bluuebunny/crossref_metadata_2025_split huggingface dataset:
DeepSSN: A deep convolutional neural network to assess spatial scene similarity
Authors: Guo Danhuai , Ge Shiyin , Zhang Shu , Gao Song , Tao Ran , Wang Yangang 
Published: April 2022

AbstractSpatial‐query‐by‐sketch is an intuitive tool to explore human spatial knowledge about geographic environments and to support communication with scene database queries. However, traditional sketch‐based spatial search methods perform inadequately due to their inability to find hidden multiscale map features from mental sketches. In this research, we propose a deep convolutional neural network, namely the Deep Spatial Scene Network (DeepSSN), to better assess the spatial scene similarity. In DeepSSN, a triplet loss function is designed as a comprehensive distance metric to support the similarity assessment. A positive and negative example mining strategy is designed to ensure a consistently increasing distinction of triplets during the training process. Moreover, we develop a prototype spatial scene search system using the proposed DeepSSN, in which the users input spatial queries via sketch maps and the system can automatically augment the sketch training data. The proposed model is validated using multisource conflated map data including 131,300 labeled scene samples after data augmentation. The empirical results demonstrate that the DeepSSN outperforms baseline methods including k‐nearest neighbors, the multilayer perceptron, AlexNet, DenseNet, and ResNet using mean reciprocal rank and precision metrics. This research advances geographic information retrieval studies by introducing a novel deep learning method tailored to spatial scene queries.
Trimetazidine and exercise offer analogous improvements to the skeletal muscle insulin resistance of mice through Nrf2 signaling
Authors: Zhang Wenliang , Dun Yaoshan , You Baiyang , Qiu Ling , Ripley-Gonzalez Jeffrey W , Cheng Jing , Fu Siqian , Li Cui , Liu Suixin 
Published: April 2022

IntroductionInsulin resistance (IR) plays a key role in the pathogenesis and clinical course of patients with multiple metabolic diseases and diabetes. This study aimed to explore the effect of trimetazidine (TMZ) on skeletal muscle IR in mice fed a high-fat diet (HFD) and explore the possible underlying mechanism.Research design and methodsIn vivo, a HFD mouse IR model was adopted and TMZ and exercise were used to intervene. Postintervention the following were determined: blood levels of glucose and insulin, homeostasis model assessment of IR index, expression of skeletal muscle insulin signaling-related proteins phosphorylated insulin receptor substrate 1 (p-IRS1/IRS1) and phosphorylated protein kinase B (p-AKT/AKT), nuclear factor erythroid 2 related factor 2 (Nrf2) signaling pathway, and oxidative stress. In vitro, a palmitate-treated C2C12 myotube IR model was constructed. Cellular glucose uptake, p-IRS1/IRS1, and p-AKT/AKT were determined, and reactive oxygen species (ROS) production was analyzed based on treatments with specific small interfering RNA of Nrf2 with or without TMZ. Western blot was used to obtain the protein expression level and ROS production by functional analysis kits.ResultsIn vivo, TMZ and exercise decreased the blood glucose and insulin levels and homeostasis model assessment of IR index, increased skeletal muscle insulin signaling-related protein ratios of p-IRS1/IRS1 and p-AKT/AKT, and both interventions activated Nrf2 signaling and reduced oxidative stress production in HFD mice. In vitro, TMZ reduced the oxidative stress reaction, increased the ratios of p-AKT/AKT and p-IRS1/IRS1, and attenuated the insulin stimulation of PA-induced glucose uptake. However, in the absence of Nrf2, TMZ failed to resist the effects of IR.ConclusionsThis study showed that TMZ, like exercise, brought about marked improvements to HFD-induced skeletal muscle IR through TMZ, a common pathway with exercise in the form of Nrf2, regulating oxidative stress. We provide new evidence to support the use of TMZ for diabetes treatment.
Development and validation of multivariable machine learning algorithms to predict risk of cancer in symptomatic patients referred urgently from primary care: a diagnostic accuracy study
Authors: Savage Richard , Messenger Mike , Neal Richard D , Ferguson Rosie , Johnston Colin , Lloyd Katherine L , Neal Matthew D , Sansom Nigel , Selby Peter , Sharma Nisha , Shinkins Bethany , Skinner Jim R , Tully Giles , Duffy Sean , Hall Geoff 
Published: April 2022

