bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of the primary motor cortex in motor imagery: A theta burst stimulation study
Authors: Barhoun Pamela , Fuelscher Ian , Do Michael , He Jason L. , Cerins Andris , Bekkali Soukayna , Youssef George J. , Corp Daniel , Major Brendan P. , Meaney Dwayne , Enticott Peter G. , Hyde Christian
Published: May 2022

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham‐controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi‐session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.
Long‐run effects of trade liberalisation on local labour markets: Evidence from South Africa
Authors: Bastos Paulo , Santos Nicolas
Published: May 2022

This paper uses municipal‐level data from South Africa for the period 1996–2011 to estimate the medium to long‐run effects of trade liberalisation on local labour markets. It finds that local labour markets that were more exposed to tariff cuts tended to experience slower growth in employment and income per capita than less exposed regions. The longer‐term effects of trade liberalisation on regional earnings are stronger than the medium‐term effects and tend to be more pronounced among municipalities that included the former homelands.
Estimation of Tissue Movement in Needle Insertion Tasks Using an Active Needle
Authors: Padasdao Blayton , Batsaikhan Zolboo , Brown Dailen , Moore Jason , Konh Bardia
Published: May 2022

Needle insertion has been used as a minimally invasive technique in many diagnostic or therapeutic procedures such as prostate biopsy or brachytherapy. While the success of these procedures relies on accurate positioning of the needle tip at target positions, the intraoperative movement of the tissue (and consequently the target) has caused physicians some difficulties in acquiring the target. This paper presents a method to estimate tissue movement during a needle insertion task within tissue. The movement of the tissue is valuable information for guidance, navigation, and control of the needle inside tissue towards the target. A needle insertion task was performed using an active needle bending. Ultrasound images were captured at four needle insertion stages of initial needle insertion, bending, unbending, and needle retraction. Ultrasound images were then analyzed to estimate the tissue movement at each stage. The study showed that needle retraction, insertion, bending, and unbending stages correspond to largest to lowest tissue movement, respectively.
A Portable Robot to Perform Prostate Brachytherapy with Active Needle Steering and Robot-Assisted Ultrasound Tracking
Authors: Rabiei Mahsa , Konh Bardia
Published: May 2022

Brachytherapy is an internal radiation therapy method for prostate cancer that involves placement of radioactive seeds close to the cancerous cells. Robotic needle insertion systems have been proposed in the past to help physicians to improve outcomes of brachytherapy. This work presents design and development of a portable robotic brachytherapy system to operate a tendon-driven active needle based on physician’s input. The system enables manual positioning of the needle to choose appropriate puncture positions as well as robotic manipulation mechanisms for needle insertion and bending. The system also allows for automatic movement of an ultrasound probe to visualize the needle tip in a needle insertion task in real time.
Computer Vision Enabled Smart Tray for Central Venous Catheterization Training
Authors: Brown Dailen , Wu Hang-Ling , Satpathy Yohaan , Gonzalez-Vargas Jessica M. , Tzamaras Haroula , Miller Scarlett , Moore Jason
Published: May 2022

A Computer Vision enabled Smart Tray (CVST) was designed for use in medical training for Central Venous Catheterization (CVC). The effects of background color on the ability of the computer vision algorithm to distinguish between tools and the tray was investigated. In addition, the computer vision algorithm was evaluated for accuracy in tool detection. Results indicate that a white monochromatic background is the most useful for segregating background from medical tools, and the algorithm was successfully able to detect 5 different CVC tools both individually and as a group in various arrangements, even when tools overlapped or touched. When the system was in error, it was nearly always due to one tool which has a color similar to that of the background. The CVST shows promise as a CVC training tool and demonstrates that computer vision can be used to accurately detect medical tools.
Design and Development of System Components for Therapeutic Ultrasound Devices: Enhancing Focused Ultrasound Treatments Using Cones with Clinical and Ergonomic Considerations
Authors: Thombre Rasika , Mess Griffin , Curry Eli , Mejia Richard , Liang Ruixing , Aghabaglou Fariba , Kerensky Max , Abramson Haley , VanSickle Roslyn , Tyler Betty , Theodore Nicholas , Manbachi Amir
Published: May 2022

Focused ultrasound (FUS) is an emerging technique with the potential to revolutionize traditional treatment methods in the fields of oncology and neurosurgery. Recently, FUS treatments have shown potential for altering neural activity in the spinal cord, with the intent to alleviate pain. Preliminary animal studies using FUS have demonstrated the need for transducer accessories that can simplify the implementation of the transducer in the clinic. The coupling cone that was supplied with the transducer was designed for larger target tissues. Thus, surgeons have expressed a desire to adapt the cone design to be easier to use for smaller targets, such as the spinal cord. Here, we developed 3D printed cones, with smaller aperture sizes, for FUS transducers to assist surgeons in localizing the focal point of the transducers in a faster, and more intuitive manner. The cones were designed to not alter the original focal region of the transducers. This was experimentally confirmed by measuring the size of the focal region for the transducer with the new cones and comparing this data to measurements provided by the manufacturer. The new coupling cones will make the FUS transducers more ergonomic for use in stimulating the spinal cord in an animal model.
Design Guidelines for Moving a Human Body on a Bed Using Traveling Waves
Authors: Mansouri Mahshid , Krishnan Girish , Hsiao-Wecksler Elizabeth T.
Published: May 2022

