bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Leukemia-Initiating Cells in Acute Lymphoblastic Leukemia
Authors: Tamiro Francesco , Weng Andrew P. , Giambra Vincenzo
Published: January 2021

The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of self-renewing and giving rise to “differentiated” or non-LICs that make up the whole tumor. Cell populations enriched with LIC activity have been characterized in different hematopoietic malignancies, including human acute lymphoblastic leukemia (ALL). Related studies have also demonstrated that LICs are functionally distinct from bulk cells and modulated by distinct molecular signaling pathways and epigenetic mechanisms. Here we review several biological and clinical aspects related to LICs in ALL, including (i) immunophenotypic characterization of LIC-enriched subsets in human and mouse models of ALL, (ii) emerging therapeutics against regulatory signaling pathways involved in LIC progression and maintenance in T- and B-cell leukemias, (iii) novel epigenetic and age-related mechanisms of LIC propagation, and (iv) ongoing efforts in immunotherapy to eradicate LIC-enriched cell subsets in relapsed and refractory ALL cases. Current conventional treatments do not efficiently eliminate LICs. Therefore, innovative therapeutics that exclusively target LICs hold great promise for developing an effective cure for ALL.
BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression
Authors: Warner Evan , Herberts Cameron , Fu Simon , Yip Steven , Wong Amanda , Wang Gang , Ritch Elie , Murtha Andrew J. , Vandekerkhove Gillian , Fonseca Nicolette M. , Angeles Arkhjamil , Beigi Arshia , Schönlau Elena , Beja Kevin , Annala Matti , Khalaf Daniel , Chi Kim N. , Wyatt Alexander W.
Published: January 2021

Purpose:

DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.

Experimental Design:

We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.

Results:

BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele–specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes.

Conclusions:

BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
Molecular Characterization and Therapeutic Targeting of Colorectal Cancers Harboring Receptor Tyrosine Kinase Fusions
Authors: Singh Harshabad , Li Yvonne Y. , Spurr Liam F. , Shinagare Atul B. , Abhyankar Ritika , Reilly Emma , Brais Lauren K. , Nag Anwesha , Ducar Matthew D. , Thorner Aaron R. , Shapiro Geoffrey I. , Keller Rachel B. , Siletti Cheta , Clark Jeffrey W. , Farago Anna F. , Lin Jessica J. , Demetri George D. , Gujrathi Rahul , Kulke Matthew H. , MacConaill Laura E. , Ligon Azra H. , Sicinska Ewa , Meyerson Matthew L. , Meyerhardt Jeffrey A. , Cherniack Andrew D. , Wolpin Brian M. , Ng Kimmie , Giannakis Marios , Hornick Jason L. , Cleary James M.
Published: January 2021

Purpose:

Receptor tyrosine kinase fusions in colorectal cancers are rare, but potentially therapeutically relevant. We describe clinical, molecular, and pathologic attributes of RTK fusion–associated colorectal cancer.

Experimental Design:

We identified all cases with RTK fusions in patients with colorectal cancer seen at Dana-Farber Cancer Institute (Boston, MA) who underwent OncoPanel testing between 2013 and 2018. Clinical, histologic, and molecular features were extracted from the patient charts and molecular testing results.

Results:

We identified 12 driver oncogenic fusions in various RTKs. These fusions occurred exclusively in BRAF and RAS wild-type tumors and were enriched in right-sided and mismatch repair–deficient (MMR-D) colorectal cancers. All of the MMR-D colorectal cancers with RTK fusions were found in tumors with acquired MMR-D due to MLH1 promoter hypermethylation and one was associated with a sessile serrated polyp. Molecular profiles of MMR-D colorectal cancer with RTK fusions largely resembled BRAF V600E–mutated MMR-D colorectal cancer, rather than those secondary to Lynch syndrome. We describe two patients with fusion-associated microsatellite stable (MSS) colorectal cancer who derived clinical benefit from therapeutic targeting of their translocation. The first harbored an ALK-CAD fusion and received sequential crizotinib and alectinib therapy for a total of 7.5 months until developing an ALK L1196Q gatekeeper mutation. The second patient, whose tumor contained an ROS1-GOPC fusion, continues to benefit from entrectinib after 9 months of therapy.

Conclusions:

RTK fusions in colorectal cancer are a rare, but important disease subgroup that occurs in RAS and BRAF wild-type tumors. Despite enrichment in acquired MMR-D tumors, RTK fusions also occur in MSS colorectal cancer and provide an important therapeutic target.
The State of Melanoma: Emergent Challenges and Opportunities
Authors: Atkins Michael B. , Curiel-Lewandrowski Clara , Fisher David E. , Swetter Susan M. , Tsao Hensin , Aguirre-Ghiso Julio A. , Soengas Maria S. , Weeraratna Ashani T. , Flaherty Keith T. , Herlyn Meenhard , Sosman Jeffrey A. , Tawbi Hussein A. , Pavlick Anna C. , Cassidy Pamela B. , Chandra Sunandana , Chapman Paul B. , Daud Adil , Eroglu Zeynep , Ferris Laura K. , Fox Bernard A. , Gershenwald Jeffrey E. , Gibney Geoffrey T. , Grossman Douglas , Hanks Brent A. , Hanniford Douglas , Hernando Eva , Jeter Joanne M. , Johnson Douglas B. , Khleif Samir N. , Kirkwood John M. , Leachman Sancy A. , Mays Darren , Nelson Kelly C. , Sondak Vernon K. , Sullivan Ryan J. , Merlino Glenn
Published: January 2021