ObjectivesTo develop and validate tests to assess the risk of any cancer for patients referred to the NHS Urgent Suspected Cancer (2-week wait, 2WW) clinical pathways.SettingPrimary and secondary care, one participating regional centre.ParticipantsRetrospective analysis of data from 371 799 consecutive 2WW referrals in the Leeds region from 2011 to 2019. The development cohort was composed of 224 669 consecutive patients with an urgent suspected cancer referral in Leeds between January 2011 and December 2016. The diagnostic algorithms developed were then externally validated on a similar consecutive sample of 147 130 patients (between January 2017 and December 2019). All such patients over the age of 18 with a minimum set of blood counts and biochemistry measurements available were included in the cohort.Primary and secondary outcome measuressensitivity, specificity, negative predictive value, positive predictive value, Receiver Operating Characteristic (ROC) curve Area Under Curve (AUC), calibration curvesResultsWe present results for two clinical use-cases. In use-case 1, the algorithms identify 20% of patients who do not have cancer and may not need an urgent 2WW referral. In use-case 2, they identify 90% of cancer cases with a high probability of cancer that could be prioritised for review.ConclusionsCombining a panel of widely available blood markers produces effective blood tests for cancer for NHS 2WW patients. The tests are affordable, and can be deployed rapidly to any NHS pathology laboratory with no additional hardware requirements.
Proactive infliximab optimisation using a pharmacokinetic dashboard versus standard of care in patients with Crohn’s disease: study protocol for a randomised, controlled, multicentre, open-label study (the OPTIMIZE trial)
Authors: Papamichael Konstantinos , Jairath Vipul , Zou Guangyong , Cohen Benjamin , Ritter Timothy , Sands Bruce , Siegel Corey , Valentine John , Smith Michelle , Vande Casteele Niels , Dubinsky Marla , Cheifetz Adam 
Published: April 2022

IntroductionPreliminary data indicates that proactive therapeutic drug monitoring (TDM) is associated with better outcomes compared with empiric dose escalation and/or reactive TDM, and that pharmacokinetic (PK) modelling can improve the precision of individual dosing schedules in Crohn’s disease (CD). However, there are no data regarding the utility of a proactive TDM combined PK-dashboard starting early during the induction phase, when disease activity and drug clearance are greatest. The aim of this randomised, controlled, multicentre, open-label trial is to evaluate the efficacy and safety of a proactive TDM combined PK dashboard-driven infliximab dosing compared with standard of care (SOC) dosing in patients with moderately to severely active CD.Methods and analysisEligible adolescent and adult (aged ≥16–80 years) patients with moderately to severely active CD will be randomised 1:1 to receive either infliximab monotherapy with proactive TDM using a PK dashboard (iDose, Projections Research) or SOC infliximab therapy, with or without a concomitant immunomodulator (IMM) (thiopurine or methotrexate) at the discretion of the investigator. The primary outcome of the study is the proportion of subjects with sustained corticosteroid-free clinical remission and no need for rescue therapy from week 14 throughout week 52. Rescue therapy is defined as any IFX dose escalation other than what is forecasted by iDose either done empirically or based on reactive TDM; addition of an IMM after week 2; reintroduction of corticosteroids after initial tapering; switch to another biologic or need for CD-related surgery. The secondary outcomes will include both efficacy and safety end points, such as endoscopic and biological remission, durability of response and CD-related surgery and hospitalisation.Ethics and disseminationThe protocol has been approved by the Institutional Review Board Committee of the Beth Israel Deaconess Medical Center (IRB#:2021P000391). Results will be disseminated in peer-reviewed journals and presented at scientific meetings.Trial registration numberNCT04835506.
Uso del polietileno poroso de alta densidad como alternativa en reconstrucción de fracturas orbitarias. Serie de 22 casos
Authors: Tapia Contreras Pedro , Sarzosa Enríquez Marcelo , Mordoh Cucurella Sebastián , Rosenberg Dueñas Benjamín , Rodríguez Castro Fernando 
Published: April 2022

