 7 TP53 mutations annotated as pathogenic by ClinVar. cfDNA fragmentation analysis attributed 5 of these novel TP53 mutations to clonal hematopoiesis of indeterminate potential (CHIP). At baseline, samples with significant differences in mutant fragment size distribution had shorter time to progression (p = 0.001). Conclusions Longitudinal testing of cfDNA by TS provides a non-invasive tool for detection of tumour-derived mutations and mechanisms of PARPi resistance that may aid in directing patients to appropriate therapeutic strategies. With cfDNA fragmentation analyses, CHIP was identified in several patients and warrants further investigation.
Data from Oncogenic drivers and therapeutic vulnerabilities in KRAS wild-type pancreatic cancer
Authors: Singh Harshabad , Keller Rachel B. , Kapner Kevin S. , Dilly Julien , Raghavan Srivatsan , Yuan Chen , Cohen Elizabeth F. , Tolstorukov Michael , Andrews Elizabeth , Brais Lauren K. , da Silva Annacarolina , Perez Kimberly , Rubinson Douglas A. , Surana Rishi , Giannakis Marios , Ng Kimmie , Clancy Thomas E. , Yurgelun Matthew B. , Schlechter Benjamin L. , Clark Jeffrey W. , Shapiro Geoffrey I. , Rosenthal Michael H. , Hornick Jason L. , Nardi Valentina , Li Yvonne Y. , Gupta Hersh , Cherniack Andrew D. , Meyerson Matthew , Cleary James M. , Nowak Jonathan A. , Wolpin Brian M. , Aguirre Andrew J.
Published: August 2023

Abstract
Purpose: Approximately 8-10% of pancreatic ductal adenocarcinomas (PDAC) do not harbor mutations in KRAS. Understanding the unique molecular and clinical features of this subset of pancreatic cancer is important to guide patient stratification for clinical trials of molecularly targeted agents. Experimental Design: We analyzed a single-institution cohort of 795 exocrine pancreatic cancer cases (including 785 PDAC cases) with a targeted multi-gene sequencing panel and identified 73 patients (9.2%) with KRAS wild-type (WT) pancreatic cancer. Results: Overall, 43.8% (32/73) of KRAS WT cases had evidence of an alternative driver of the mitogen activated kinase (MAPK) pathway, including BRAF mutations and in-frame deletions and receptor-tyrosine kinase (RTK) fusions. Conversely, 56.2% of cases did not harbor a clear MAPK driver alteration, but 29.3% of these MAPK-negative KRAS WT cases (12/41) demonstrated activating alterations in other oncogenic drivers such as GNAS, MYC, PIK3CA and CTNNB1. We demonstrate potent efficacy of pan-RAF and MEK inhibition in patient-derived organoid (PDO) models carrying BRAF in-frame deletions. Moreover, we demonstrate durable clinical benefit of targeted therapy in a patient harboring a KRAS WT tumor with a ROS1fusion. Clinically, patients with KRAS WT tumors were significantly younger in age of onset (Median Age: 62.6 vs. 65.7 years , p = 0.037). SMAD4 mutations were associated with a particularly poor prognosis in KRAS WT cases. Conclusions: This study defines the genomic underpinnings of KRAS WT pancreatic cancer and highlights potential therapeutic avenues for future investigation in molecularly directed clinical trials.
Data from Dual role of CXCL8 in maintaining the mesenchymal state of glioblastoma stem cells and M2-like tumor-associated macrophages
Authors: Yuan Wei , Zhang Qian , Gu Danling , Lu Chenfei , Dixit Deobrat , Gimple Ryan C. , Gao Yisu , Gao Jiancheng , Li Daqi , Shan Danyan , Hu Lang , Li Lu , Li Yangqing , Ci Shusheng , You Hao , Yan Linping , Chen Kexin , Zhao Ningwei , Xu Chuanhai , Lan Jianyun , Liu Dong , Zhang Junxia , Shi Zhumei , Wu Qiulian , Yang Kailin , Zhao Linjie , Qiu Zhixin , Lv Deguan , Gao Wei , Yang Hui , Lin Fan , Wang Qianghu , Man Jianghong , Li Chaojun , Tao Weiwei , Agnihotri Sameer , Qian Xu , Mack Stephen C. , Zhang Nu , You Yongping , Rich Jeremy N. , Sun Guan , Wang Xiuxing
Published: August 2023

