bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effect of Atmosphere-Ocean Coupling on the Structure and Intensity of Tropical Cyclone Bejisa in the Southwest Indian Ocean
Authors: Bielli Soline , Barthe Christelle , Bousquet Olivier , Tulet Pierre , Pianezze Joris
Published: May 2021

A set of numerical simulations is relied upon to evaluate the impact of air-sea interactions on the behaviour of tropical cyclone (TC) Bejisa (2014), using various configurations of the coupled ocean-atmosphere numerical system Meso-NH-NEMO. Uncoupled (SST constant) as well as 1D (use of a 1D ocean mixed layer) and 3D (full 3D ocean) coupled experiments are conducted to evaluate the impact of the oceanic response and dynamic processes, with emphasis on the simulated structure and intensity of TC Bejisa. Although the three experiments are shown to properly capture the track of the tropical cyclone, the intensity and the spatial distribution of the sea surface cooling show strong differences from one coupled experiment to another. In the 1D experiment, sea surface cooling (∼1 °C) is reduced by a factor 2 with respect to observations and appears restricted to the depth of the ocean mixed layer. Cooling is maximized along the right-hand side of the TC track, in apparent disagreement with satellite-derived sea surface temperature observations. In the 3D experiment, surface cooling of up to 2.5 °C is simulated along the left hand side of the TC track, which shows more consistency with observations both in terms of intensity and spatial structure. In-depth cooling is also shown to extend to a much deeper depth, with a secondary maximum of nearly 1.5 °C simulated near 250 m. With respect to the uncoupled experiment, heat fluxes are reduced from about 20% in both 1D and 3D coupling configurations. The tropical cyclone intensity in terms of occurrence of 10-m TC wind is globally reduced in both cases by about 10%. 3D-coupling tends to asymmetrize winds aloft with little impact on intensity but rather a modification of the secondary circulation, resulting in a slight change in structure.
Impact of Tropical Cyclones on Inhabited Areas of the SWIO Basin at Present and Future Horizons. Part 2: Modeling Component of the Research Program RENOVRISK-CYCLONE
Authors: Barthe Christelle , Bousquet Olivier , Bielli Soline , Tulet Pierre , Pianezze Joris , Claeys Marine , Tsai Chia-Lun , Thompson Callum , Bonnardot François , Chauvin Fabrice , Cattiaux Julien , Bouin Marie-Noëlle , Amelie Vincent , Barruol Guilhem , Calmer Radiance , Ciccione Stéphane , Cordier Emmanuel , Duong Quoc-Phi , Durand Jonathan , Fleischer-Dogley Frauke , Husson Romain , Lees Edouard , Malardel Sylvie , Marquestaut Nicolas , Mavume Alberto , Mékiès Dominique , Mouche Alexis , Ravoson Navalona Manitriniana , Razafindradina Bruno , Rindraharisaona Elisa , Roberts Gregory , Singh Manvendra , Zakariasy Lova , Zucule Jonas
Published: May 2021

The ReNovRisk-Cyclone program aimed at developing an observation network in the south-west Indian ocean (SWIO) in close synergy with the implementation of numerical tools to model and analyze the impacts of tropical cyclones (TC) in the present and in a context of climate change. This paper addresses the modeling part of the program. First, a unique coupled system to simulate TCs in the SWIO is developed. The ocean–wave–atmosphere coupling is considered along with a coherent coupling between sea surface state, wind field, aerosol, microphysics, and radiation. This coupled system is illustrated through several simulations of TCs: the impact of air–sea flux parameterizations on the evolution of TC Fantala is examined, the full coupling developed during the program is illustrated on TC Idai, and the potential of novel observations like space-borne synthetic aperture radar and sea turtles to validate the atmosphere and ocean models is presented with TC Herold. Secondly, the evolution of cyclonic activity in the SWIO during the second half of the 21st century is assessed. It was addressed both using climate simulation and through the implementation of a pseudo global warming method in the high-resolution coupled modeling platform. Our results suggest that the Mascarene Archipelago should experience an increase of TC related hazards in the medium term.
Effect of Auditory Distraction on Working Memory, Attention Switching, and Listening Comprehension
Authors: Nagaraj Naveen K.
Published: May 2021

The effect of non-informational speech spectrum noise as a distractor on cognitive and listening comprehension ability was examined in fifty-three young, normal hearing adults. Time-controlled tasks were used to measure auditory working memory (WM) capacity and attention switching (AS) ability. Listening comprehension was measured using a lecture, interview, and spoken narratives test. Noise level was individually set to achieve at least 90% or higher speech intelligibility. Participants’ listening comprehension in the presence of distracting noise was better on inference questions compared to listening in quiet. Their speed of information processing was also significantly faster in WM and AS tasks in noise. These results were consistent with the view that noise may enhance arousal levels leading to faster information processing during cognitive tasks. Whereas the speed of AS was faster in noise, this rapid switching of attention resulted in more errors in updating items. Participants who processed information faster in noise and did so accurately, more effectively switched their attention to refresh/rehearse recall items within WM. More efficient processing deployed in the presence of noise appeared to have led to improvements in WM performance and making inferences in a listening comprehension task. Additional research is required to examine these findings using background noise that can cause informational masking.
When a Ciliate Meets a Flagellate: A Rare Case of Colpoda spp. and Colpodella spp. Isolated from the Urine of a Human Patient. Case Report and Brief Review of Literature
Authors: Neculicioiu Vlad S. , Colosi Ioana A. , Toc Dan A. , Lesan Andrei , Costache Carmen
Published: May 2021