Inspired by natural waves such as water waves that can carry objects, this study presents design guidelines for moving a human body using traveling waves created on the surface of a bed. Particularly, through kinematic analysis and simulation of a traveling wave, the study explores various parameters, such as the wave’s frequency, wavelength, amplitude, number of wave-generating actuators and their movement pattern under the body. The study also investigates how these parameters affect human transportation speed and movement smoothness. The study results suggest that transportation speed is linearly proportional to the wave frequency. Additionally, to increase movement smoothness, the wave amplitude should be reduced while the number of actuators should be maximized. However, there is a tradeoff between the number of actuators that can be used and the complexity of the system’s design and control.
Neonatal hydrocolpos presenting as a rapidly progressive abdominal mass with inferior caval vein syndrome
Authors: Nowacki Relana M E , Derikx Joep P M , Roeleveld-Versteegh Angelique B C , Leroy Piet L J M
Published: May 2022

A 7-week-old infant was presented at the emergency department with an abdominal mass, unilateral swelling of the groin and suspicion of an inferior caval vein syndrome with bluish discolouration and oedema of the lower extremities. Abdominal imaging showed two large cysts and profound bilateral hydronephrosis. Following laparotomy, an extreme hydrocolpos and an overdistended urinary bladder were found. These findings turned out to be secondary to a transverse vaginal septum. She was treated surgically and was hospitalised for 2 weeks. Long-term follow-up showed normalisation of previously present hypercalciuria and hydronephrosis.

A hydro(metro)colpos should be considered in the differential diagnosis of a female infant presenting with an abdominal mass, to apply the appropriate investigations and therapy.
Macrophage behaviour 72 hours after implantation of biodegradable polymer-based sirolimus-eluting stent in a case of ST elevation myocardial infarction
Authors: Nakano Koji , Koizumi Tomomi , Abe Yuto , Ono Masao
Published: May 2022

While the vascular healing process after drug-eluting stent implantation is not fully elucidated, it is generally accepted that macrophages play an important role in inflammation. It is also known that macrophages involved in the pathogenesis of atherosclerosis may stem from several origins, that is, monocyte-derived macrophages versus resident macrophages. However, little is known about the role of human macrophages on reperfusion of culprit coronary arteries in patients with atherosclerotic disease who have sustained acute coronary syndrome. In this present case report, we describe the presence of cluster of differentiation (CD) 163-positive macrophages in close proximity to the stent struts at the luminal site 72 hours after drug-eluting stent implantation in the culprit coronary lesion for ST elevation myocardial infarction by postmortem examination.
Demographic, exposure and clinical characteristics in a multinational registry of engineered stone workers with silicosis
Authors: Hua Jeremy Tang , Zell-Baran Lauren , Go Leonard H T , Kramer Mordechai R , Van Bree Johanna B , Chambers Daniel , Deller David , Newbigin Katrina , Matula Michael , Fireman Elizabeth , Dahbash Mor , Martinez-Gonzalez Cristina , León-Jimenez Antonio , Sack Coralynn , Ferrer Jaume , Villar Ana , Almberg Kirsten S , Cohen Robert A , Rose Cecile S
Published: May 2022

Objectives

To investigate differences in workplace exposure, demographic and clinical findings in engineered stone (ES) workers from a multinational consortium using the Engineered Stone Silicosis Investigators (ESSI) Global Silicosis Registry.

Methods

With ethics board approval in Israel, Spain, Australia and the USA, ES workers ages 18+ with a physician diagnosis of work-related silicosis were enrolled. Demographic, occupational, radiologic, pulmonary function and silica-related comorbidity data were compared cross-sectionally among countries using analysis of variance, Fisher’s exact tests and logistic regression.

Results

Among 169 ES workers with silicosis, most were men, with mean age 51.7 (±11.4) years. Mean work tenure in stone fabrication or masonry was 19.9 (±9.8) years. Different methods of case ascertainment explained some inter-country differences, for example, workers in Queensland, Australia with a state-based surveillance program were likely to be identified earlier and with shorter work tenure. Overall, 32.5% of workers had progressive massive fibrosis, the most severe form of dust-related pneumoconiosis, of whom 18.5% reported ≤10 years of work tenure. Lung function impairment including restriction, reduced diffusion capacity and hypoxaemia was common, as was autoimmunity.

Conclusions

Findings from a multinational registry represent a unique effort to compare demographic, exposure and clinical information from ES workers with silicosis, and suggest a substantial emerging population of workers worldwide with severe and irreversible silica-associated diseases. This younger worker population is at high risk for disease progression, multiple comorbidities and severe disability. The ESSI registry provides an ongoing framework for investigating epidemiological trends and developing prospective studies for prevention and treatment of these workers.
Occupational trichloroethylene exposure and antinuclear antibodies: a cross-sectional study in China
Authors: Purdue Mark , Zhang Luoping , Vermeulen Roel , Smith Martyn T , Hu Wei , Rhee Jongeun , Wen Cuiju , Huang Yongshun , Tang Xiaojiang , Berndt Sonja I , Frazer-Abel Ashley A , Deane Kevin D , Rothman Nathaniel , Lan Qing
Published: May 2022

Objectives

There has been concern over the possible risk of autoimmune diseases from exposure to trichloroethylene (TCE), an industrial solvent and common pollutant near hazardous waste sites. Studies of TCE-exposed lupus-prone mouse strains have reported increases in serum antinuclear antibodies (ANAs), a marker of autoimmunity, and autoimmune pathologic changes, while epidemiologic studies have provided limited support for an association between TCE exposure and scleroderma. To investigate exposure-related biologic evidence of autoimmunity in humans, we measured ANA levels in sera from a cross-sectional study of TCE-exposed (n=80) and TCE-unexposed (n=96) workers in Guangdong, China.