Abstract
Purpose: The dynamic interplay between glioblastoma stem cells (GSC) and tumor-associated macrophages (TAM) sculpts the tumor immune microenvironment (TIME) and promotes malignant progression of glioblastoma (GBM). However, the mechanisms underlying this interaction are still incompletely understood. Here, we investigate the role of CXCL8 in the maintenance of the mesenchymal state of glioblastoma stem cell populations and reprogramming the TIME to an immunosuppressive state. Experimental Design: We performed an integrative multi-omics analyses of RNA sequencing, GBM mRNA expression datasets, immune signatures, and epigenetic profiling to define the specific genes expressed in the mesenchymal GSC subsets. We then used patient-derived GSCs and xenograft murine model to investigate the mechanisms of tumor-intrinsic and extrinsic factor to maintain the mesenchymal state of GSCs and induce TAM polarization. Results: We identified CXCL8 was preferentially expressed and secreted by mesenchymal GSCs and activated PI3K/AKT and NF-κB signaling to maintain GSC proliferation, survival, and self-renewal through a cell-intrinsic mechanism. CXCL8 induced signaling through a CXCR2-JAK2/STAT3 axis in TAMs, which supported an M2-like TAM phenotype through a paracrine, cell-extrinsic pathway. Genetic- and small molecule-based inhibition of these dual complementary signaling cascades in GSCs and TAMs suppressed GBM tumor growth and prolonged survival of orthotopic xenograft-bearing mice. Conclusions: CXCL8 plays critical roles in maintaining the mesenchymal state of GSCs and M2-like TAM polarization in GBM, highlighting an interplay between cell-autonomous and cell-extrinsic mechanisms. Targeting CXCL8 and its downstream effectors may effectively improve GBM treatment.
Conditional Dependency of LP-184 on Prostaglandin Reductase 1 is Synthetic Lethal in Pancreatic Cancers with DNA Damage Repair Deficiencies
Authors: Restifo Diana , McDermott Joseph R. , Cvetkovic Dusica , Dos Santos Troy , Ogier Charline , Surumbayeva Aizhan , Handorf Elizabeth A. , Schimke Caleb , Ma Charlie , Cai Kathy Q. , Olszanski Anthony J. , Kathad Umesh , Bhatia Kishor , Sharma Panna , Kulkarni Aditya , Astsaturov Igor
Published: August 2023

The greater efficacy of DNA-damaging drugs for pancreatic adenocarcinoma (PDAC) relies on targeting cancer-specific vulnerabilities while sparing normal organs and tissues due to their inherent toxicities. We tested LP-184, a novel acylfulvene analog, for its activity in preclinical models of PDAC carrying mutations in the DNA damage repair (DDR) pathways.

Cytotoxicity of LP-184 is solely dependent on prostaglandin reductase 1 (PTGR1), so that PTGR1 expression robustly correlates with LP-184 cytotoxicity in vitro and in vivo. Low-passage patient-derived PDAC xenografts with DDR deficiencies treated ex vivo are more sensitive to LP-184 compared with DDR-proficient tumors. Additional in vivo testing of PDAC xenografts for their sensitivity to LP-184 demonstrates marked tumor growth inhibition in models harboring pathogenic mutations in ATR, BRCA1, and BRCA2. Depletion of PTGR1, however, completely abrogates the antitumor effect of LP-184. Testing combinatorial strategies for LP-184 aimed at deregulation of nucleotide excision repair proteins ERCC3 and ERCC4 established synergy.

Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.
Targeted Investigational Oncology Agents in the NCI-60: A Phenotypic Systems–based Resource
Authors: Morris Joel , Kunkel Mark W. , White Stephen L. , Wishka Donn G. , Lopez Omar D. , Bowles Lori , Sellers Brady Penny , Ramsey Patricia , Grams Julie , Rohrer Tiffany , Martin Karen , Dexheimer Thomas S. , Coussens Nathan P. , Evans David , Risbood Prabhakar , Sonkin Dmitriy , Williams John D. , Polley Eric C. , Collins Jerry M. , Doroshow James H. , Teicher Beverly A.
Published: August 2023