An often-overlooked side of the population aging process and the steady rise of non-communicable diseases reflects the emergence of novel infectious pathogens on the background of an altered host immune response. The aim of this article was to present the first record of a ciliate and flagellate protozoa recovered from the urine of an elderly patient and to review the existing medical literature involving these parasites. A 70-year-old female patient was admitted for breathing difficulties on the basis of an acute exacerbation of COPD (Chronic obstructive pulmonary disease) with respiratory insufficiency. The patient reported a long history of multiple comorbidities including COPD Gold II, chronic respiratory insufficiency, chronic heart failure NYHA III (New York Heart Association Functional Classification), type 2 diabetes and morbid obesity. During routine examinations, we ascertained the presence of two unusual protozoa, a ciliate and a flagellate, in the patient’s urine samples, identified on morphological criteria to be most likely Colpoda spp. and Colpodella spp., with similarities to C. steinii and C. gonderi. The presence of these parasites was not associated with any clinical signs of urinary disease. Following a combined treatment with ceftriaxone and metronidazole, we observed the disappearance of these pathogens upon discharge from the primary care clinic. This study highlights the importance of including unusual pathogens in the differential diagnosis of cases which involve immunosuppression.
Rhizospheric Communication through Mobile Genetic Element Transfers for the Regulation of Microbe–Plant Interactions
Authors: Ku Yee-Shan , Wang Zhili , Duan Shaowei , Lam Hon-Ming
Published: May 2021

The transfer of mobile genetic elements (MGEs) has been known as a strategy adopted by organisms for survival and adaptation to the environment. The rhizosphere, where microbes and plants coexist, is a hotspot of MGE transfers. In this review, we discuss the classic mechanisms as well as novel mechanisms of MGE transfers in the rhizosphere. Both intra-kingdom and cross-kingdom MGE transfers will be addressed. MGE transfers could be ancient events which drove evolution or recurrent events which regulate adaptations. Recent findings on MGE transfers between plant and its interacting microbes suggest gene regulations brought forth by such transfers for symbiosis or defense mechanisms. In the natural environment, factors such as temperature and soil composition constantly influence the interactions among different parties in the rhizosphere. In this review, we will also address the effects of various environmental factors on MGE transfers in the rhizosphere. Besides environmental factors, plant root exudates also play a role in the regulation of MGE transfer among microbes in the rhizosphere. The potential use of microbes and plants for bioremediation will be discussed.
Disulfide and Fully Reduced HMGB1 Induce Different Macrophage Polarization and Migration Patterns
Authors: Salo Henna , Qu Heshuang , Mitsiou Dimitra , Aucott Hannah , Han Jinming , Zhang Xingmei , Aulin Cecilia , Erlandsson Harris Helena
Published: May 2021

Macrophage plasticity enables cells to obtain different functions over a broad proinflammatory and repairing spectrum. In different conditions, macrophages can be induced by high-mobility group box 1 (HMGB1), a nuclear DNA-binding protein that activates innate immunity, to polarize towards a pro- (M1) or anti-inflammatory (M2) phenotype. In this study, we investigated the phenotypes of murine bone-marrow-derived macrophages (BMDMs) induced by different HMGB1 redox isoforms in depth. Our results demonstrate that disulfide HMGB1 (dsHMGB1) induces a unique macrophage phenotype that secretes pro-inflammatory cytokines, rather than inducing metabolic changes leading to nitric oxide production. Fully reduced HMGB1 (frHMGB1) did not induce macrophage polarization. The migrating function of BMDMs was measured by scratch assay after the stimulation with dsHMGB1 and frHMGB1. Both dsHMGB1 and frHMGB1 induced cell migration. We found that dsHMGB1 mediates cytokine secretion and cellular motility, mainly through toll-like receptor 4 (TLR4). Importantly, our data shows that dsHMGB1 and frHMGB1 induce distinct BMDM polarization phenotypes, and that dsHMGB1 induces a unique phenotype differing from the classical proinflammatory macrophage phenotype.
Consumption of Enriched Yogurt with PAF Inhibitors from Olive Pomace Affects the Major Enzymes of PAF Metabolism: A Randomized, Double Blind, Three Arm Trial
Authors: Detopoulou Maria , Ntzouvani Agathi , Petsini Filio , Gavriil Labrini , Fragopoulou Elizabeth , Antonopoulou Smaragdi
Published: May 2021