Methods

Full-shift personal air exposure measurements for TCE were taken prior to blood collection. Serum ANAs were detected by immunofluorescence on HEp-2 cells. We calculated ORs and 95% CI relating levels of TCE exposure (categorised using tertiles as cut-points) and ANA positivity (1+ intensity at 1:320 dilution) using multivariable logistic regression.

Results

Samples from 16 of 176 participants were ANA-positive. We found higher levels of TCE exposure (concentrations>17.27 ppm) to be associated with an elevated odds of ANA positivity (OR 4.7, 95% CI 1.3 to 16.8) compared with unexposed controls. This association remained after excluding two subjects with diagnosed autoimmune disease (OR 4.5, 95% CI 1.2 to 16.2). We did not observe an association with ANAs at lower exposure levels.

Conclusions

Our findings, to our knowledge the first direct human evidence of an association between TCE exposure and systemic autoimmunity, provide biologic plausibility to epidemiologic evidence relating TCE and autoimmune disease.
Unified f(R) gravity at local scales
Authors: Sharma Vipin Kumar , Verma Murli Manohar
Published: May 2022

We explore the shifted $$f(R) (\propto R^{1+\delta })$$

f

(
R
)

(
∝

R

1
+
δ

)

model with $${\delta }$$
δ
as a distinguishing physical parameter for the study of constraints at local scales. The corresponding dynamics confronted with different geodesics (null and non-null) along with their conformal analog are investigated. For null geodesics, we discuss the light deflection angle, whereas, for non-null geodesics under the weak field limit, we investigate the perihelion advance of the Mercury orbit in f(R) Schwarzschild background, respectively. The extent of an additional force, appearing for non-null geodesics, depends on $$\delta $$
δ
. Such phenomenological investigations allow us to strictly constrain $$\delta $$
δ
to be approximately $${\mathcal {O}}(10^{-6})$$

O
(

10

-
6

)

with a difference of unity in orders at galactic and planetary scales and seem to provide a unique f(R) at local scales. Our results suggest that the present form of the model is suitable for the alternative explanation of dark matter-like effects at local scales.
Survey on Knowledge, Attitude and Practice of Organ Donation Among Dental Students in Chennai
Authors: Ganta Lasya , Keerthi Sasanka L , Prathap Lavanya
Published: May 2022

Organ donation is the procedure when an individual permits their very own organ to be expelled and transplanted to someone else, legitimately, either by assent while the contributor is alive or dead with the consent of the closest relative. Donation might be for research or, all the more ordinarily, solid transplantable organs and tissues might be given to be transplanted into another person. Common transplantations include kidneys, heart, liver, pancreas, digestive tracts, lungs, bones, bone marrow, skin, and corneas. Some organs and tissues can be given by living contributors, for example, a kidney or part of the liver, some portion of the pancreas, some portion of the lungs or part of the intestines,however most donations happen after the giver has died.In 2017 Spain had the most elevated contributor rate on the planet at 46.9 per million individuals, trailed by Portugal (34.0 per million), Belgium (33.6 per million), Croatia (33.0 per million) and the US (32.0 per million). As of February 2, 2019, there were 120,000 individuals sitting tight forever sparing organ transplants in the US. Of these, 74,897 individuals were dynamic up-and-comers hanging tight for a donor.While perspectives on organ gift are certain, there is an enormous hole between the quantities of enrolled contributors contrasted with those anticipating organ gifts on a worldwide level.
Study on Ion Transport Mechanism of Zinc-Nickel Single-Flow Battery with Different Porous Electrode Structures based on Lattice Boltzmann Method
Authors: Luo Jianguo , Yao Shouguang , Liu Rui , Kan Xin , Yang Yihao , Cheng Jie
Published: May 2022

Since the microstructure of porous electrode is very important to the performance of zinc-nickel single-flow battery, this paper reconstructed the microstructure of porous nickel oxide electrode by quartet structure generation set (QSGS) method. The flow mass transfer and electrochemical reaction in porous electrode were simulated by lattice Boltzmann method (LBM). The effects of different porous electrode structures (porosity, particle size and electrode thickness) on local ion concentration distribution and charging performance are studied from the perspective of seepage and mass transfer in pores. It is found that the ion concentration in the electrode presents an uneven distribution due to the randomness of the particle size and distribution of active substances. The uneven distribution of OH
− concentration caused the difference of charging depth in the direction of electrode thickness, and the uneven distribution of H
+ concentration caused the difference of charging depth in the radial direction of particles. Under different pore structures, the decrease of porosity and particle size can increase the diffusion rates of OH
− and H
+, and then promote the electrochemical reaction rate, improve the charging speed of the battery, and improve the performance of the battery. The larger electrode thickness will increase the OH
− diffusion resistance in the electrode, which is not conducive to the diffusion of OH
− and reduce the electrochemical reaction rate, thus affecting the diffusion of H
+, increasing the concentration polarization and affecting the charging efficiency of the battery. The uneven distribution of OH
− concentration caused the difference of charging depth in the direction of electrode thickness, while the uneven distribution of H
+ concentration caused the difference of charging depth in the radial direction of particles. Under different pore structures, the decrease of porosity and particle size can increase the diffusion rate of OH
− and solid phase H
+, and then promote the electrochemical reaction rate and accelerate the charging speed. The larger electrode thickness increases the OH
− diffusion resistance in the electrode, which is not conducive to OH
− diffusion, and then affects H
+ diffusion and increases concentration polarization.
SnS Nanoparticles and MoS2 Nanosheets Co-Decorated TiO2 Nanorod Film with Remarkable Photocatalytic and Photoelectrochemical Properties
Authors: Deng Jiale , Gao Juan , Liu Mei , Wang Yanfen , Zheng Lingcheng , Li Yang , Liu Yin
Published: May 2022

