bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor-penetrating therapy for β5 integrin-rich pancreas cancer
Authors: Hurtado de Mendoza Tatiana , Mose Evangeline S. , Botta Gregory P. , Braun Gary B. , Kotamraju Venkata R. , French Randall P. , Suzuki Kodai , Miyamura Norio , Teesalu Tambet , Ruoslahti Erkki , Lowy Andrew M. , Sugahara Kazuki N. 
Published: March 2021

AbstractPancreatic ductal adenocarcinoma (PDAC) is characterized by marked desmoplasia and drug resistance due, in part, to poor drug delivery to extravascular tumor tissue. Here, we report that carcinoma-associated fibroblasts (CAFs) induce β5 integrin expression in tumor cells in a TGF-β dependent manner, making them an efficient drug delivery target for the tumor-penetrating peptide iRGD. The capacity of iRGD to deliver conjugated and co-injected payloads is markedly suppressed when β5 integrins are knocked out in the tumor cells. Of note, β5 integrin knock-out in tumor cells leads to reduced disease burden and prolonged survival of the mice, demonstrating its contribution to PDAC progression. iRGD significantly potentiates co-injected chemotherapy in KPC mice with high β5 integrin expression and may be a powerful strategy to target an aggressive PDAC subpopulation.
A noncanonical AR addiction drives enzalutamide resistance in prostate cancer
Authors: He Yundong , Wei Ting , Ye Zhenqing , Orme Jacob J. , Lin Dong , Sheng Haoyue , Fazli Ladan , Jeffrey Karnes R. , Jimenez Rafael , Wang Liguo , Wang Liewei , Gleave Martin E. , Wang Yuzhuo , Shi Lei , Huang Haojie 
Published: March 2021

AbstractResistance to next-generation anti-androgen enzalutamide (ENZ) constitutes a major challenge for the treatment of castration-resistant prostate cancer (CRPC). By performing genome-wide ChIP-seq profiling in ENZ-resistant CRPC cells we identify a set of androgen receptor (AR) binding sites with increased AR binding intensity (ARBS-gained). While ARBS-gained loci lack the canonical androgen response elements (ARE) and pioneer factor FOXA1 binding motifs, they are highly enriched with CpG islands and the binding sites of unmethylated CpG dinucleotide-binding protein CXXC5 and the partner TET2. RNA-seq analysis reveals that both CXXC5 and its regulated genes including ID1 are upregulated in ENZ-resistant cell lines and these results are further confirmed in patient-derived xenografts (PDXs) and patient specimens. Consistent with the finding that ARBS-gained loci are highly enriched with H3K27ac modification, ENZ-resistant PCa cells, organoids, xenografts and PDXs are hyper-sensitive to NEO2734, a dual inhibitor of BET and CBP/p300 proteins. These results not only reveal a noncanonical AR function in acquisition of ENZ resistance, but also posit a treatment strategy to target this vulnerability in ENZ-resistant CRPC.
A study of quantum Berezinskii–Kosterlitz–Thouless transition for parity-time symmetric quantum criticality
Authors: Sarkar Sujit 
Published: March 2021

AbstractThe Berezinskii–Kosterlitz–Thouless (BKT) mechanism governs the critical behavior of a wide range of many-body systems. We show here that this phenomenon is not restricted to conventional many body system but also for the strongly correlated parity-time (PT) symmetry quantum criticality. We show explicitly behaviour of topological excitation for the real and imaginary part of the potential are different through the analysis of second order and third order renormalization group (RG). One of the most interesting feature that we observe from our study the presence of hidden QBKT and also conventional QBKT for the real part of the potential whereas there is no such evidence for the imaginary part of the potential. We also present the exact solution for the RG flow lines. We show explicitly how the physics of single field double frequencies sine-Gordon Hamiltonian effectively transform to the dual field double frequencies sine-Gordon Hamiltonian for a certain regime of parameter space. This is the first example in any quantum many body systems. We present the results of second order and third order RG flow results explicitly for the real and imaginary part of the potential. This PT symmetric system can be experimentally tested in ultra-cold atoms. This work provides a new perspective for the PT symmetric quantum criticality.
Mathematical model for the thermal enhancement of radiation response: thermodynamic approach
Authors: De Mendoza Adriana M. , Michlíková Soňa , Berger Johann , Karschau Jens , Kunz-Schughart Leoni A. , McLeod Damian D. 
Published: March 2021