Five years ago, the Melanoma Research Foundation (MRF) conducted an assessment of the challenges and opportunities facing the melanoma research community and patients with melanoma. Since then, remarkable progress has been made on both the basic and clinical research fronts. However, the incidence, recurrence, and death rates for melanoma remain unacceptably high and significant challenges remain. Hence, the MRF Scientific Advisory Council and Breakthrough Consortium, a group that includes clinicians and scientists, reconvened to facilitate intensive discussions on thematic areas essential to melanoma researchers and patients alike, prevention, detection, diagnosis, metastatic dormancy and progression, response and resistance to targeted and immune-based therapy, and the clinical consequences of COVID-19 for patients with melanoma and providers. These extensive discussions helped to crystalize our understanding of the challenges and opportunities facing the broader melanoma community today. In this report, we discuss the progress made since the last MRF assessment, comment on what remains to be overcome, and offer recommendations for the best path forward.
Paracentral Acute Middle Maculopathy following Surgically Induced Branch Retinal Artery Occlusion During Vitrectomy
Authors: Stavrakas Panagiotis , Karmiris Efthymios , Tranos Paris , Ananikas Konstantinos , Tooulias Christos , Rouvas Alexandros , Androu Angeliki
Published: January 2021

Paracentral acute middle maculopathy (PAMM) is a spectral-domain OCT finding of a thickened hyperreflective band at the level of the intermediate layers of the inner retina, attributed to the acute phase of intermediate capillary ischemia. The purpose of this paper is to report a case of PAMM deriving from a surgically induced branch retinal artery occlusion (BRAO) during vitrectomy for vitreous hemorrhage. A 70-year-old female referred to the posterior segment office with a 1-month history of visual loss in her right eye. Best-corrected visual acuity (BCVA) was “counting-fingers” (CF) due to a dense vitreous hemorrhage. She underwent a standard 23-gauge vitrectomy with a relatively close to the optic disc endodiathermy application to an avulsed vessel. Follow-up examination revealed a well-demarcated retinal whitening involving the inferior macula. SD OCT showed a surgically induced branch retinal artery occlusion exhibiting both a cotton wool spot and a PAMM lesion. Our case affords an insight into those pathological processes involved with PAMM, providing angiographic evidence of the retinal ischemic changes responsible for its development, by angiographically proving that branch retinal artery occlusion leads to a prompt formation of both a cotton wool spot and a PAMM lesion. Our aim is to raise awareness of this potential complication of vitrectomy surgery, especially when involving multiple traumatic manipulations onto the retinal surface.
Clinical-Radiomic Analysis for Pretreatment Prediction of Objective Response to First Transarterial Chemoembolization in Hepatocellular Carcinoma
Authors: Chen Mingyu , Cao Jiasheng , Hu Jiahao , Topatana Win , Li Shijie , Juengpanich Sarun , Lin Jian , Tong Chenhao , Shen Jiliang , Zhang Bin , Wu Jennifer , Pocha Christine , Kudo Masatoshi , Amedei Amedeo , Trevisani Franco , Sung Pil Soo , Zaydfudim Victor M. , Kanda Tatsuo , Cai Xiujun ,   AME Hepatocellular Carcinoma Collaborative Group
Published: January 2021

Background: The preoperative selection of patients with intermediate-stage hepatocellular carcinoma (HCC) who are likely to have an objective response to first transarterial chemoembolization (TACE) remains challenging. Objective: To develop and validate a clinical-radiomic model (CR model) for preoperatively predicting treatment response to first TACE in patients with intermediate-stage HCC. Methods: A total of 595 patients with intermediate-stage HCC were included in this retrospective study. A tumoral and peritumoral (10 mm) radiomic signature (TPR-signature) was constructed based on 3,404 radiomic features from 4 regions of interest. A predictive CR model based on TPR-signature and clinical factors was developed using multivariate logistic regression. Calibration curves and area under the receiver operating characteristic curves (AUCs) were used to evaluate the model’s performance. Results: The final CR model consisted of 5 independent predictors, including TPR-signature (p < 0.001), AFP (p = 0.004), Barcelona Clinic Liver Cancer System Stage B (BCLC B) subclassification (p = 0.01), tumor location (p = 0.039), and arterial hyperenhancement (p = 0.050). The internal and external validation results demonstrated the high-performance level of this model, with internal and external AUCs of 0.94 and 0.90, respectively. In addition, the predicted objective response via the CR model was associated with improved survival in the external validation cohort (hazard ratio: 2.43; 95% confidence interval: 1.60–3.69; p < 0.001). The predicted treatment response also allowed for significant discrimination between the Kaplan-Meier curves of each BCLC B subclassification. Conclusions: The CR model had an excellent performance in predicting the first TACE response in patients with intermediate-stage HCC and could provide a robust predictive tool to assist with the selection of patients for TACE.
Multiple Linear Regression Allows Weighted Burden Analysis of Rare Coding Variants in an Ethnically Heterogeneous Population
Authors: Curtis David
Published: January 2021

