bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between PD-L1 expression of the tumour cells and lymphocytes infiltration in the invasive front of urothelial carcinoma
Authors: Chen Xiaohu , Chen Hanbin , Lin Rixu , Li Yulian , Guo Ying , Chen Qi , Zhang Yanyan , Cai Guoping , Hu Mengjun , Chen Guorong
Published: November 2022

Purpose

Programmed cell death-ligand 1 (PD-L1) as a cell surface glycoprotein can inhibit T cell function when binding to its receptor, PD-1. The newly developed therapy of targeting PD-1/PD-L1 signal pathway has shown great promise for the treatment of non-small cell lung cancer as well as melanoma. Approved by Food and Drug Administration, atezolizumab has become the first new drug to treat advanced bladder cancer. The aim of this study is to evaluate whether PD-L1 is associated with the lymphocytes infiltration in the tumour microenvironment and to assess the prognostic value of PD-L1 expression.

Materials and methods

Among 96 invasive bladder urothelial carcinomas, some were used to construct tissue-microarrays, and some cases with shallow infiltration or large heterogeneity were performed, respectively, for the following work. By means of immunohistochemistry and HE, PD-L1 expression and immune cell infiltration in the invasive front of urothelial carcinoma were analysed.

Results

We find that PD-L1 expression in tumour cells and lymphocytes are significantly associated with more tumour infiltrating lymphocytes (TILs) and more T cells. The integrated TILs, T-PD-L1 and I-PD-L1 are not significantly correlated with the overall survival (OS) of patients. However, the combination of T-PD-L1 and TILs, T-PD-L1 and I-PD-L1 is significantly correlated with the OS of patients. The T-PD-L1 (−)/TIL (−) group show the best prognosis and the T-PD-L1 (+)/I-PD-L1 (−) group show the worst prognosis. Furthermore, a multivariate analysis reveal that PD-L1 expression of lymphocytes is an independent prognostic factor for OS of patients.

Conclusions

Our study reveal that PD-L1 of tumour cells are associated with the corresponding T cells infiltration and that the combination of T-PD-L1 and I-PD-L1, T-PD-L1 and TILs could be a relevant marker for the determination of the prognostic role of patients with the urothelial carcinoma.
MiR-125b-5p modulates the function of regulatory T cells in tumor microenvironment by targeting TNFR2
Authors: Jiang Mengmeng , Yang Yang , Niu Liling , Li Ping , Chen Yibo , Liao Ping , Wang Yifei , Zheng Jingbin , Chen Fengyang , He Huanhuan , Li Hui , Chen Xin
Published: November 2022

Background

Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4+FoxP3+regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy.

Methods

MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8+cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs.

Results

In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγ+CD8+T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated.

Conclusions

Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.
Tolerance and efficacy of targeted therapies prescribed for off-label indications in refractory systemic autoimmune diseases: data of the first 100 patients enrolled in the TATA registry (TArgeted Therapy in Autoimmune Diseases)
Authors: Gottenberg Jacques-Eric , Chaudier Aurore , Allenbach Yves , Mekinian Arsène , Amoura Zahir , Cacoub Patrice , Cornec Divi , Hachulla Eric , Quartier Pierre , Melki Isabelle , Richez Christophe , Seror Raphaele , Terrier Benjamin , Devauchelle-Pensec Valérie , Henry Julien , Gatfosse Marc , Bouillet Laurence , Gaigneux Emeline , Andre Vincent , Baulier Gildas , Saunier Aurélie , Desmurs Marie , Poulet Antoine , Ete Mathieu , Bienvenu Boris , Truchetet Marie-Elise , Michaud Martin , Larroche Claire , Dellal Azeddine , Leurs Amélie , Ottaviani Sebastien , Nielly Hubert , Vial Guillaume , Jaussaud Roland , Rouvière Bénedicte , Jeandel Pierre-Yves , Guffroy Aurelien , Korganow Anne-Sophie , Jouvray Mathieu , Meyer Alain , Chatelus Emmanuel , Sordet Christelle , Felten Renaud , Sibilia Jean , Litim-Ahmed-Yahia Samira , Kleinmann Jean-Francois , Mariette Xavier
Published: November 2022

Objectives

To assess the tolerance and efficacy of targeted therapies prescribed off-label in refractory low-prevalence autoimmune and inflammatory systemic diseases.

Methods

The TATA registry (TArgeted Therapy in Autoimmune Diseases) is a prospective, observational, national and independent cohort follow-up. The inclusion criteria in the registry are as follows: age >18 years; low-prevalence autoimmune and inflammatory systemic disease treated with off-label drugs started after 1 January 2019.

Results

Hundred (100) patients (79 women) were enrolled. The median age was 52.5 years (95% CI 49 to 56) and the median disease duration before enrolment was 5 years (3 to 7). The targeted therapies at enrolment were as follows: Janus kinase/signal transducers and activators of transcription inhibitors (44%), anti-interleukin (IL)-6R (22%), anti-IL-12/23, anti-IL-23 and anti-IL-17 (9%), anti-B cell activating factor of the tumour necrosis factor family (5%), abatacept (5%), other targeted treatments (9%) and combination of targeted treatments (6%). 73% of patients were receiving corticosteroid therapy at enrolment (median dose 10 mg/day). The current median follow-up time is 9 months (8 to 10).

