bluuebunny/crossref_metadata_2025 huggingface dataset:
Time fractional gradient flows: Theory and numerics
Authors: Li Wenbo , Salgado Abner J.
Published: January 2023

We develop the theory of fractional gradient flows: an evolution aimed at the minimization of a convex, lower semicontinuous energy, with memory effects. This memory is characterized by the fact that the negative of the (sub)gradient of the energy equals the so-called Caputo derivative of the state. We introduce the notion of energy solutions, for which we provide existence, uniqueness and certain regularizing effects. We also consider Lipschitz perturbations of this energy. For these problems we provide an a posteriori error estimate and show its reliability. This estimate depends only on the problem data, and imposes no constraints between consecutive time-steps. On the basis of this estimate we provide an a priori error analysis that makes no assumptions on the smoothness of the solution.
Thallium isotopes as indicators of ore mineralization at the Zn-rich sediment-hosted massive sulfide TL Deposit, British Columbia, Canada
Authors: Knaack Derek R. , Sullivan K. V. , Leybourne M. I. , Dunn C. E. , Layton-Matthews D.
Published: January 2023

Few studies have focused on the application of the Tl isotopic system for geochemical exploration. We report

ε

205
Tl values of rock samples from the TL Deposit, British Columbia, Canada – a sediment-hosted massive sulfide (SHMS) deposit with characteristics of a Broken Hill-type deposit – and investigate relationships with major and trace element geochemistry. Maps generated using Tl isotope and trace element data indicate that

ε

205
Tl values can potentially be used to fingerprint ore mineralization at the TL Deposit. The sources of Tl and other metals (Ag, Pb, Zn) are assessed using Tl isotope data. Measured

ε

205
Tl values exhibit positive correlations with Pb, sedimentary exhalative metal index (Zn + 100*Pb + 100*Tl), and the redox proxy, U/Th, and negative correlations with Be, Cd, Ce, La, Ni and Th. Individual lithologies have distinct Tl isotopic compositions. Metal-rich heavily altered samples have relatively high

ε

205
Tl values (−5.0 to −2.5

ε

-units) reflecting the euxinic conditions of the global Paleoproterozoic ocean and hydrothermal influence. Samples with lower

ε

205
Tl values (−15 to −7.6

ε

-units) reflect a combination of their mineralogy (phyllosilicate minerals such as biotite and clinochlore), Tl from sediments reflecting the Tl isotopic composition of modern seawater, and possible low-temperature alteration processes. Samples with high Pb and Ag contents have high

ε

205
Tl values, indicating a hydrothermal origin of these metals, whereas Zn is highest in samples with low

ε

205
Tl values, indicating a low-temperature or sedimentary origin. Thallium isotopes, paired with conventional geochemical data, show promise as a useful tool for exploration of SHMS deposits with Broken Hill-type characteristics.

Supplementary material:
Major, minor and trace element contents of samples and reference materials, blank values, correlation coefficient values, and XRD patterns are available at
https://doi.org/10.6084/m9.figshare.c.6370671

Thematic collection:
This article is part of the Geochemical processes related to mined, milled, or natural metal deposits collection available at:
https://www.lyellcollection.org/topic/collections/geochemical-processes-related-to-mined-milled-or-natural-metal-deposits
Marine bioturbation collapse during Early Jurassic deoxygenation: implications for post-extinction marine ecosystem functioning
Authors: Caswell Bryony A. , Herringshaw Liam
Published: January 2023

Climate change is undermining the health and integrity of seafloor ecosystems, with declines in bioturbation expected to impact future ecosystem functioning. We explored changes in the nature and degree of bioturbation during Early Jurassic global warming and ocean deoxygenation. Understanding how these communities responded can help anticipate how bioturbation and ecosystem functioning might change over large spatial and temporal scales. Trace and body fossils from outcrop and core in the Cleveland Basin, UK show how healthy seafloor communities deteriorated through the Pliensbachian
spinatum
Zone, and macroinfaunal behaviour fluctuated across the Pliensbachian–Toarcian boundary coincident with mass extinction. Deoxygenation began above the stage boundary, and conditions deteriorated until bioturbation ceased completely (upper
tenuicostatum
Zone) for 0.6–2.5 Ma, longer than anywhere else in NW Tethys. The macroinfaunal record revealed new details on the progression and timing of deoxygenation, benthic recovery and fluctuations in the palaeoredox boundary. After the oceanic anoxic event infauna were fewer, smaller and did not mix sediments to depth, and while the depth and diversity of bioturbation had increased by the
fibulatum
Subzone (
bifrons
Zone), the benthos had not recovered to late Pliensbachian pre-oceanic anoxic event state. Bioturbation collapse over large parts of the Northern Hemisphere probably contributed to regional-scale changes in ecosystem functioning.
Multi-FPGA Designs and Scaling of HPC Challenge Benchmarks via MPI and Circuit-switched Inter-FPGA Networks
Authors: Meyer Marius , Kenter Tobias , Plessl Christian
Published: January 2023

While FPGA accelerator boards and their respective high-level design tools are maturing, there is still a lack of multi-FPGA applications, libraries, and not least, benchmarks and reference implementations towards sustained HPC usage of these devices. As in the early days of GPUs in HPC, for workloads that can reasonably be decoupled into loosely coupled working sets, multi-accelerator support can be achieved by using standard communication interfaces like MPI on the host side. However, for performance and productivity, some applications can profit from a tighter coupling of the accelerators. FPGAs offer unique opportunities here when extending the dataflow characteristics to their communication interfaces.

