bluuebunny/crossref_metadata_2025 huggingface dataset:
Hanging by a thread? Forests and drought
Authors: Brodribb Timothy J. , Powers Jennifer , Cochard Hervé , Choat Brendan
Published: April 2020

Trees are the living foundations on which most terrestrial biodiversity is built. Central to the success of trees are their woody bodies, which connect their elevated photosynthetic canopies with the essential belowground activities of water and nutrient acquisition. The slow construction of these carbon-dense, woody skeletons leads to a slow generation time, leaving trees and forests highly susceptible to rapid changes in climate. Other long-lived, sessile organisms such as corals appear to be poorly equipped to survive rapid changes, which raises questions about the vulnerability of contemporary forests to future climate change. The emerging view that, similar to corals, tree species have rather inflexible damage thresholds, particularly in terms of water stress, is especially concerning. This Review examines recent progress in our understanding of how the future looks for forests growing in a hotter and drier atmosphere.
The Ccr4-Not complex monitors the translating ribosome for codon optimality
Authors: Buschauer Robert , Matsuo Yoshitaka , Sugiyama Takato , Chen Ying-Hsin , Alhusaini Najwa , Sweet Thomas , Ikeuchi Ken , Cheng Jingdong , Matsuki Yasuko , Nobuta Risa , Gilmozzi Andrea , Berninghausen Otto , Tesina Petr , Becker Thomas , Coller Jeff , Inada Toshifumi , Beckmann Roland
Published: April 2020

Coupling translation and mRNA decay

Gene expression requires messenger RNAs (mRNAs)—DNA-derived blueprints of genes—to be translated by protein-producing ribosomes. The levels of mRNAs are tightly regulated, in part by controlling their half-lives. In eukaryotic cells, mRNA half-life is largely linked to translational efficiency, but the mechanism underlying this link has remained elusive. Buschauer
et al.
used cryo–electron microscopy and RNA sequencing to show how a key regulator of mRNA degradation, the Ccr4-Not complex, monitors the ribosome during mRNA translation. They found that the Not5 subunit directly binds to a ribosomal site exposed specifically during inefficient decoding, thereby triggering mRNA degradation. Analysis of mutants revealed the importance of this sensing mechanism for mRNA homeostasis.

Science
, this issue p.
eaay6912
Temperature-dependent sex determination is mediated by pSTAT3 repression of
Kdm6b
Authors: Weber Ceri , Zhou Yingjie , Lee Jong Gwan , Looger Loren L. , Qian Guoying , Ge Chutian , Capel Blanche
Published: April 2020

How egg temperature sets sex

In many reptiles, sex is determined by nest temperature during egg incubation. Temperature regulates the expression of an epigenetic modifier gene called
Kdm6b
, which is responsible for testis development. However, the molecular connection between temperature and sex-specific expression of this factor was previously unknown. Weber
et al.
have identified a link between temperature and the activation of a key regulator of
Kdm6b
called signal transducer and activator of transcription 3 (STAT3). After an influx of Ca
2+
at the warmer, female-producing temperature, STAT3 is phosphorylated and silences
Kdm6b
transcription to repress testis development.

Science
, this issue p.
303
Robots with insect brains
Authors: Webb Barbara
Published: April 2020

A literal approach to mechanistic explanation provides insight in neuroscience
The physiology of plant responses to drought
Authors: Gupta Aditi , Rico-Medina Andrés , Caño-Delgado Ana I.
Published: April 2020

Drought alone causes more annual loss in crop yield than all pathogens combined. To adapt to moisture gradients in soil, plants alter their physiology, modify root growth and architecture, and close stomata on their aboveground segments. These tissue-specific responses modify the flux of cellular signals, resulting in early flowering or stunted growth and, often, reduced yield. Physiological and molecular analyses of the model plant
Arabidopsis thaliana
have identified phytohormone signaling as key for regulating the response to drought or water insufficiency. Here we discuss how engineering hormone signaling in specific cells and cellular domains can facilitate improved plant responses to drought. We explore current knowledge and future questions central to the quest to produce high-yield, drought-resistant crops.
Mechanisms generating cancer genome complexity from a single cell division error
Authors: Umbreit Neil T. , Zhang Cheng-Zhong , Lynch Luke D. , Blaine Logan J. , Cheng Anna M. , Tourdot Richard , Sun Lili , Almubarak Hannah F. , Judge Kim , Mitchell Thomas J. , Spektor Alexander , Pellman David
Published: April 2020

Genomic havoc from one fateful mistake

Many human tumors display scrambled genomes that arise from two distinct mutational processes. The first, the chromosome breakage-fusion-bridge (BFB) cycle, produces gene amplification and genomic instability. The second, chromothripsis, generates massive, clustered genomic rearrangements in one or a few chromosomes. Umbreit
et al.
hypothesized that these two processes are mechanistically related and tested this idea by recreating essential steps of the BFB cycle in cultured cells (see the Perspective by Paiano and Nussenzweig). They found that chromothripsis arises from a cascade of events that begins with aberrant chromosome bridge formation during mitosis, followed by chromosome fragmentation, DNA damage, chromosome missegregation, and the formation of micronuclei. They propose a model that explains how a single cell division error (chromosome bridge formation) can generate many hallmark features of cancer genomes.