Safety:11 serious infections (incidence rate of 14.8/100 patient-years) and 1 cancer (1.3 cancers/100 patient-years) were observed. Two patients died from severe COVID-19 (2.7 deaths/100 patient-years).

Efficacy:the targeted treatment was considered effective by the clinician in 56% of patients and allowed, in responders, a median reduction of oral corticosteroids of 15 (9 to 21) mg/day, below 7.5 mg/day in 76% of patients, while 28% discontinued.

Conclusion

These initial results of the TATA registry confirm the diversity of targeted treatments prescribed off-label in refractory autoimmune diseases and their corticosteroid-sparing effect when effective. Tolerance was acceptable in these refractory patients with a long history of treatment with immunosuppressive drugs.
Experimental study on swelling pressure of low dry density compacted bentonites during saturation combining X-ray diffraction
Authors: Ruan Kunlin , Komine Hideo , Wang Hailong , Ito Dachi , Gotoh Takahiro
Published: November 2022

A multi-ring and a newly developed swelling pressure apparatus were adopted for measuring swelling pressure of three low dry density bentonites (sodium type: MX-80 and Kunigel-V1; calcium type: Kunibond). Subsequently, slices from the multi-ring were observed using X-ray diffraction to obtain basal spacings. Distance between particles was calculated from a basal spacing database. Relations between microstructural changes, including basal spacing and distance between particles, and swelling pressure are discussed. Results show that calcium-type bentonites have greater swelling pressure than sodium-type bentonites during saturation. When bentonites have the same cation type, lower montmorillonite content bentonite obtains smaller swelling pressures than the high montmorillonite content ones. Basal spacing increases drastically first and then maintains a stable value during saturation. All three bentonites gradually reach the 3  w state along with wetting (MX-80 and Kunigel-V1: 1–3  w; Kunibond: 2–3  w). The distance between particles increases with the saturation time. During saturation, swelling pressure generally rises with increasing basal spacing and increasing distance between particles. The mechanism for swelling pressure development is discussed.
Enumeration of Far-apart Pairs by Decreasing Distance for Faster Hyperbolicity Computation
Authors: Coudert David , Nusser André , Viennot Laurent
Published: November 2022

Hyperbolicity is a graph parameter that indicates how much the shortest-path distance metric of a graph deviates from a tree metric. It is used in various fields such as networking, security, and bioinformatics for the classification of complex networks, the design of routing schemes, and the analysis of graph algorithms. Despite recent progress, computing the hyperbolicity of a graph remains challenging. Indeed, the best known algorithm has time complexity

O(n
3.69
)

, which is prohibitive for large graphs, and the most efficient algorithms in practice have space complexity

O(n
2
)

. Thus, time as well as space are bottlenecks for computing the hyperbolicity.

In this article, we design a tool for enumerating all far-apart pairs of a graph by decreasing distances. A node pair
(u, v)
of a graph is far-apart if both
v
is a leaf of all shortest-path trees rooted at
u
and
u
is a leaf of all shortest-path trees rooted at
v
. This notion was previously used to drastically reduce the computation time for hyperbolicity in practice. However, it required the computation of the distance matrix to sort all pairs of nodes by decreasing distance, which requires an infeasible amount of memory already for medium-sized graphs. We present a new data structure that avoids this memory bottleneck in practice and for the first time enables computing the hyperbolicity of several large graphs that were far out of reach using previous algorithms. For some instances, we reduce the memory consumption by at least two orders of magnitude. Furthermore, we show that for many graphs, only a very small fraction of far-apart pairs has to be considered for the hyperbolicity computation, explaining this drastic reduction of memory.

As iterating over far-apart pairs in decreasing order without storing them explicitly is a very general tool, we believe that our approach might also be relevant to other problems.
Model Diagnostics and Forecast Evaluation for Quantiles
Authors: Gneiting Tilmann , Wolffram Daniel , Resin Johannes , Kraus Kristof , Bracher Johannes , Dimitriadis Timo , Hagenmeyer Veit , Jordan Alexander I. , Lerch Sebastian , Phipps Kaleb , Schienle Melanie
Published: November 2022

Model diagnostics and forecast evaluation are closely related tasks, with the former concerning in-sample goodness (or lack) of fit and the latter addressing predictive performance out-of-sample. We review the ubiquitous setting in which forecasts are cast in the form of quantiles or quantile-bounded prediction intervals. We distinguish unconditional calibration, which corresponds to classical coverage criteria, from the stronger notion of conditional calibration, as can be visualized in quantile reliability diagrams. Consistent scoring functions—including, but not limited to, the widely used asymmetricpiecewise linear score or pinball loss—provide for comparative assessment and ranking, and link to the coefficient of determination and skill scores. We illustrate the use of these tools on Engel's food expenditure data, the Global Energy Forecasting Competition 2014, and the US COVID-19 Forecast Hub.
Study of Vertical Ga2O3 FinFET Short Circuit Ruggedness using Robust TCAD Simulation
Authors: Lu Albert , Elwailly Adam , Zhang Yuhao , Wong Hiu Yung
Published: November 2022