Platelet-activating factor (PAF), a proinflammatory lipid mediator, plays a crucial role in the formation of the atherosclerotic plaque. Therefore, the inhibition of endothelium inflammation by nutraceuticals, such as PAF inhibitors, is a promising alternative for preventing cardiovascular diseases. The aim of the present study was to evaluate the impact of a new functional yogurt enriched with PAF inhibitors of natural origin from olive oil by-products on PAF metabolism. Ninety-two apparently healthy, but mainly overweight volunteers (35–65 years) were randomly allocated into three groups by block-randomization. The activities of PAF’s biosynthetic and catabolic enzymes were measured, specifically two isoforms of acetyl-CoA:lyso-PAF acetyltransferase (LPCATs), cytidine 5′-diphospho-choline:1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase (PAF-CPT) and two isoforms of platelet activating factor acetylhydrolase in leucocytes (PAF-AH) and plasma (lipoprotein associated phospholipase-A2, LpPLA2). The intake of the enriched yogurt resulted in reduced PAF-CPT and LpPLA2 activities. No difference was observed in the activities of the two isoforms of lyso PAF-AT. In conclusion, intake of yogurt enriched in PAF inhibitors could favorably modulate PAF biosynthetic and catabolic pathways.
Binding of SARS-CoV Covalent Non-Covalent Inhibitors to the SARS-CoV-2 Papain-Like Protease and Ovarian Tumor Domain Deubiquitinases
Authors: Sivakumar Dakshinamurthy , Stein Matthias
Published: May 2021

The urgent need for novel and effective drugs against the SARS-CoV-2 coronavirus pandemic has stimulated research worldwide. The Papain-like protease (PLpro), which is essential for viral replication, shares a similar active site structural architecture to other cysteine proteases. Here, we have used representatives of the Ovarian Tumor Domain deubiquitinase family OTUB1 and OTUB2 along with the PLpro of SARS-CoV-2 to validate and rationalize the binding of inhibitors from previous SARS-CoV candidate compounds. By forming a new chemical bond with the cysteine residue of the catalytic triad, covalent inhibitors irreversibly suppress the protein’s activity. Modeling covalent inhibitor binding requires detailed knowledge about the compounds’ reactivities and binding. Molecular Dynamics refinement simulations of top poses reveal detailed ligand-protein interactions and show their stability over time. The recently discovered selective OTUB2 covalent inhibitors were used to establish and validate the computational protocol. Structural parameters and ligand dynamics are in excellent agreement with the ligand-bound OTUB2 crystal structures. For SARS-CoV-2 PLpro, recent covalent peptidomimetic inhibitors were simulated and reveal that the ligand-protein interaction is very dynamic. The covalent and non-covalent docking plus subsequent MD refinement of known SARS-CoV inhibitors into DUBs and the SARS-CoV-2 PLpro point out a possible approach to target the PLpro cysteine protease from SARS-CoV-2. The results show that such an approach gives insight into ligand-protein interactions, their dynamic character, and indicates a path for selective ligand design.
The Role of the Key Effector of Necroptotic Cell Death, MLKL, in Mouse Models of Disease
Authors: Tovey Crutchfield Emma C. , Garnish Sarah E. , Hildebrand Joanne M.
Published: May 2021

Necroptosis is an inflammatory form of lytic programmed cell death that is thought to have evolved to defend against pathogens. Genetic deletion of the terminal effector protein—MLKL—shows no overt phenotype in the C57BL/6 mouse strain under conventional laboratory housing conditions. Small molecules that inhibit necroptosis by targeting the kinase activity of RIPK1, one of the main upstream conduits to MLKL activation, have shown promise in several murine models of non-infectious disease and in phase II human clinical trials. This has triggered in excess of one billion dollars (USD) in investment into the emerging class of necroptosis blocking drugs, and the potential utility of targeting the terminal effector is being closely scrutinised. Here we review murine models of disease, both genetic deletion and mutation, that investigate the role of MLKL. We summarize a series of examples from several broad disease categories including ischemia reperfusion injury, sterile inflammation, pathogen infection and hematological stress. Elucidating MLKL’s contribution to mouse models of disease is an important first step to identify human indications that stand to benefit most from MLKL-targeted drug therapies.
Planet of the AAVs: The Spinal Cord Injury Episode
Authors: Stepankova Katerina , Jendelova Pavla , Machova Urdzikova Lucia
Published: May 2021

The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising approach for the treatment of neurological and neurodegenerative disorders by delivering remedial genes to the central nervous system (CNS), of which the spinal cord is a part. For gene therapy, multiple vectors have been introduced, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors. AAV vectors are a promising system for transgene delivery into the CNS due to their safety profile as well as long-term gene expression. Gene therapy mediated by AAV vectors shows potential for treating SCI by delivering certain genetic information to specific cell types. This review has focused on a potential treatment of SCI by gene therapy using AAV vectors.
Light-Addressable Actuator-Sensor Platform for Monitoring and Manipulation of pH Gradients in Microfluidics: A Case Study with the Enzyme Penicillinase
Authors: Welden Rene , Jablonski Melanie , Wege Christina , Keusgen Michael , Wagner Patrick Hermann , Wagner Torsten , Schöning Michael J.
Published: May 2021