Weighted burden analysis has been used in exome-sequenced case-control studies to identify genes in which there is an excess of rare and/or functional variants associated with phenotype. Implementation in a ridge regression framework allows simultaneous analysis of all variants along with relevant covariates, such as population principal components. In order to apply the approach to a quantitative phenotype, a weighted burden score is derived for each subject and included in a linear regression analysis. The weighting scheme is adjusted in order to apply differential weights to rare and very rare variants and a score is derived based on both the frequency and predicted effect of each variant. When applied to an ethnically heterogeneous dataset consisting of 49,790 exome-sequenced UK Biobank subjects and using body mass index as the phenotype, the method produces a very inflated test statistic. However, this is almost completely corrected by including 20 population principal components as covariates. When this is done, the top 30 genes include a few which are quite plausibly associated with the phenotype, including LYPLAL1 and NSDHL. This approach offers a way to carry out gene-based analyses of rare variants identified by exome sequencing in heterogeneous datasets without requiring that data from ethnic minority subjects be discarded. This research has been conducted using the UK Biobank Resource.
Algunos aportes teóricos y metodológicos de Amado Luiz Cervo al estudio de las relaciones internacionales de Brasil y América Latina
Authors: Bernal-Meza Raúl
Published: January 2021

El artículo presenta la obra del profesor Amado Luiz Cervo, citando sus trabajos sobre metodología de investigación, historia de las relaciones internacionales de Brasil y América y Latina y sus aportes teórico-metodológicos para el estudio de las relaciones internacionales y la política exterior. Se pone atención preferencial y específica en los aportes del profesor al desarrollo de un pensamiento teórico y analítico original, que sea propio de América Latina, a través de la elaboración de paradigmas, conceptos y categorías. El trabajo del profesor Cervo  sobre la formulación de un pensamiento regional y brasileño para estudiar la inserción internacional, junto a otros profesores latinoamericanos, ha contrapuesto la visión dominante del pensamiento anglosajón con la elaboración la región para comprender la especificidad de las relaciones internacionales de nuestra región a partir de las condiciones que derivan de las características histórico-estructurales de la inserción internacional de América Latina. Después de presentar su metodología de trabajo, el texto analiza algunos de los aportes conceptuales más importantes, entre ellos la formulación de paradigmas y conceptos, poniendo de relevancia su aplicación e influencia sobre otras comunidades de pensamiento en Sudamérica.
MEF2 (Myocyte Enhancer Factor 2) Is Essential for Endothelial Homeostasis and the Atheroprotective Gene Expression Program
Authors: Lu Yao Wei , Martino Nina , Gerlach Brennan D. , Lamar John M. , Vincent Peter A. , Adam Alejandro P. , Schwarz John J.
Published: January 2021

Objective:

Atherosclerosis predominantly forms in regions of oscillatory shear stress while regions of laminar shear stress are protected. This protection is partly through the endothelium in laminar flow regions expressing an anti-inflammatory and antithrombotic gene expression program. Several molecular pathways transmitting these distinct flow patterns to the endothelium have been defined. Our objective is to define the role of the MEF2 (myocyte enhancer factor 2) family of transcription factors in promoting an atheroprotective endothelium.

Approach and Results:

Here, we show through endothelial-specific deletion of the 3 MEF2 factors in the endothelium, Mef2a, -c, and -d, that MEF2 is a critical regulator of vascular homeostasis. MEF2 deficiency results in systemic inflammation, hemorrhage, thrombocytopenia, leukocytosis, and rapid lethality. Transcriptome analysis reveals that MEF2 is required for normal regulation of 3 pathways implicated in determining the flow responsiveness of the endothelium. Specifically, MEF2 is required for expression of Klf2 and Klf4, 2 partially redundant factors essential for promoting an anti-inflammatory and antithrombotic endothelium. This critical requirement results in phenotypic similarities between endothelial-specific deletions of
Mef2a/c/d
and
Klf2/4
. In addition, MEF2 regulates the expression of Notch family genes, Notch1, Dll1, and Jag1, which also promote an atheroprotective endothelium. In contrast to these atheroprotective pathways, MEF2 deficiency upregulates an atherosclerosis promoting pathway through increasing the amount of TAZ (transcriptional coactivator with PDZ-binding motif).

Conclusions:

Our results implicate MEF2 as a critical upstream regulator of several transcription factors responsible for gene expression programs that affect development of atherosclerosis and promote an anti-inflammatory and antithrombotic endothelium.

Graphic Abstract:

A graphic abstract is available for this article.
ODC (Ornithine Decarboxylase)-Dependent Putrescine Synthesis Maintains MerTK (MER Tyrosine-Protein Kinase) Expression to Drive Resolution
Authors: Yurdagul Arif , Kong Na , Gerlach Brennan D. , Wang Xiaobo , Ampomah Patrick , Kuriakose George , Tao Wei , Shi Jinjun , Tabas Ira
Published: January 2021

Objective:

ODC (ornithine decarboxylase)-dependent putrescine synthesis promotes the successive clearance of apoptotic cells (ACs) by macrophages, contributing to inflammation resolution. However, it remains unknown whether ODC is required for other arms of the resolution program.

