bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developing a reporting guideline for artificial intelligence-centred diagnostic test accuracy studies: the STARD-AI protocol
Authors: Sounderajah Viknesh , Ashrafian Hutan , Golub Robert M , Shetty Shravya , De Fauw Jeffrey , Hooft Lotty , Moons Karel , Collins Gary , Moher David , Bossuyt Patrick M , Darzi Ara , Karthikesalingam Alan , Denniston Alastair K , Mateen Bilal Akhter , Ting Daniel , Treanor Darren , King Dominic , Greaves Felix , Godwin Jonathan , Pearson-Stuttard Jonathan , Harling Leanne , McInnes Matthew , Rifai Nader , Tomasev Nenad , Normahani Pasha , Whiting Penny , Aggarwal Ravi , Vollmer Sebastian , Markar Sheraz R , Panch Trishan , Liu Xiaoxuan 
Published: June 2021

IntroductionStandards for Reporting of Diagnostic Accuracy Study (STARD) was developed to improve the completeness and transparency of reporting in studies investigating diagnostic test accuracy. However, its current form, STARD 2015 does not address the issues and challenges raised by artificial intelligence (AI)-centred interventions. As such, we propose an AI-specific version of the STARD checklist (STARD-AI), which focuses on the reporting of AI diagnostic test accuracy studies. This paper describes the methods that will be used to develop STARD-AI.Methods and analysisThe development of the STARD-AI checklist can be distilled into six stages. (1) A project organisation phase has been undertaken, during which a Project Team and a Steering Committee were established; (2) An item generation process has been completed following a literature review, a patient and public involvement and engagement exercise and an online scoping survey of international experts; (3) A three-round modified Delphi consensus methodology is underway, which will culminate in a teleconference consensus meeting of experts; (4) Thereafter, the Project Team will draft the initial STARD-AI checklist and the accompanying documents; (5) A piloting phase among expert users will be undertaken to identify items which are either unclear or missing. This process, consisting of surveys and semistructured interviews, will contribute towards the explanation and elaboration document and (6) On finalisation of the manuscripts, the group’s efforts turn towards an organised dissemination and implementation strategy to maximise end-user adoption.Ethics and disseminationEthical approval has been granted by the Joint Research Compliance Office at Imperial College London (reference number: 19IC5679). A dissemination strategy will be aimed towards five groups of stakeholders: (1) academia, (2) policy, (3) guidelines and regulation, (4) industry and (5) public and non-specific stakeholders. We anticipate that dissemination will take place in Q3 of 2021.
Study protocol for SKIPMDD: subcutaneous ketamine infusion in palliative care patients with advanced life limiting illnesses for major depressive disorder (phase II pilot feasibility study)
Authors: Lee Wei , Sheehan Caitlin , Chye Richard , Chang Sungwon , Loo Colleen , Draper Brian , Agar Meera , Currow David C 
Published: June 2021

IntroductionMajor depressive disorder (MDD) in people with advanced life-limiting illnesses can have significant impact on the quality-of-life of those affected. The management of MDD in the palliative care setting can be challenging as typical antidepressants may not work in time nor be tolerated due to coexisting organ dysfunctions, symptom burden and frailty. Parenteral ketamine was found to exhibit effective and rapid-onset antidepressant effect even against treatment-resistant depression in the psychiatric population. However, there is currently neither feasibility study nor available prospective study available to inform of the safety, tolerability and efficacy of such for MDD in the palliative setting.Methods and analysisThis is an open-labelled, single arm, phase II pilot feasibility study involving adult patients with advanced life-limiting illnesses and MDD across four palliative care services in Australia. It has an individual dose-titration design (0.1–0.4 mg/kg) with weekly treatments of subcutaneous ketamine infusion over 2 hours. The primary outcome is feasibility. The secondary outcomes are related to the safety, tolerability and antidepressant efficacy of ketamine, participants’ satisfaction in relation to the trial process and the reasons for not completing the study at various stages. The feasibility data will be reported using descriptive statistics. Meanwhile, side effects, tolerability and efficacy data will be analysed using change of assessment scores from baseline.Ethics and disseminationEthics approval was acquired (South Western Sydney Local Health District: HREC/18/LPOOL/466). The results of this study will be submitted for publication in peer-reviewed journals and presented at relevant conferences.Trial registration numberAustralian New Zealand Clinical Trial Registry Number: ACTRN12618001586202; Pre-results.
PAX6is frequently expressed in ependymal tumours and associated with prognostic relevant subgroups
Authors: Tabasaran Julian , Schuhmann Martin , Ebinger Martin , Honegger Jürgen , Renovanz Mirjam , Schittenhelm Jens 
Published: June 2021