AbstractRadiotherapy can effectively kill malignant cells, but the doses required to cure cancer patients may inflict severe collateral damage to adjacent healthy tissues. Recent technological advances in the clinical application has revitalized hyperthermia treatment (HT) as an option to improve radiotherapy (RT) outcomes. Understanding the synergistic effect of simultaneous thermoradiotherapy via mathematical modelling is essential for treatment planning. We here propose a theoretical model in which the thermal enhancement ratio (TER) relates to the cell fraction being radiosensitised by the infliction of sublethal damage through HT. Further damage finally kills the cell or abrogates its proliferative capacity in a non-reversible process. We suggest the TER to be proportional to the energy invested in the sensitisation, which is modelled as a simple rate process. Assuming protein denaturation as the main driver of HT-induced sublethal damage and considering the temperature dependence of the heat capacity of cellular proteins, the sensitisation rates were found to depend exponentially on temperature; in agreement with previous empirical observations. Our findings point towards an improved definition of thermal dose in concordance with the thermodynamics of protein denaturation. Our predictions well reproduce experimental in vitro and in vivo data, explaining the thermal modulation of cellular radioresponse for simultaneous thermoradiotherapy.
Functional connectivity and upper limb function in patients after pediatric arterial ischemic stroke with contralateral corticospinal tract wiring
Authors: Steiner Leonie , Homan Stephanie , Everts Regula , Federspiel Andrea , Kamal Sandeep , Rodriguez Juan Antonio Delgado , Kornfeld Salome , Slavova Nedelina , Wiest Roland , Kaelin-Lang Alain , Steinlin Maja , Grunt Sebastian 
Published: March 2021

AbstractTo develop individualized motor rehabilitation, knowledge of the relationship between neuroplastic reorganization and motor recovery after pediatric arterial ischemic stroke (AIS) is crucial. Thus, we investigated functional connectivity in patients after AIS with good motor outcome and in patients with hemiparesis compared with typically developing peers. We included 18 patients (n = 9 with hemiparesis, n = 9 with good motor outcome) with pediatric AIS in the chronic phase (≥ 2 years after diagnosis, diagnosed > 16 years) and 18 peers matched by age and gender. Participants underwent a standardized motor assessment, single-pulse transcranial magnetic stimulation to determine the type of corticospinal tract wiring, and resting-state functional magnetic resonance imaging to examine motor network connectivity. Corticospinal tract wiring was contralateral in all participants. Patients with hemiparesis had lower interhemispheric connectivity strength compared with patients with good clinical outcome and peers. Patients with good clinical outcome had higher intrahemispheric connectivity strength compared with peers. Further, higher intrahemispheric connectivity was related to better motor outcome in patients. Our findings suggest that better motor outcome after pediatric AIS is related to higher motor network connectivity strength. Thus, resting-state functional connectivity might be predictive for motor recovery after pediatric AIS.
Human cerebral organoids as a therapeutic drug screening model for Creutzfeldt–Jakob disease
Authors: Groveman Bradley R. , Ferreira Natalia C. , Foliaki Simote T. , Walters Ryan O. , Winkler Clayton W. , Race Brent , Hughson Andrew G. , Zanusso Gianluigi , Haigh Cathryn L. 
Published: March 2021

AbstractCreutzfeldt–Jakob Disease (CJD) is a fatal, currently incurable, neurodegenerative disease. The search for candidate treatments would be greatly facilitated by the availability of human cell-based models of prion disease. Recently, an induced pluripotent stem cell derived human cerebral organoid model was shown to take up and propagate human CJD prions. This model offers new opportunities to screen drug candidates for the treatment of human prion diseases in an entirely human genetic background. Here we provide the first evidence that human cerebral organoids can be a viable model for CJD drug screening by using an established anti-prion compound, pentosan polysulfate (PPS). PPS delayed prion propagation in a prophylactic-like treatment paradigm and also alleviated propagation when applied following establishment of infection in a therapeutic-like treatment paradigm. This study demonstrates the utility of cerebral organoids as the first human 3D cell culture system for screening therapeutic drug candidates for human prion diseases.
Effects of white Gaussian noise on dynamic balance in healthy young adults
Authors: Zhou Ziyou , Wu Can , Hu Zhen , Chai Yujuan , Chen Kai , Asakawa Tetsuya 
Published: March 2021