Approach and Results:

RNA sequencing of ODC-deficient macrophages exposed to ACs showed increases in mRNAs associated with heightened inflammation and decreases in mRNAs related to resolution and repair compared with WT (wild type) macrophages. In zymosan peritonitis, myeloid ODC deletion led to delayed clearance of neutrophils and a decrease in the proresolving cytokine, IL (interleukin)-10. Nanoparticle-mediated silencing of macrophage ODC in a model of atherosclerosis regression lowered IL-10 expression, decreased efferocytosis, enhanced necrotic core area, and reduced fibrous cap thickness. Mechanistically, ODC deletion lowered basal expression of MerTK (MER tyrosine-protein kinase)—an AC receptor—via a histone methylation–dependent transcriptional mechanism. Owing to lower basal MerTK, subsequent exposure to ACs resulted in lower MerTK-Erk (extracellular signal-regulated kinase) 1/2–dependent IL-10 production. Putrescine treatment of ODC-deficient macrophages restored the expression of both MerTK and AC-induced IL-10.

Conclusions:

These findings demonstrate that ODC-dependent putrescine synthesis in macrophages maintains a basal level of MerTK expression needed to optimally resolve inflammation upon subsequent AC exposure.

Graphic Abstract:

A graphic abstract is available for this article.
Early NT-ProBNP (N-Terminal Probrain Natriuretic Peptide) Elevation Predicts Malignant Edema and Death After Reperfusion Therapy in Acute Ischemic Stroke Patients
Authors: Zhang Xuting , Yan Shenqiang , Zhong Wansi , Yu Yannan , Lou Min
Published: January 2021

Background and Purpose:

We aimed to investigate the relationship between early NT-proBNP (N-terminal probrain natriuretic peptide) and all-cause death in patients receiving reperfusion therapy, including intravenous thrombolysis and endovascular thrombectomy (EVT).

Methods:

This study included 1039 acute ischemic stroke patients with early NT-proBNP data at 2 hours after the beginning of alteplase infusion for those with intravenous thrombolysis only or immediately at the end of EVT for those with EVT. We performed natural log transformation for NT-proBNP (Ln(NT-proBNP)). Malignant brain edema was ascertained by using the SITS-MOST (Safe Implementation of Thrombolysis in Stroke-Monitoring Study) criteria.

Results:

Median serum NT-proBNP level was 349 pg/mL (interquartile range, 89–1250 pg/mL). One hundred twenty-one (11.6%) patients died. Malignant edema was observed in 78 (7.5%) patients. Ln(NT-proBNP) was independently associated with 3-month mortality in patients with intravenous thrombolysis only (odds ratio, 1.465 [95% CI, 1.169–1.836];
P
=0.001) and in those receiving EVT (odds ratio, 1.563 [95% CI, 1.139–2.145];
P
=0.006). The elevation of Ln(NT-proBNP) was also independently associated with malignant edema in patients with intravenous thrombolysis only (odds ratio, 1.334 [95% CI, 1.020–1.745];
P
=0.036), and in those with EVT (odds ratio, 1.455 [95% CI, 1.057–2.003];
P
=0.022).

Conclusions:

An early increase in NT-proBNP levels was related to malignant edema and stroke mortality after reperfusion therapy.
Two new aphid species of the genus Cryptomyzus Oestlund, 1922 (Hemiptera, Aphididae) from Kazakhstan, and keys to apterous and alate viviparous females
Authors: KADYRBEKOV RUSTEM KH.
Published: January 2021

Two new species of the genus Cryptomyzus Oestlund, 1922 are described from Lamiaceae in the Kazakhstan part of West Tien Shan: Cryptomyzus (Cryptomyzus) sairamugamicus sp. n. living on Phlomis salicifolia and C. (C.) karzhantavicus sp. n. living on Stachys betonicifolia. Keys are provided for identification of apterous viviparous females and alate viviparous females of the world’s fauna of the genus Cryptomyzus.
Dynamics of Simulated High-Shear, Low-CAPE Supercells
Authors: Wade Andrew R. , Parker Matthew D.
Published: January 2021

High-shear, low-CAPE environments prevalent in the southeastern United States account for a large fraction of tornadoes and pose challenges for operational meteorologists. Yet, existing knowledge of supercell dynamics, particularly in the context of cloud-resolving modeling, is dominated by moderate- to high-CAPE environments typical of the Great Plains. This study applies high-resolution modeling to clarify the behavior of supercells in the more poorly understood low-CAPE environments, and compares them to a benchmark simulation in a higher-CAPE environment. Simulated low-CAPE supercells’ main updrafts do not approach the theoretical equilibrium level; their largest vertical velocities result not from buoyancy, but from dynamic accelerations associated with low-level mesocyclones and vortices. Surprisingly, low-CAPE tornado-like vortex parcels also sometimes stop ascending near the vortex top instead of carrying large vorticity upward into the midlevel updraft, contributing to vortex shallowness. Each of these low-CAPE behaviors is attributed to dynamic perturbation pressure gradient accelerations that are maximized in low levels, which predominate when the buoyancy is small.
Extreme Temperatures in the Antarctic
Authors: Turner John , Lu Hua , King John , Marshall Gareth J. , Phillips Tony , Bannister Dan , Colwell Steve
Published: January 2021