TiO2/SnS/MoS2 ternary nanorod arrays were synthesized on a fluorine-doped tin oxide (FTO) conductive glass by a successive hydrothermal method. The morphology, microstructure, optical properties, photodegradation activity, photoelectrochemical performance, and charge transport mechanism of TiO2/SnS/MoS2 were systematically studied. It was found that SnS and MoS2 with a narrow bandgap can facilitate light absorbance of TiO2/SnS/MoS2 heterostructures across the visible range, improving the utilization of sunlight. TiO2/SnS/MoS2 exhibits the maximum photodegradation rate (61.54%) for Rhodamine B (RhB) in 60 min with a pseudo-first-order rate constant (0.0122 min−1), which is about 5.16 times better than that of TiO2. As a photoanode, TiO2/SnS/MoS2 has the highest photocurrent (0.841 mA cm−2), which is approximately 8.32 times better than those of TiO2. The enhanced photocatalytic and photoelectrochemical performance of TiO2/SnS/MoS2 is ascribed to the Z-scheme mechanism determined by the detection of active species and the synergistic effect of SnS and MoS2 co-decoration.
Detection of Falsified Antimalarial Sulfadoxine-Pyrimethamine and Dihydroartemisinin-Piperaquine Drugs Using a Low-Cost Handheld Near-Infrared Spectrometer
Authors: Yabré Moussa , Sakira Abdoul Karim , Bandé Moumouni , Goumbri Bertrand W. F. , Ouattara Sandrine M. , Fofana Souleymane , Somé Touridomon Issa
Published: May 2022

Falsified drugs are of serious concern to public health worldwide, particularly for developing countries where quality control of drugs is inefficient. In law enforcement against such fake medicines, there is a need to develop reliable, fast, and inexpensive screening methods. In this work, the ability of an innovative low-cost handheld near-infrared spectrometer to identify falsifications among two antimalarial fixed dose combination tablets, dihydroartemisinin/piperaquine and sulfadoxine/pyrimethamine, has been investigated. Analyzed samples were collected in Burkina Faso mainly in rural transborder areas that could be infiltrated by illicit drugs. A principal component analysis was applied on the acquired near-infrared spectra to identify trends, similarities, and differences between collected samples. This allowed to detect some samples of dihydroartemisinin/piperaquine and sulfadoxine/pyrimethamine which seemed to be falsified. These suspicious samples were semiquantitatively analyzed by thin-layer chromatography using Minalab® kits. Obtained results allowed to confirm the falsifications since the suspected samples did not contain any of the expected active pharmaceutical ingredients. The capacity of the low-cost near-infrared device to identify specifically a brand name of dihydroartemisinin/piperaquine or sulfadoxine/pyrimethamine has been also studied using soft independent modelling of class analogy (SIMCA) in the classical and data driven versions. The built models allowed a clear brand identification with 100% of both sensitivity and specificity in the studied cases. All these results demonstrate the potential of these low-cost near-infrared spectrometers to be used as first line screening tools, particularly in resource limited laboratories, for the detection of falsified antimalarial drugs.
Computational and Functional Analyses of HER2 Mutations Reveal Allosteric Activation Mechanisms and Altered Pharmacologic Effects
Authors: Ishiyama Noboru , O'Connor Matthew , Salomatov Andrei , Romashko Darlene , Thakur Shalabh , Mentes Ahmet , Hopkins Julia F. , Frampton Garrett M. , Albacker Lee A. , Kohlmann Anna , Roberts Christopher , Buck Elizabeth
Published: May 2022

Amplification of HER2 can drive the proliferation of cancer cells, and several inhibitors of HER2 have been successfully developed. Recent advances in next-generation sequencing now reveal that HER2 is subject to mutation, with over 2,000 unique variants observed in human cancers. Several examples of oncogenic HER2 mutations have been described, and these primarily occur at allosteric sites outside the ATP-binding site. To identify the full spectrum of oncogenic HER2 driver mutations aside from a few well-studied mutations, we developed mutation-allostery-pharmacology (MAP), an in silico prediction algorithm based on machine learning. By applying this computational approach to 820 single-nucleotide variants, a list of 222 known and potential driver mutations was produced. Of these 222 mutations, 111 were screened by Ba/F3-retrovirus proliferation assays; 37 HER2 mutations were experimentally determined to be driver mutations, comprising 15 previously characterized and 22 newly identified oncogenic mutations. These oncogenic mutations mostly affected allosteric sites in the extracellular domain (ECD), transmembrane domain, and kinase domain of HER2, with only a single mutation in the HER2 orthosteric ATP site. Covalent homodimerization was established as a common mechanism of activation among HER2 ECD allosteric mutations, including the most prevalent HER2 mutation, S310F. Furthermore, HER2 allosteric mutants with enhanced covalent homodimerization were characterized by altered pharmacology that reduces the activity of existing anti-HER2 agents, including the mAb trastuzumab and the tyrosine kinase inhibitor lapatinib. Overall, the MAP-scoring and functional validation analyses provided new insights into the oncogenic activity and therapeutic targeting of HER2 mutations in cancer.