The feasibility of light-addressed detection and manipulation of pH gradients inside an electrochemical microfluidic cell was studied. Local pH changes, induced by a light-addressable electrode (LAE), were detected using a light-addressable potentiometric sensor (LAPS) with different measurement modes representing an actuator-sensor system. Biosensor functionality was examined depending on locally induced pH gradients with the help of the model enzyme penicillinase, which had been immobilized in the microfluidic channel. The surface morphology of the LAE and enzyme-functionalized LAPS was studied by scanning electron microscopy. Furthermore, the penicillin sensitivity of the LAPS inside the microfluidic channel was determined with regard to the analyte’s pH influence on the enzymatic reaction rate. In a final experiment, the LAE-controlled pH inhibition of the enzyme activity was monitored by the LAPS.
Electrochemical Sensors for Determination of Bromate in Water and Food Samples—Review
Authors: Balogun Sheriff A. , Fayemi Omolola E.
Published: May 2021

The application of potassium bromate in the baking industry is used in most parts of the world to avert the human health compromise that characterizes bromates carcinogenic effect. Herein, various methods of its analysis, especially the electrochemical methods of bromate detection, were extensively discussed. Amperometry (AP), cyclic voltammetry (CV), square wave voltammetry (SWV), electrochemiluminescence (ECL), differential pulse voltammetry and electrochemical impedance spectroscopy (EIS) are the techniques that have been deployed for bromate detection in the last two decades, with 50%, 23%, 7.7%, 7.7%, 7.7% and 3.9% application, respectively. Despite the unique electrocatalytic activity of metal phthalocyanine (MP) and carbon quantum dots (CQDs), only few sensors based on MP and CQDs are available compared to the conducting polymers, carbon nanotubes (CNTs), metal (oxide) and graphene-based sensors. This review emboldens the underutilization of CQDs and metal phthalocyanines as sensing materials and briefly discusses the future perspective on MP and CQDs application in bromate detection via EIS.
Semi-Supervised Learning in Medical MRI Segmentation: Brain Tissue with White Matter Hyperintensity Segmentation Using FLAIR MRI
Authors: Rieu ZunHyan , Kim JeeYoung , Kim Regina EY , Lee Minho , Lee Min Kyoung , Oh Se Won , Wang Sheng-Min , Kim Nak-Young , Kang Dong Woo , Lim Hyun Kook , Kim Donghyeon
Published: May 2021

White-matter hyperintensity (WMH) is a primary biomarker for small-vessel cerebrovascular disease, Alzheimer’s disease (AD), and others. The association of WMH with brain structural changes has also recently been reported. Although fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) provide valuable information about WMH, FLAIR does not provide other normal tissue information. The multi-modal analysis of FLAIR and T1-weighted (T1w) MRI is thus desirable for WMH-related brain aging studies. In clinical settings, however, FLAIR is often the only available modality. In this study, we thus propose a semi-supervised learning method for full brain segmentation using FLAIR. The results of our proposed method were compared with the reference labels, which were obtained by FreeSurfer segmentation on T1w MRI. The relative volume difference between the two sets of results shows that our proposed method has high reliability. We further evaluated our proposed WMH segmentation by comparing the Dice similarity coefficients of the reference and the results of our proposed method. We believe our semi-supervised learning method has a great potential for use for other MRI sequences and will encourage others to perform brain tissue segmentation using MRI modalities other than T1w.
Selecting the Most Relevant Brain Regions to Classify Children with Developmental Dyslexia and Typical Readers by Using Complex Magnocellular Stimuli and Multiple Kernel Learning
Authors: Mascheretti Sara , Peruzzo Denis , Andreola Chiara , Villa Martina , Ciceri Tommaso , Trezzi Vittoria , Marino Cecilia , Arrigoni Filippo
Published: May 2021

Increasing evidence supports the presence of deficits in the visual magnocellular (M) system in developmental dyslexia (DD). The M system is related to the fronto-parietal attentional network. Previous neuroimaging studies have revealed reduced/absent activation within the visual M pathway in DD, but they have failed to characterize the extensive brain network activated by M stimuli. We performed a multivariate pattern analysis on a Region of Interest (ROI) level to differentiate between children with DD and age-matched typical readers (TRs) by combining full-field sinusoidal gratings, controlled for spatial and temporal frequencies and luminance contrast, and a coherent motion (CM) sensitivity task at 6%-CML6, 15%-CML15 and 40%-CML40. ROIs spanning the entire visual dorsal stream and ventral attention network (VAN) had higher discriminative weights and showed higher act1ivation in TRs than in children with DD. Of the two tasks, CM had the greatest weight when classifying TRs and children with DD in most of the ROIs spanning these streams. For the CML6, activation within the right superior parietal cortex positively correlated with reading skills. Our approach highlighted the dorsal stream and the VAN as highly discriminative areas between children with DD and TRs and allowed for a better characterization of the “dorsal stream vulnerability” underlying DD.
A Comprehensive Framework for Standardising System Boundary Definition in Life Cycle Energy Assessments
Authors: Omrany Hossein , Soebarto Veronica , Zuo Jian , Chang Ruidong
Published: May 2021