In this work, we extend the HPCC FPGA benchmark suite by multi-FPGA support and three missing benchmarks that particularly characterize or stress inter-device communication: b_eff, PTRANS, and LINPACK. With all benchmarks implemented for current boards with Intel and Xilinx FPGAs, we established a baseline for multi-FPGA performance. Additionally, for the communication-centric benchmarks, we explored the potential of direct FPGA-to-FPGA communication with a circuit-switched inter-FPGA network that is currently only available for one of the boards. The evaluation with parallel execution on up to 26 FPGA boards makes use of one of the largest academic FPGA installations.
Clustering-based Active Learning Classification towards Data Stream
Authors: Yin Chunyong , Chen Shuangshuang , Yin Zhichao
Published: January 2023

Many practical applications, such as social media and monitoring system, will constantly generate streaming data, which has problems of instability, lack of labels and multiclass imbalance. In order to solve these problems, a cluster-based active learning method is proposed to achieve data stream classification. Firstly, a label query strategy combining marginal threshold matrix is proposed, which selects difficult to classify or potential concept drift samples for marking, to solve the problem of high cost label and unbalanced data. Secondly, dynamic maintenance of a group of micro clusters, by adjusting the weight of micro clusters in the model, correctly reflects the current data distribution, and finally, uses the buffer to store new micro clusters to participate in the update of the model, to adapt to the new data environment. Experimental results on three real data sets and three synthetic data sets show that compared with the classical data stream classification algorithm, it is less affected by concept drift and has higher classification accuracy than the online semi-supervised learning algorithm ADSM. The average accuracy of the six datasets increased by 5.56%, 2.32%, 1.77%, 1.83%, 3.78%, and 2.04%, respectively. The model processes data streams online and improves classification performance with less memory consumption.
Pd-based Metallic Glasses as Promising Materials for Hydrogen Energy Applications
Authors: Sarac Baran , Sarac A. Sezai , Eckert Jürgen
Published: January 2023

Hydrogen storage and production via electrochemistry using advanced amorphous metal catalysts with enhanced performance, cost, and durability may offer dynamic and intermittent power generation opportunities. As a new sub-class of materials, Pd-based metallic-glasses (MGs) have drawn intense attention because of their grain-free, randomly packed atomic structure with intrinsic chemical heterogeneity, bestowing unique physical, structural and chemical properties for energy applications. The first section of this review gives a general introduction to crystalline Pd and Pd-based MGs, including the fabrication techniques of MGs and their hydrogen applications. The second section is devoted to hydrogen sorption of Pd-based MGs examined under ribbons, nanowires/microrods, and thin-films subsections. Hydrogen evolution via Pd-based MGs is analyzed in the third section under the bulk rod, ribbons and thin-films subsections. The fourth section consists of hydrogenation kinetics and sensing, pseudocapacitance, and electron transfer kinetics subsections. The final section provides a broad summary of Pd-based metallic glasses and future prospects. Altogether, this review provides a thorough and inspirational overview of hydrogen sorption and evolution of Pd-based MGs targeted for future large-scale hydrogen energy storage and production systems.
An Orthotropic Nonlinear Thermoviscoelastic Model for Polymeric Battery Separators
Authors: Ihuaenyi Royal Chibuzor , Deng Jie , Bae Chulheung , Xiao Xinran
Published: January 2023

Structural responses of separators are critical to battery safety. Commonly used separators are dry-processed polymers with anisotropic microstructures. Due to the material anisotropy, rate dependence, and temperature dependence, developing a model for predicting the thermomechanical response of polymeric battery separators has been challenging. This paper presents an orthotropic nonlinear thermoviscoelastic model for predicting the response of polymeric battery separators in thermal ramp scenarios. The model was based on the Schapery nonlinear viscoelastic model and the temperature dependence was introduced through the time-temperature superposition principle (TTSP). The model was implemented in LS-DYNA® finite element (FE) package as a user-defined material model. The model parameters were determined for a polypropylene (PP) separator. The predicted material responses under large deformations in isothermal and non-isothermal temperature conditions for stress relaxation, creep and tensile loadings at different rates agree well with the experimental data.
miR-542-5p targets c-myc and negates the cell proliferation effect of SphK1 in intestinal epithelial cells
Authors: Li Ruiyun , Rao Jaladanki N. , Smith Alexis D. , Chung Hee Kyoung , Xiao Lan , Wang Jian-Ying , Turner Douglas J.
Published: January 2023