The NCI-60 human tumor cell line panel has proved to be a useful tool for the global cancer research community in the search for novel chemotherapeutics. The publicly available cell line characterization and compound screening data from the NCI-60 assay have significantly contributed to the understanding of cellular mechanisms targeted by new oncology agents. Signature sensitivity/resistance patterns generated for a given chemotherapeutic agent against the NCI-60 panel have long served as fingerprint presentations that encompass target information and the mechanism of action associated with the tested agent. We report the establishment of a new public NCI-60 resource based on the cell line screening of a large and growing set of 175 FDA-approved oncology drugs (AOD) plus >825 clinical and investigational oncology agents (IOA), representing a diverse set (>250) of therapeutic targets and mechanisms. This data resource is available to the public (https://ioa.cancer.gov) and includes the raw data from the screening of the IOA and AOD collection along with an extensive set of visualization and analysis tools to allow for comparative study of individual test compounds and multiple compound sets.
Rare Case of Managing and Evaluating Viability after Replantation of a Serial Self-Amputated Bilateral Testis by a Patient with Schizophrenia: A Case Report
Authors: Ahn Il Young , Ha Moon Soo , Kim Woo Ju , Bae Tae Hui , Kim Sun Mi , Choi Se Young , Kang Shin Hyuk
Published: August 2023

Amputation of the testis is very rare in clinical situations; therefore, most surgeons have no experience with an amputated testis. In this case, a 31-year-old male with schizophrenia amputated both testes due to self-mutilation. We performed replantation surgery via microscopy. On postoperative day 1, he removed his right testis by using his hand, even though his hands were restrained. The second attack disrupted the viability of the right testis. However, after proper management, we checked the normal sex hormone level by preserving the replanted left testis. We evaluated the viability of the replanted testis by performing five examinations, namely, intraoperative indocyanine green injection, testicular scan with technetium pertechnetate, contrast-enhanced computerized tomography, Doppler ultrasonography, and serum testosterone level. In this report, we aimed to describe our rare experience about management with replantation of the amputated testes and evaluation of their viability.
Other Pathologies Were Rarely Reported after Laparoscopic Surgery for Suspected Appendicitis: A Systematic Review and Meta-Analysis
Authors: Henriksen Siri Rønholdt , Rosenberg Jacob , Fonnes Siv
Published: August 2023

Background: Diagnostic laparoscopy is often used when a patient is suspected of having acute appendicitis. The aim of this study was to assess the rate of other pathologies found during diagnostic laparoscopy for suspected acute appendicitis. Methods: This systematic search included studies with ≥100 patients who received laparoscopy for suspected acute appendicitis and reported on the histopathologic and other intra-abdominal findings. We performed a meta-analysis estimating the rate of other pathologies, and a sensitivity analysis excluding smaller cohorts (≤500 patients). Age groups, sex, specific findings, and geographic regions were investigated. Certainty of evidence was assessed with GRADE. Results: A total of 27 studies were included covering 25,547 patients and of these 793 had an unexpected pathology. The findings were benign pathology in the appendix (34%), malignancy (30%), gynecologic pathology (5%), gastrointestinal pathology (4%), or unspecified (27%). Meta-analysis showed an overall rate of unexpected findings of 3.5% (95% CI 2.7–4.3; moderate certainty), and the sensitivity analysis showed similar results. Malignancy found in the appendix when treating suspected acute appendicitis was 1.0% (95% CI 0.8–1.3%; high certainty). Conclusion: The rate of other histopathological findings in patients with suspected acute appendicitis was low and a malignancy in appendix was found in 1% of patients.
The Role of Urine and Washing Cytology in Primary Transurethral Resection of Bladder Tumours
Authors: Struck Julian P. , Ozimek Tomasz , Schnoor Maike , Offermann Anne , Guenther Marlis , Roesch Marie C. , Wießmeye Judith R. , Katalinic Alexander , Perner Sven , Borgmann Hendrik , Merseburger Axel S. , Kramer Mario W.
Published: August 2023