AbstractIt has been known that short-time auditory stimulation can contribute to the improvement of the balancing ability of the human body. The present study aims to explore the effects of white Gaussian noise (WGN) of different intensities and frequencies on dynamic balance performance in healthy young adults. A total of 20 healthy young participants were asked to stand at a dynamic balance force platform, which swung along the x-axis with an amplitude of ± 4° and frequency of 1 Hz. Their center of pressure (COP) trajectories were recorded when they were stimulated by WGN of different intensities (block 1) and different frequencies (block 2). A traditional method and detrended fluctuation analysis (DFA) were used for data preprocessing. The authors found that only with 75–85 dB WGN, the COP parameters improved. WGN frequency did not affect the dynamic balance performance of all the participants. The DFA results indicated stimulation with 75 dB WGN enhanced the short-term index and reduced the crossover point. Stimulation with 500 Hz and 2500 Hz WGN significantly enhanced the short-term index. These results suggest that 75 dB WGN and 500 Hz and 2500 Hz WGN improved the participants’ dynamic balance performance. The results of this study indicate that a certain intensity of WGN is indispensable to achieve a remarkable improvement in dynamic balance. The DFA results suggest that WGN only affected the short-term persistence, indicating the potential of WGN being considered as an adjuvant therapy in low-speed rehabilitation training.
Magnitude of the 8.2 ka event freshwater forcing based on stable isotope modelling and comparison to future Greenland melting
Authors: Aguiar Wilton , Meissner Katrin J. , Montenegro Alvaro , Prado Luciana , Wainer Ilana , Carlson Anders E. , Mata Mauricio M. 
Published: March 2021

AbstractThe northern hemisphere experienced an abrupt cold event ~ 8200 years ago (the 8.2 ka event) that was triggered by the release of meltwater into the Labrador Sea, and resulting in a weakening of the poleward oceanic heat transport. Although this event has been considered a possible analogue for future ocean circulation changes due to the projected Greenland Ice Sheet (GIS) melting, large uncertainties in the amount and rate of freshwater released during the 8.2 ka event make such a comparison difficult. In this study, we compare sea surface temperatures and oxygen isotope ratios from 28 isotope-enabled model simulations with 35 paleoproxy records to constrain the meltwater released during the 8.2 ka event. Our results suggest that a combination of 5.3 m of meltwater in sea level rise equivalent (SLR) released over a thousand years, with a short intensification over ~ 130 years (an additional 2.2 m of equivalent SLR) due to routing of the Canadian river discharge, best reproduces the proxy anomalies. Our estimate is of the same order of magnitude as projected future GIS melting rates under the high emission scenario RCP8.5.
Hair and salivary cortisol and their relationship with lifestyle, mood and cognitive outcomes in premanifest Huntington’s disease
Authors: Cruickshank Travis , Porter Tenielle , Laws Simon M. , Ziman Mel , Bartlett Danielle M. 
Published: March 2021

AbstractSalivary cortisol dysrhythmias have been reported in some, but not all studies assessing hypothalamic–pituitary–adrenal (HPA) axis function in Huntington’s disease (HD). These differences are presumed to be due to environmental influences on temporal salivary cortisol measurement. Further exploration of HPA-axis function using a more stable and longer-term measure, such as hair cortisol, is needed to confirm earlier findings. This study aimed to evaluate hair and salivary cortisol concentrations and their associations with clinical and lifestyle outcomes in individuals with premanifest HD (n = 26) compared to healthy controls (n = 14). Participants provided saliva and hair samples and data were collected on clinical disease outcomes, mood, cognition, physical activity, cognitive reserve, sleep quality and social network size to investigate relationships between clinical and lifestyle outcomes and cortisol concentrations. Hair and salivary cortisol concentrations did not significantly differ between the premanifest HD and control groups. No significant associations were observed between hair or salivary cortisol concentrations and cognitive, mood or lifestyle outcomes. However, hair cortisol concentrations were significantly associated with disease outcomes in individuals with premanifest HD. Significant associations between hair cortisol concentrations and measures of disease burden and onset may suggest a potential disease marker and should be explored longitudinally in a larger sample of individuals with HD.
Ex vivo characterization of Breg cells in patients with chronic Chagas disease
Authors: Girard Magalí C. , Acevedo Gonzalo R. , Ossowski Micaela S. , Fernández Marisa , Hernández Yolanda , Chadi Raúl , Gómez Karina A. 
Published: March 2021