This paper aims to propose a comprehensive framework for a clear description of system boundary conditions in life cycle energy assessment (LCEA) analysis in order to promote the incorporation of embodied energy impacts into building energy-efficiency regulations (BEERs). The proposed framework was developed based on an extensive review of 66 studies representing 243 case studies in over 15 countries. The framework consists of six distinctive dimensions, i.e., temporal, physical, methodological, hypothetical, spatial, and functional. These dimensions encapsulate 15 components collectively. The proposed framework possesses two key characteristics; first, its application facilitates defining the conditions of a system boundary within a transparent context. This consequently leads to increasing reliability of obtained LCEA results for decision-making purposes since any particular conditions (e.g., truncation or assumption) considered in establishing the boundaries of a system under study can be revealed. Second, the use of a framework can also provide a meaningful basis for cross comparing cases within a global context. This characteristic can further result in identifying best practices for the design of buildings with low life cycle energy use performance. Furthermore, this paper applies the proposed framework to analyse the LCEA performance of a case study in Adelaide, Australia. Thereafter, the framework is utilised to cross compare the achieved LCEA results with a case study retrieved from literature in order to demonstrate the framework’s capacity for cross comparison. The results indicate the capability of the framework for maintaining transparency in establishing a system boundary in an LCEA analysis, as well as a standardised basis for cross comparing cases. This study also offers recommendations for policy makers in the building sector to incorporate embodied energy into BEERs.
LncRNA PART1 Promotes Proliferation and Migration, Is Associated with Cancer Stem Cells, and Alters the miRNA Landscape in Triple-Negative Breast Cancer
Authors: Cruickshank Brianne M. , Wasson Marie-Claire D. , Brown Justin M. , Fernando Wasundara , Venkatesh Jaganathan , Walker Olivia L. , Morales-Quintanilla Fiorella , Dahn Margaret L. , Vidovic Dejan , Dean Cheryl A. , VanIderstine Carter , Dellaire Graham , Marcato Paola
Published: May 2021

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.
Small Cell Lung Cancer: A New Era Is Beginning?
Authors: Morabito Alessandro , Rolfo Christian
Published: May 2021

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers and it is the most aggressive one [...]
Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma
Authors: Hasipek Metis , Grabowski Dale , Guan Yihong , Alugubelli Raghunandan Reddy , Tiwari Anand D. , Gu Xiaorong , DeAvila Gabriel A. , Silva Ariosto S. , Meads Mark B. , Parker Yvonne , Lindner Daniel J. , Saunthararajah Yogen , Shain Kenneth H. , Maciejewski Jaroslaw P. , Reu Frederic J. , Phillips James G. , Jha Babal K.
Published: May 2021

Multiple myeloma is a genetically complex hematologic neoplasia in which malignant plasma cells constantly operate at the maximum limit of their unfolded protein response (UPR) due to a high secretory burden of immunoglobulins and cytokines. The endoplasmic reticulum (ER) resident protein disulfide isomerase, PDIA1 is indispensable for maintaining structural integrity of cysteine-rich antibodies and cytokines that require accurate intramolecular disulfide bond arrangement. PDIA1 expression analysis from RNA-seq of multiple myeloma patients demonstrated an inverse relationship with survival in relapsed or refractory disease, supporting its critical role in myeloma persistence. Using a structure-guided medicinal chemistry approach, we developed a potent, orally bioavailable small molecule PDIA1 inhibitor CCF642-34. The inhibition of PDIA1 overwhelms the UPR in myeloma cells, resulting in their apoptotic cell death at doses that do not affect the normal CD34+ hematopoietic stem and progenitor cells. Bortezomib resistance leads to increased PDIA1 expression and thus CCF642-34 sensitivity, suggesting that proteasome inhibitor resistance leads to PDIA1 dependence for proteostasis and survival. CCF642-34 induces acute unresolvable UPR in myeloma cells, and oral treatment increased survival of mice in the syngeneic 5TGM1 model of myeloma. Results support development of CCF642-34 to selectively target the plasma cell program and overcome the treatment-refractory state in myeloma.
Changes in Overall Survival over Time for Patients with de novo Metastatic Breast Cancer
Authors: Iwase Toshiaki , Shrimanker Tushaar Vishal , Rodriguez-Bautista Ruben , Sahin Onur , James Anjali , Wu Jimin , Shen Yu , Ueno Naoto T.
Published: May 2021

The purpose of this study was to determine the change in overall survival (OS) for patients with de novo metastatic breast cancer (dnMBC) over time. We conducted a retrospective cohort study with 1981 patients with dnMBC diagnosed between January 1995 and December 2017 at The University of Texas MD Anderson Cancer Center. OS was measured from the date of diagnosis of dnMBC. OS was compared between patients diagnosed during different time periods: 5-year periods and periods defined according to when key agents were approved for clinical use. The median OS was 3.4 years. The 5- and 10-year OS rates improved over time across both types of time periods. A subgroup analysis showed that OS improved significantly over time for the estrogen-receptor-positive/HER2-positive (ER+/HER2+) subtype and exhibited a tendency toward improvement over time for the ER-negative (ER−)/HER2+ subtype. In addition, median OS was significantly longer in patients with non-inflammatory breast cancer (p = 0.02) and patients with ER+ disease, progesterone-receptor-positive disease, HER2+ disease, lower nuclear grade, locoregional therapy, and metastasis to a single organ (all p < 0.0001). These findings showed that OS at 5 and 10 years after diagnosis in patients with dnMBC improved over time. The significant improvements in OS over time for the ER+/HER2+ subtype and the tendency toward improvement for the ER−/HER2+ subtype suggest the contribution of HER2-targeted therapy to survival.
The Landscape of lncRNAs in Hepatocellular Carcinoma: A Translational Perspective
Authors: Unfried Juan Pablo , Sangro Paloma , Prats-Mari Laura , Sangro Bruno , Fortes Puri
Published: May 2021