Science
, this issue p.
240
; see also p.
eaba0712
Light expands a catalyst's repertoire
Authors: Kathe Prasad , Fleischer Ivana
Published: April 2020

Visible light helps a Pd carbonylation catalyst both break and make carbon-halogen bonds
Recalibrating the risk of hamstring strain injury (HSI): A 2020 systematic review and meta-analysis of risk factors for index and recurrent hamstring strain injury in sport
Authors: Green Brady , Bourne Matthew N , van Dyk Nicol , Pizzari Tania
Published: April 2020

Objective

To systematically review risk factors for hamstring strain injury (HSI).

Design

Systematic review update.

Data sources

Database searches: (1) inception to 2011 (original), and (2) 2011 to December 2018 (update). Citation tracking, manual reference and ahead of press searches.

Eligibility criteria for selecting studies

Studies presenting prospective data evaluating factors associated with the risk of index and/or recurrent HSI.

Method

Search result screening and risk of bias assessment. A best evidence synthesis for each factor and meta-analysis, where possible, to determine the association with risk of HSI.

Results

The 78 studies captured 8,319 total HSIs, including 967 recurrences, in 71,324 athletes. Older age (standardised mean difference=1.6, p=0.002), any history of HSI (risk ratio (RR)=2.7, p<0.001), a recent HSI (RR=4.8, p<0.001), previous anterior cruciate ligament (ACL) injury (RR=1.7, p=0.002) and previous calf strain injury (RR=1.5, p<0.001) were significant risk factors for HSI. From the best evidence synthesis, factors relating to sports performance and match play, running and hamstring strength were most consistently associated with HSI risk. The risk of recurrent HSI is best evaluated using clinical data and not the MRI characteristics of the index injury.

Summary/conclusion

Older age and a history of HSI are the strongest risk factors for HSI. Future research may be directed towards exploring the interaction of risk factors and how these relationships fluctuate over time given the occurrence of index and recurrent HSI in sport is multifactorial.
Personalised yoga for burnout and traumatic stress in junior doctors
Authors: Taylor Jennifer , McLean Loyola , Richards Bethan , Glozier Nicholas
Published: April 2020

Objectives

Junior doctors are frequently exposed to occupational and traumatic stress, sometimes with tragic consequences. Mindfulness-based and fitness interventions are increasingly used to mitigate this, but have not been compared.

We conducted a randomised, controlled pilot trial to assess the feasibility, acceptability and effectiveness of these interventions in junior doctors.

Methods

We randomised participants (n=21) to weekly 1-hour sessions of personalised, trauma-informed yoga (n=10), with a 4-hour workshop, and eHealth homework; or group-format fitness (n=8) in an existing wellness programme, MDOK. Burnout, traumatic stress and suicidality were measured at baseline and 8 weeks.

Results

Both interventions reduced burnout, and yoga increased compassion satisfaction within group on the Professional Quality of Life scale, without difference between groups on this measure.

Personalised yoga significantly reduced depersonalisation (z=−1.99, p=0.05) compared with group fitness on the Maslach Burnout Inventory (MBI-HSS (MP)) and showed greater flexibility changes. Both interventions increased MBI Personal Accomplishment, with no changes in other self-report psychological or physiological metrics, including breath-counting.

Participants doing one-to-one yoga rated it more highly overall (p=0.02) than group fitness, and reported it comparatively more beneficial for mental (p=0.01) and physical health (p=0.05). Face-to-face weekly sessions were 100% attended in yoga, but only 45% in fitness.

Conclusion

In this pilot trial, both yoga and fitness improved burnout, but trauma-informed yoga reduced depersonalisation in junior doctors more than group-format fitness. One-to-one yoga was better adhered than fitness, but was more resource intensive. Junior doctors need larger-scale comparative research of the effectiveness and implementation of individual, organisational and systemic mental health interventions.

Trial registration number

ANZCTR 12618001467224.
IQOS is not an acronym: a call to researchers and journals
Authors: Seidenberg Andrew , Freeman Becky
Published: April 2020

In 2014, Philip Morris International (PMI) introduced the IQOS heated tobacco product system. It has been widely reported in the media that IQOS is an acronym for 'I quit ordinary smoking'. To our knowledge, PMI has never publicly used any acronym to describe or market IQOS. Moreover, PMI has repeatedly denied that IQOS is an acronym. The acronym, which is an implicit cessation claim, has also appeared in numerous peer-reviewed publications. While the origins of the acronym are unknown, PMI stands to benefit from the publicity and associated positive connotations. It is possible that early adopters of IQOS created the acronym online, which was then picked by reporters and the research community. Alternatively, given that tobacco manufacturers have used social media influencers to promote their products, it is also possible that PMI may have surreptitiously helped popularize the acronym. Regardless of its origin, researchers and journals should stop disseminating this internet myth that promotes a potentially misleading claim.
Location of menaquinone and menaquinol headgroups in model membranes
Authors: Van Cleave Cameron , Murakami Heide A. , Samart Nuttaporn , Koehn Jordan T. , Maldonado Pablo , Kreckel Heidi D. , Cope Elana J. , Basile Andrea , Crick Dean C. , Crans Debbie C.
Published: April 2020