AbstractDespite the growing importance of the regulatory function of B cells in many infectious diseases, their immunosuppressive role remains elusive in chronic Chagas disease (CCD). Here, we studied the proportion of different B cell subsets and their capacity to secrete IL-10 ex vivo in peripheral blood from patients with or without CCD cardiomyopathy. First, we immunophenotyped peripheral blood mononuclear cells from patients according to the expression of markers CD19, CD24, CD38 and CD27 and we showed an expansion of total B cell and transitional CD24highCD38high B cell subsets in CCD patients with cardiac involvement compared to non-infected donors. Although no differences were observed in the frequency of total IL-10 producing B cells (B10) among the groups, CCD patients with cardiac involvement showed an increased proportion of naïve B10 cells and a tendency to a higher frequency of transitional B10 cells compared to non-infected donors. Our research demonstrates that transitional B cells are greatly expanded in patients with the cardiac form of CCD and these cells retain the ability to secrete IL-10. These findings provide insight into the phenotypic distribution of regulatory B cells in CCD, an important step towards new strategies to prevent cardiomyopathy associated with T. cruzi infection.
COVID-19-related school closing aggravate obesity and glucose intolerance in pediatric patients with obesity
Authors: Kim Eun Sil , Kwon Yiyoung , Choe Yon Ho , Kim Mi Jin 
Published: March 2021

AbstractIt is important to pay attention to the indirect effects of the social distancing implemented to prevent the spread of coronavirus disease 2019 (COVID-19) pandemic on children and adolescent health. The aim of the present study was to explore impacts of a reduction in physical activity caused by COVID-19 outbreak in pediatric patients diagnosed with obesity. This study conducted between pre-school closing and school closing period and 90 patients aged between 6- and 18-year-old were included. Comparing the variables between pre-school closing period and school closing period in patients suffering from obesity revealed significant differences in variables related to metabolism such as body weight z-score, body mass index z-score, liver enzymes and lipid profile. We further evaluated the metabolic factors related to obesity. When comparing patients with or without nonalcoholic fatty liver disease (NAFLD), only hemoglobin A1c (HbA1c) was the only difference between the two time points (p < 0.05). We found that reduced physical activity due to school closing during COVID-19 pandemic exacerbated obesity among children and adolescents and negatively affects the HbA1C increase in NAFLD patients compared to non-NAFLD patients.
Bombyx mori β1,4-N-acetylgalactosaminyltransferase possesses relaxed donor substrate specificity in N-glycan synthesis
Authors: Kajiura Hiroyuki , Miyauchi Ryousuke , Kakudo Akemi , Ohashi Takao , Misaki Ryo , Fujiyama Kazuhito 
Published: March 2021

AbstractN-Glycosylation is one of the most important post-translational protein modifications in eukaryotic cells. Although more than 200 N-glycogenes contributing to N-glycan biosynthesis have been identified and characterized, the information on insect N-glycosylation is still limited. Here, focusing on insect N-glycosylation, we characterized Bombyx mori N-acetylgalactosaminyltransferase (BmGalNAcT) participating in complex N-glycan biosynthesis in mammals. BmGalNAcT localized at the Golgi and was ubiquitously expressed in every organ and in the developmental stage of the middle silk gland of fifth instar larvae. Analysis of recombinant BmGalNAcT expressed in Sf9 cells showed that BmGalNAcT transferred GalNAc to non-reducing terminals of GlcNAcβ1,2-R with β1,4-linkage. In addition, BmGalNAcT mediated transfer of galactose and N-acetylglucosamine residues but not transfer of either glucose or glucuronic acid from the UDP-sugar donor substrate to the N-glycan. Despite this tri-functional sugar transfer activity, however, most of the endogenous glycoproteins of insect cells were present without GalNAc, Gal, or GlcNAc residues at the non-reducing terminal of β1,2-GlcNAc residue(s). Moreover, overexpression of BmGalNAcT in insect cells had no effect on N-acetylgalactosaminylation, galactosylation, or N-acetylglucosaminylation of the major N-glycan during biosynthesis. These results suggested that B. mori has a novel multifunctional glycosyltransferase, but the N-glycosylation is highly and strictly regulated by the endogenous N-glycosylation machineries.
Brain fMRI during orientation selective epidural spinal cord stimulation
Authors: Canna Antonietta , Lehto Lauri J. , Wu Lin , Sang Sheng , Laakso Hanne , Ma Jun , Filip Pavel , Zhang Yuan , Gröhn Olli , Esposito Fabrizio , Chen Clark C. , Lavrov Igor , Michaeli Shalom , Mangia Silvia 
Published: March 2021