Significance:

This study identified new oncogenic HER2 allosteric mutations, including ECD mutations that share covalent dimerization as a mechanism of oncogenicity, suggesting the need for novel inhibitors to treat HER2-mutant cancers.
JNK Signaling Promotes Bladder Cancer Immune Escape by Regulating METTL3-Mediated m6A Modification of PD-L1 mRNA
Authors: Ni Zegui , Sun Pengli , Zheng Jin , Wu Mingqing , Yang Congcong , Cheng Maosheng , Yin Mingwei , Cui Chengying , Wang Guangxian , Yuan Lin , Gao Qian , Li Yang
Published: May 2022

The RNA N6-methyladenosine (m6A) writer methyltransferase-like 3 (METTL3) is upregulated in many types of cancer and promotes cancer progression by increasing expression of several oncogenes. Therefore, a better understanding of the mechanisms regulating METTL3 expression and the key targets of METTL3 in cancer cells could provide new therapeutic targets. In this study, we found that activated JNK signaling is associated with increased METTL3 expression in bladder cancer. Knockdown of JNK1 or administration of a JNK inhibitor impaired the binding of c-Jun with the METTL3 promoter, thereby decreasing the expression of METTL3 and global RNA m6A levels. Moreover, RNA m6A sequencing indicated enrichment of m6A in the 3′-UTR of immune checkpoint PD-L1 mRNA, which could be recognized by the m6A reader IGF2BP1 to mediate RNA stability and expression levels of PD-L1. Inhibition of JNK signaling suppressed m6A abundance in PD-L1 mRNA, leading to decreased PD-L1 expression. Functionally, METTL3 was essential for bladder cancer cells to resist the cytotoxicity of CD8+ T cells by regulating PD-L1 expression. Additionally, JNK signaling contributed to tumor immune escape in a METTL3-dependent manner both in vitro and in vivo. These data reveal the JNK/METTL3 axis as a mechanism of aberrant m6A modification and immune regulation in bladder cancer.

Significance:

The identification of a novel m6A-dependent mechanism underlying immune system evasion by bladder cancer cells reveals JNK signaling as a potential target for bladder cancer immunotherapy.
Whole-Genome Duplication Shapes the Aneuploidy Landscape of Human Cancers
Authors: Prasad Kavya , Bloomfield Mathew , Levi Hagai , Keuper Kristina , Bernhard Sara V. , Baudoin Nicolaas C. , Leor Gil , Eliezer Yonatan , Giam Maybelline , Wong Cheng Kit , Rancati Giulia , Storchová Zuzana , Cimini Daniela , Ben-David Uri
Published: May 2022

Aneuploidy is a hallmark of cancer with tissue-specific prevalence patterns that suggest it plays a driving role in cancer initiation and progression. However, the contribution of aneuploidy to tumorigenesis depends on both cellular and genomic contexts. Whole-genome duplication (WGD) is a common macroevolutionary event that occurs in more than 30% of human tumors early in tumorigenesis. Although tumors that have undergone WGD are reported to be more permissive to aneuploidy, it remains unknown whether WGD also affects aneuploidy prevalence patterns. Here we analyzed clinical tumor samples from 5,586 WGD− tumors and 3,435 WGD+ tumors across 22 tumor types and found distinct patterns of aneuploidy in WGD− and WGD+ tumors. WGD+ tumors were characterized by more promiscuous aneuploidy patterns, in line with increased aneuploidy tolerance. Moreover, the genetic interactions between chromosome arms differed between WGD− and WGD+ tumors, giving rise to distinct cooccurrence and mutual exclusivity aneuploidy patterns. The proportion of whole-chromosome aneuploidy compared with arm-level aneuploidy was significantly higher in WGD+ tumors, indicating distinct dominant mechanisms for aneuploidy formation. Human cancer cell lines successfully reproduced these WGD/aneuploidy interactions, confirming the relevance of studying this phenomenon in culture. Finally, induction of WGD and assessment of aneuploidy in isogenic WGD−/WGD+ human colon cancer cell lines under standard or selective conditions validated key findings from the clinical tumor analysis, supporting a causal link between WGD and altered aneuploidy landscapes. We conclude that WGD shapes the aneuploidy landscape of human tumors and propose that this interaction contributes to tumor evolution.