Menaquinones are lipoquinones that consist of a headgroup (naphthoquinone, menadione) and an isoprenyl sidechain. They function as electron transporters in prokaryotes such as Mycobacterium tuberculosis. For these studies, we used Langmuir monolayers and microemulsions to investigate how the menaquinone headgroup (menadione) and the menahydroquinone headgroup (menadiol) interact with model membrane interfaces to determine if differences are observed in the location of these headgroups in a membrane. It has been suggested that the differences in the locations are mainly caused by the isoprenyl sidechain rather than the headgroup quinone-to-quinol reduction during electron transport. This study presents evidence that suggests the influence of the headgroup drives the movement of the oxidized quinone and the reduced hydroquinone to different locations within the interface. Utilizing the model membranes of microemulsions and Langmuir monolayers, it is determined whether or not there is a difference in the location of menadione and menadiol within the interface. Based on our findings, we conclude that the menadione and menadiol may reside in different locations within model membranes. It follows that if menaquinone moves within the cell membrane upon menaquinol formation, it is due at least in part, to the differences in the properties of headgroup interactions with the membrane in addition to the isoprenyl sidechain.
Effect of hydrogen-bond strength on photoresponsive properties of polymer-azobenzene complexes
Authors: Vapaavuori Jaana , Koskela Jenni E. , Wang Xiaoxiao , Ras Robin H.A. , Priimagi Arri , Bazuin C. Geraldine , Pellerin Christian
Published: April 2020

Supramolecular complexation between photoresponsive azobenzene chromophores and a photopassive polymer host offers synthetic and design advantages compared with conventional covalent azo-containing polymers. In this context, it is important to understand the impact of the strength of the supramolecular interaction on the optical response. Herein, we study the effect of hydrogen-bonding strength between a photopassive polymer host [poly(4-vinylpyridine), or P4VP] and three azobenzene analogues capable of forming weaker (hydroxyl), stronger (carboxylic acid), or no H-bonding with P4VP. The hydroxyl-functionalized azo forms complete H-bonding complexation up to equimolar ratio with VP, whereas the COOH-functionalized azo reaches only up to 30% H-bond complexation due to competing acid dimerization that leads to partial phase separation and azo crystallization. We show that the stronger azo-polymer H-bonding nevertheless provides higher photoinduced orientation and better performance during optical surface patterning, in terms of grating depth and diffraction efficiency, when phase separation is either avoided altogether or is limited by using relatively low azo contents. These results demonstrate the importance of the H-bonding strength on the photoresponse of azopolymer complexes, as well as the need to consider the interplay between different intermolecular interactions that can affect complexation.
Enacting workplace culture change for excellence in research: a gender lens
Authors: Haine-Bennett Eleanor , Bergsieker Hilary B. , Coe Imogen R. , Koch-Kraft Andrea , Langelier Eve , Morrison Suzanne , Nikoleyczik Katrin , Schmader Toni , Trivailo Olga , Twine Sue , Decker Jennifer E.
Published: April 2020

Science and engineering research excellence can be maximized if the selection of researchers is made from 100% of the pool of human talent. This requires policies and approaches that encourage broad sections of society, including women and other underrepresented groups, to participate in research. Institutional policies, interpersonal interactions, and individuals’ attitudes are drivers of workplace culture. Here, some new evidence-based and systematic approaches with a focus on culture are proposed to foster women’s inclusion and success in science and engineering.
Lump solutions to nonlinear PDEs involving Hirota derivative Dt2DxDy
Authors: Wang Fudong , Ma Wen Xiu
Published: April 2020

This paper aims to study lump solutions to a class of (2[Formula: see text]+[Formula: see text]1)-dimensional nonlinear PDE systems, which involve the fourth-order Hirota derivative term: [Formula: see text]. This Hirota derivative term generates higher-order derivatives of the temporal variable. Lump solutions to the resulting new class of nonlinear PDE systems are studied in detail via the Hirota bilinear method.
A full-scale computational study on the electrodynamics of a rigid particle in an optically induced dielectrophoresis chip
Authors: Shi Liuyong , Shi Xiaoming , Zhou Teng , Liu Zhenyu , Liu Zhiyuan , Joo Sangwoo
Published: April 2020

A transient continuum model of the ODEP chip containing single circular particle inside is constructed based on multi-physical field coupling. The dielectrophoresis force and liquid viscous resistance acting on particle are calculated by employing the full Maxwell stress tensor. The coupled flow field, electric field and particle are solved by the arbitrary Lagrange–Euler (ALE) method simultaneously. The throughout dynamic process of particle in the ODEP chip is demonstrated, and the effect of several critical parameters on particle electrodynamics is illuminated. The additional disturbing effect of the photoconductive layer on the electric field as well as the micro-channel wall on the flow field is presented to clarify the particle motion in the vertical direction. The results in this study provide a detailed understanding of the particle dynamics in the ODEP chip.
Development of an Ensemble Intelligent Model for Assessing the Strength of Cemented Paste Backfill
Authors: Sun Yuantian , Li Guichen , Zhang Junfei , Sun Junbo , Xu Jiahui
Published: April 2020

Cemented paste backfill (CPB) is an eco‐friendly composite containing mine waste or tailings and has been widely used as construction materials in underground stopes. In the field, the uniaxial compressive strength (UCS) of CPB is critical as it is closely related to the stability of stopes. Predicting the UCS of CPB using traditional mathematical models is far from being satisfactory due to the highly nonlinear relationships between the UCS and a large number of influencing variables. To solve this problem, this study uses a support vector machine (SVM) to predict the UCS of CPB. The hyperparameters of the SVM model are tuned using the beetle antennae search (BAS) algorithm; then, the model is called BSVM. The BSVM is then trained on a dataset collected from the experimental results. To explain the importance of each input variable on the UCS of CPB, the variable importance is obtained using a sensitivity study with the BSVM as the objective function. The results show that the proposed BSVM has high prediction accuracy on the test set with a high correlation coefficient (0.97) and low root‐mean‐square error (0.27 MPa). The proposed model can guide the design of CPB during mining.
Effect of Extraction Methods on Antioxidant Activity of Papery Skin Extracts and Fractions of Maja Cipanas Onion (Allium cepa L. var. ascalonicum)
Authors: Saptarini Nyi M. , Wardati Yulia
Published: April 2020