LncRNAs are emerging as relevant regulators of multiple cellular processes involved in cell physiology as well as in the development and progression of human diseases, most notably, cancer. Hepatocellular carcinoma (HCC) is a prominent cause of cancer-related death worldwide due to the high prevalence of causative factors, usual cirrhotic status of the tumor-harboring livers and the suboptimal benefit of locoregional and systemic therapies. Despite huge progress in the molecular characterization of HCC, no oncogenic loop addiction has been identified and most genetic alterations remain non-druggable, underscoring the importance of advancing research in novel approaches for HCC treatment. In this context, long non-coding RNAs (lncRNAs) appear as potentially useful targets as they often exhibit high tumor- and tissue-specific expression and many studies have reported an outstanding dysregulation of lncRNAs in HCC. However, there is a limited perspective of the potential role that deregulated lncRNAs may play in HCC progression and aggressiveness or the mechanisms and therapeutic implications behind such effects. In this review, we offer a clarifying landscape of current efforts to evaluate lncRNA potential as therapeutic targets in HCC using evidence from preclinical models as well as from recent studies on novel oncogenic pathways that show lncRNA-dependency.
Urine as a Source of Liquid Biopsy for Cancer
Authors: Oshi Masanori , Murthy Vijayashree , Takahashi Hideo , Huyser Michelle , Okano Maiko , Tokumaru Yoshihisa , Rashid Omar M. , Matsuyama Ryusei , Endo Itaru , Takabe Kazuaki
Published: May 2021

Tissue biopsy is the gold standard for diagnosis and morphological and immunohistochemical analyses to characterize cancer. However, tissue biopsy usually requires an invasive procedure, and it can be challenging depending on the condition of the patient and the location of the tumor. Even liquid biopsy analysis of body fluids such as blood, saliva, gastric juice, sweat, tears and cerebrospinal fluid may require invasive procedures to obtain samples. Liquid biopsy can be applied to circulating tumor cells (CTCs) or nucleic acids (NAs) in blood. Recently, urine has gained popularity due to its less invasive sampling, ability to easily repeat samples, and ability to follow tumor evolution in real-time, making it a powerful tool for diagnosis and treatment monitoring in cancer patients. With the development and advancements in extraction methods of urinary substances, urinary NAs have been found to be closely related to carcinogenesis, metastasis, and therapeutic response, not only in urological cancers but also in non-urological cancers. This review mainly highlights the components of urine liquid biopsy and their utility and limitations in oncology, especially in non-urological cancers.
Molecular and Clinical Features of Hospital Admissions in Patients with Thoracic Malignancies on Immune Checkpoint Inhibitors
Authors: Zhao Dan , Li Haiqing , Mambetsariev Isa , Chen Chen , Pharaon Rebecca , Fricke Jeremy , Baroz Angel R. , Kulkarni Prakash , Xing Yan , Massarelli Erminia , Koczywas Marianna , Reckamp Karen L. , Margolin Kim , Salgia Ravi
Published: May 2021

Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%; odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1); p < 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%; OR (95% CI): 8.4 (1.3–49.3), p < 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months; HR (95% CI): 3.1 (0.57–17.1); p < 0.05) or FANCA (median OS of 3.0 vs. 12.4 months; HR (95% CI): 3.1 (0.70–13.8); p < 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months; HR (95% CI): 0.47 (0.28–0.79); p < 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.
Deep Learning Improves Pancreatic Cancer Diagnosis Using RNA-Based Variants
Authors: Al-Fatlawi Ali , Malekian Negin , García Sebastián , Henschel Andreas , Kim Ilwook , Dahl Andreas , Jahnke Beatrix , Bailey Peter , Bolz Sarah Naomi , Poetsch Anna R. , Mahler Sandra , Grützmann Robert , Pilarsky Christian , Schroeder Michael
Published: May 2021

For optimal pancreatic cancer treatment, early and accurate diagnosis is vital. Blood-derived biomarkers and genetic predispositions can contribute to early diagnosis, but they often have limited accuracy or applicability. Here, we seek to exploit the synergy between them by combining the biomarker CA19-9 with RNA-based variants. We use deep sequencing and deep learning to improve differentiating pancreatic cancer and chronic pancreatitis. We obtained samples of nucleated cells found in peripheral blood from 268 patients suffering from resectable, non-resectable pancreatic cancer, and chronic pancreatitis. We sequenced RNA with high coverage and obtained millions of variants. The high-quality variants served as input together with CA19-9 values to deep learning models. Our model achieved an area under the curve (AUC) of 96% in differentiating resectable cancer from pancreatitis using a test cohort. Moreover, we identified variants to estimate survival in resectable cancer. We show that the blood transcriptome harbours variants, which can substantially improve noninvasive clinical diagnosis.
Chromosomal Instability in Acute Myeloid Leukemia
Authors: de Oliveira Lisboa Mateus , Brofman Paulo Roberto Slud , Schmid-Braz Ana Teresa , Rangel-Pozzo Aline , Mai Sabine
Published: May 2021