Significance:

These findings suggest that the interactions between whole-genome duplication and aneuploidy are important for tumor evolution, highlighting the need to consider genome status in the analysis and modeling of cancer aneuploidy.
Comprehensive Analysis of Metabolic Isozyme Targets in Cancer
Authors: Marczyk Michal , Gunasekharan Vignesh , Casadevall David , Qing Tao , Foldi Julia , Sehgal Raghav , Shan Naing Lin , Blenman Kim R.M. , O'Meara Tess A. , Umlauf Sheila , Surovtseva Yulia V. , Muthusamy Viswanathan , Rinehart Jesse , Perry Rachel J. , Kibbey Richard , Hatzis Christos , Pusztai Lajos
Published: May 2022

Metabolic reprogramming is a hallmark of malignant transformation, and loss of isozyme diversity (LID) contributes to this process. Isozymes are distinct proteins that catalyze the same enzymatic reaction but can have different kinetic characteristics, subcellular localization, and tissue specificity. Cancer-dominant isozymes that catalyze rate-limiting reactions in critical metabolic processes represent potential therapeutic targets. Here, we examined the isozyme expression patterns of 1,319 enzymatic reactions in 14 cancer types and their matching normal tissues using The Cancer Genome Atlas mRNA expression data to identify isozymes that become cancer-dominant. Of the reactions analyzed, 357 demonstrated LID in at least one cancer type. Assessment of the expression patterns in over 600 cell lines in the Cancer Cell Line Encyclopedia showed that these reactions reflect cellular changes instead of differences in tissue composition; 50% of the LID-affected isozymes showed cancer-dominant expression in the corresponding cell lines. The functional importance of the cancer-dominant isozymes was assessed in genome-wide CRISPR and RNAi loss-of-function screens: 17% were critical for cell proliferation, indicating their potential as therapeutic targets. Lists of prioritized novel metabolic targets were developed for 14 cancer types; the most broadly shared and functionally validated target was acetyl-CoA carboxylase 1 (ACC1). Small molecule inhibition of ACC reduced breast cancer viability in vitro and suppressed tumor growth in cell line– and patient-derived xenografts in vivo. Evaluation of the effects of drug treatment revealed significant metabolic and transcriptional perturbations. Overall, this systematic analysis of isozyme expression patterns elucidates an important aspect of cancer metabolic plasticity and reveals putative metabolic vulnerabilities.

Significance:

This study exploits the loss of metabolic isozyme diversity common in cancer and reveals a rich pool of potential therapeutic targets that will allow the repurposing of existing inhibitors for anticancer therapy.

See related commentary by Kehinde and Parker, p. 1695
Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax
Authors: Lund Amanda W.
Published: May 2022

Melanomas coopt tumor-draining lymph nodes to support metastatic potential and install immunosuppression. The specific mechanisms that mediate lymph node education, however, remain incompletely understood. In this issue, Rovera and colleagues describe the deactivation of contractile lymph node fibroblasts by dedifferentiated melanoma cells, leading to lymph node expansion and enhanced melanoma invasive potential. Fibroblastic reticular cell relaxation depended upon inhibition of constitutive JAK1/STAT3 and YAP/TAZ signaling, which was mediated in part by tumor secretion of the inflammatory cytokine, IL1. These data support an emerging hypothesis that intrinsic melanoma heterogeneity feeds forward to drive microenvironmental adaptations that mediate invasion and progression.

See related article by Rovera et al., p. 1774
Exploiting Dependence of Castration-Resistant Prostate Cancer on the Arginine Vasopressin Signaling Axis by Repurposing Vaptans
Authors: Heidman Laine M. , Peinetti Nahuel , Copello Valeria A. , Burnstein Kerry L.
Published: May 2022

Men with advanced prostate cancer are treated by androgen deprivation therapy but the disease recurs as incurable castration-resistant prostate cancer (CRPC), requiring new treatment options. We previously demonstrated that the G protein–coupled receptor (GPCR) arginine vasopressin receptor type1A (AVPR1A) is expressed in CRPC and promotes castration-resistant growth in vitro and in vivo. AVPR1A is part of a family of GPCR's including arginine vasopressin receptor type 2 (AVPR2). Interrogation of prostate cancer patient sample data revealed that coexpression of AVPR1A and AVPR2 is highly correlated with disease progression. Stimulation of AVPR2 with a selective agonist desmopressin promoted CRPC cell proliferation through cAMP/protein kinase A signaling, consistent with AVPR2 coupling to the G protein subunit alpha s. In contrast, blocking AVPR2 with a selective FDA-approved antagonist, tolvaptan, reduced cell growth. In CRPC xenografts, antagonizing AVPR2, AVPR1A, or both significantly reduced CRPC tumor growth as well as decreased on-target markers of tumor burden. Combinatorial use of AVPR1A and AVPR2 antagonists promoted apoptosis synergistically in CRPC cells. Furthermore, we found that castration-resistant cells produced AVP, the endogenous ligand for arginine vasopressin receptors, and knockout of AVP in CRPC cells significantly reduced proliferation suggesting possible AVP autocrine signaling. These data indicate that the AVP/arginine vasopressin receptor signaling axis represents a promising and clinically actionable target for CRPC.