Extraction can be carried out at ambient temperature or high temperature to accelerate the extraction process of secondary metabolites from simplicia. This study aimed to determine the effectiveness of extraction methods on antioxidant activity of secondary metabolites of papery skin extracts and fractions of Maja Cipanas onion (Allium cepa L. var. ascalonicum). Extraction methods were maceration, percolation, reflux, and Soxhlet method, and then, concentrated extracts were fractionated by liquid-liquid extraction based on the polarity of secondary metabolites. Antioxidant activity was determined by the DPPH (2,2-diphenyl-1-picrylhydrazyl) method. The phytochemical screening showed that onion papery skin contained alkaloids, polyphenols, flavonoids, and tannins. The IC50 value of the extract, ethyl acetate fraction, and water fraction of the four extraction methods in the concentration range 25–400  μg/mL were in the range of 55.62–107.08, 31.31–84.06, and 126.05–139.82  μg/mL, respectively, while the IAA value was in the ranges of 0.25–0.49, 0.32–0.86, and 0.19–0.21, respectively. Variation in IC50 and IAA values indicate that the extraction method affects antioxidant activity, due to extracted secondary metabolites from simplicia. The highest antioxidant activity was an ethyl acetate fraction by the reflux method, while the lowest was water fraction by the percolation method.
FDA-MIMO Beampattern Synthesis with Hamming Window Weighted Linear Frequency Increments
Authors: Tan Ming , Wang Chunyang , Yuan Hui , Bai Juan , An Lei
Published: April 2020

By utilizing a tiny frequency increment across the array elements, frequency diverse array (FDA) generates a beampattern possessing the property of range-angle-dependent. However, the beampattern of the conventional FDA is “S”-shaped, which means it is coupled in range-angle domains, resulting in low target indication accuracy and poor jamming suppression ability. In this paper, taking advantage of multiple-input multiple-output (MIMO) technique and multiple matched filters, a new FDA framework using Hamming window weighted linear frequency increments is proposed. Correct FDA-MIMO framework and multiple matched filters are used to remove the influence of the time parameter. A range-angle-decoupled beampattern with sharp pencil-shaped mainlobe and low sidelobe levels can be produced. Comparing with the existing FDA-decoupled transmit beampattern design methods, a more focusing beampattern can be achieved. Simulation results validate the superiority of the proposed system.
Current State of Geospatial Methodologic Approaches in Canadian Population Oncology Research
Authors: Simkin Jonathan , Erickson Anders C. , Otterstatter Michael C. , Dummer Trevor J.B. , Ogilvie Gina
Published: April 2020

Geospatial analyses are increasingly used in population oncology. We provide a first review of geospatial analysis in Canadian population oncology research, compare to international peers, and identify future directions. Geospatial-focused peer-reviewed publications from 1992–2020 were compiled using PubMed, MEDLINE, Web of Science, and Google Scholar. Abstracts were screened for data derived from a Canadian cancer registry and use of geographic information systems. Studies were classified by geospatial methodology, geospatial unit, location, cancer site, and study year. Common limitations were documented from article discussion sections. Our search identified 71 publications using data from all provincial and national cancer registries. Thirty-nine percent (N = 28) were published in the most recent 5-year period (2016–2020). Geospatial methodologies included exposure assessment (32.4%), identifying spatial associations (21.1%), proximity analysis (16.9%), cluster detection (15.5%), and descriptive mapping (14.1%). Common limitations included confounding, ecologic fallacy, not accounting for residential mobility, and small case/population sizes. Geospatial analyses are increasingly used in Canadian population oncology; however, efforts are concentrated among a few provinces and common cancer sites, and data are over a decade old. Limitations were similar to those documented internationally, and more work is needed to address them. Organized efforts are needed to identify common challenges, develop leading practices, and identify shared priorities.
Low-dose versus High-dose Carfilzomib with Dexamethasone (S1304) in Patients with Relapsed-Refractory Multiple Myeloma
Authors: Ailawadhi Sikander , Sexton Rachael , Lentzsch Suzanne , Abidi Muneer H. , Voorhees Peter M. , Cohen Adam D. , Rohren Eric M. , Heitner Stephen , Kelly Kevin , Mackler Niklas J. , Baer David M. , Hoering Antje , Durie Brian , Orlowski Robert Z.
Published: April 2020

Purpose:

Treatment of multiple myeloma has evolved tremendously and optimal utilization of available therapies will ensure maximal patient benefits.

Patients and Methods:

We report the Southwest Oncology Group randomized phase II trial (S1304) comparing twice weekly low-dose (27 mg/m2; arm 1) to high-dose carfilzomib (56 mg/m2; arm 2), both with dexamethasone, administered for 12 cycles (11 months) for relapsed and/or refractory multiple myeloma with up to six prior lines of therapy (NCT01903811). The primary endpoint was progression-free survival (PFS), and patients on arm 1 could cross-over to arm 2 after progression on treatment.