AimsAn ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 (PAX6) transcription factor is a putative tumour suppressor and drives cancer cells towards a stem cell-like state. A transcriptome study reported highPAX6expression in ependymal tumours, but data on protein expression are lacking.MethodsWe, therefore, analysedPAX6expression by immunohistochemistry in 172 ependymoma samples and correlated its expression to histology, WHO grade, anatomical location and molecular subgroups.ResultsMeanPAX6nuclear expression in ependymoma was 27.5% (95% CI 23.3 to 31.7).PAX6expression in subependymoma (mean: 5%) was significantly lower compared with myxopapillary (30%), WHO grade II (26%) and anaplastic ependymoma (35%). Supratentorial ependymomas also displayed significant lowerPAX6levels (15%) compared with spinal cord tumours (30%). Expression levels in YAP1-fused ependymoma (41%) were higher compared with REL-associated protein (RELA)-fusion positive tumours (17%), whilePAX6expression was similar in posterior fossa group A (33%) and B (29%) ependymomas. Kaplan-Meier analysis in RELA-fusion positive ependymomas and posterior fossa group B showed a significant better outcome forPAX6at or above the cut-off of 19.45% compared with tumours withPAX6below the cut-off.ConclusionsWe demonstrate thatPAX6is frequently expressed in human ependymal tumours and immunohistochemistry may be helpful in determining prognostic relevant subgroups.
Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability
Authors: Tan Natalie B , Pagnamenta Alistair T , Ferla Matteo P , Gadian Jonathan , Chung Brian HY , Chan Marcus CY , Fung Jasmine LF , Cook Edwin , Guter Stephen , Boschann Felix , Heinen Andre , Schallner Jens , Mignot Cyril , Keren Boris , Whalen Sandra , Sarret Catherine , Mittag Dana , Demmer Laurie , Stapleton Rachel , Saida Ken , Matsumoto Naomichi , Miyake Noriko , Sheffer Ruth , Mor-Shaked Hagar , Barnett Christopher P , Byrne Alicia B , Scott Hamish S , Kraus Alison , Cappuccio Gerarda , Brunetti-Pierri Nicola , Iorio Raffaele , Di Dato Fabiola , Pais Lynn S , Yeung Alison , Tan Tiong Y , Taylor Jenny C , Christodoulou John , White Susan M 
Published: June 2021

PurposeBinding proteins (G-proteins) mediate signalling pathways involved in diverse cellular functions and comprise Gα and Gβγ units. Human diseases have been reported for all five Gβ proteins. A de novo missense variant in GNB2 was recently reported in one individual with developmental delay/intellectual disability (DD/ID) and dysmorphism. We aim to confirm GNB2 as a neurodevelopmental disease gene, and elucidate the GNB2-associated neurodevelopmental phenotype in a patient cohort.MethodsWe discovered a GNB2 variant in the index case via exome sequencing and sought individuals with GNB2 variants via international data-sharing initiatives. In silico modelling of the variants was assessed, along with multiple lines of evidence in keeping with American College of Medical Genetics and Genomics guidelines for interpretation of sequence variants.ResultsWe identified 12 unrelated individuals with five de novo missense variants in GNB2, four of which are recurrent: p.(Ala73Thr), p.(Gly77Arg), p.(Lys89Glu) and p.(Lys89Thr). All individuals have DD/ID with variable dysmorphism and extraneurologic features. The variants are located at the universally conserved shared interface with the Gα subunit, which modelling suggests weaken this interaction.ConclusionMissense variants in GNB2 cause a congenital neurodevelopmental disorder with variable syndromic features, broadening the spectrum of multisystem phenotypes associated with variants in genes encoding G-proteins.
A new well-behaved class of compact strange astrophysical model consistent with observational data
Authors: Errehymy Abdelghani , Daoud Mohammed 
Published: June 2021