In this paper, the short circuit ruggedness of Gallium Oxide (Ga2O3) vertical FinFET is studied using Technology Computer-Aided-Design (TCAD) simulations. Ga2O3 is an emerging ultra-wide bandgap material and Ga2O3 vertical FinFET can achieve the normally-off operation for high voltage applications. Ga2O3 has a relatively low thermal conductivity and, thus, it is critical to explore the design space of Ga2O3 vertical FinFETs to achieve an acceptable short-circuit capability for power applications. In this study, appropriate TCAD models and parameters calibrated to experimental data are used. For the first time, the breakdown voltage simulation accuracy of Ga2O3 vertical FinFETs is studied systematically. It is found that a background carrier generation rate between 105 cm−3s−1 and 1012 cm−3s−1 is required in simulation to obtain correct results. The calibrated and robust setup is then used to study the short circuit withstand time (SCWT) of an 800 V-rated Ga2O3 vertical FinFET with different inter-fin architectures. It is found that, due to the high thermal resistance in Ga2O3, to achieve an SCWT >1 μs, low gate overdrive is needed which increases Ron,sp by 66% and that Ga2O3 might melt before the occurrence of thermal runaway. These results provide important guidance for developing rugged Ga2O3 power transistors.
Review—Magnetic Skyrmions in Chiral Ferromagnets: Electrical Transport Properties and Device Applications
Authors: Kaviraj Bhaskar , Sinha Jaivardhan
Published: November 2022

In this review article, we provide an overview of skyrmion dynamics in the transport behavior of skyrmions based on the existing theoretical and experimental works in addition to the device applications. Swirling spin textures, namely, skyrmions are expected to play extremely important role in future energy efficient spintronic devices. We emphasize specifically on the electrical control of the skyrmion dynamics from the fundamental to application point of view. To begin with, we discuss the role of antisymmetric exchange interaction, namely, the Dzyaloshinskii-Moriya interaction which has its origin in spin–orbit coupling and symmetry breaking at the interface in stabilizing the skyrmion. In-depth understanding of the role of in-plane and out of plane spin torque in governing the skyrmion dynamics is discussed. Importantly, the skyrmion Hall effect, voltage control of skyrmion dynamics, and various important experimental techniques for generating and detecting skyrmion have been elaborated. Given the delicate physics involved with the manipulation and detection of skyrmion, the crucial understanding of the experimental results and theory from the perspective of electrical transport are discussed. Finally, the application of skyrmions in various devices e.g., magnetic memory, transistors and logic gates along with challenges involved are summarized briefly.
LSTM Recurrent Neural Network-Based Frequency Control Enhancement of the Power System with Electric Vehicles and Demand Management
Authors: Sundararajan G. , Sivakumar P.
Published: November 2022

Due to the unpredictable and stochastic nature of renewables, current power networks confront operational issues as renewable energy sources are more widely used. Frequency stability of modern power systems has been considerably harmed by fast and unpredictable power variations generated by intermittent power generation sources and flexible loads. The main objective of the power system frequency control is to ensure the generation demand balance at all times. In reality, obtaining precise estimates of the imbalance of power in both transmission and distribution systems is challenging, especially when renewable energy penetration is high. Electric vehicles have become a viable tool to reduce the occasional impact of renewable energy sources engaged in frequency regulation mainly because of vehicle-to-grid technologies and the quick output power management of EV batteries. The rapid response of EVs enhances the effectiveness of the LFC system significantly. This research work investigates a deep learning strategy based on a long short-term memory recurrent neural network to identify active power fluctuations in real-time. The new approach assesses power fluctuations from a real-time observed frequency signal precisely and quickly. The observed power fluctuations can be used as a control reference, allowing automatic generation control to maintain better system frequency and ensure optimum generation cost with the use of demand management techniques. To validate the suggested method and compare it with several classical methods, a realistic model of the Indian power system integrated with distributed generation technology is used. The simulation results clearly indicate the importance of power fluctuation identification as well as the benefits of the proposed strategy. The results clearly show a considerable improvement in response performance indices, as the maximum peak overshoot was decreased by 21.25% to 51.2%, and settling time was lowered by about 23.34% to 65.40% for the suggested control technique compared to other controllers.
Time-Leveled Hypersoft Matrix, Level Cuts, Operators, and COVID-19 Collective Patient Health State Ranking Model
Authors: Rana Shazia , Saeed Muhammad , Almaz Ali Yousif Badria , Smarandache Florentin , Abd El-Wahed Khalifa Hamiden
Published: November 2022