Results:

Among 143 enrolled patients, of whom 121 were eligible and analyzable, the overall response rate was 42.8%, with no significant difference between the arms (P = 0.113). Also, neither the median PFS [5 months and 8 months, respectively; HR, 1.061; 80% Wald confidence interval (CI), 0.821–1.370; P = 0.384] nor the median overall survival were significantly different (26 and 22 months, respectively; HR, 1.149, 80% Wald CI, 0.841–.571; P = 0.284). Sixteen patients crossed over to arm 2 with a median PFS benefit of 3 months. Certain adverse events (AE) were more frequent in arm 2, including fatigue, thrombocytopenia, and peripheral neuropathy, but there was no significant difference in cardiopulmonary AEs.

Conclusions:

This randomized trial did not support a benefit of fixed duration, twice weekly 56 mg/m2 dosing of carfilzomib over the 27 mg/m2 dose for the treatment of relapsed and/or refractory multiple myeloma. However, treatment to progression in earlier patient populations with high-dose carfilzomib using different schedules should still be considered as part of the standard of care.
A Multianalyte Panel Consisting of Extracellular Vesicle miRNAs and mRNAs, cfDNA, and CA19-9 Shows Utility for Diagnosis and Staging of Pancreatic Ductal Adenocarcinoma
Authors: Yang Zijian , LaRiviere Michael J. , Ko Jina , Till Jacob E. , Christensen Theresa , Yee Stephanie S. , Black Taylor A. , Tien Kyle , Lin Andrew , Shen Hanfei , Bhagwat Neha , Herman Daniel , Adallah Andrew , O'Hara Mark H. , Vollmer Charles M. , Katona Bryson W. , Stanger Ben Z. , Issadore David , Carpenter Erica L.
Published: April 2020

Purpose:

To determine whether a multianalyte liquid biopsy can improve the detection and staging of pancreatic ductal adenocarcinoma (PDAC).

Experimental Design:

We analyzed plasma from 204 subjects (71 healthy, 44 non-PDAC pancreatic disease, and 89 PDAC) for the following biomarkers: tumor-associated extracellular vesicle miRNA and mRNA isolated on a nanomagnetic platform that we developed and measured by next-generation sequencing or qPCR, circulating cell-free DNA (ccfDNA) concentration measured by qPCR, ccfDNA KRAS G12D/V/R mutations detected by droplet digital PCR, and CA19-9 measured by electrochemiluminescence immunoassay. We applied machine learning to training sets and subsequently evaluated model performance in independent, user-blinded test sets.

Results:

To identify patients with PDAC versus those without, we generated a classification model using a training set of 47 subjects (20 PDAC and 27 noncancer). When applied to a blinded test set (N = 136), the model achieved an AUC of 0.95 and accuracy of 92%, superior to the best individual biomarker, CA19-9 (89%). We next used a cohort of 20 patients with PDAC to train our model for disease staging and applied it to a blinded test set of 25 patients clinically staged by imaging as metastasis-free, including 9 subsequently determined to have had occult metastasis. Our workflow achieved significantly higher accuracy for disease staging (84%) than imaging alone (accuracy = 64%; P < 0.05).

Conclusions:

Algorithmically combining blood-based biomarkers may improve PDAC diagnostic accuracy and preoperative identification of nonmetastatic patients best suited for surgery, although larger validation studies are necessary.
Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity
Authors: Bruun Jarle , Kryeziu Kushtrim , Eide Peter W. , Moosavi Seyed H. , Eilertsen Ina A. , Langerud Jonas , Røsok Bård , Totland Max Z. , Brunsell Tuva H. , Pellinen Teijo , Saarela Jani , Bergsland Christian H. , Palmer Hector G. , Brudvik Kristoffer W. , Guren Tormod , Dienstmann Rodrigo , Guren Marianne G. , Nesbakken Arild , Bjørnbeth Bjørn Atle , Sveen Anita , Lothe Ragnhild A.
Published: April 2020

Purpose:

Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer.

Experimental Design:

We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients.

Results:

Three drug–response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2–5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression.

Conclusions:

Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression–based predictive signatures to guide experimental therapies.
A20 and RBX1 Regulate Brentuximab Vedotin Sensitivity in Hodgkin Lymphoma Models
Authors: Wei Wei , Lin Yuquan , Song Zhihui , Xiao Wenming , Chen Liqi , Yin Jiejing , Zhou Yan , Barta Stefan K. , Petrus Michael , Waldmann Thomas A. , Yang Yibin
Published: April 2020

Purpose:

For patients with refractory/relapsed Hodgkin lymphoma (roughly 20% of total cases), few effective therapeutic options exist. Currently, brentuximab vedotin (BV), a drug-conjugated anti-CD30 antibody, is one of the most effective approved therapy agents for these patients. However, many patients do not achieve complete remission and ultimately develop BV-resistant disease, necessitating a more detailed understanding of the molecular circuitry that drives BV sensitivity and the mechanism of BV resistance.

Experimental Design:

Here, we established a ubiquitin regulator–focused CRISPR library screening platform in Hodgkin lymphoma and carried out a drug sensitization screen against BV to identify genes regulating BV treatment sensitivity.