AbstractThe main focus of this paper is to discuss the solutions of Einstein’s Field Equations (EFEs) for compact spherical objects study. To supply exact solution of the EFEs, we have considered the distribution of anisotropic matter governed by a new version of Chaplygin fluid equation of state (EoS). To determine different constants, we have represented the outer space-time by the Schwarzschild metric. Using the observed values of the mass for the various strange spherical object candidates, we have expanded anisotropic emphasize at the surface to forecast accurate radius estimates. Moreover, we implement various analysis to examine the physical acceptability and stability of our suggested stellar model viz., the energy conditions, cracking method, adiabatic index, etc. Graphical survey exhibits that the obtained stellar system fulfills the physical and mathematical prerequisites of the strange astrophysical object candidates Cyg X-2, Vela X-1, 4U 1636-536, 4U 1608-52, PSR J1903+327 to examine the various physical parameters and their effects on the anisotropic stellar model. The investigation reveals that complicated geometries arise from the interior matter distribution obeys a new version of Chaplygin fluid EoS and they are physically pertinent in the investigation of discovered compact structures.
Voltage-Based Covert Channels Using FPGAs
Authors: Gnad Dennis R. E. , Nguyen Cong Dang Khoa , Gillani Syed Hashim , Tahoori Mehdi B. 
Published: June 2021

Field Programmable Gate Arrays
(
FPGAs
) are increasingly used in cloud applications and being integrated into Systems-on-Chip. For these systems, various side-channel attacks on cryptographic implementations have been reported, motivating one to apply proper countermeasures. Beyond cryptographic implementations, maliciously introduced covert channel receivers and transmitters can allow one to exfiltrate other secret information from the FPGA. In this article, we present a fast covert channel on FPGAs, which exploits the on-chip power distribution network. This can be achieved without any logical connection between the transmitter and receiver blocks. Compared to a recently published covert channel with an estimated 4.8 Mbit/s transmission speed, we show 8 Mbit/s transmission and reduced errors from around 3% to less than 0.003%. Furthermore, we demonstrate proper transmissions of word-size messages and test the channel in the presence of noise generated from other residing tenants’ modules in the FPGA. When we place and operate other co-tenant modules that require 85% of the total FPGA area, the error rate increases to 0.02%, depending on the platform and setup. This error rate is still reasonably low for a covert channel. Overall, the transmitter and receiver work with less than 3–5% FPGA LUT resources together. We also show the feasibility of other types of covert channel transmitters, in the form of synchronous circuits within the FPGA.
On the Existence of Long-Time Classical Solutions for the 2D Inviscid Boussinesq Equations
Authors: Xu Jiafa , Liu Lishan 
Published: June 2021

In this paper, we consider the Cauchy problem for the 2D inviscid Boussinesq equations with

N

being the buoyancy frequency. It is proved that for general initial data

u

0

∈

H

s

with

s
>
3

, the life span of the classical solutions satisfies

T
>
C

ln

N

3
/
4

.
Activity Screening of the Herb Caesalpinia sappan and an Analysis of Its Antitumor Effects
Authors: Li Yuan , Dong Minghong , Wu Zijun , Huang Yongqi , Qian Haibing , Huang Cong 
Published: June 2021

Aim. Traditionally, C. sappan medicine was the heartwood, which needs to be cut down as a whole. In this research, the antitumor activity and mechanisms of the leaves and stems were compared with the roots of Caesalpinia sappan; it was in order to investigate whether stems and leaves of C. sappan could be used to replace heartwood for antitumor treatment, thereby reducing resource destruction. Methods. MTT assays were used to identify the active sites of C. sappan based on the application of human liver cancer (HuH-7) cells. High-performance liquid chromatography (HPLC) was used to analyze polar extracts. We also established a H22 hepatoma-bearing mouse model by administering intraperitoneal injections of petroleum ether extracts from the leaves and stems (SY②) at doses of 20 and 65 mg/kg. Mice in the i.g. group were administered intragastrically with the same extracts (at doses of 100 and 325 mg/kg) at the same time (12 days). Results. The antitumor site of C. sappan was the petroleum ether extract. The IC50 for the petroleum ether extract of roots (SG②) was 56.10 μg/ml, while that for the leaves and stems (SY②) was 77.20 μg/ml. Grey relational analysis indicated 11 active fraction peaks that were closely related to antitumor activity. The size of tumors in H22 hepatoma-bearing mice was reduced significantly in mice administered with petroleum ether extracts from the leaves and stems (inhibition rates of high doses were 55.31% and 60.56%). Fibrous tissue proliferation, inflammatory cell infiltration, tumor cell necrosis, and the expression of proliferating cell nuclear antigen (PCNA) and vascular endothelial growth factor (VEGF) were all lower than in the control group (VEGF