Intestinal epithelial barrier defects occur commonly during a variety of pathological conditions, though their underlying mechanisms are not completely understood. Sphingosine-1-phosphate (S1P) has been shown to be a critical regulator of proliferation and of maintenance of an intact intestinal epithelial barrier, as is also sphingosine kinase 1 (SphK1), the rate-limiting enzyme for S1P synthesis. SphK1 has been shown to modulate its effect on intestinal epithelial proliferation through increased levels of c-myc. We conducted genome-wide profile analysis to search for differential microRNA expression related to overexpressed SphK1 demonstrating adjusted expression of microRNA 542-5p (miR-542-5p). Here, we show that miR-542-5p is regulated by SphK1 activity and is an effector of c-myc translation that ultimately serves as a critical regulator of the intestinal epithelial barrier. miR-542-5p directly regulates c-myc translation through direct binding to the c-myc mRNA. Exogenous S1P analogs administered in vivo protect murine intestinal barrier from damage due to mesenteric ischemia reperfusion, and damaged intestinal tissue had increased levels of miR-542-5p. These results indicate that miR-542-5p plays a critical role in the regulation of S1P-mediated intestinal barrier function, and may highlight a novel role in potential therapies.
The lactate receptor GPR81 is predominantly expressed in type II human skeletal muscle fibers: potential for lactate autocrine signaling
Authors: Nordström Fabian , Liegnell Rasmus , Apró William , Blackwood Sarah J. , Katz Abram , Moberg Marcus
Published: January 2023

Gi-coupled protein receptor 81 (GPR81) was first identified in adipocytes as a receptor for l-lactate, which upon binding inhibits cyclicAMP (cAMP)-protein kinase (PKA)-cAMP-response element binding (CREB) signaling. Moreover, incubation of myotubes with lactate augments expression of GPR81 and genes and proteins involved in lactate- and energy metabolism. However, characterization of GPR81 expression and investigation of related signaling in human skeletal muscle under conditions of elevated circulating lactate levels are lacking. Muscle biopsies were obtained from healthy men and women at rest, after leg extension exercise, with or without venous infusion of sodium lactate, and 90 and 180 min after exercise (8 men and 8 women). Analyses included protein and mRNA levels of GPR81, as well as GPR81-dependent signaling molecules. GPR81 expression was 2.5-fold higher in type II glycolytic compared with type I oxidative muscle fibers, and the expression was inversely related to the percentage of type I muscle fibers. Muscle from women expressed about 25% more GPR81 protein than from men. Global PKA activity increased by 5%–8% after exercise, with no differences between trials. CREBS133 phosphorylation was reduced by 30% after exercise and remained repressed during the entire trials, with no influence of the lactate infusion. The mRNA expression of vascular endothelial growth factor (VEGF) and peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) were increased by 2.5–6-fold during recovery, and that of lactate dehydrogenase reduced by 15% with no differences between trials for any gene at any time point. The high expression of GPR81-protein in type II fibers suggests that lactate functions as an autocrine signaling molecule in muscle; however, lactate does not appear to regulate CREB signaling during exercise.
Resident muscle stem cell myogenic characteristics in postnatal muscle growth impairments in children with cerebral palsy
Authors: Kahn Ryan E. , Krater Timothy , Larson Jill E. , Encarnacion Marysol , Karakostas Tasos , Patel Neeraj M. , Swaroop Vineeta T. , Dayanidhi Sudarshan
Published: January 2023

Children with cerebral palsy (CP), a perinatal brain alteration, have impaired postnatal muscle growth, with some muscles developing contractures. Functionally, children are either able to walk or primarily use wheelchairs. Satellite cells are muscle stem cells (MuSCs) required for postnatal development and source of myonuclei. Only MuSC abundance has been previously reported in contractured muscles, with myogenic characteristics assessed only in vitro. We investigated whether MuSC myogenic, myonuclear, and myofiber characteristics in situ differ between contractured and noncontractured muscles, across functional levels, and compared with typically developing (TD) children with musculoskeletal injury. Open muscle biopsies were obtained from 36 children (30 CP, 6 TD) during surgery; contracture correction for adductors or gastrocnemius, or from vastus lateralis [bony surgery in CP, anterior cruciate ligament (ACL) repair in TD]. Muscle cross sections were immunohistochemically labeled for MuSC abundance, activation, proliferation, nuclei, myofiber borders, type-1 fibers, and collagen content in serial sections. Although MuSC abundance was greater in contractured muscles, primarily in type-1 fibers, their myogenic characteristics (activation, proliferation) were lower compared with noncontractured muscles. Overall, MuSC abundance, activation, and proliferation appear to be associated with collagen content. Myonuclear number was similar between all muscles, but only in contractured muscles were there associations between myonuclear number, MuSC abundance, and fiber cross-sectional area. Puzzlingly, MuSC characteristics were similar between ambulatory and nonambulatory children. Noncontractured muscles in children with CP had a lower MuSC abundance compared with TD-ACL injured children, but similar myogenic characteristics. Contractured muscles may have an intrinsic deficiency in developmental progression for postnatal MuSC pool establishment, needed for lifelong efficient growth and repair.
Effect of reflex and mechanical decreases in skin perfusion on thermal- and agonist-induced eccrine sweating in humans
Authors: Metzler-Wilson Kristen , Fang Milie M. , Alibegovic Kenan , Daggett James W. , Narra Seetharam C. , Dazé Robert P. , Miller Olivia G. , Wilson Thad E.
Published: January 2023