Introduction: Urine cytology (UC) is a recommended tool for the diagnosis of urothelial malignancies. Thus far, no specific recommendations regarding the role of washing cytology (WC) have been included in the guidelines. The goal of our study was to analyse the relationship between the histology of transurethrally (transurethral resection of the bladder [TURBT]) resected bladder tumours (BCa) and intraoperative UC or WC findings. Materials and Methods: Five hundred consecutive primary TURBT cases conducted between November 2010 and 2015 at our department of the University Hospital Luebeck were retrospectively analysed. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of UC and WC were evaluated to detect BCa. Multivariate logistic regression models were fit to further examine associations between patient- and tumour-related factors and a bladder UC or WC positive for BCa. Results: UC was performed in 297 patients, WC in 294 patients, and both in 261 patients. Sensitivity was 50.7% in UC, 58.1% in WC, and 62.1% for both tests combined. Specificity was 97.8% for UC, 98.0% for WC, and 96.4% for the combined tests. PPV was 98.0% for UC, 98.1% for WC, and 97.2% for combined tests. NPV was 47.8% for UC, 54.5% for WC, and 55.9% for the combined tests. The multivariate analyses revealed no association between positive UC or WC results and subsequent radical cystectomy (UC OR 1.35, 95% CI: 0.3–5.7; WC OR 2.0, 95% CI: 0.4–11.4). Neither UC nor WC was significantly correlated with local recurrence. Conclusions: Cytologic testing is an important diagnostic tool in BCa detection, showing acceptable sensitivity of around 60% and excellent specificity of over 90%. UC and WC present similar sensitivity. Our results advocate, however, against cytologic testing during primary TURBT, especially with regard to the lack of value in assessing the risk of recurrence. The clinical benefit of taking both types of samples at once is minimal. Furthermore, intraoperative WC collection does not reliably predict subsequent cystectomies.
Fetal Growth Velocity according to the Mode of Assisted Conception
Authors: Caradeux Javier , Ávila Francisco , Vargas Francisco , Fernández Benjamín , Winkler Carolina , Mondión Mauricio , Rojas Iván , Figueras Francesc
Published: August 2023

Introduction: Pregnancies conceived through assisted reproductive techniques (ARTs) are on the rise worldwide and have been associated with a higher risk of placental-related disease in the third trimester. Methods: A cohort was created of singleton pregnancies after assisted reproduction, admitted at our institution for delivery, between January 2020 and August 2022. Fetal growth velocity from the second trimester to delivery was compared against a gestational-age-matched group of pregnancies spontaneously conceived according to the origin of the selected oocyte (i.e., autologous vs. donated). Results: 125 singleton pregnancies conceived through ART were compared to 315 singleton spontaneous conceptions. Overall, after adjusting for possible confounders, multivariate analysis demonstrated that ART pregnancies had a significantly lower estimated fetal weight (EFW) z-velocity from the second trimester to delivery (adjusted mean difference = −0.002; p = 0.035) and a higher frequency of EFW z-velocity in the lowest decile (adjusted OR = 2.32 [95% CI, 1.15–4.68]). Also, when ART pregnancies were compared according to the type of oocyte, those conceived with donated oocytes showed a significantly lower EFW z-velocity from the second trimester to delivery (adjusted mean difference = −0.008; p = 0.001) and a higher frequency of EFW z-velocity in the lowest decile (adjusted OR = 5.33 [95% CI, 1.34–21.5]). Conclusions: Pregnancies achieved through ART exhibit a pattern of lower growth velocity across the third trimester, especially those conceived with donated oocytes. The former represents a sub-group at the highest risk of placental dysfunction that may warrant closer follow-up.
Endobronchial Ultrasound for the Screening of Pulmonary Embolism in Patients with Suspected Lung Cancer: A Prospective Cohort Study
Authors: Juul Amanda Dandanell , Laursen Christian B. , Christophersen Alice , Arshad Arman , Luef Stefan Møller , Panou Vasiliki , Larsen Julie Gellert , Reimer Jacob , Paaby Jens , Falster Casper
Published: August 2023