This article is the first step to formulate such higher dimensional mathematical structures in the extended fuzzy set theory that includes time as a fundamental source of variation. To deal with such higher dimensional information, some modern data processing structures had to be built. Classical matrices (connecting equations and variables through rows and columns) are a limited approach to organizing higher dimensional data, composed of scattered information in numerous forms and vague appearances that differ on time levels. To extend the approach of organizing and classifying the higher dimensional information in terms of specific time levels, this unique plithogenic crisp time-leveled hypersoft-matrix (PCTLHS matrix) model is introduced. This hypersoft matrix has multiple parallel layers that describe parallel universes/realities/information on some specific time levels as a combined view of events. Furthermore, a specific kind of view of the matrix is described as a top view. According to this view, i-level cuts, sublevel cuts, and sub-sublevel cuts are introduced. These level cuts sort the clusters of information initially, subject-wise then attribute-wise, and finally time-wise. These level cuts are such matrix layers that focus on one required piece of information while allowing the variation of others, which is like viewing higher dimensional images in lower dimensions as a single layer of the PCTLHS matrix. In addition, some local aggregation operators are designed to unify i-level cuts. These local operators serve the purpose of unifying the material bodies of the universe. This means that all elements of the universe are fused and represented as a single body of matter, reflecting multiple attributes on different time planes. This is how the concept of a unified global matter (something like dark matter) is visualized. Finally, to describe the model in detail, a numerical example is constructed to organize and classify the states of patients with COVID-19.
Cost-Effectiveness of a New Outpatient Pulmonology Care Model Based on Physician-to-Physician Electronic Consultation
Authors: Álvarez-Dobaño José Manuel , Toubes Malena , Novo-Platas José Ángel , Reyes-Santías Francisco , Atienza Gerardo , Portela Manuel , Rábade Carlos , Lourido Tamara , Casal Ana , Rodríguez-García Carlota , Riveiro Vanessa , Abelleira Romina , Ricoy Jorge , Rodríguez-Núñez Nuria , Zamarrón Carlos , Calle Felipe , Gude Francisco , Valdés Luis
Published: November 2022

Introduction. This study assesses the impact of an electronic physician-to-physician consultation program on the waiting list and the costs of a Pulmonology Unit. Materials and Methods. A prepost intervention study was conducted after a new ambulatory pulmonary care protocol was implemented and the capacity of the unit was adopted. In the new model, physicians at all levels of healthcare send electronic consultations to specialists. Results. In the preintervention year (2019), the Unit of Pulmonology attended 7,055 consultations (466 e-consultations and 6,589 first face-to-face visits), which decreased to 6,157 (3,934 e-consultations and 2,223 first face-to-face visits; 12.7% reduction) in the postintervention year (all were e-consultations). The mean wait time for the first appointment was 25.7 days in 2019 versus 3.2 days in 2021 (

p
<
0.001

). In total, 43.5% of cases were solved via physician-to-physiciane-consultation. A total of 2,223 patients needed a face-to-face visit, with a mean wait time of 7.5 days. The mean of patients in the waiting listing decreased from 450.8 in 2019 to 44.8 in 2021 (90% reduction). The annual time devoted to e-consultations and first face-to-face visits following an e-consultation diminished significantly after the intervention (1,724 hours versus 2,312.8; 25.4% reduction). Each query solved via e-consultation represented a saving of €652.8, resulting in a total annual saving of €827,062. Conclusions. Physician-to-physiciane-consultations reduce waiting times, improve access of complex patients to specialty care, and ensure that cases are managed at the appropriate level. E-consultation reduces costs, which benefits both, society and the healthcare system.
Diagnostic Accuracy Rates of Appendicitis Scoring Systems for the Stratified Age Groups
Authors: Gonullu Emre , Bayhan Zulfu , Capoglu Recayi , Mantoglu Barış , Kamburoglu Burak , Harmantepe Tarık , Altıntoprak Fatih , Erkorkmaz Unal
Published: November 2022

Background. Many scoring systems have been developed for acute appendicitis, which is the most common emergent disorder in surgical practice. Considering the physiological changes and chronic diseases occurring with advancing age, an applied scoring system may not produce the same score in similar patients in all age groups. Objectives. We aimed to compare the predictive values of scoring systems in different age groups. Methods. In this prospective study, the patients operated on in our clinic with a prediagnosis of acute appendicitis between March 2020 and March 2021 were included. We divided them into three age groups as 18–45 years (group 1), 46–65 years (group 2), and >65 years (group 3). We compared the scores of the nine acute appendicitis scoring systems most commonly used in the literature for these age groups. Results. A total of 203 patients were included in our study. The Alvarado scoring system yielded the most accurate results for group 1, whereas the Fenyo–Linberg scoring system was the most accurate system for group 2 and the Eskelinen scoring system for group 3. Conclusion. Age should be considered as a major parameter during the selection of the scoring system to be applied for patients with prediagnosis of acute appendicitis. Our study revealed the Alvarado and the Fenyo–Lindberg scoring systems as the most accurate systems for the differential diagnosis of appendicitis in the 18–45 and 46–65 years age groups, respectively. Although we found the Eskelinen scoring system as the most accurate one in the >65 years age group, the confidence intervals indicated that it may not be appropriate for use alone in this group.
Oligochaeta ramosa (Roxb.) Extract Regulates Lipid Metabolism and Exerts Hepatoprotective Effects in Cadmium-Induced Hepatic Injury in Rats
Authors: Aslam Saira , Ahmad Fiaz-ud-Din , Hassan Waseem , Buabeid Manal Ali , Mukhtar Imran , Umar Muhammad Ihtisham , Ibrahim Nihal Abdallah
Published: November 2022