In humans, skin blood flux (SkBF) and eccrine sweating are tightly coupled, suggesting common neural control and regulation. This study was designed to separate these two sympathetic nervous system end-organ responses via nonadrenergic SkBF-decreasing mechanical perturbations during heightened sudomotor drive. We induced sweating physiologically via whole body heat stress using a high-density tube-lined suit ( protocol 1; 2 women, 4 men), and pharmacologically via forearm intradermal microdialysis of two steady-state doses of a cholinergic agonist, pilocarpine ( protocol 2; 4 women, 3 men). During sweating induction, we decreased SkBF via three mechanical perturbations: arm and leg dependency to engage the cutaneous venoarteriolar response (CVAR), limb venous occlusion to engage the CVAR and decrease perfusion pressure, and limb arterial occlusion to cause ischemia. In protocol 1, heat stress increased arm cutaneous vascular conductance and forearm sweat rate (capacitance hygrometry). During heat stress, despite decreases in SkBF during each of the acute (3 min) mechanical perturbations, eccrine sweat rate was unaffected. During heat stress with extended (10 min) ischemia, sweat rate decreased. In protocol 2, both pilocarpine doses (ED50 and EMAX) increased SkBF and sweat rate. Each mechanical perturbation resulted in decreased SkBF but minimal changes in eccrine sweat rate. Taken together, these data indicate that a wide range of acute decreases in SkBF do not appear to proportionally decrease either physiologically- or pharmacologically induced eccrine sweating in peripheral skin. This preservation of evaporative cooling despite acutely decreased SkBF could have consequential impacts for heat storage and balance during changes in body posture, limb position, or blood flow restrictive conditions.
Differential engagement of inhibitory and excitatory cardiopulmonary reflexes by capsaicin and phenylbiguanide in C57BL/6 mice
Authors: Larson Robert A. , Chapleau Mark W.
Published: January 2023

The Bezold–Jarisch reflex is a powerful inhibitory reflex initiated by activation of cardiopulmonary vagal nerves during myocardial ischemia, hemorrhage, and orthostatic stress leading to bradycardia, vasodilation, hypotension, and vasovagal syncope. This clinically relevant reflex has been studied by measuring heart rate (HR) and mean arterial pressure (MAP) responses to injections of a variety of chemical compounds. We hypothesized that reflex responses to different compounds vary due to differential activation of vagal afferent subtypes and/or variable coactivation of excitatory afferents. HR and MAP responses to intravenous injections of the transient receptor potential vanilloid-1 (TRPV1) agonist capsaicin and the serotonin 5-HT3 receptor agonist phenylbiguanide (PBG) were measured in anesthetized C57BL/6 mice before and after bilateral cervical vagotomy. Capsaicin and PBG evoked rapid dose-dependent decreases in HR and MAP followed by increases in HR and MAP above baseline. Bezold–Jarisch reflex responses were abolished after vagotomy, whereas the delayed tachycardic and pressor responses to capsaicin and PBG were differentially enhanced. The relative magnitude of bradycardic versus depressor responses (↓HR/↓MAP) in vagus-intact mice was greater with capsaicin. In contrast, after vagotomy, the magnitude of excitatory tachycardic versus pressor responses (↑HR/↑MAP) was greater with PBG. Although capsaicin-induced increases in MAP and HR postvagotomy were strongly attenuated or abolished after administration of the ganglionic blocker hexamethonium, PBG-induced increases in MAP and HR were mildly attenuated and unchanged, respectively. We conclude that responses to capsaicin and PBG differ in mice, with implications for delineating the role of endogenous agonists of TRPV1 and 5-HT3 receptors in evoking cardiopulmonary reflexes in pathophysiological states.
Perturbed Keplerian Hamiltonian Systems
Authors: Chteoui Riadh
Published: January 2023

This paper deals with a class of perturbation planar Keplerian Hamiltonian systems, by exploiting the nondegeneracy properties of the circular solutions of the planar Keplerian Hamiltonian systems, and by applying the implicit function theorem, we show that noncollision periodic solutions of such perturbed system bifurcate from the manifold of circular solutions for the Keplerian Hamiltonian system.
LIGHT Amplification by NF-κB Contributes to TLR3 Signaling Pathway-Induced Acute Hepatitis
Authors: Lai Dongming , Lv Zejian , Lu Xiaohua , Shang Peng , Geng Yunyun , Wang Pu
Published: January 2023

LIGHT is a member of the TNF superfamily and a proinflammatory cytokine involved in liver pathogenesis. Many liver diseases involve activation of Toll-like receptor 3 (TLR3), which is activated by double-stranded RNA (dsRNA). However, the involvement of LIGHT in TLR3 implicated liver diseases is not clear. In this study, we investigated the role of LIGHT in TLR3 involved liver pathogenesis by using a mouse model of TLR3 agonist poly(I:C)-induced hepatitis. We found LIGHT expression at both protein and mRNA level in liver tissues is dramatically increased during the course of poly(I:C)-induced liver injury. This induction depends on NF-κB activation as pretreating the mice with a NF-κB inhibitor abrogates LIGHT upregulation. Importantly, blockade of the LIGHT signaling pathway with the recombinant LIGHT receptor HVEM protein ameliorates liver injury in poly(I:C)-induced hepatitis. Conclusions. These results indicate that LIGHT amplification by NF-κB plays a significant role in TLR3 involved hepatitis and points LIGHT to be a potential drug target for liver disease therapy.
Highly Accessible Computational Prediction and In Vivo/In Vitro Experimental Validation: Novel Synthetic Phenyl Ketone Derivatives as Promising Agents against NAFLD via Modulating Oxidoreductase Activity
Authors: Qiao Yanan , Deng Huifang , Liu Lihua , Liu Shuran , Ren Luyao , Shi Chuandao , Chen Xi , Guan Lixia , Liu Weiran , Li Zehua , Li Yunlan
Published: January 2023

Nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions with no pharmacological treatment approved. Several highly accessible computational tools were employed to predict the activities of twelve novel compounds prior to actual chemical synthesis. We began our work by designing two or three hydroxyl groups appended to the phenyl ketone core, followed by prediction of drug-likeness and targets. Most predicted targets for each compound overlapped with NAFLD targets (≥80%). Enrichment analysis showed that these compounds might regulate oxidoreductase activity. Then, these compounds were synthesized and confirmed by IR, MS, 1H, and 13C NMR. Their cell viability demonstrated that twelve compounds exhibited appreciable potencies against NAFLD (

E

C

50

 
values
≤
13.5
 
μ
M

). Furthermore, the most potent compound 5f effectively prevented NAFLD progression as evidenced by the change in histological features. 5f significantly reduced total cholesterol and triglyceride levels in vitro/in vivo, and the effects of 5f were significantly stronger than those of the control drug. The proteomic data showed that oxidoreductase activity was the most significantly enriched, and this finding was consistent with docking results. In summary, this validated presynthesis prediction approach was cost-saving and worthy of popularization. The novel synthetic phenyl ketone derivative 5f holds great therapeutic potential by modulating oxidoreductase activity to counter NAFLD.
A Case of Esophago-Respiratory Fistula due to Inhalation Smoke Injury Diagnosed by Upper Endoscopy
Authors: Nasirishargh Aida , Nguyen Bao Sean Huy , Lawson Michael J. , Mao Eric J.
Published: January 2023

Esophago-respiratory fistula (ERF) refers to the formation of a pathological connection between the esophagus and respiratory tract. Acquired ERF is a rare but life-threatening diagnosis in adults. We describe a 79-year-old male who was admitted with an inhalation smoke injury. He was diagnosed with ERF by endoscopic visualization and sampling of the hyaline cartilage within the wall of the esophagus. Percutaneous endoscopic gastrostomy placement and conservative measures were effective in the management of ERF.
Myo1b Promotes Premature Endothelial Senescence and Dysfunction via Suppressing Autophagy: Implications for Vascular Aging
Authors: Yu Yi , Ren Yuanyuan , Li Zi , Li Yang , Li Yirong , Zhang Yan , Gui Runlin , Cui Yue , Qian Lu , Xiong Yuyan
Published: January 2023

Endothelial cell (EC) senescence characterized by an irreversible growth arrest leading to endothelial dysfunction has been implicated in vascular aging and aging-associated cardiovascular diseases. Autophagy plays a crucial role in the modulation of cellular senescence. Our previous showed that myosin 1b (Myo1b), one family of nonfilamentous class-1 myosin, was reported to be involved in the modulation of human smooth muscle cell senescence. However, the role of Myo1b in the modulation of EC senescence with links to autophagy has yet to be elucidated. In this study, we sought to explore the role of Myo1b in endothelial senescence and further elucidate the underlying mechanisms. Here, we show prominent upregulation of Myo1b in senescent ECs in comparison with nonsenescence ECs in both mRNA and protein expression levels. Silencing Myo1b in senescent cells ameliorates endothelial dysfunctions and reverses endothelial senescence phenotypic changes such as senescence-associated-β-galactosidase activity, cyclin-dependent kinase inhibitor p21WAF1, expression of vascular adhesion molecule-1 (VCAM1) and intercellular adhesion molecule-1 (ICAM1), and the senescence-associated cytokines. In contrast, in nonsenescent cells, overexpressing Myo1b promotes endothelial senescence and suppresses autophagy through the impairment of autophagosome and lysosome fusion. The interaction between Myo1b and LRRK2 through Myo1b tail domain promotes intracellular calcium elevation, which results in the inhibition of autophagic flux. In vitro and in vivo aging models, Myo1b knockdown in senescent ECs and wild type-aged mice is able to enhance autophagy and ameliorate aging-associated endothelial dysfunction. Taken together, our studies reveal a new function for Myo1b, that is, to couple LRRK2 assembly to promote an increase in intracellular calcium level, which impairs the autophagosome-lysosome fusion, and ultimately the promotion of EC senescence and vascular aging.
TRIM6 Reduces Ferroptosis and Chemosensitivity by Targeting SLC1A5 in Lung Cancer
Authors: Zhang Ying , Dong Ping , Liu Nian , Yang Jun-Yuan , Wang Hui-Min , Geng Qing
Published: January 2023