Implications:

The arginine vasopressin signaling axis in CRPC provides a therapeutic window that is targetable through repurposing safe and effective AVPR1A and AVPR2 antagonists.
Combinatorial Treatment with PARP-1 Inhibitors and Cisplatin Attenuates Cervical Cancer Growth through Fos-Driven Changes in Gene Expression
Authors: Gupte Rebecca , Lin Ken Y. , Nandu Tulip , Lea Jayanthi S. , Kraus W. Lee
Published: May 2022

Cervical cancer continues to be a significant cause of cancer-related deaths in women. The most common treatment for cervical cancer involves the use of the drug cisplatin in conjunction with other therapeutics. However, the development of cisplatin resistance in patients can hinder the efficacy of these treatments, so alternatives are needed. In this study, we found that PARP inhibitors (PARPi) could attenuate the growth of cells representing cervical adenocarcinoma and cervical squamous cell carcinoma. Moreover, a combination of PARPi with cisplatin increased cisplatin-mediated cytotoxicity in cervical cancer cells. This was accompanied by a dramatic alteration of the transcriptome. The FOS gene, which encodes the transcription factor Fos, was one of the most highly upregulated genes in the dual treatment condition, leading to increased Fos protein levels, greater Fos binding to chromatin, and the subsequent induction of Fos target genes. Increased expression of Fos was sufficient to hinder cervical cancer growth, as shown by ectopic expression of Fos in cervical cancer cells. Conversely, Fos knockdown enhanced cell growth. Collectively, these results indicate that by inducing FOS expression, PARPi treatment in combination with cisplatin leads to inhibition of cervical cancer proliferation, likely through a Fos-specific gene expression program.

Implications:

Our observations, which link the gene regulatory effects of PARPi + cisplatin to the growth inhibitory effects of FOS expression in cervical cancer cells, strengthen the rationale for using PARPi with cisplatin as a therapy for cervical cancer.
Lessons Learned from the Impact of COVID-19 on NCI-sponsored Cancer Prevention Clinical Trials: Moving Toward Participant-centric Study Designs
Authors: Samimi Goli , House Margaret , Benante Kelly , Bengtson Lisa , Budd Troy , Dermody Bridget , DeShong Katina , Dyer Valerie , Kimler Bruce F. , Sahasrabuddhe Vikrant V. , Siminski Suzanne , Ford Leslie G. , Vilar Eduardo , Szabo Eva
Published: May 2022

The COVID-19 pandemic overloaded health care systems around the globe and brought travel restrictions and other mandates. These effects critically impacted cancer care and conduct of clinical trials, and required medical and research communities to incorporate changes and novel flexible workflows within clinical trials and regulations to improve efficiency. We report the impact of the pandemic on cancer prevention clinical trials managed by the Division of Cancer Prevention within the NCI, focusing on participant-centric, study staff-centric and regulatory elements. Learning lessons from this challenging period, the cancer prevention community has the opportunity to incorporate many of these necessitated novel approaches to future design of clinical trials, to streamline and improve clinical trial efficiency and impact.
Report from an NCI Roundtable: Cancer Prevention in Primary Care
Authors: Samimi Goli , Douglas Jasmine , Heckman-Stoddard Brandy M. , Ford Leslie G. , Szabo Eva , Minasian Lori M.
Published: May 2022

The Division of Cancer Prevention in the NCI sponsored a Roundtable with primary care providers (PCP) to determine barriers for integrating cancer prevention within primary care and discuss potential opportunities to overcome these barriers. The goals were to: (i) assess the cancer risk assessment tools available to PCPs; (ii) gather information on use of cancer prevention resources; and (iii) understand the needs of PCPs to facilitate the implementation of cancer prevention interventions beyond routine screening and interventions. The Roundtable discussion focused on challenges and potential research opportunities related to: (i) cancer risk assessment and management of high-risk individuals; (ii) cancer prevention interventions for risk reduction; (iii) electronic health records/electronic medical records; and (iv) patient engagement and information dissemination. Time constraints and inconsistent/evolving clinical guidelines are major barriers to effective implementation of cancer prevention within primary care. Social determinants of health are important factors that influence patients' adoption of recommended preventive interventions. Research is needed to determine the best means for implementation of cancer prevention across various communities and clinical settings. Additional studies are needed to develop tools that can help providers collect clinical data that can enable them to assess patients' cancer risk and implement appropriate preventive interventions.
The Role of 18F-FDG PET/CT in Predicting the Neoadjuvant Treatment Response in Patients with Locally Advanced Breast Cancer
Authors: Goktas Aydin Sabin , Bilici Ahmet , Olmez Omer Fatih , Oven Basak B. , Acikgoz Ozgur , Cakir Tansel , Basim Pelin , Cakir Asli , Kutlu Yasin , Hamdard Jamshid
Published: May 2022