Environmental pollutants present a potential source of toxicity when exposed to humans. The study was aimed at investigating the potential of Oligochaeta ramosa (Roxb.) as a hepatoprotective agent in cadmium-induced hepatotoxicity causing lipid profile disturbance. The aqueous methanolic (30 : 70 v/v) extract of O. ramosa Roxb. (AME.Or) was subjected to preliminary phytochemical analysis, whereas the antioxidant activity of its constituents was investigated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay. The hepatoprotective and antihyperlipidemic effects of AME.Or was investigated by dividing animals into five groups (A–E). Animals were either treated with normal saline or CdCl2 (6.5 mg/kg, intraperitoneally) followed by treatment with silymarin (100 mg/kg), or AME.Or (200 mg/kg) and AME.Or (400 mg/kg) for consecutive three weeks. Blood samples were collected, and the serum lipid profile was assessed on the 11th and 21st day of treatment. Histopathological analysis was performed after euthanization. In vitro analysis of AME.Or revealed 64% inhibition as free radicals scavenging potential during DPPH, total phenolic content (TPC) (79.92 mgGAE/g), and total flavonoids content (TFC) (38.75 mgRE/g). The group intoxicated with CdCl2 showed significantly high (

p
≤
0.05

) levels of the liver function indicators and lipid profile than in the control group. The higher dose of AME.Or (400 mg/kg) significantly decreased the aspartate aminotransferase (AST), alanine transferase (ALT), alkaline phosphatase (ALP), total bilirubin (

p
≤
0.001

), decreased total cholesterol and triglycerides (

p
≤
0.01

) while significantly increased high density lipoprotein (HDL;

p
≤
0.01

) as compared to the intoxicated group. The histopathological analysis of the liver revealed signs of necrosis in the intoxicated group, while AME.Or treated groups showed marked improvement. The findings accentuate the therapeutic importance of O. ramosa (Roxb.) as a hepatoprotective remedy.
Comparison of Tongue Acupuncture and Traditional Acupuncture in the Treatment of Poststroke Dysarthria: A Meta-Analysis and Tongue Acupuncture System Classification Evaluation
Authors: Yang Xinming , Shi Lei , Ran Dawei , Kong Ying , Shi Weiping , Zhou Jiaxiao , Gao Huasong , Han Yutong , Zhang Huixue
Published: November 2022

Objective. To discuss whether tongue acupuncture is more effective than traditional acupuncture in the treatment of poststroke dysarthria and explore the advantage of tongue acupuncture treatment parameters. Methods. We evaluated the efficacy of tongue acupuncture compared with traditional acupuncture through a rigorous meta-analysis process. The included studies were from eight databases in English and Chinese. The Cochrane risk of bias assessment tool was used to evaluate the quality of studies. Stata15.1 software was used for meta-analysis and sensitivity analysis. Tongue acupuncture therapeutic parameters were classified and counted based on tongue acupoint location, acupuncture manipulation, and the number of manipulations. Subgroup analysis was used to compare the differences between various treatment parameters. Outcome The meta-analysis eventually included a total of 9 studies. Tongue acupuncture is superior to traditional acupuncture in clinical efficacy [OR = 3.62, 95%Cl (2.24, 5.85),

P
<
0.0001

], FDA score [SMD = −1.99, 95%Cl (−3.77, −0.21),

P
=
0.028

], and NIHSS score [WMD = 0.86, 95%Cl (0.15, 1.57),

P
=
0.017

, I2 = 31.7%] in the treatment of poststroke dysarthria. According to the classified statistics of tongue acupuncture treatment parameters, there are three kinds of tongue acupuncture points in 9 studies: lingual surface, sublingual, and both lingual surface and sublingual acupoints. The operation methods include the oblique stabbing of the root of the tongue, twisting after stabbing, and acupoint pricking. The number of operation methods varies from 1 to 3. Conclusion. Tongue acupuncture outperforms traditional acupuncture in terms of clinical efficacy, FDA score, and NIHSS score in the treatment of poststroke dysarthria. The curative effect of sublingual acupoints is better than that of lingual surface acupoints, the combined use of multiple manipulations is better than that of a single manipulation, and acupuncture manipulation has a cumulative effect. PROSPERO registration number: CRD42021285722.
Two-Phase Turbulent Fluid Flow in a Geothermal Pipe with Chemical Reaction
Authors: Eric Nyariki M. , Kinyanjui Mathew N. , Abonyo Jeconia O.
Published: November 2022

In this study, two-phase non-Newtonian turbulent fluid flow in an inclined geothermal pipe with chemical reaction was considered. The governing nonlinear partial differential equations derived were solved numerically using Finite Difference Method. Influence of flow parameters on the temperature, concentration and velocity profiles were analyzed graphically. From the mathematical analysis of the model, it was established that the chemical reaction parameter significantly influenced the concentration distribution in both gaseous and liquid phases. Findings further revealed that decreasing the chemical reaction parameter resulted in decreased concentration of the geothermal fluid, which causes corrosion of geothermal pipes. These findings provide important information to engineers and researchers in making better decisions in terms of design, sizing and maintenance of flow systems in geothermal pipes.
Incentive Regulation of Construction Waste Resource Recycling: Subsidy and Tax Incentive
Authors: Xiang Qing , Jing Zhang , Ruwen Tan , Minjiu Yu
Published: November 2022