Objective. Ferroptosis, a newly identified form of cell death, plays critical roles in the development and chemoresistance of lung cancer. Tripartite motif 6 (TRIM6) acts as an E3-ubiquitin ligase and can promote the progression of human colorectal cancer. The present study is aimed at investigating its role and potential mechanisms in lung cancer. Methods. Lentiviral vectors were used to overexpress or knock down TRIM6 in human lung cancer cells. Cell survival, colony formation, lipid peroxidation, intracellular iron levels, and other ferroptotic markers were examined. The role of TRIM6 on ferroptosis and chemosensitivity was further tested in mouse tumor xenograft models. Results. TRIM6 was highly expressed in human lung cancer tissues and cells, and its expression in the lung cancer cells was further increased by ferroptotic stimulation. TRIM6 overexpression inhibited, while TRIM6 silence promoted erastin- and RSL3-induced glutaminolysis and ferroptosis in the lung cancer cells. Mechanistically, TRIM6 directly interacted with solute carrier family 1 member 5 to promote its ubiquitination and degradation, thereby inhibiting glutamine import, glutaminolysis, lipid peroxidation, and ferroptotic cell death. Moreover, we observed that TRIM6 overexpression reduced the chemotherapeutic effects of cisplatin and paclitaxel. In contrast, TRIM6 silence sensitized human lung cancer cells to cisplatin and paclitaxel in vivo and in vitro. Conclusion. Our findings for the first time define TRIM6 as a negative regulator of ferroptosis in the lung cancer cells, and TRIM6 overexpression enhances the resistance of human lung cancer cells to chemotherapeutic drugs. Overall, targeting TRIM6 may help to establish novel strategies to treat lung cancer.
Chronic Exposure to Drinking Water Arsenic and Gallbladder Cancer Risk: Preliminary Evidence from Endemic Regions of India
Authors: Shridhar Krithiga , Krishnatreya Manigreeva , Sarkar Soumyajit , Kumar Ranjit , Kondal Dimple , Kuriakose Steena , RS Vinutha , Singh Amulya K. , Kataki Amal Chandra , Ghosh Ashok , Mukherjee Abhijit , Prabhakaran D. , Mondal Debapriya , Prabhakaran Poornima , Dhillon Preet K.
Published: January 2023

Background:

Evidence linking arsenic in drinking water to digestive tract cancers is limited. We evaluated the association between arsenic levels in groundwater and gallbladder cancer risk in a case–control study (2019–2021) of long-term residents (≥10years) in two arsenic-impacted and high gallbladder cancer risk states of India—Assam and Bihar.

Methods:

We recruited men and women aged 30 to 69 years from hospitals (73.4% women), with newly diagnosed, biopsy-confirmed gallbladder cancer (N = 214) and unrelated controls frequency-matched for 5-year age, sex, and state (N = 166). Long-term residential history, lifestyle factors, family history, socio-demographics, and physical measurements were collected. Average-weighted arsenic concentration (AwAC) was extrapolated from district-level groundwater monitoring data (2017–2018) and residential history. We evaluated gallbladder cancer risk for tertiles of AwAC (μg/L) in multivariable logistic regression models adjusted for important confounders [Range: 0–448.39; median (interquartile range), T1–0.45 (0.0–1.19); T2–3.75 (2.83–7.38); T3–17.6 (12.34–20.54)].

Results:

We observed a dose–response increase in gallbladder cancer risk based on AwAC tertiles [OR = 2.00 (95% confidence interval, 1.05–3.79) and 2.43 (1.30–4.54); Ptrend = 0.007]. Participants in the highest AwAC tertile consumed more tubewell water (67.7% vs. 27.9%) and reported more sediments (37.9% vs. 18.7%) with unsatisfactory color, odor, and taste (49.2% vs. 25.0%) than those in the lowest tertile.

Conclusions:

These findings suggest chronic arsenic exposure in drinking water at low-moderate levels may be a potential risk factor for gallbladder cancer.

Impact:

Risk factors for gallbladder cancer, a lethal digestive tract cancer, are not fully understood. Data from arsenic-endemic regions of India, with a high incidence of gallbladder cancer, may offer unique insights. Tackling ‘arsenic pollution’ may help reduce the burden of several health outcomes.
Moving beyond the “Health Halo” of Alcohol: What Will it Take to Achieve Population Awareness of the Cancer Risks of Alcohol?
Authors: Hay Jennifer L. , Kiviniemi Marc T. , Orom Heather , Waters Erika A.
Published: January 2023

We discuss the implications of Seidenberg and colleagues’ report confirming low levels of accurate awareness of the cancer harms associated with alcohol use, including wine, beer, and liquor consumption. The authors propose that academic and lay messaging describing consumption of wine and other forms of alcohol as reducing heart disease risk has created generalized beliefs about the health benefits of drinking alcohol. This “health halo” surrounding alcohol consumption leads the public to overgeneralize alcohol health benefits to other diseases, including cancer. We discuss the need to address high levels of perceived risk uncertainty to help the public distinguish between the impact of alcohol on heart disease versus cancer, and to overcome other barriers to including alcohol use reduction as a cancer prevention strategy. Given recent increases in U.S. population drinking rates, as well as morbidity and mortality associated with alcohol use, the time is right to marshal multilevel efforts to educate the public regarding the fact that alcohol is carcinogenic. If successful, these efforts will have multiple downstream benefits, including the ability of the lay public to use the most up-to-date scientific evidence to make informed decisions about whether, and how much, to engage in a risky behavior.