We present the first Antarctic-wide analysis of extreme near-surface air temperatures based on data collected up to the end of 2019 as part of the synoptic meteorological observing programs. We consider temperatures at 17 stations on the Antarctic continent and nearby sub-Antarctic islands. We examine the frequency distributions of temperatures and the highest and lowest individual temperatures observed. The variability and trends in the number of extreme temperatures were examined via the mean daily temperatures computed from the 0000, 0600, 1200, and 1800 UTC observations, with the thresholds for extreme warm and cold days taken as the 5th and 95th percentiles. The five stations examined from the Antarctic Peninsula region all experienced a statistically significant increase (p < 0.01) in the number of extreme high temperatures in the late-twentieth-century part of their records, although the number of extremes decreased in subsequent years. For the period after 1979 we investigate the synoptic background to the extreme events using ECMWF interim reanalysis (ERA-Interim) fields. The majority of record high temperatures were recorded after the passage of air masses over high orography, with the air being warmed by the foehn effect. At some stations in coastal East Antarctica the highest temperatures were recorded after air with a high potential temperature descended from the Antarctic plateau, resulting in an air mass 5°–7°C warmer than the maritime air. Record low temperatures at the Antarctic Peninsula stations were observed during winters with positive sea ice anomalies over the Bellingshausen and Weddell Seas.
Experimental analysis of the efficacy of vegetable oil-based nanolubricants for improving journal-bearing performance
Authors: Dhanola Anil , Garg Hem Chander
Published: January 2021

The present experimental study explores the performance of Hydrodynamic journal bearings operating with vegetable oil-based nanolubricants. For this study, titanium oxide nanoparticles have been added to canola oil by varying the volume fraction from 0% to 0.04%. An assessment of performance characteristics has been done by using a journal-bearing test rig under different operating conditions. The outcome of the experimental results aimed at the addition of nanoparticles to base lubricants to improve the performance was observed to be favorable. However, under high operating conditions, the influence of nanoparticles is observed to be less useful. The fluid film pressure of nanolubricants increased up to a specific volume concentration of titanium oxide nanoparticles (i.e. 0.02%) beyond which no further enhancement was observed. At a load of 3000 N, the fluid film pressure increased up to 10%, when a bearing is lubricated using canola oil with a 0.02% volume fraction of nanoparticles. The heat transfer rate was found to be higher for nanolubricants in comparison to a base oil and the fluid film temperature was reduced by up to 15% at a volume fraction of 0.04%. Furthermore, rheological studies reveal that the prepared nanolubricants exhibited Newtonian behavior under the given conditions. The percentage increment of viscosity varied from 2.1% to 15.4% and 2.43% to 13.89% for a volume fraction ranging from 0.01% to 0.04% at a temperature of 40 °C and 100 °C, respectively. The dynamic light scattering results confirmed that the particles were well distributed in a base lubricant without much aggregation.
Genomic imbalances in the placenta are associated with poor fetal growth
Authors: Del Gobbo Giulia F. , Yin Yue , Choufani Sanaa , Butcher Emma A. , Wei John , Rajcan-Separovic Evica , Bos Hayley , von Dadelszen Peter , Weksberg Rosanna , Robinson Wendy P. , Yuen Ryan K. C.
Published: January 2021

Background

Fetal growth restriction (FGR) is associated with increased risks for complications before, during, and after birth, in addition to risk of disease through to adulthood. Although placental insufficiency, failure to supply the fetus with adequate nutrients, underlies most cases of FGR, its causes are diverse and not fully understood. One of the few diagnosable causes of placental insufficiency in ongoing pregnancies is the presence of large chromosomal imbalances such as trisomy confined to the placenta; however, the impact of smaller copy number variants (CNVs) has not yet been adequately addressed. In this study, we confirm the importance of placental aneuploidy, and assess the potential contribution of CNVs to fetal growth.

Methods

We used molecular-cytogenetic approaches to identify aneuploidy in placentas from 101 infants born small-for-gestational age (SGA), typically used as a surrogate for FGR, and from 173 non-SGA controls from uncomplicated pregnancies. We confirmed aneuploidies and assessed mosaicism by microsatellite genotyping. We then profiled CNVs using high-resolution microarrays in a subset of 53 SGA and 61 control euploid placentas, and compared the load, impact, gene enrichment and clinical relevance of CNVs between groups. Candidate CNVs were confirmed using quantitative PCR.

Results

Aneuploidy was over tenfold more frequent in SGA-associated placentas compared to controls (11.9% vs. 1.1%; p = 0.0002, OR = 11.4, 95% CI 2.5–107.4), was confined to the placenta, and typically involved autosomes, whereas only sex chromosome abnormalities were observed in controls. We found no significant difference in CNV load or number of placental-expressed or imprinted genes in CNVs between SGA and controls, however, a rare and likely clinically-relevant germline CNV was identified in 5.7% of SGA cases. These CNVs involved candidate genes INHBB, HSD11B2, CTCF, and CSMD3.