Purpose: Patients with locally advanced breast cancer (LABC) should be treated with neoadjuvant chemotherapy (NAC). Pathological complete response (pCR) is related to better disease-free survival (DFS). The best strategy for assessing the efficacy of NAC has not been established yet, but several studies have shown that 18F-FDG PET/CT is a potential imaging tool for assessing pCR. The aim of this study is to investigate the merits of 18F-FDG PET/CT imaging in predicting pCR in both axillary and breast tissue and to establish a threshold maximum standard uptake value (SUVmax) for predicting the response after completion of NAC. Methods: A total of 186 LABC patients, treated with an NAC regimen according to tumor subtype, were retrospectively analyzed in this study. All patients underwent 18F-FDG PET/CT imaging before and after completion of NAC. PET parameters were measured in the most FDG avid breast tissue and axillary lymph nodes. We analyzed the correlation between the tumor SUVmax of the PET/CT response and the pCR after surgery. DFS was also evaluated with respect to pCR. Results: Higher pCR rates were significantly associated with a higher tumor grade, an initial Ki-67 ≥20% (p = 0.03 and p = 0.003, respectively), a triple-negative subtype (32.9%), and a human epidermal growth factor receptor 2 (HER-2)-positive subtype (24.7%) (p < 0.001). There was a significant correlation between the pCR and a complete response in 18F-FDG PET/CT (p < 0.001). The overall sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 18F-FDG PET/CT to determine the pCR after NAC were 100%, 72.2%, 85%, 75.2%, and 100%, respectively. We demonstrated a 1.1 cutoff SUVmax for breast tumors after NAC (OR: 3.94, 95% CI: 1.14–5.05, p = 0.004), the 18F-FDG PET/CT response to NAC (OR: 0.50, 95% CI: 0.25–0.99, p = 0.003), and the molecular subtype of breast tumors (OR: 0.58, 95% CI: 0.38–0.88, p = 0.011). Conclusion: Our results confirm that 18F-FDG PET/CT is a useful method for predicting the NAC response in LABC.
Francfort, Didier. Beethoven, un encombrant génie
Authors: Castro Marcos Câmara de
Published: May 2022

Resenha do livro de Didier Francfort (Universidade de Lorena), publicado em 2020.
Validating a Simulated Emergency Course for Nurses Working in ENT
Authors: de Cates Catherine , Swords Chloe , Kenyon Olivia , MacGinley-Kerr, RN Karen , Watson, BSc, RN Katy , Smith Matthew E. , Bhargava Eishaan , Tysome James R.
Published: May 2022

Objectives:

Nurses are increasingly providing routine and emergency ENT care; yet there are often limited training opportunities. The aim of this study was to validate an intensive 1-day ENT emergency simulation course for nurses.

Methods:

The course included short lectures, practical skills stations and mannequin simulation scenarios. Sixteen nurse participants were video-recorded managing simulated scenarios before and after the course. Two assessors scored individual participant performance on a 15-point competency grid (maximum score 30), blinded to the timing of the recording. Participants also rated their confidence and skill before and immediately following the course across 11 items using a 5-point Likert score (maximum score 55).

Results:

Blinded assessor ratings for performance were significantly improved after the course compared to baseline (overall score 12 vs 7, respectively; P = .015). There was strong assessor inter-rater reliability ( R = 0.965). Self-rated skills and confidence also increased following the course (46.7 vs 24.4 at baseline; P < .01).

Conclusion:

Simulation-based training is an effective and desirable method of teaching ENT emergency management to nurses, with greatest impact on participant confidence. Future courses need to refine the content and increase the validation sample size using a nurse-specific scoring system.
Pediatric Low-Grade Spindle Cell Neoplasm With A Novel AK5::ALK Fusion: A Case Report
Authors: Kikawa Caroline , Ketterl Tyler G. , Liu PhD Yajuan J. , Reed Robyn C. , Dahl John P.
Published: May 2022

Objectives:

Spindle cell neoplasms (SCN) share a single commonality of spindle-shaped cells on histopathology but are diverse in etiology. Expanding our collective knowledge of these neoplasms could further research in targeted therapies. We present a case of pediatric cutaneous SCN with a novel etiology, and the methods used to identify its origination.

Case Presentation and Results:

A 1.5-year-old child presented with a 7-month history of a rapidly enlarging, erythematous, non-painful scalp mass without ulceration or bleeding. The child underwent ultrasound and magnetic resonance imaging, revealing a 2.9 × 3 × 2 cm vascular mass without intracranial connections. The mass was successfully resected at surgery. Subsequent histopathologic and genetic testing indicated a SCN harboring a previously undescribed gene rearrangement between adenylate kinase 5 (AK5) and anaplastic lymphoma kinase (ALK). The patient received close clinical follow-up and at 6 months post-surgery had no recurrent disease.

Conclusions:

ALK rearrangements are common amongst many tumor types, but to our knowledge, AK5::ALK rearrangement has never been reported in SCN. Considering the rapid development of targeted clinical therapies, including those targeting ALK activity, this finding could be significant in the treatment of future patients with similar clinicopathologic and genetic presentation.
A comparison of anxiety levels before and during the COVID-19 pandemic
Authors: Voss Claire , Shorter Phoebe , Weatrowski Grace , Mueller-Coyne Jessica , Turner Katherine
Published: May 2022

The COVID-19 Pandemic upended the lives of nearly everyone worldwide, and recent studies have reported higher rates of anxiety, depression, and other mental health problems. Using a repeated crosssectional design, the current study compares anxiety levels from a representative sample of college students prior-to and during the COVID-19 Pandemic. Additionally, differences in anxiety prior to and following U.S. approval for use of the Pfizer-BioNTtech COVID-19 vaccine were also compared. Findings indicate that state-anxiety levels did not differ significantly prior to and during the Pandemic as well as before the vaccine and during and after the vaccine ( M = 43.01, 44.10, 44.77, respectively). Surprisingly, trait anxiety levels were significantly higher during the Pandemic than before ( p = .003), and anxiety levels trend down after the approval of the vaccine, but not significantly ( M = 45.10, 48.85, 47.58, respectively). Future research should continue to investigate and compare anxiety levels during the COVID-19 Pandemic.