Background: Patients with lung cancer exhibit increased risk of pulmonary embolism (PE). While the contrast phase of computed tomography of the chest in the diagnostic work-up of suspected chest malignancy does not allow reliable detection of PE, it may be feasible to screen for present PE during endobronchial ultrasound (EBUS) examination. Objectives: The aim of this study was to establish if screening during EBUS for PE in patients with suspected lung cancer is feasible and if positive findings are predictive of PE. Methods: Patients undergoing EBUS due to suspicion of malignancy of the chest were prospectively enrolled. The pulmonary arteries were assessed during EBUS using a standardized protocol. Patients in whom PE suspicion was raised were referred to confirmatory imaging. Results: From December 2020 to August 2021, 100 patients were included. Median time for vascular assessment during EBUS was 2 min (Q1–Q3: 1–3 min). EBUS identified two suspected PEs (2%), and the number needed to scan was 50. The positive predictive value of EBUS for PE was 100%. Conclusion: EBUS for PE screening seems feasible and with limited time use. The PPV of positive findings for the diagnosis of PE is high, but the utility is somewhat limited by a high number needed to scan even in a high-risk population. Based on our findings, we believe that EBUS assessment of the pulmonary vasculature may have a role as a routine screening tool for PE. The assessment for PE should be implemented in EBUS training programmes, as operators should be able to recognize incidental PEs.
Women in Interventional Pulmonology: Results from a Worldwide Survey
Authors: Brock Judith , Zehetmayer Sonja , Gompelmann Daniela
Published: August 2023

Background and Objectives: Gender inequality in medicine remains an issue. Despite the increasing proportion of female physicians, women still appear underrepresented in interventional pulmonology (IP) careers. To date, no data are available on the gender distribution in IP. Method: An online survey was sent to pulmonary physicians internationally between July and December 2022. The survey included questions on gender diversity in the pulmonology departments, such as the proportion of male, female, and gender diverse physicians performing bronchoscopy, career progression, and social life. Results: Responses from 92 physicians (mean age 45 ± 10 years) from 47 hospitals across 17 countries were analysed, of whom 52% were women. Overall, 79% of the respondents were pulmonologists and 83% perform bronchoscopy. Although men continue to dominate bronchoscopy (65 vs. 43%) and are more likely to be involved in research (89 vs. 77%), the observed difference is statistically not significant (p = 0.135 and p = 0.281). Leading positions are held by 60% of male respondents and 23% of female respondents (p = 0.002). Men are also more often reported to have academic awards. Discrimination based on gender was reported by 5.3% of all men and 26.8% of all women (p = 0.023). Conclusions: Men and women are almost equally involved in IP, especially in female-led bronchoscopy units. However, leading positions and academic awards are still predominantly held by men.
Tortuosity and Proximal-Specific Hemodynamics Associated with Plaque Location in the Carotid Bulb Stenosis
Authors: Ren Lei , Xu Rongjie , Zhao Chenxi , Li Wenfei , Wang Shu , Cao Chen , Gong Yan , Zhu Jinxia , Feng Xuequan , Ren Bo , Xia Shuang
Published: August 2023

Background: Atherosclerotic plaque locations in the carotid bulb increasingly have been found to be associated with patterns of ischemic lesions and plaque progression. However, the occurrence of carotid bulb plaque is a complex process. We aimed to investigate plaque characteristics and geometric and hemodynamic parameters among patients with body and apical plaques of the carotid bulb and to identify the mechanism of bulb plaque formation and location. Methods: Consecutive patients with single carotid bulb stenosis (50–99%) were enrolled retrospectively. Patients were divided into body and apical plaque groups based on plaque location. Plaque location and characteristics were identified and measured on high-resolution vessel wall magnetic resonance imaging. Geometric parameters were derived from time-of-flight magnetic resonance imaging. Computational fluid dynamics simulations were performed to quantify wall shear stress (WSS) and four associated WSS-based metrics on the plaque side, on the non-plaque side, and in different parts of the lesion. Plaque characteristics and geometric and hemodynamic parameters were compared, and their associations with the plaque location were determined. Results: Seventy patients were recruited (41 body plaques and 29 apical plaques). WSSplaque values were lower than WSSnon-plaque values for all plaques (median [interquartile range], 12.59 [9.83–22.14] vs. 17.27 [11.63–27.63] Pa, p = 0.001). In a multivariate binary logistic regression, the tortuosity of the stenosed region, the magnitudes of the mean relative residence time, and the minimum transverse WSS in the proximal part of the lesion were the key factors independently associated with plaque location (p = 0.022, 0.013, and 0.012, respectively). Conclusions: Plaque formation was associated with the local flow pattern, and the tortuosity and proximal-specific hemodynamics were significantly associated with plaque location in the carotid bulb.