See related article by Seidenberg et al., p. 46
Nifuroxazide Activates the Parthanatos to Overcome TMPRSS2:ERG Fusion-Positive Prostate Cancer
Authors: Li Chengxun , Zhang Jiale , Wu Qiming , Kumar Anuj , Pan Guihong , Kelvin David J.
Published: January 2023

Fusion of the E-26 transformation-specific (ETS)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)–based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide (NFZ) inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145, and WPMY cells). Poly [ADP-ribose] polymerase 1, the critical mediator of parthanatos, is known to bind ERG and is required for ERG-mediated transcription. NFZ blocked this interaction and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that NFZ inhibits ERG, leading to parthanatic cell death.
Abstract A023: Racial differences in lung cancer burden: A retrospective analysis of TriNetX data
Authors: Park SoHye , Urdang Zachary , Barta Julie , Wen Kuang-Yi , Curry Joseph , Juon Hee-Soon
Published: January 2023

Background. Lung cancer is the number one cause of cancer-related deaths in the U.S. and many other countries. Lung cancer incidence and mortality rates have decreased for all races over the past 20 years, in part because of decreased tobacco use. Yet, there have been few clinical studies of lung cancer morbidity and mortality by race. The purpose of this study is to examine racial differences in lung cancer mortality in the U.S. using the electronic health records (EHR) database, TriNetX. Method. This retrospective cohort study was conducted based on the data from US Collaborative Network in TriNetX, a real-time, EHR database providing 42.7-million patient data from 49 health care organizations (HCOs). The cohort of interest was lung cancer patients in the U.S., which were identified using the ICD-10 code of C34 with an index diagnosis date of January 1, 2010. Kaplan-Meier curves, log-rank chi-square statistics, and hazard ratio (HR) were compared among different racial groups in the EHR data. Results. Of 42.7-million patients in the U.S., the majority (60.3%) were people who are non-Hispanic white (NHW) followed by people who are Black/African American (15.4%), Hispanic (7.2%), Asian (4.6%), and others (Native Hawaiian/Pacific Islander, 0.5%). 394,560 lung cancer patients were identified. Kaplan-Meier survival curves showed that Asians had the highest survival probability with median overall survival (OS) from the initial lung cancer diagnosis of 127.3 months, compared to 92.1 months for Hispanic, 69.1 months for African American/Black, 61.4 months for others, and 53.8 months for NHW. The HR was highest among NHW (HR=1.71, 95% CI=1.62-1.81), others (HR=1.62, 95% CI=1.41-1.85), African American/Black (HR=1.52, 95% CI=1.43-1.61), and Hispanic patients (HR=1.40, 95% CI=1.30-1.52) compared to Asian patients Conclusion. These findings suggest racial disparities in lung cancer survival, with NHW having the lowest and Asians having the highest median survival. These findings are inconsistent with the results from the Multiethnic Cohort study (prospective population based study), which reported blacks having the lowest median survival. It indicates that there are different racial burdens of lung cancer from clinical data and population data. Further analyses are needed to adjust potential confounders such as smoking status and stage of diagnosis.

Citation Format: SoHye Park, Zachary Urdang, Julie Barta, Kuang-Yi Wen, Joseph Curry, Hee-Soon Juon. Racial differences in lung cancer burden: A retrospective analysis of TriNetX data [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr A023.
Abstract B105: Patient-reported access to telehealth: An important and unmeasured social determinant of health
Authors: Iasiello John A. , Rajan Arvind , Zervos Emmanuel , Parikh Alexander A. , Snyder Rebecca A.
Published: January 2023

Background: The recent COVID-19 pandemic expanded opportunities for remote oncology telehealth visits. However, reliable internet connectivity, digital literacy, and patient comfort with virtual medical visits may differ among patients, especially socially disadvantaged groups. The primary aim of this study was to identify patient demographics and social determinants of health (SDOH) which might limit access to remote telehealth services. Methods: First, a retrospective analysis was performed of composite administrative data of all patient visits to a large regional cancer center over the COVID-19 pandemic (3/2020-4/2022). Second, a prospective, cross-sectional study was conducted of patients with known or suspected malignancy presenting to the same center over six-months (11/2021-5/2022). Participants were asked a standard set of survey questions regarding telehealth accessibility during an in-person clinic visit. Demographics and SDOH were abstracted from the electronic health record (EHR). Results: Although Black patients comprised 43% (n=9,021) of all patient visits (n=20,953), the proportion of telehealth visits conducted among Black patients (29%; n=889) was significantly lower compared to White patients (71%, n=2,142, p<0.0001). Within the cross-sectional study cohort (n=149), 51% (n=76) were Black, 39% (n=58) resided in a rural county, and 8.7% (n=13) were uninsured or Medicaid-insured. Black participants were more likely to self-report lack of internet access (73.7% vs. 90.4%, p<0.01) and were less likely to report having access to or actively using a patient portal in the EHR compared to White patients (47.4% and 79.5%, respectively; p<0.001). Rates of self-reported access to video-capable devices (82.9% vs. 90.4%) and confidence in conducting video visits without assistance (59.2% vs. 68.5%) were similar among Black and White patients (p>0.05). The most common self-identified challenge to telehealth usage among both races was limited digital literacy. Conclusions: Black patients disproportionally under-participated in telehealth visits, suggesting underlying structural disparities in access to digital care. A greater proportion of Black participants self-reported lack of internet access and access to a patient portal to the EHR compared to White patients. Ensuring equal internet access and digital literacy will be critical to reduce further disparities in cancer care among racial minorities.