Introducción: las fracturas de pared de órbita pueden producir secuelas funcionales y estéticas. La indicación de reconstrucción quirúrgica, es indispensable para la recuperación de la motilidad y estética ocular. Los materiales reconstructivos más utilizados son los aloplásticos, como el titanio y el polietileno poroso de alta densidad (PPAD), el cual ha resultado exitoso en reconstrucción maxilofacial. El propósito de este estudio retrospectivo, es exponer los resultados tras el uso del PPAD en reconstrucciones orbitarias y sus posibles complicaciones. Materiales y métodos: se realizó una revisión retrospectiva de 22 pacientes donde se utilizó PPAD como material de reconstrucción en fracturas orbitarias. Se consideró para la indicación quirúrgica que el paciente presentara alguno de los siguientes signos: diplopía o síntomas vasovagales por atrapamiento muscular, restricciones en la motilidad ocular, enoftalmo mayor a 4mm. El material utilizado fue PPAD (Medpor Stryker®) puro en 17 casos y PPAD reforzado con una malla de titanio en el interior de su estructura (Medpor Titan Stryker®), en los 5 restantes. Resultados: se registraron 3 casos con complicaciones; ectropión, diplopía y ectropión con diplopía, los cuales todos fueron reversibles. No se registraron casos de infección ni complicaciones oftalmológicas postoperatoria. Discusión: los injertos autólogos fueron los primeros utilizados con resultados de compatibilidad y resistencia óptimos. El uso de PPAD como material de reconstrucción ha sido bien documentado con buenos resultados en términos de una baja incidencia de infección y óptima motilidad ocular a largo plazo.
Thymosin α-1 Reverses M2 Polarization of Tumor-Associated Macrophages during Efferocytosis
Authors: Wei Yi-ting , Wang Xu-ru , Yan Chunguang , Huang Fang , Zhang Yunpeng , Liu Xueming , Wen Zhi-fa , Sun Xiao-tong , Zhang Yue , Chen Yong-qiang , Gao Rong , Pan Ning , Wang Li-xin 
Published: April 2022

AbstractThe immunologic effects of chemotherapy-induced tumor cell death are not completely understood. Accumulating evidence suggests that phagocytic clearance of apoptotic tumor cells, also known as efferocytosis, is an immunologically silent process, thus maintaining an immunosuppressive tumor microenvironment (TME). Here we report that, in the breast tumor microenvironment, thymosin α-1 (Tα-1) significantly reverses M2 polarization of IL10-producing tumor-associated macrophages (TAM) during efferocytosis induced by apoptotic cells. Mechanistically, Tα-1, which bound to phosphatidylserine on the surface of apoptotic tumor cells and was internalized by macrophages, triggered the activation of SH2-containing inositol 5′-phosphatase 1 (SHIP1) through the lysosomal Toll-like receptor 7 (TLR7)/MyD88 pathway, subsequently resulting in dephosphorylation of efferocytosis-activated TBK1 and reduction of efferocytosis-induced IL10. Tα-1 combined with epirubicin chemotherapy markedly suppressed tumor growth in an in vivo breast cancer model by reducing macrophage-derived IL10 and enhancing the number and function of tumor-infiltrating CD4+ and CD8+ T cells. In conclusion, Tα-1 improved the curative effect of chemotherapy by reversing M2 polarization of efferocytosis-activated macrophages, suggesting that Tα-1 injection immediately after chemotherapy may contribute to highly synergistic antitumor effects in patients with breast cancer.Significance:Thymosin α-1 improves the curative effect of chemotherapy by reversing efferocytosis-induced M2 polarization of macrophages via activation of a TLR7/SHIP1 axis.
Phase II Clinical Trial of Neoadjuvant and Adjuvant Pembrolizumab in Resectable Local–Regionally Advanced Head and Neck Squamous Cell Carcinoma
Authors: Wise-Draper Trisha M. , Gulati Shuchi , Palackdharry Sarah , Hinrichs Benjamin H. , Worden Francis P. , Old Matthew O. , Dunlap Neal E. , Kaczmar John M. , Patil Yash , Riaz Muhammed Kashif , Tang Alice , Mark Jonathan , Zender Chad , Gillenwater Ann M. , Bell Diana , Kurtzweil Nicky , Mathews Maria , Allen Casey L. , Mierzwa Michelle L. , Casper Keith , Jandarov Roman , Medvedovic Mario , Lee J. Jack , Harun Nusrat , Takiar Vinita , Gillison Maura 
Published: April 2022

Abstract

Purpose:
Patients with resected, local–regionally advanced, head and neck squamous cell carcinoma (HNSCC) have a one-year disease-free survival (DFS) rate of 65%–69% despite adjuvant (chemo)radiotherapy. Neoadjuvant PD-1 immune-checkpoint blockade (ICB) has demonstrated clinical activity, but biomarkers of response and effect on survival remain unclear.