P

< 0.001 and PCNA

P

< 0.05). Conclusion. Petroleum ether extracts of the roots, leaves, and stems of C. sappan exhibit certain antitumor effects. Our data indicate that the mechanisms underlying these effects may relate to a reduction in the expression of PCNA and VEGF and the inhibition of angiogenesis. Our findings indicate that we can expand the medicinal use of C. sappan to the leaves and stems, thus improving resource utilization and reducing resource damage.
The CD200–CD200R Axis Promotes Squamous Cell Carcinoma Metastasis via Regulation of Cathepsin K
Authors: Khan Iasha Z. , Del Guzzo Christina A. , Shao Anqi , Cho Jiyoon , Du Rong , Cohen Adrienne O. , Owens David M. 
Published: June 2021

Abstract

The CD200–CD200R immunoregulatory signaling axis plays an etiologic role in the survival and spread of numerous cancers, primarily through suppression of antitumor immune surveillance. Our previous work outlined a prometastatic role for the CD200–CD200R axis in cutaneous squamous cell carcinoma (cSCC) that is independent of direct T-cell suppression but modulates the function of infiltrating myeloid cells. To identify effectors of the CD200–CD200R axis important for cSCC metastasis, we conducted RNA sequencing profiling of infiltrating CD11B+Cd200R+ cells isolated from CD200+ versus CD200-null cSCCs and identified the cysteine protease cathepsin K (Ctsk) to be highly upregulated in CD200+ cSCCs. CD11B+Cd200R+ cells expressed phenotypic markers associated with myeloid-derived suppressor cell–like cells and tumor-associated macrophages and were the primary source of Ctsk expression in cSCC. A Cd200R+ myeloid cell–cSCC coculture system showed that induction of Ctsk was dependent on engagement of the CD200–CD200R axis, indicating that Ctsk is a target gene of this pathway in the cSCC tumor microenvironment. Inhibition of Ctsk, but not matrix metalloproteinases, significantly blocked cSCC cell migration in vitro. Finally, targeted CD200 disruption in tumor cells and Ctsk pharmacologic inhibition significantly reduced cSCC metastasis in vivo. Collectively, these findings support the conclusion that CD200 stimulates cSCC invasion and metastasis via induction of Ctsk in CD200R+ infiltrating myeloid cells.

Significance:
These findings highlight the relationship between CD200–CD200R and cathepsin K in cutaneous squamous cell carcinoma metastasis and suggest that either of these components may serve as a viable therapeutic target in this disease.
IQGAP3, a YAP Target, Is Required for Proper Cell-Cycle Progression and Genome Stability
Authors: Leone Marina , Cazorla-Vázquez Salvador , Ferrazzi Fulvia , Wiederstein Janica L. , Gründl Marco , Weinstock Grit , Vergarajauregui Silvia , Eckstein Markus , Krüger Marcus , Gaubatz Stefan , Engel Felix B. 
Published: June 2021

AbstractControlling cell proliferation is critical for organism development, tissue homeostasis, disease, and regeneration. IQGAP3 has been shown to be required for proper cell proliferation and migration, and is associated to a number of cancers. Moreover, its expression is inversely correlated with the overall survival rate in the majority of cancers. Here, we show that IQGAP3 expression is elevated in cervical cancer and that in these cancers IQGAP3 high expression is correlated with an increased lethality. Furthermore, we demonstrate that IQGAP3 is a target of YAP, a regulator of cell cycle gene expression. IQGAP3 knockdown resulted in an increased percentage of HeLa cells in S phase, delayed progression through mitosis, and caused multipolar spindle formation and consequentially aneuploidy. Protein–protein interaction studies revealed that IQGAP3 interacts with MMS19, which is known in Drosophila to permit, by competitive binding to Xpd, Cdk7 to be fully active as a Cdk-activating kinase (CAK). Notably, IQGAP3 knockdown caused decreased MMS19 protein levels and XPD knockdown partially rescued the reduced proliferation rate upon IQGAP3 knockdown. This suggests that IQGAP3 modulates the cell cycle via the MMS19/XPD/CAK axis. Thus, in addition to governing proliferation and migration, IQGAP3 is a critical regulator of mitotic progression and genome stability.Implications:Our data indicate that, while IQGAP3 inhibition might be initially effective in decreasing cancer cell proliferation, this approach harbors the risk to promote aneuploidy and, therefore, the formation of more aggressive cancers.
REX-1 Represses RASSF1a and Activates the MEK/ERK Pathway to Promote Tumorigenesis in Prostate Cancer
Authors: Liu Weijing , Xie An , Tu Chunhua , Liu Weipeng 
Published: June 2021