Results:

Our CRISPR library screens revealed the ubiquitin-editing enzymes A20 and RBX1 as key molecule effectors that regulate BV sensitivity in Hodgkin lymphoma line L428. A20 negatively regulates NF-κB activity which is required to prevent BV cytotoxicity. In line with these results, the RNA-seq analysis of the BV-resistant single-cell clones demonstrated a consistent upregulation of NF-κB signature genes, as well as the ABC transporter gene ABCB1. Mechanically, NF-κB regulates BV treatment sensitivity through mediating ABCB1 expression. Targeting NF-κB activity synergized well with BV in killing Hodgkin lymphoma cell lines, augmented BV sensitivity, and overcame BV resistance in vitro and in Hodgkin lymphoma xenograft mouse models.

Conclusions:

Our identification of this previously unrecognized mechanism provides novel knowledge of possible BV responsiveness and resistance mechanisms in Hodgkin lymphoma, as well as leads to promising hypotheses for the development of therapeutic strategies to overcome BV resistance in this disease.
Renal Outcomes in Brazilian Patients with Immunoglobulin A Nephropathy and Cellular Crescentic Lesions
Authors: Neves Precil Diego Miranda de Menezes , Pinheiro Rafaela Bezerra Brito , Dias Cristiane Bitencourt , Yu Luis , Testagrossa Leonardo de Abreu , Cavalcante Lívia Barreira , Malheiros Denise Maria Avancini Costa , Jorge Lectícia Barbosa , Woronik Viktoria
Published: April 2020

Background and Aim: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulopathy. The Oxford classification was recently updated to include crescents as markers of poor prognosis. The aim of this study was to evaluate the impact of cellular crescents on the prognosis of patients with IgAN in Brazil. Methods: This was a single-centre retrospective analysis of medical records and renal biopsies in patients with IgAN. The renal biopsy findings were classified according to the revised Oxford classification: mesangial hypercellularity, endocapillary hypercellularity (E), segmental glomerulosclerosis (S), tubular atrophy or interstitial fibrosis (T), and crescent formation (C). We evaluated a composite outcome (progression to end-stage renal disease or creatinine doubling). We performed analyses between the patients with crescents in the renal biopsy specimen (C1/C2 group) and those without such crescents (C0 group). Results: We evaluated 111 patients, of whom 72 (65.0%) were women, 80 (72.0%) self-identified as White, 73 (65.6%) were hypertensive, and 95 (85.6%) had haematuria. The distribution of patients according to cellular crescentic lesions was: C0, 80 (72%); C1, 27 (24.4%); C2, 4 (3.6%). The composite outcome was observed in 33 (29.72%) of the 111 patients. In comparison with the C0 group, the C1/C2 group had higher proportions of patients with hypertension (p = 0.04), haematuria (p = 0.03), worse serum creatinine (p = 0.0007), and worse estimated glomerular filtration rate (p = 0.0007). The C1/C2 group also had higher proportions of patients in whom the biopsy specimen was classified as E1 (p = 0.009), S1 (p = 0.001), or T1/T2 (p = 0.03), In addition, the mean follow-up period was shorter in the C1/C2 group (p < 0.0001). Furthermore, the composite outcome was observed in a greater proportion of patients and in a shorter length of time in the C1/C2 group than in the C0 group (p = 0.002 and p = 0.0014, respectively). In a Cox regression analysis, the independent risk factors for the composite outcome had Oxford classifications of S1, T1/T2, and C1/C2. Conclusion: Oxford classification findings of S1, T1/T2, or C1/C2 were independent risk factors for the composite outcome, corroborating previous studies.
Novel Indices of Coronary Physiology
Authors: De Maria Giovanni Luigi , Garcia-Garcia Hector M. , Scarsini Roberto , Hideo-Kajita Alexandre , Gonzalo López Nieves , Leone Antonio Maria , Sarno Giovanna , Daemen Joost , Shlofmitz Evan , Jeremias Allen , Tebaldi Matteo , Bezerra Hiram Grando , Tu Shengxian , Lemos Pedro A. , Ozaki Yuichi , Dan Kazuhiro , Collet Carlos , Banning Adrian P. , Barbato Emanuele , Johnson Nils P. , Waksman Ron
Published: April 2020

Fractional flow reserve is the current invasive gold standard for assessing the ischemic potential of an angiographically intermediate coronary stenosis. Procedural cost and time, the need for coronary vessel instrumentation, and the need to administer adenosine to achieve maximal hyperemia remain integral components of invasive fractional flow reserve. The number of new alternatives to fractional flow reserve has proliferated over the last ten years using techniques ranging from alternative pressure wire metrics to anatomic simulation via angiography or intravascular imaging. This review article provides a critical description of the currently available or under-development alternatives to fractional flow reserve with a special focus on the available evidence, pros, and cons for each with a view towards their clinical application in the near future for the functional assessment of coronary artery disease.
Effects of Acute Colchicine Administration Prior to Percutaneous Coronary Intervention
Authors: Shah Binita , Pillinger Michael , Zhong Hua , Cronstein Bruce , Xia Yuhe , Lorin Jeffrey D. , Smilowitz Nathaniel R. , Feit Frederick , Ratnapala Nicole , Keller Norma M. , Katz Stuart D.
Published: April 2020

Background:

Vascular injury and inflammation during percutaneous coronary intervention (PCI) are associated with increased risk of post-PCI adverse outcomes. Colchicine decreases neutrophil recruitment to sites of vascular injury. The anti-inflammatory effects of acute colchicine administration before PCI on subsequent myocardial injury are unknown.

Methods:

In a prospective, single-site trial, subjects referred for possible PCI (n=714) were randomized to acute preprocedural oral administration of colchicine 1.8 mg or placebo.