Patients and Methods:
Eligible patients had resectable squamous cell carcinoma of the oral cavity, larynx, hypopharynx, or oropharynx (p16-negative) and clinical stage T3-T4 and/or two or more nodal metastases or clinical extracapsular nodal extension (ENE). Patients received neoadjuvant pembrolizumab 200 mg 1–3 weeks prior to surgery, were stratified by absence (intermediate-risk) or presence (high-risk) of positive margins and/or ENE, and received adjuvant radiotherapy (60–66 Gy) and concurrent pembrolizumab (every 3 weeks × 6 doses). Patients with high-risk HNSCC also received weekly, concurrent cisplatin (40 mg/m2). Primary outcome was one-year DFS. Secondary endpoints were one-year overall survival (OS) and pathologic response (PR). Safety was evaluated with CTCAE v5.0.

Results:
From February 2016 to October 2020, 92 patients enrolled. The median age was 59 years (range, 27–80), 30% were female, 86% had stage T3–T4, and 69% had ≥N2. At a median follow-up of 28 months, one-year DFS was 97% (95% CI, 71%–90%) in the intermediate-risk group and 66% (95% CI, 55%–84%) in the high-risk group. Patients with a PR had significantly improved one-year DFS relative to patients without response (93% vs. 72%, hazard ratio 0.29; 95% CI, 11%–77%). No new safety signals were identified.

Conclusions:
Neoadjuvant and adjuvant pembrolizumab increased one-year DFS rate in intermediate-risk, but not high-risk, HNSCC relative to historical control. PR to neoadjuvant ICB is a promising surrogate for DFS.
Precision Medicine in Pancreatic Cancer: Patient-Derived Organoid Pharmacotyping Is a Predictive Biomarker of Clinical Treatment Response
Authors: Seppälä Toni T. , Zimmerman Jacquelyn W. , Suri Reecha , Zlomke Haley , Ivey Gabriel D. , Szabolcs Annamaria , Shubert Christopher R. , Cameron John L. , Burns William R. , Lafaro Kelly J. , He Jin , Wolfgang Christopher L. , Zou Ying S. , Zheng Lei , Tuveson David A. , Eshlemann James R. , Ryan David P. , Kimmelman Alec C. , Hong Theodore S. , Ting David T. , Jaffee Elizabeth M. , Burkhart Richard A. 
Published: April 2022

Abstract

Purpose:
Patient-derived organoids (PDO) are a promising technology to support precision medicine initiatives for patients with pancreatic ductal adenocarcinoma (PDAC). PDOs may improve clinical next-generation sequencing (NGS) and enable rapid ex vivo chemotherapeutic screening (pharmacotyping).

Experimental Design:
PDOs were derived from tissues obtained during surgical resection and endoscopic biopsies and studied with NGS and pharmacotyping. PDO-specific pharmacotype is assessed prospectively as a predictive biomarker of clinical therapeutic response by leveraging data from a randomized controlled clinical trial.

Results:
Clinical sequencing pipelines often fail to detect PDAC-associated somatic mutations in surgical specimens that demonstrate a good pathologic response to previously administered chemotherapy. Sequencing the PDOs derived from these surgical specimens, after biomass expansion, improves the detection of somatic mutations and enables quantification of copy number variants. The detection of clinically relevant mutations and structural variants is improved following PDO biomass expansion. On clinical trial, PDOs were derived from biopsies of treatment-naïve patients prior to treatment with FOLFIRINOX (FFX). Ex vivo PDO pharmacotyping with FFX components predicted clinical therapeutic response in these patients with borderline resectable or locally advanced PDAC treated in a neoadjuvant or induction paradigm. PDO pharmacotypes suggesting sensitivity to FFX components were associated with longitudinal declines of tumor marker, carbohydrate-antigen 19–9 (CA-19–9), and favorable RECIST imaging response.

Conclusions:
PDOs established from tissues obtained from patients previously receiving cytotoxic chemotherapies can be accomplished in a clinically certified laboratory. Sequencing PDOs following biomass expansion improves clinical sequencing quality. High in vitro sensitivity to standard-of-care chemotherapeutics predicts good clinical response to systemic chemotherapy in PDAC.
See related commentary by Zhang et al., p. 3176
Phase Ib/II Dose Expansion Study of Lenvatinib Combined with Letrozole in Postmenopausal Women with Hormone Receptor–Positive Breast Cancer
Authors: Lim Joline S.J. , Wong Andrea L.A. , Ow Samuel G.W. , Ngoi Natalie Y.L. , Chan Gloria H.J. , Ang Yvonne L.E. , Chong Wan Qin , Lim Siew Eng , Lim Yi Wan , Lee Matilda , Choo Joan R.E. , Tan Hon Lyn , Yong Wei Peng , Soo Ross A. , Tan David S.P. , Chee Cheng Ean , Sundar Raghav , Yadav Kritika , Jain Supriya , Wang Lingzhi , Tai Bee Choo , Goh Boon Cher , Lee Soo-Chin 
Published: April 2022

Abstract

Purpose:
RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer.