Citation Format: John A. Iasiello, Arvind Rajan, Emmanuel Zervos, Alexander A. Parikh, Rebecca A. Snyder. Patient-reported access to telehealth: An important and unmeasured social determinant of health [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B105.
Abstract C052: Endometrial cancer genomics varies by race
Authors: Sanchez-Covarrubias Alex P. , Sowamber Ramlogan , Dodds Leah , Pinto Andre , George Sophia , Schlumbrecht Matthew
Published: January 2023

Introduction Variability in endometrial cancer (EC) risk and outcomes exist, with Black women disproportionately negatively affected related to White women. The biologic etiologies of these observations are poorly understood. Our objective was to describe the somatic mutations of the tumor genome and compare them to RNA expression in self-identified Black and White women diagnosed with EC. Methods Women with newly diagnosed EC and undergoing hysterectomy were recruited prospectively. Fresh tumors obtained at the time of surgery were flash-frozen, underwent DNA and RNA extraction and were submitted for whole exome sequencing (WES) analysis (DNA) or bulk RNA sequencing analysis. Differentially expressed genes between racial groups and tumor grade were calculated using Deseq2. Genomic ancestry was determined using ADMIXTURE. Chi-square and Mann Whitney U tests were used for analyses, with a threshold for significance of p<0.05. Results A total of 49 patients with EC were included. Thirty (61.2%) women were diagnosed with low-grade EC and 19 (38.8%) with high grade EC. Twenty (40.8%) women self-identified as Black, 27 (55.1%) as White and 2 (4.1%) as Asian/other. Admixture analysis showed that 36 (73.4%) had >14% African ancestry. The remaining 13 (26.5%) patients had admixed European and Native American ancestry, with <1% African ancestry. In the RNA-seq, we found significant DEGs by tumor grade; with 2132 DEG in High grade compared to Low grade tumors with a false discovery rate of <0.05 and a fold change (FC) of ≤-1.5 or ≥1.5. Top 10 DEG included MT4, TAF15, SLFN5 and PLEKHS1 (upregulated) and MCRIP1, MAZ, MYOM3, PRPH, BCL7C, AC016700.5 (downregulated). In the WES analysis, 8 Black women had mutations in GON4L compared to 1 in the White woman (44.4% vs 3.7%, padj=0.04); and 7 Black women had a mutation in PRAMEF14 compared to 1 White woman (38.8% vs 3.7%, padj= 0.06). Conclusion GON4L, which is a transcription factor associated with decreased apoptosis and promotion of tumor growth through CD24 regulation, was significantly more mutated in the EC genome of Black women relative to White women. Somatic mutation and transcriptional changes are seen between tumor grade and self-identified race and require further exploration for its relationship to aggressive disease.

Citation Format: Alex P. Sanchez-Covarrubias, Ramlogan Sowamber, Leah Dodds, Andre Pinto, Sophia George, Matthew Schlumbrecht. Endometrial cancer genomics varies by race [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C052.
Abstract C058: Deregulated microRNA-mRNA reciprocal pairs as novel precision biomarkers and therapeutic targets for African American prostate cancer
Authors: Gujrati Himali , Ha Siyoung , Wang Bi-Dar
Published: January 2023

Prostate cancer (PCa) is the most frequently diagnosed cancer and second leading cause of cancer death among American men. Notably, African American (AA) men exhibit 1.6-fold higher incidence rate and 2.4-fold higher mortality rate when compared to European American (EA) men. Besides socioeconomic factors, accumulating genomic data suggest that intrinsic genetic risk elements also play critical roles in promoting PCa disparities. MicroRNAs (miRNAs) are involved in epigenetic mechanisms regulating mRNA expression in various human diseases, including cancers. In this study, we have applied a systems biology approach (by integrating mRNA and miRNA profiling data, target prediction, and pathway analysis) to identify critical signaling networks differentially regulated between AA and EA PCa. Using miRNA-drive algorithm mirPath V.3 coupled with mRNA mapping, and global test algorithm coupled with miRNA mapping, we identified several cancer pathways, such as ERBB, mTOR, HIF, and VEGF signaling, that are significantly regulated by AA-depleted/enriched miRNAs and mRNAs. Specifically, reciprocal miRNA-mRNA pairs miR-34a-5p/HIF1A, miR-34a-5p/PIK3CB, miR-34a-5p/IGFBP2, and miR-99b-5p/MTOR (downregulated/upregulated in AA vs. EA PCa), and miR-96-5p/MAPKAPK2 (upregulated/downregulated in AA vs. EA PCa) were identified as core miRNA/mRNA regulators in activation of mTOR and VEGF signaling in AA PCa. RT-qPCR, Western blotting, and immunohistochemistry assays in AA and EA PCa cell lines and patient samples have confirmed that these miRNAs and mRNAs are differentially expressed in AA and EA PCa. Furthermore, molecular targeting miRNA/mRNA pairings using miR-34a-5p, miR-99b-5p mimics and/or miR-96-5p antagomir consequently reduced cell proliferation and enhanced docetaxel-induced cytotoxicity in AA PCa cells. In summary, these results suggest that deregulated miRNA/mRNA reciprocal pairs play critical roles in promoting cancer aggressiveness and chemoresistance in AA PCa. Further development of these miRNA/mRNA pairings as precision diagnostic/prognostic biomarkers and novel therapeutic targets may pave a new path for PCa diagnosis and treatment.

Citation Format: Himali Gujrati, Siyoung Ha, Bi-Dar Wang. Deregulated microRNA-mRNA reciprocal pairs as novel precision biomarkers and therapeutic targets for African American prostate cancer [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr C058.