Results:

Among the 400 subjects who underwent PCI, the primary outcome of PCI-related myocardial injury did not differ between colchicine (n=206) and placebo (n=194) groups (57.3% versus 64.2%,
P
=0.19). The composite outcome of death, nonfatal myocardial infarction, and target vessel revascularization at 30 days (11.7% versus 12.9%,
P
=0.82), and the outcome of PCI-related myocardial infarction defined by the Society for Cardiovascular Angiography and Interventions (2.9% versus 4.7%,
P
=0.49) did not differ between colchicine and placebo groups. Among 280 PCI subjects in a nested inflammatory biomarker substudy, the primary biomarker end point, change in interleukin-6 concentrations did not differ between groups 1-hour post-PCI but increased less 24 hours post-PCI in the colchicine (n=141) versus placebo group (n=139; 76% [−6 to 898] versus 338% [27 to 1264],
P
=0.02). High-sensitivity C-reactive protein concentration also increased less after 24 hours in the colchicine versus placebo groups (11% [−14 to 80] versus 66% [1 to 172],
P
=0.001).

Conclusions:

Acute preprocedural administration of colchicine attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo but did not lower the risk of PCI-related myocardial injury.

Registration:

URL:
https://www.clinicaltrials.gov
; Unique Identifiers: NCT02594111, NCT01709981.
Description and Proposed Management of the Acute COVID-19 Cardiovascular Syndrome
Authors: Hendren Nicholas S. , Drazner Mark H. , Bozkurt Biykem , Cooper Leslie T.
Published: April 2020

Coronavirus disease 2019 (COVID-19) is a rapidly expanding global pandemic caused by severe acute respiratory syndrome coronavirus 2, resulting in significant morbidity and mortality. A substantial minority of patients hospitalized develop an acute COVID-19 cardiovascular syndrome, which can manifest with a variety of clinical presentations but often presents as an acute cardiac injury with cardiomyopathy, ventricular arrhythmias, and hemodynamic instability in the absence of obstructive coronary artery disease. The cause of this injury is uncertain but is suspected to be related to myocarditis, microvascular injury, systemic cytokine-mediated injury, or stress-related cardiomyopathy. Although histologically unproven, severe acute respiratory syndrome coronavirus 2 has the potential to directly replicate within cardiomyocytes and pericytes, leading to viral myocarditis. Systemically elevated cytokines are also known to be cardiotoxic and have the potential to result in profound myocardial injury. Prior experience with severe acute respiratory syndrome coronavirus 1 has helped expedite the evaluation of several promising therapies, including antiviral agents, interleukin-6 inhibitors, and convalescent serum. Management of acute COVID-19 cardiovascular syndrome should involve a multidisciplinary team including intensive care specialists, infectious disease specialists, and cardiologists. Priorities for managing acute COVID-19 cardiovascular syndrome include balancing the goals of minimizing healthcare staff exposure for testing that will not change clinical management with early recognition of the syndrome at a time point at which intervention may be most effective. This article aims to review the best available data on acute COVID-19 cardiovascular syndrome epidemiology, pathogenesis, diagnosis, and treatment. From these data, we propose a surveillance, diagnostic, and management strategy that balances potential patient risks and healthcare staff exposure with improvement in meaningful clinical outcomes.
Misdiagnosis of Cervicocephalic Artery Dissection in the Emergency Department
Authors: Liberman Ava L. , Navi Babak B. , Esenwa Charles C. , Zhang Cenai , Song Justin , Cheng Natalie T. , Labovitz Daniel L. , Kamel Hooman , Merkler Alexander E.
Published: April 2020

Background and Purpose—

Cervicocephalic artery dissection is an important cause of stroke. The clinical presentation of dissection can resemble that of benign neurological conditions leading to delayed or missed diagnosis.

Methods—

We performed a retrospective cohort study using statewide administrative claims data from all Emergency Department visits and admissions at nonfederal hospitals in Florida from 2005 to 2015 and New York from 2006 to 2015. Using validated
International Classification of Diseases, Ninth Revision, CM codes
, we identified adult patients hospitalized for cervicocephalic artery dissection. We defined probable misdiagnosis of dissection as having an Emergency Department treat-and-release visit for symptoms or signs of dissection, including headache, neck pain, and focal neurological deficits in the 14 days before dissection diagnosis. Multivariable logistic regression was used to compare adverse clinical outcomes in patients with and without probable misdiagnosis.

Results—

Among 7090 patients diagnosed with a dissection (mean age 52.7 years, 44.9% women), 218 (3.1% [95% CI, 2.7%–3.5%]) had a preceding probable Emergency Department misdiagnosis. After adjustment for demographics and vascular risk factors, there were no differences in rates of stroke (odds ratio, 0.82 [95% CI, 0.62–1.09]) or in-hospital death (odds ratio, 0.26 [95% CI, 0.07–1.08]) between dissection patients with and without a probable misdiagnosis at index hospitalization.