Construction waste destroys the sustainability of environment and economy. In the study of game theory at present, the construction waste resource-based products supply chain only considers that there is only one type of enterprise producing renewable building materials or new building materials in the market, but in the construction market, there is no single type of enterprise. It isvery important for government to protect the environment and promote the resource utilization and development of construction waste. Therefore, this study establishes a game theory model between traditional building materials enterprise and construction waste recycling enterprise, which considers the decision-making behavior of enterprise under no regulation, subsidy incentive regulation, or tax incentive regulation. The findings are listed as follows: (1) both subsidies and tax incentives can effectively improve the economic benefits and production initiative of construction waste recycling enterprise. (2) The impact coefficient of unit new building materials on the environment and the tax rate of unit new building materials are the key factors that affect government decision-making. (3) Resource utilization cost coefficient and builder’s preference for renewable building materials have a great impact on the profits of construction waste recycling enterprise. These results will provide reference for the government to formulate incentive regulations and promote the development of construction waste resources.
Gene Fusion Detection and Characterization in Long-Read Cancer Transcriptome Sequencing Data with FusionSeeker
Authors: Chen Yu , Wang Yiqing , Chen Weisheng , Tan Zhengzhi , Song Yuwei ,   Human Genome Structural Variation Consortium, Chen Herbert , Chong Zechen
Published: November 2022

Gene fusions are prevalent in a wide array of cancer types with different frequencies. Long-read transcriptome sequencing technologies, such as PacBio, Iso-Seq, and Nanopore direct RNA sequencing, provide full-length transcript sequencing reads, which could facilitate detection of gene fusions. In this work, we developed a method, FusionSeeker, to comprehensively characterize gene fusions in long-read cancer transcriptome data and reconstruct accurate fused transcripts from raw reads. FusionSeeker identified gene fusions in both exonic and intronic regions, allowing comprehensive characterization of gene fusions in cancer transcriptomes. Fused transcript sequences were reconstructed with FusionSeeker by correcting sequencing errors in the raw reads through partial order alignment algorithm. Using these accurate transcript sequences, FusionSeeker refined gene fusion breakpoint positions and predicted breakpoints at single bp resolution. Overall, FusionSeeker will enable users to discover gene fusions accurately using long-read data, which can facilitate downstream functional analysis as well as improved cancer diagnosis and treatment.

Significance:

FusionSeeker is a new method to discover gene fusions and reconstruct fused transcript sequences in long-read cancer transcriptome sequencing data to help identify novel gene fusions important for tumorigenesis and progression.
Lifetime Exposure to Cigarette Smoke and Risk of Ovarian Cancer by T-cell Tumor Immune Infiltration
Authors: Hathaway Cassandra A. , Wang Tianyi , Townsend Mary K. , Vinci Christine , Jake-Schoffman Danielle E. , Saeed-Vafa Daryoush , Moran Segura Carlos , Nguyen Jonathan V. , Conejo-Garcia Jose R. , Fridley Brooke L. , Tworoger Shelley S.
Published: November 2022

Background:

Exposure to cigarette smoke, particularly in early life, is modestly associated with ovarian cancer risk and may impact systemic immunity and the tumor immune response. However, no studies have evaluated whether cigarette smoke exposure impacts the ovarian tumor immune microenvironment.

Methods:

Participants in the Nurses’ Health Study (NHS) and NHSII reported on early life exposure to cigarette smoke and personal smoking history on questionnaires (n = 165,760). Multiplex immunofluorescence assays were used to measure markers of T cells and immune checkpoints in tumor tissue from 385 incident ovarian cancer cases. We used Cox proportional hazards models to evaluate HRs and 95% confidence intervals (CI) for developing ovarian tumors with a low (<median) or high (≥median) immune cell percentage by cigarette exposure categories.

Results:

Women exposed versus not to cigarette smoke early in life had a higher risk of developing ovarian cancer with low levels of T cells overall (CD3+: HR: 1.54, 95% CI: 1.08–2.20) and recently activated cytotoxic T cells (CD3+CD8+CD69+: HR: 1.45, 95% CI: 1.05–2.00). These findings were not statistically significant at the Bonferroni-corrected P value of 0.0083. Adult smoking was not significantly associated with tumor immune markers after Bonferroni correction.

Conclusions:

These results suggest early life cigarette smoke exposure may modestly increase risk of developing ovarian tumors with low abundance of total T cells and recently activated cytotoxic T cells.

Impact:

Future research should focus on understanding the impact of exposures throughout the life course on the ovarian tumor immune microenvironment.
Olaparib Efficacy in Patients with Metastatic Castration-resistant Prostate Cancer and BRCA1, BRCA2, or ATM Alterations Identified by Testing Circulating Tumor DNA
Authors: Matsubara Nobuaki , de Bono Johann , Olmos David , Procopio Giuseppe , Kawakami Satoru , Ürün Yüksel , van Alphen Robbert , Flechon Aude , Carducci Michael A. , Choi Young Deuk , Hotte Sebastien J. , Korbenfeld Ernesto , Kramer Gero , Agarwal Neeraj , Chi Kim N. , Dearden Simon , Gresty Christopher , Kang Jinyu , Poehlein Christian , Harrington Elizabeth A. , Hussain Maha
Published: November 2022

Purpose:

The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of circulating tumor DNA (ctDNA) testing as an additional method to identify patients with mCRPC with HRR gene alterations who may be eligible for olaparib treatment.