Patients and Methods:
Patients with advanced ER+/HER2− breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion.

Results:
Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0–11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%–42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%–68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%–40.7%), median DoR 6.9 months (IQR 5.9–13.1), and CBR 52.0% (95% CI, 31.3%–72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index.

Conclusions:
Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.
CDK2 Inhibition Enhances Antitumor Immunity by Increasing IFN Response to Endogenous Retroviruses
Authors: Chen Yu , Cai Qiaomei , Pan Chaohu , Liu Wancheng , Li Lili , Liu Junxiao , Gao Meiling , Li Xiaorong , Wang Liguo , Rao Yu , Yang Heng , Cheng Genhong 
Published: April 2022

Abstract

Inhibitors of cyclin-dependent kinase-2 (CDK2) are commonly used against several solid tumors, and their primary mechanisms of action were thought to include cell proliferation arrest, induction of cancer cell apoptosis and induction of differentiation. Here, we found that CDK2 inhibition by either small molecular inhibitors or genetic Cdk2 deficiency promoted antitumor immunity in murine models of fibrosarcoma and lung carcinoma. Mechanistically, CDK2 inhibition reduced phosphorylation of RB protein and transcription of E2F-mediated DNA methyltransferase 1 (DNMT1), which resulted in increased expression of endogenous retroviral RNA and type I IFN (IFN-I) response. The increased IFN-I response subsequently promoted antitumor immunity by enhancing tumor antigen presentation and CD8+ T-cell infiltration. Our studies provide evidence that inhibition of CDK2 in cancer cells suppresses tumor growth by enhancing antitumor immune responses in the tumor microenvironment, suggesting a new mechanism to enhance antitumor immunity by CDK2 inhibitors.
Gendered Skill: Skill and Knowledge in Weaving and Archery
Authors: Raphals Lisa 
Published: April 2022

Abstract
Weaving and archery are strongly gendered skills, and both occur repeatedly in both Chinese and Greek accounts of skill and ethics. I examine both metaphors and narratives that liken these skills to various aspects of ethics, wisdom and government, with particular interest in how or whether the account of the skill reflects the experience of the gender of its typical expert.
The Most Controversial Submission before the CLCS: With Reference to the 2019 Malaysia Submission
Authors: Gau Michael Sheng-ti 
Published: April 2022

Abstract
In December 2019 Malaysia submitted information on the outer limits of its continental shelf beyond 200 miles (OL) in the South China Sea (SCS) to the Commission on the Limits of the Continental Shelf (CLCS). According to Article 76(8) of the UN Convention on the Law of the Sea, Malaysia shall seek CLCS recommendations as the basis for establishing its OL. If notified of a land or maritime dispute, the CLCS shall not consider the submission unless consent is given by all disputants. As of 16 March 2022, the CLCS has received 28 note verbales (NVs) concerning Malaysia’s submission. Apart from those challenging the submission, there are 12 NVs invoking the 2016 SCS Arbitration award to oppose territorial and maritime claims by China in its NVs initially objecting the submission. This article reviews relevant CLCS rules and practice, analyses all 28 NVs, and examines the disputes reflected in the NVs.
Strategic Environmental Assessment in Marine Areas beyond National Jurisdiction: Implementing Integration
Authors: Craik Neil , Gu Kristine 
Published: April 2022

Abstract
Whereas environmental impact assessment (EIA) is broadly accepted as a legal requirement for managing the marine environment in areas beyond national jurisdiction (ABNJ), there has been a greater reluctance by States to adopt strategic environmental assessment (SEA) requirements. This suggests the legal basis for SEA is different and less firmly established in international law than EIA. This article examines the distinct legal and policy roles of SEA in managing ABNJ, which then informs our understanding of its legal basis. We argue, unlike EIA’s close association with due diligence obligations to prevent harm, SEA is better understood as a legal mechanism for the implementation of the principle of integration. Recognised as central to marine governance, integration has normative dimensions that must be addressed by States. SEA, we argue, is well-suited to this task. This article addresses SEA for ABNJ generally, but attention is paid to negotiations regarding marine biodiversity of ABNJ.