Conclusions—

We found that ≈1 in 30 dissection patients was probably misdiagnosed in the 2 weeks before their diagnosis.
Optical Changes and Writing on Hydrotalcite Supported Gold Nanoparticles
Authors: Bonifacio Leonardo S. , Gordijo Claudia R. , Constantino Vera R. L. , Silva Denise O. , Kiyohara Pedro K. , Araki Koiti , Toma Henrique E.
Published: April 2020

Gold nanoparticles (AuNP) incorporated into hydrotalcite (HT), provide an interesting type of pigment in which temperature can modulate the plasmon resonance and the aggregation phenomenon. As inferred from microscopy techniques, the preferential binding sites are located at the border
of the HT external basal surface, leading to aggregates of gold nanoparticles displaying characteristic plasmon resonance and interference bands around 520 and 700 nm, respectively. The thermally induced color changes in the HT-supported gold material arise from the competition between of
nanoparticles aggregation and fusion processes, as characterized by TEM and STM. A laser beam can also induce such changes, allowing the writing of optical information on this type of material.
119Sn Magic Angle Spinning NMR of Nanocrystalline SnO2
Authors: Sabarinathan V. , Vinod Chandran C. , Ramasamy S. , Ganapathy S.
Published: April 2020

Nanocrystalline SnO2 samples of different grain sizes, prepared by inert gas condensation technique (IGCT) and chemical precipitation method and conforming to the tetragonal phase, have been studied by variable speed (3–10 kHz) 119Sn MAS NMR at 11.74 Tesla
field. 119Sn solid-state NMR results show that the IGCT prepared samples have good crystallinity and phase purity compared to the samples prepared by the chemical method. The determination of 119Sn chemical shielding parameters (δiso, Δδ
and η) from slow MAS spectra shows that the 119Sn isotropic chemical shift (δiso) is strongly influenced at smaller grain sizes, attributable to the change in the O2− local symmetry for the surface 119Sn ions at smaller
grain sizes. The observed line widths in MAS spectra are significantly larger than the life-time broadening due to spin–lattice (T1) and spin–spin (T2) relaxation. The 119Sn MAS NMR spectra are thus inhomogeneously broadened by a distribution
of isotropic chemical shifts, the line broadening increasing with decrease in grain size.
Enhancement of Electroluminescent Properties in Ethanol Dispersible Nanocrystalline Silicon Particles
Authors: Sato Keisuke , Kishimoto Naoki , Hirakuri Kenji
Published: April 2020

We have fabricated two kinds of electroluminescent (EL) devices of which the luminous layer differs in order to improve an amount of injected carriers into the nanocrystalline silicon (nc-Si) particles. These EL devices showed red luminescence by the injection of carriers into the nc-Si
particles after applying the direct current voltage. A large amount of carriers could be injected in the EL device prepared by the adhesion of ethanol dispersible nc-Si particles onto the dimples of Si substrate. The increase in the amount of injected carriers led to the enhancement of luminescent
intensity. These results were achieved by the reduction of oxide layer surrounding nc-Si particles and the use of nc-Si particles without the nonradiative recombination centers (Pb centers).
Growth of Nano-Needles of Manganese(IV) Oxide by Atomic Layer Deposition
Authors: Nilsen Ola , Foss Steinar , Kjekshus Arne , Fjellvåg Helmer
Published: April 2020

Needles of manganese(IV) oxide in the nanometer range have been synthesised using the atomic layer deposition technique. Traditionally the atomic layer deposition technique is used for the fabrication of thin films, however, we find that needles of β-MnO2 are
formed when manganese(IV) oxide is deposited as relatively thick (ca. 800 nm) thin films on substrates of α-Al2O3 [(001) and (012) oriented]. There is no formation of needles when the film is deposited on substrates such as Si(100) or soda lime glass. The
film is formed using Mn(thd)3 (Hthd = 2,2,6,6-tetramethylheptane-3,5-dione) and ozone as precursors. While thin films (ca. 100 nm) consist of ε′-MnO2,22, 23 the same process applied to thicker films results in the formation of nano-needles
of β-MnO2. These needles of β-MnO2 have dimensions ranging from approximately 1.5 μm at the base down to very sharp tips. The nano-needles and the bulk of the films have been analysed by atomic force microscopy, scanning electron microscopy,
X-ray diffraction, and transmission electron microscopy.
Inorganic Lanthanide Nanophosphors in Biotechnology
Authors: Dosev Dosi , Nichkova Mikaela , Kennedy Ian M.
Published: April 2020

Recently different types of fluorescent nanoparticles and other nanostructures have been promoted as alternatives for the fluorescent organic dyes that are traditionally used in biotechnology. Quantum dots, dye-doped polymer and silica particles have found many applications in biochemical
protocols and are extensively discussed in the literature. Nanostructures based on inorganic phosphors (nanophosphors) are a new emerging class of materials with unique properties that make them very attractive for bio-application. Some results for the successful application of nanophosphors
in biochemical applications have been reported. In this review we summarize the types of materials, their properties that are relevant to bio-applications, and the current status of their implementation in biotechnology.
Non-Linear Optical Properties of Zinc Oxide Nanowires
Authors: Tang C. F. , Deng H. , Tang B. , Cheng H. , Wang J. C. , Chen J. J.
Published: April 2020

High quality zinc oxide (ZnO) nanowires were grown on n-type Si (100) using vapor-liquid-solid process. We obtained the photoluminescence spectra of ZnO nanowires based on nonlinear optical process using an ultrashort wavelength femtosecond laser as a pumping source. The spectra shows
the second harmonic generation phenomenon, as well as the exciton–exciton collision peak at 388 nm and the green emission peak at 515 nm caused by oxygen vacancy. A laser emission peak near 392 nm was observed when pump intensity surpassed 52 mJ/cm2 and a sharp peak about
0.5 nm wide emerged when the energy intensity reached 700 mJ/cm2. We attribute this excitation process to a two-photon absorption process enhanced by Rabi oscillation.