Patients and Methods:

Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne®Liquid CDx test for BRCA1, BRCA2 (BRCA), and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.

Results:

Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients’ baseline demographics and characteristics, and the prevalence of HRR alterations were comparable with the Cohort A intention-to-treat (ITT) population. rPFS was longer in the olaparib group versus control [median 7.4 vs. 3.5 months; hazard ratio (HR), 0.33; 95% confidence interval (CI), 0.21–0.53; nominal P < 0.0001], which is consistent with Cohort A ITT population (HR, 0.34; 95% CI, 0.25–0.47).

Conclusions:

When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
Combination of Ribociclib with BET-Bromodomain and PI3K/mTOR Inhibitors for Medulloblastoma Treatment In Vitro and In Vivo
Authors: Jonchere Barbara , Williams Justin , Zindy Frederique , Liu Jingjing , Robinson Sarah , Farmer Dana M. , Min Jaeki , Yang Lei , Stripay Jennifer L. , Wang Yingzhe , Freeman Burgess B. , Yu Jiyang , Shelat Anang A. , Rankovic Zoran , Roussel Martine F.
Published: November 2022

Despite improvement in the treatment of medulloblastoma over the last years, numerous patients with MYC- and MYCN-driven tumors still fail current therapies. Medulloblastomas have an intact retinoblastoma protein RB, suggesting that CDK4/6 inhibition might represent a therapeutic strategy for which drug combination remains understudied. We conducted high-throughput drug combination screens in a Group3 (G3) medulloblastoma line using the CDK4/6 inhibitor (CDK4/6i) ribociclib at IC20, referred to as an anchor, and 87 oncology drugs approved by FDA or in clinical trials. Bromodomain and extra terminal (BET) and PI3K/mTOR inhibitors potentiated ribociclib inhibition of proliferation in an established cell line and freshly dissociated tumor cells from intracranial xenografts of G3 and Sonic hedgehog (SHH) medulloblastomas in vitro. A reverse combination screen using the BET inhibitor JQ1 as anchor, revealed CDK4/6i as the most potentiating drugs. In vivo, ribociclib showed single-agent activity in medulloblastoma models whereas JQ1 failed to show efficacy due to high clearance and insufficient free brain concentration. Despite in vitro synergy, combination of ribociclib with the PI3K/mTOR inhibitor paxalisib did not significantly improve the survival of G3 and SHH medulloblastoma-bearing mice compared with ribociclib alone. Molecular analysis of ribociclib and paxalisib-treated tumors revealed that E2F targets and PI3K/AKT/MTORC1 signaling genes were depleted, as expected. Importantly, in one untreated G3MB model HD-MB03, the PI3K/AKT/MTORC1 gene set was enriched in vitro compared with in vivo suggesting that the pathway displayed increased activity in vitro. Our data illustrate the difficulty in translating in vitro findings in vivo.

See related article in Mol Cancer Ther (2022) 21(8):1306–1317.
Cancer Prevention from the Viewpoint of UVA Comprehensive Cancer Center
Authors: Loughran Thomas P. , Cohn Wendy , Bonilla Gloribel , Anderson Roger T.
Published: November 2022

Prevention is a cornerstone of the guiding mission of the University of Virginia Comprehensive Cancer Center, which is “to reduce the burden of cancer for the patients of today, through skilled, integrated, and compassionate care and to eliminate the threat of cancer for the patients of tomorrow, through research and education in an environment that promotes diversity, equity, and inclusion.” We find it useful to conceptualize different opportunities for cancer prevention using NCI's Health Behaviors Research Branch's multilevel translational framework. The latter considers three intersecting continuums: cancer control—from prevention through survivorship; translation—from basic sciences to dissemination and implementation; and level of influence or impact—from genetics to policy. An advantage of this heuristic is that “prevention” is inherently defined as an inter-programmatic concept cutting across basic, clinical, and population science research rather than solely as a programmatic domain of Population Sciences. Through the UVA community outreach and engagement, we apply this multilevel framework to mitigate the social determinants of cancer risk and outcomes that drive cancer inequities in our catchment area. Below, we provide examples of our prevention research and translation along the model continuums and focus on equity.
Surveying Mechanisms of Immune Checkpoint Blockade from a VISTA
Authors: Wei Spencer C.
Published: November 2022

Defining the mechanisms of action of immune checkpoint blockade therapies is essential for effectively designing combination therapeutic approaches and developing the next generation of immunotherapies. In this issue, Schaafsma and colleagues report that V-domain immunoglobulin suppressor of T-cell activation antagonism acts through mechanisms distinct from anti–CTLA-4 and anti—programmed cell death protein 1 via remodeling of the myeloid-cell compartment and modulating T-cell quiescence.