Conclusions

We conclude that placental genomic imbalances at the cytogenetic and submicroscopic level may underlie up to ~ 18% of SGA cases in our population. This work contributes to the understanding of the underlying causes of placental insufficiency and FGR, which is important for counselling and prediction of long term outcomes for affected cases.
Immunogenicity of biologic therapies for migraine: a review of current evidence
Authors: Cohen Joshua M. , Ning Xiaoping , Kessler Yoel , Rasamoelisolo Michele , Campos Verena Ramirez , Seminerio Michael J. , Krasenbaum Lynda J. , Shen Honglue , Stratton Jennifer
Published: January 2021

Background

Monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway have been shown to be effective in migraine prevention. Eptinezumab, erenumab, fremanezumab, and galcanezumb have shown efficacy in clinical trials along with favorable safety and tolerability profiles. Although erenumab is a human mAb and the others have been humanized to varying degrees, they all have the capacity to provoke immune reactions. The present review article aims to discuss the current relationship between mAbs targeting the CGRP pathway (CGRP mAbs) and immunogenicity and their potential clinical implications.

Findings

The incidence of patients developing anti-drug antibodies (ADAs), their titer, and clinical significance are highly variable and depend on a variety of different drug and patient factors. Neutralizing ADAs (NAbs) bind to and inhibit or reduce the pharmacologic activity of the biologic drug molecule, whereas non-neutralizing antibodies (Non-NAbs) bind to the biologic drug molecule without affecting pharmacologic activity in an in vitro test, although pharmacokinetics and drug clearance may be affected. A direct comparison of immunogenicity data across clinical trials with different biologics is not possible due to a lack of standardized assays. Several phase 2, phase 3, and long-term studies evaluating CGRP mAbs for migraine prevention have reported immunogenicity data (5 studies each for eptinezumab, erenumab, fremanezumab, and galcanezumab). Across these studies, prevalence of ADAs varied, ranging from < 1% to ~ 18%. Neutralizing ADAs were slightly less common, with a prevalence ranging from 0 to 12%. Adverse events related to ADA formation were rare.

Conclusions

As more CGRP mAb studies are conducted and more long-term follow-up data become available, evidence is increasing that immunogenicity rates of biologic therapies for migraine are low, and adverse events related to ADAs are rare. Taken together, these results add to the growing body of evidence for the safety and tolerability of this class of migraine medications.
Emergency medicine in Japan: past, present, and future
Authors: Shimizu Kentaro , Hibino Seikei , Biros Michelle H. , Irisawa Taro , Shimazu Takeshi
Published: January 2021

Quite a few changes and challenges have arisen in society in general as technology has advanced and the aging population has increased. These can lead to the recognition of the shortcomings of a society’s traditional systems and the various changes that are needed, especially in providing emergency medical care. A super-aged society has been developing in Japan, and the emergency care system needs to change according to these new demographics and society’s needs. The focus has been shifting from critical care and trauma to medical and surgical conditions involving the elderly. Challenges in triage, ambulance diversion, and staffing are discussed in this review. Possible solutions currently underway, such as a public helpline, smartphone app system, coordination by designated hospitals, and universal coverage/government support, are discussed as future directions. Emergency medicine in Japan needs to develop in a more flexible way to meet the upcoming robust challenges of the changing demographics.
Adaptation Mechanism of Roots to Low and High Nitrogen Revealed by Proteomic Analysis
Authors: Xin Wei , Zhang Lina , Gao Jiping , Zhang Wenzhong , Yi Jun , Zhen Xiaoxi , Bi Congyuan , He Dawei , Liu Shiming , Zhao Xinyu
Published: January 2021

Background

Nitrogen-based nutrients are the main factors affecting rice growth and development. Root systems play an important role in helping plants to obtain nutrients from the soil. Root morphology and physiology are often closely related to above-ground plant organs performance. Therefore, it is important to understand the regulatory effects of nitrogen (N) on rice root growth to improve nitrogen use efficiency.

Results

In this study, changes in the rice root traits under low N (13.33 ppm), normal N (40 ppm) and high N (120 ppm) conditions were performed through root morphology analysis. These results show that, compared with normal N conditions, root growth is promoted under low N conditions, and inhibited under high N conditions. To understand the molecular mechanism underlying the rice root response to low and high N conditions, comparative proteomics analysis was performed using a tandem mass tag (TMT)-based approach, and differentially abundant proteins (DAPs) were further characterized. Compared with normal N conditions, a total of 291 and 211 DAPs were identified under low and high N conditions, respectively. The abundance of proteins involved in cell differentiation, cell wall modification, phenylpropanoid biosynthesis, and protein synthesis was differentially altered, which was an important reason for changes in root morphology. Furthermore, although both low and high N can cause nitrogen stress, rice roots revealed obvious differences in adaptation to low and high N.