Abstract

Epigenetics play an important role in the pathogenesis of prostate cancer; it is urgent to investigate vital transcription factors in methylation regulation with the aim to develop novel treatment strategies targeting prostate cancer. As a member of the zinc finger protein family, REX-1 (reduced expression-1) is a transcription factor that has been reported to be closely linked to the development of several cancers. So far, the expression level and precise function of REX-1 in prostate cancer remain largely unknown. Here, we show that REX-1 was overexpressed in prostate cancer clinical tissues, and its expression level was closely correlated with patient prognosis. REX-1 affected prostate tumor growth in vivo by MEK/ERK phosphorylation. Mechanistic studies indicated that REX-1 recruited DNMT3b (DNA methyltransferase 3b), inhibited the transcription of RASSF1a (RAS association domain family 1a), and further modulated methylation of RASSF1a promoter. Intervention of the REX-1/DNMT3b/RASSF1a axis may shed light on the development of novel therapeutic approaches for prostate cancer treatment.

Implications:
REX1 overexpression recruits DNMT3b and downregulates RASSF1a by promoter methylation, suggesting that epigenetic intervention may contribute to prostate cancer treatment.
Membrane-Associated RING-CH 8 Functions as a Novel PD-L1 E3 Ligase to Mediate PD-L1 Degradation Induced by EGFR Inhibitors
Authors: Qian Guoqing , Guo Jianping , Vallega Karin A. , Hu Changjiang , Chen Zhen , Deng Yunfu , Wang Qiming , Fan Songqing , Ramalingam Suresh S. , Owonikoko Taofeek K. , Wei Wenyi , Sun Shi-Yong 
Published: June 2021

Abstract

Expression of programmed death-ligand 1 (PD-L1) on cancer cells is a critical mechanism contributing to immunosuppression and immune escape. PD-L1 expression may also affect therapeutic outcomes of epidermal growth factor receptor (EGFR)-targeted therapy (e.g., with osimertinib/AZD9291) against EGFR-mutant non–small cell lung cancers (NSCLC) and can even be altered during the treatment albeit with largely undefined mechanisms. This study primarily focuses on elucidating the mechanism by which osimertinib induces PD-L1 degradation in addition to validating osimertinib's effect on decreasing PD-L1 expression in EGFR-mutant NSCLC cells and tumors. Osimertinib and other EGFR inhibitors effectively decreased PD-L1 levels primarily in EGFR-mutant NSCLCs and xenografted tumors. Osimertinib not only decreased PD-L1 mRNA expression, but also prompted proteasomal degradation of PD-L1 protein, indicating both transcriptional and posttranslational mechanisms accounting for osimertinib-induced reduction of PD-L1. Knockdown of β-TrCP or inhibition of GSK3 failed to prevent PD-L1 reduction induced by osimertinib. Rather, knockdown of membrane-associated RING-CH 8 (MARCH8) that encodes a membrane-bound E3 ubiquitin ligase rescued osimertinib-induced PD-L1 reduction. Furthermore, manipulation of MARCH8 expression accordingly altered PD-L1 degradation rate. Critically, MARCH8 interacted with PD-L1 through its N-terminal region and also ubiquitinated PD-L1 in cells. Collectively, these results strongly suggest that MARCH8 is a previously undiscovered E3 ubiquitin ligase responsible for PD-L1 degradation including osimertinib-induced PD-L1 degradation, establishing a novel connection between MARCH8 and PD-L1 regulation.

Implications:
This study has demonstrated a previously undiscovered function of MARCH8 in mediating PD-L1 degradation induced by EGFR inhibitors in EGFR-mutant NSCLC cells, establishing a novel connection between MARCH8 and PD-L1 regulation.