Chromosomal instability (CIN), the increasing rate in which cells acquire new chromosomal alterations, is one of the hallmarks of cancer. Many studies highlighted CIN as an important mechanism in the origin, progression, and relapse of acute myeloid leukemia (AML). The ambivalent feature of CIN as a cancer-promoting or cancer-suppressing mechanism might explain the prognostic variability. The latter, however, is described in very few studies. This review highlights the important CIN mechanisms in AML, showing that CIN signatures can occur largely in all the three major AML types (de novo AML, secondary-AML, and therapy-related-AML). CIN features in AML could also be age-related and reflect the heterogeneity of the disease. Although most of these abnormalities show an adverse prognostic value, they also offer a strong new perspective on personalized therapy approaches, which goes beyond assessing CIN in vitro in patient tumor samples to predict prognosis. Current and emerging AML therapies are exploring CIN to improve AML treatment, which includes blocking CIN or increasing CIN beyond the limit threshold to induce cell death. We argue that the characterization of CIN features, not included yet in the routine diagnostic of AML patients, might provide a better stratification of patients and be extended to a more personalized therapeutic approach.
Advances in Multidisciplinary Management of Skull Base Meningiomas
Authors: Ius Tamara , Tel Alessandro , Minniti Giuseppe , Somma Teresa , Solari Domenico , Longhi Michele , De Bonis Pasquale , Scerrati Alba , Caccese Mario , Barresi Valeria , Fiorentino Alba , Gorgoglione Leonardo , Lombardi Giuseppe , Robiony Massimo
Published: May 2021

The surgical management of Skull Base Meningiomas (SBMs) has radically changed over the last two decades. Extensive surgery for patients with SBMs represents the mainstream treatment; however, it is often challenging due to narrow surgical corridors and proximity to critical neurovascular structures. Novel surgical technologies, including three-dimensional (3D) preoperative imaging, neuromonitoring, and surgical instruments, have gradually facilitated the surgical resectability of SBMs, reducing postoperative morbidity. Total removal is not always feasible considering a risky tumor location and invasion of surrounding structures and brain parenchyma. In recent years, the use of primary or adjuvant stereotactic radiosurgery (SRS) has progressively increased due to its safety and efficacy in the control of grade I and II meningiomas, especially for small to moderate size lesions. Patients with WHO grade SBMs receiving subtotal surgery can be monitored over time with surveillance imaging. Postoperative management remains highly controversial for grade II meningiomas, and depends on the presence of residual disease, with optional upfront adjuvant radiation therapy or close surveillance imaging in cases with total resection. Adjuvant radiation is strongly recommended in patients with grade III tumors. Although the currently available chemotherapy or targeted therapies available have a low efficacy, the molecular profiling of SBMs has shown genetic alterations that could be potentially targeted with novel tailored treatments. This multidisciplinary review provides an update on the advances in surgical technology, postoperative management and molecular profile of SBMs.
The Australian Youth Cancer Service: Developing and Monitoring the Activity of Nationally Coordinated Adolescent and Young Adult Cancer Care
Authors: Patterson Pandora , Allison Kimberley R. , Bibby Helen , Thompson Kate , Lewin Jeremy , Briggs Taia , Walker Rick , Osborn Michael , Plaster Meg , Hayward Allan , Henney Roslyn , George Shannyn , Keuskamp Dominic , Anazodo Antoinette
Published: May 2021

Adolescents and young adults (aged 15–25 years) diagnosed with cancer have unique medical and psychosocial experiences and care needs, distinct from those of paediatric and older adult patients. Since 2011, the Australian Youth Cancer Services have provided developmentally appropriate, multidisciplinary and comprehensive care to these young patients, facilitated by national service coordination and activity data collection and monitoring. This paper reports on how the Youth Cancer Services have conceptualised and delivered quality youth cancer care in four priority areas: clinical trial participation, oncofertility, psychosocial care and survivorship. National activity data collected by the Youth Cancer Services between 2016–17 and 2019–20 are used to illustrate how service monitoring processes have facilitated improvements in coordination and accountability across multiple indicators of quality youth cancer care, including clinical trial participation, access to fertility information and preservation, psychosocial screening and care and the transition from active treatment to survivorship. Accounts of both service delivery and monitoring and evaluation processes within the Australian Youth Cancer Services provide an exemplar of how coordinated initiatives may be employed to deliver, monitor and improve quality cancer care for adolescents and young adults.
Modification of the Acyl Chloride Quench-Labeling Method for Counting Active Sites in Catalytic Olefin Polymerization
Authors: Yang Haoyang , Zhang Biao , Zhong Wentao , Fu Zhisheng , Fan Zhiqiang
Published: May 2021