Conclusions

These results provide insights into global changes in the response of rice roots to nitrogen availability and may facilitate the development of rice cultivars with high nitrogen use efficiency through root-based genetic improvements.
G-Tric: generating three-way synthetic datasets with triclustering solutions
Authors: Lobo João , Henriques Rui , Madeira Sara C.
Published: January 2021

Background

Three-way data started to gain popularity due to their increasing capacity to describe inherently multivariate and temporal events, such as biological responses, social interactions along time, urban dynamics, or complex geophysical phenomena. Triclustering, subspace clustering of three-way data, enables the discovery of patterns corresponding to data subspaces (triclusters) with values correlated across the three dimensions (observations $$\times$$
×
features $$\times$$
×
contexts). With increasing number of algorithms being proposed, effectively comparing them with state-of-the-art algorithms is paramount. These comparisons are usually performed using real data, without a known ground-truth, thus limiting the assessments. In this context, we propose a synthetic data generator, G-Tric, allowing the creation of synthetic datasets with configurable properties and the possibility to plant triclusters. The generator is prepared to create datasets resembling real 3-way data from biomedical and social data domains, with the additional advantage of further providing the ground truth (triclustering solution) as output.

Results

G-Tric can replicate real-world datasets and create new ones that match researchers needs across several properties, including data type (numeric or symbolic), dimensions, and background distribution. Users can tune the patterns and structure that characterize the planted triclusters (subspaces) and how they interact (overlapping). Data quality can also be controlled, by defining the amount of missing, noise or errors. Furthermore, a benchmark of datasets resembling real data is made available, together with the corresponding triclustering solutions (planted triclusters) and generating parameters.

Conclusions

Triclustering evaluation using G-Tric provides the possibility to combine both intrinsic and extrinsic metrics to compare solutions that produce more reliable analyses. A set of predefined datasets, mimicking widely used three-way data and exploring crucial properties was generated and made available, highlighting G-Tric’s potential to advance triclustering state-of-the-art by easing the process of evaluating the quality of new triclustering approaches.
PyConvU-Net: a lightweight and multiscale network for biomedical image segmentation
Authors: Li Changyong , Fan Yongxian , Cai Xiaodong
Published: January 2021

Background

With the development of deep learning (DL), more and more methods based on deep learning are proposed and achieve state-of-the-art performance in biomedical image segmentation. However, these methods are usually complex and require the support of powerful computing resources. According to the actual situation, it is impractical that we use huge computing resources in clinical situations. Thus, it is significant to develop accurate DL based biomedical image segmentation methods which depend on resources-constraint computing.

Results

A lightweight and multiscale network called PyConvU-Net is proposed to potentially work with low-resources computing. Through strictly controlled experiments, PyConvU-Net predictions have a good performance on three biomedical image segmentation tasks with the fewest parameters.

Conclusions

Our experimental results preliminarily demonstrate the potential of proposed PyConvU-Net in biomedical image segmentation with resources-constraint computing.
First insights into the molecular basis association between promoter polymorphisms of the IL1B gene and Helicobacter pylori infection in the Sudanese population: computational approach
Authors: Idris Abeer Babiker , Idris Einas Babiker , Ataelmanan Amany Eltayib , Mohamed Ali Elbagir Ali , Osman Arbab Bashir M. , Ibrahim El-Amin Mohamed , Hassan Mohamed A.
Published: January 2021

Background

Helicobacter pylori (H. pylori) infects nearly half of the world’s population with a variation in incidence among different geographic regions. Genetic variants in the promoter regions of the IL1B gene can affect cytokine expression and creates a condition of hypoacidity which favors the survival and colonization of H. pylori. Therefore, the aim of this study was to characterize the polymorphic sites in the 5′- region [−687_ + 297] of IL1B in H. pylori infection using in silico tools.

Results

A total of five nucleotide variations were detected in the 5′-regulatory region [−687_ + 297] of IL1B which led to the addition or alteration of transcription factor binding sites (TFBSs) or composite regulatory elements (CEs). Genotyping of IL1B − 31 C > T revealed a significant association between -31 T and susceptibility to H. pylori infection in the studied population (P = 0.0363). Comparative analysis showed conservation rates of IL1B upstream [−368_ + 10] region above 70% in chimpanzee, rhesus monkey, a domesticated dog, cow and rat.

Conclusions

In H. pylori-infected patients, three detected SNPs (− 338, − 155 and − 31) located in the IL1B promoter were predicted to alter TFBSs and CE, which might affect the gene expression. These in silico predictions provide insight for further experimental in vitro and in vivo studies of the regulation of IL1B expression and its relationship to H. pylori infection. However, the recognition of regulatory motifs by computer algorithms is fundamental for understanding gene expression patterns.
Metagenomic analysis revealed a wide distribution of antibiotic resistance genes and biosynthesis of antibiotics in the gut of giant pandas
Authors: Mustafa Ghulam Raza , Li Caiwu , Zhao Siyue , Jin Lei , He Xueping , Shabbir Muhammad Zubair , He Yongguo , Li Ti , Deng Wenwen , Xu Lin , Xiong Yaowu , Zhang Guiquan , Zhang Hemin , Huang Yan , Zou Likou
Published: January 2021

Background

The gut microbiome is essential for the host’s health and serves as an essential reservoir of antibiotic resistance genes (ARGs). We investigated the effects of different factors, including the dietary shifts and age, on the functional characteristics of the giant panda’s gut microbiome (GPs) through shotgun metagenome sequencing. We explored the association between gut bacterial genera and ARGs within the gut based on network analysis.