AbstractEpidural spinal cord stimulation (ESCS) is widely used for chronic pain treatment, and is also a promising tool for restoring motor function after spinal cord injury. Despite significant positive impact of ESCS, currently available protocols provide limited specificity and efficiency partially due to the limited number of contacts of the leads and to the limited flexibility to vary the spatial distribution of the stimulation field in respect to the spinal cord. Recently, we introduced Orientation Selective (OS) stimulation strategies for deep brain stimulation, and demonstrated their selectivity in rats using functional MRI (fMRI). The method achieves orientation selectivity by controlling the main direction of the electric field gradients using individually driven channels. Here, we introduced a similar OS approach for ESCS, and demonstrated orientation dependent brain activations as detected by brain fMRI. The fMRI activation patterns during spinal cord stimulation demonstrated the complexity of brain networks stimulated by OS-ESCS paradigms, involving brain areas responsible for the transmission of the motor and sensory information. The OS approach may allow targeting ESCS to spinal fibers of different orientations, ultimately making stimulation less dependent on the precision of the electrode implantation.
Omics data integration identifies ELOVL7 and MMD gene regions as novel loci for adalimumab response in patients with Crohn’s disease
Authors: Gorenjak Mario , Zupin Mateja , Jezernik Gregor , Skok Pavel , Potočnik Uroš 
Published: March 2021

AbstractResponse to anti-TNF therapy is of pivotal importance in patients with Crohn’s disease (CD). Here we integrated our and previously reported PBMC derived transcriptomic and genomic data for identification of biomarkers for discrimination between responders and non-responders to anti-TNF therapy. CD patients, who were naïve with respect to the treatment with biologicals, were enrolled in the study. DNA and RNA were extracted from peripheral blood mononuclear cells. RNA-seq was performed using BGISEQ-500. Genotyping was performed using Infinium Global Screening Array. Association regressions were carried out with 12 week response to adalimumab as an outcome variable. RNA-seq analysis confirmed 7 out of 65 previously suggested genes involved in anti-TNF response. Subsequently, analysis of single nucleotide variants in regions of confirmed genes identified 5 variants near MMD and two in ELOVL7 intronic regions associated with treatment response to anti-TNF. Functional analysis has shown that rs1465352, rs4422035 and rs78620886 are listed at H3K9ac_Pro histone modification epigenetic mark. The present study confirmed MMD and ELOVL7 involvement in anti-TNF response and revealed that the regulation of MMD and ELOVL7 gene regions in ADA response may be a part of a complex interplay extending from genetic to epigenetic and to transcriptomic level.
Development of multifunctional nanocomposites for controlled drug delivery and hyperthermia
Authors: Hovhannisyan Vladimir , Siposova Katarina , Musatov Andrey , Chen Shean-Jen 
Published: March 2021

AbstractMagnetic nano/micro-particles based on clinoptilolite-type of natural zeolite (CZ) were fabricated and were expected to act as carriers for controlled drug delivery/release, imaging and local heating in biological systems. Adsorption of rhodamine B, sulfonated aluminum phthalocyanine and hypericin by magnetic CZ nano/micro-particles was investigated, as was the release of hypericin. Using an alternating magnetic field, local temperature increase by 10 °C in animal tissue with injected magnetic CZ particles was demonstrated. In addition, the CZ-based particles have been found to exhibit an anti-amyloidogenic effect on the amyloid aggregation of insulin and lysozyme in a dose- and temperature-dependent manner. Therefore, the mesoporous structure of CZ particles provided a unique platform for preparation of multifunctional magnetic and optical probes suitable for optical imaging, MRI, thermo- and phototherapy and as effective containers for controlled drug delivery. We concluded that magnetic CZ nano/micro-particles could be evaluated for further application in cancer hyperthermia therapy and as anti-amyloidogenic agents.