The reliable and efficient counting of active sites in catalytic olefin polymerization has been realized by using acyl chloride as the quench-labeling agent. However, the molar ratio of acyl chloride to the alkylaluminum cocatalyst must be larger than 1 in order to completely depress side reactions between the quencher and Al-polymeryl that is formed via chain transfer reaction. In this work, a tetrahydrofuran/thiophene-2-carbonyl chloride (THF/TPCC) mixture was used as the quenching agent when counting the active sites of propylene polymerization catalyzed by MgCl2/Di/TiCl4 (Di = internal electron donor)-type Ziegler–Natta catalyst activated with triethylaluminum (TEA). When the THF/TEA molar ratio was 1 and the TPCC/TEA molar ratio was smaller than 1, the [S]/[Ti] ratio of the polymer quenched with the THF/TPCC mixture was the same as that quenched with only TPCC at TPCC/TEA > 1, indicating quench-labeling of all active sites bearing a propagation chain. The replacement of a part of the TPCC with THF did not influence the precision of active site counting by the acyl chloride quench-labeling method, but it effectively reduced the amount of acyl chloride. This modification to the acyl chloride quench-labeling method significantly reduced the amount of precious acyl chloride quencher and brought the benefit of simplifying polymer purification procedures after the quenching step.
Synthesis and Characterization of Nickel(II) Homogeneous and Supported Complexes for the Hydrogenation of Furfural to Furfuryl Alcohol
Authors: Kalumpha Menala , Matsinha Leah Charlie , Makhubela Banothile C. E.
Published: May 2021

Nickel(II) complexes have been synthesized and characterized using nuclear magnetic resonance (NMR), infrared spectroscopy, high resolution mass spectroscopy, and elemental analysis. The complexes were evaluated as pre-catalysts in the direct hydrogenation of furfural to furfuryl alcohol. The pre-catalysts C1 and C4 gave higher furfural conversion (97% and 96%, respectively), as a result, they were also evaluated in the transfer hydrogenation of furfural using formic acid as the hydrogen source where higher furfural conversion (93%) was obtained and selectivity (100%) toward the formation of furfuryl alcohol at 4 h. The catalyst C1 was recycled three times with and it was observed that the catalytic activity might be due to a mixture of both molecular catalysis and nanoparticles, as evidenced by the decrease in activity in mercury poisoning experiments. The hydrogenation reactions were also extended to alpha-β unsaturated substrates and were selective toward saturation of the carbonyl functionality over alkene groups.
Effect of Pyrolysis Temperature during Valorization of Date Stones on Physiochemical Properties of Activated Carbon and Its Catalytic Activity for the Oxidation of Cycloalkenes
Authors: Alshammari Hamed M. , Abbas Nadir
Published: May 2021

This study presents findings on the chemical synthesis of activated carbon from Saudi dates and its structural, chemical, and catalytic properties. Dates are among the top biowaste materials in the Kingdom of Saudi Arabia, and efforts are underway to utilize this resource. A chemical pyrolysis method was used to synthesize activated carbon from date stones. Synthesized activated carbon was calcined at different temperatures of 400, 500, 600, and 700 °C, and the impact of calcination temperature on the properties of activated carbon was investigated. For this purpose, contemporary characterization tools, namely, XRD, Raman spectroscopy, FTIR, SEM, TEM, TGA, DSC, and XPS, were employed. Results are discussed and compared with associated studies. Finally, the catalytic activity of gold-deposited activated carbon for the oxidation of cycloalkenes was evaluated, and it was found that the calcination temperature has a linear positive relationship with the catalytic activity.
Autotetraploid Emergence via Somatic Embryogenesis in Vitis vinifera Induces Marked Morphological Changes in Shoots, Mature Leaves, and Stomata
Authors: Catalano Caterina , Abbate Loredana , Motisi Antonio , Crucitti Dalila , Cangelosi Vincenzo , Pisciotta Antonino , Di Lorenzo Rosario , Carimi Francesco , Carra Angela
Published: May 2021

Polyploidy plays an important role in plant adaptation to biotic and abiotic stresses. Alterations of the ploidy in grapevine plants regenerated via somatic embryogenesis (SE) may provide a source of genetic variability useful for the improvement of agronomic characteristics of crops. In the grapevine, the SE induction process may cause ploidy changes without alterations in DNA profile. In the present research, tetraploid plants were observed for 9.3% of ‘Frappato’ grapevine somatic embryos regenerated in medium supplemented with the growth regulators β-naphthoxyacetic acid (10 µM) and N6-benzylaminopurine (4.4 µM). Autotetraploid plants regenerated via SE without detectable changes in the DNA profiles were transferred in field conditions to analyze the effect of polyploidization. Different ploidy levels induced several anatomical and morphological changes of the shoots and mature leaves. Alterations have been also observed in stomata. The length and width of stomata of tetraploid leaves were 39.9 and 18.6% higher than diploids, respectively. The chloroplast number per guard cell pair was higher (5.2%) in tetraploid leaves. On the contrary, the stomatal index was markedly decreased (12%) in tetraploid leaves. The observed morphological alterations might be useful traits for breeding of grapevine varieties in a changing environment.