Results

Fecal samples (n=60) from captive juvenile, adult, and geriatric GPs were processed, and variations were identified in the gut microbiome according to different ages, the abundance of novel ARGs and the biosynthesis of antibiotics. Among 667 ARGs identified, nine from the top ten ARGs had a higher abundance in juveniles. For 102 ARGs against bacteria, a co-occurrence pattern revealed a positive association for predominant ARGs withStreptococcus. A comparative KEGG pathways analysis revealed an abundant biosynthesis of antibiotics among three different groups of GPs, where it was more significantly observed in the juvenile group. A co-occurrence pattern further revealed a positive association for the top ten ARGs, biosynthesis of antibiotics, and metabolic pathways.

Conclusion

Gut of GPs serve as a reservoir for novel ARGs and biosynthesis of antibiotics. Dietary changes and age may influence the gut microbiome’s functional characteristics; however, it needs further studies to ascertain the study outcomes.
Sucrose-phosphate phosphatase from sugarcane reveals an ancestral tandem duplication
Authors: Partida Vania Gabriela Sedano , Dias Henrique Moura , Corcino Diana Susana Martinez , Van Sluys Marie-Anne
Published: January 2021

Background

Sugarcane is capable to store large amounts of sucrose in the culm at maturity hence it became a major source of sucrose for the food and the renewable energy industries. Sucrose, the main disaccharide produced by photosynthesis, is mainly stored in the vacuole of the cells of non-photosynthetic tissues. Two pathways are known to release free sucrose in plant cells, one is de novo synthesis dependent on sucrose phosphate synthase (SPS) and sucrose phosphate phosphatase (S6PP) while the other is regulatory and dependent on sucrose synthase (SuSy) activity. The molecular understanding of genes that give rise to the expression of the enzyme sucrose phosphate phosphatase, responsible for the release of sucrose in the last synthetic step lag behind the regulatory SuSy gene.

Results

Sugarcane genome sequencing effort disclosed the existence of a tandem duplication and the present work further support that both S6PP.1 and S6PP_2D isoforms are actively transcribed in young sugarcane plants but significantly less at maturity. Two commercial hybrids (SP80–3280 and R570) and both Saccharum spontaneum (IN84–58) and S.officinarum (BADILLA) exhibit transcriptional activity at three-month-old plants of the tandem S6PP_2D in leaves, culm, meristem and root system with a cultivar-specific distribution. Moreover, this tandem duplication is shared with other grasses and is ancestral in the group.

Conclusion

Detection of a new isoform of S6PP resulting from the translation of 14 exon-containing transcript (S6PP_2D) will contribute to the knowledge of sucrose metabolism in plants. In addition, expression varies along plant development and between sugarcane cultivars and parental species.
Efficacy and cost-effectiveness of a therapist-assisted web-based intervention for depression and anxiety in patients with ischemic heart disease attending cardiac rehabilitation [eMindYourHeart trial]: a randomised controlled trial protocol
Authors: Pedersen Susanne S. , Andersen Christina M. , Ahm Robert , Skovbakke Søren J. , Kok Robin , Helmark Charlotte , Wiil Uffe K. , Schmidt Thomas , Olsen Kim Rose , Hjelmborg Jacob , Zwisler Ann-Dorthe , Frostholm Lisbeth
Published: January 2021

Background

One in five patients with ischaemic heart disease (IHD) develop comorbid depression or anxiety. Depression is associated with risk of non-adherence to cardiac rehabilitation (CR) and dropout, inadequate risk factor management, poor quality of life (QoL), increased healthcare costs and premature death. In 2020, IHD and depression are expected to be among the top contributors to the disease-burden worldwide. Hence, it is paramount to treat both the underlying somatic disease as well as depression and anxiety. eMindYourHeart will evaluate the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention targeting depression and anxiety in patients with IHD, which may help fill this gap in clinical care.

Methods

eMindYourHeart is a multi-center, two-armed, unblinded randomised controlled trial that will compare a therapist-assisted eHealth intervention to treatment as usual in 188 CR patients with IHD and comorbid depression or anxiety. The primary outcome of the trial is symptoms of depression, measured with the Hospital Anxiety and Depression Scale (HADS) at 3 months. Secondary outcomes evaluated at 3, 6, and 12 months include symptoms of depression and anxiety (HADS), perceived stress, health complaints, QoL (HeartQoL), trial dropout (number of patients dropped out in either arm at 3 months) and cost-effectiveness.

Discussion

To our knowledge, this is the first trial to evaluate both the efficacy and cost-effectiveness of a therapist-assisted eHealth intervention in patients with IHD and comorbid psychological distress as part of CR. Integrating screening for and treatment of depression and anxiety into standard CR may decrease dropout and facilitate better risk factor management, as it is presented as “one package” to patients, and they can access the eMindYourHeart program in their own time and at their own convenience. The trial holds a strong potential for improving the quality of care for an increasing population of patients with IHD and comorbid depression, anxiety or both, with likely benefits to patients, families, and society at large due to potential reductions in direct and indirect costs, if proven successful.

Trial registration The trial was prospectively registered on https://clinicaltrials.gov/ct2/show/NCT04172974 on November 21, 2019 with registration number [NCT04172974].