See related article by Schaafsma et al. p. 38 (1).
Multiparametric Neuroimaging and Its Association with Non-Contrast Computed Tomography in Late-Window Large Vessel Occlusion Acute Stroke
Authors: Rodrigo-Gisbert Marc , Requena Manuel , De Dios Lascuevas Marta , García-Tornel Álvaro , Olivé-Gadea Marta , Boned Sandra , Muchada Marian , Deck Matías , Rodríguez-Villatoro Noelia , Rodríguez-Luna David , Juega Jesús , Pagola Jorge , Tomasello Alejandro , Piñana Carlos , Hernández David , Coscojuela Pilar , Ribó Marc , Molina Carlos A. , Rubiera Marta
Published: November 2022

Introduction: Endovascular treatment (EVT) for acute ischemic stroke (AIS) between 6 and 24 h is established as a standard of care among patients selected by multiparametric neuroimaging. We aimed to explore neuroimaging parameters in late-window large vessel occlusion (LVO) patients and its association with non-contrast computed tomography (NCCT) findings. Methods: We included consecutive AIS patients within 6–24 h from the symptoms onset with LVO. We described multiparametric imaging findings, the rate of patients who fulfilled imaging perfusion criteria according to the DAWN and DEFUSE-3 trials that define the computed tomography perfusion mismatch (CTP-MM) group and its association with NCCT focused on Alberta Stroke Program Early CT Score (ASPECTS). We also analyzed the association between neuroimaging parameters and the clinical outcome determined by the 90-day modified Rankin scale (mRS). Results: We included 206 patients, of them, 176 (85.4%) presented CTP-MM and 184 (89.3%) presented an ASPECTS ≥6 on admission. The rate of CTP-MM was 90.8% in patients with ASPECTS ≥6, compared with 40.9% in those with low ASPECTS. ASPECTS was moderately correlated with ischemic core determined by cerebral blood flow <30% volume (rS = −0.557, p < 0.001). In EVT-treated patients (185, 89.8%), after adjusting for identifiable confounders, the presence of CTP-MM was a predictor of 90-day functional independence (OR: 3.38; 95% CI: 1.01–11.29; p = 0.048). We did not find an association between CTP-MM and 90-day functional disability (ordinal mRS shift, aOR: 1.39; 95% CI: 0.58–3.34; p = 0.459). Conclusions: A great majority of patients who presented a LVO in the late window fulfilled guidelines imaging criteria to undergo EVT, especially those with high ASPECTS (≥6). Our data suggest that NCCT with CT angiography could be a reasonable approach for AIS treatment selection also in the late window.
Clinical Comparison between Three Single-Use Flexible Ureteroscope Models: A Real-World Experience
Authors: Salvadó José A. , Elorrieta Vicente , Cabello José M. , Cabello Renato , Velasco Alfredo
Published: November 2022

Introduction: Studies comparing different single-use flexible ureteroscope (su-fURS) models are lacking. The objective was to compare three types of su-fURS: the Uscope 3022 (PUSEN), LithoVue (Boston Scientific), and EU-scope (Innovex). Methods: This was a retrospective study comparing the clinical outcomes from patients undergoing flexible ureteroscopy with one of the three su-fURS for upper urinary tract stone treatment between September 2019 and 2021. Analysis included total surgery and fluoroscopy time, post-procedure ureteral catheter, stone-free rate (SFR), and complications. Results: There were 104 cases with the Uscope 3022, 141 with LithoVue, and 80 with EU-scope. Groups were comparable in terms of stone size, location and density, and prior double-J stent presence. Multivariate analysis showed no difference in terms of SFR: 79% (Uscope 3022), 77.5% (LithoVue), and 81% (EU-scope); p = 0.38. Significant differences were found for total surgery and fluoroscopy time, as well as ureteral access sheath use (p < 0.001), favoring the EU-scope group. Discussion/Conclusion: The three devices evaluated are highly effective in treatment of kidney stones. Reasons for difference in total surgery and fluoroscopy time and access sheath use are not clear. However, this could be explained by technical aspects of these devices, such as external diameter, optical resolution, and field of view.
Predictive Value of Pediatric Stroke Diagnoses in Administrative Data: A Systematic Literature Review
Authors: Bindslev Julie Brix , Ciochon Urszula Maria , Hansen Klaus , Engel Hoei-Hansen Christina , Truelsen Thomas
Published: November 2022

Background and Aim: Administrative healthcare data are frequently used for studying incidence, prevalence, risk factors, and outcome of pediatric stroke. However, the accuracy of these data sources is uncertain. The aim of this study was to systematically analyze published data on the positive predictive value (PPV) and sensitivity of diagnoses used to identify pediatric stroke patients in administrative data. Methods: This systematic review was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched PubMed and Embase for studies, published in year 2000 or later, describing the PPV or sensitivity of diagnoses used to identify children with stroke in administrative data. The search was performed on June 9, 2022. Studies written in other languages than English, with less than 30 participants, and conference abstracts were excluded. Results: Eight studies were included after full-text review from 2,475 potentially eligible records. These included 3,137 children. All studies reported data from high-income countries. Reported PPVs varied considerably across studies and stroke subtypes: acute ischemic stroke, range 0.27–0.89; cerebral venous thrombosis, range 0.45–0.72; spontaneous subarachnoid hemorrhage, range 0.52–0.83; and spontaneous intracerebral hemorrhage, range 0.62–0.66. One study examined sensitivity of an ICD-9 search compared to a radiology report search and found that the ICD search had poor sensitivity (33%). Conclusion: Caution is recommended in the use and interpretation of nonvalidated administrative data for pediatric stroke. Data on the PPV and sensitivity of pediatric stroke diagnoses in administrative data remain limited and are only available from high-income countries.