bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of measurable residual disease in acute myeloid leukemia by DNA methylation patterns
Authors: Božić Tanja , Kuo Chao-Chung , Hapala Jan , Franzen Julia , Eipel Monika , Platzbecker Uwe , Kirschner Martin , Beier Fabian , Jost Edgar , Thiede Christian , Wagner Wolfgang 
Published: June 2021

AbstractAssessment of measurable residual disease (MRD) upon treatment of acute myeloid leukemia (AML) remains challenging. It is usually addressed by highly sensitive PCR- or sequencing-based screening of specific mutations, or by multiparametric flow cytometry. However, not all patients have suitable mutations and heterogeneity of surface markers hampers standardization in clinical routine. In this study, we propose an alternative approach to estimate MRD based on AML-associated DNA methylation (DNAm) patterns. We identified four CG dinucleotides (CpGs) that commonly reveal aberrant DNAm in AML and their combination could reliably discern healthy and AML samples. Interestingly, bisulfite amplicon sequencing demonstrated that aberrant DNAm patterns were symmetric on both alleles, indicating that there is epigenetic crosstalk between homologous chromosomes. We trained shallow-learning and deep-learning algorithms to identify anomalous DNAm patterns. The method was then tested on follow-up samples with and without MRD. Notably, even samples that were classified as MRD negative often revealed higher anomaly ratios than healthy controls, which may reflect clonal hematopoiesis. Our results demonstrate that targeted DNAm analysis facilitates reliable discrimination of malignant and healthy samples. However, since healthy samples also comprise few abnormal-classified DNAm reads the approach does not yet reliably discriminate MRD positive and negative samples.
A 3D-printed magnetic digital microfluidic diagnostic platform for rapid colorimetric sensing of carbapenemase-producing Enterobacteriaceae
Authors: Kanitthamniyom Pojchanun , Hon Pei Yun , Zhou Aiwu , Abdad Mohammad Yazid , Leow Zhi Yun , Yazid Nurhidayah Binte Mohamed , Xun Vanessa Lim Wei , Vasoo Shawn , Zhang Yi 
Published: June 2021

AbstractCarbapenemase-producing Enterobacteriaceae (CPE) are a group of drug-resistant Gram-negative pathogens that are classified as a critical threat by the World Health Organization (WHO). Conventional methods of detecting antibiotic-resistant pathogens do not assess the resistance mechanism and are often time-consuming and laborious. We have developed a magnetic digital microfluidic (MDM) platform, known as MDM Carba, for the identification of CPE by measuring their ability to hydrolyze carbapenem antibiotics. MDM Carba offers the ability to rapidly test CPE and reduce the amount of reagents used compared with conventional phenotypic testing. On the MDM Carba platform, tests are performed in droplets that function as reaction chambers, and fluidic operations are accomplished by manipulating these droplets with magnetic force. The simple droplet-based magnetic fluidic operation allows easy system automation and simplified hands-on operation. Because of the unique “power-free” operation of MDM technology, the MDM Carba platform can also be operated manually, showing great potential for point-of-care testing in resource-limited settings. We tested 27 bacterial isolates on the MDM Carba platform, and the results showed sensitivity and specificity that were comparable to those of the widely used Carba NP test. MDM Carba may shorten the overall turnaround time for CPE identification, thereby enabling more timely clinical decisions for better clinical outcomes. MDM Carba is a technological platform that can be further developed to improve diagnostics for other types of antibiotic resistance with minor modifications.
Genetic-guided pharmacotherapy for venous thromboembolism: a systematic and critical review of economic evaluations
Authors: Lim Ka Keat , Koleva-Kolarova Rositsa , Chowienczyk Philip , Wolfe Charles D. A. , Fox-Rushby Julia 
Published: June 2021

AbstractDespite the known contributions of genes, genetic-guided pharmacotherapy has not been routinely implemented for venous thromboembolism (VTE). To examine evidence on cost-effectiveness of genetic-guided pharmacotherapy for VTE, we searched six databases, websites of four HTA agencies and citations, with independent double-reviewers in screening, data extraction, and quality rating. The ten eligible studies, all model-based, examined heterogeneous interventions and comparators. Findings varied widely; testing was cost-saving in two base-cases, cost-effective in four, not cost-effective in three, dominated in one. Of 22 model variables that changed decisions about cost-effectiveness, effectiveness/relative effectiveness of the intervention was the most frequent, albeit of poor quality. Studies consistently lacked details on the provision of interventions and comparators as well as on model development and validation. Besides improving the reporting of interventions, comparators, and methodological details, future economic evaluations should examine strategies recommended in guidelines and testing key model variables for decision uncertainty, to advise clinical implementations.
Cancer Grade Model: a multi-gene machine learning-based risk classification for improving prognosis in breast cancer
Authors: Amiri Souri E. , Chenoweth A. , Cheung A. , Karagiannis S. N. , Tsoka S. 
Published: June 2021

Abstract
Background
Prognostic stratification of breast cancers remains a challenge to improve clinical decision making. We employ machine learning on breast cancer transcriptomics from multiple studies to link the expression of specific genes to histological grade and classify tumours into a more or less aggressive prognostic type.

Materials and methods
Microarray data of 5031 untreated breast tumours spanning 33 published datasets and corresponding clinical data were integrated. A machine learning model based on gradient boosted trees was trained on histological grade-1 and grade-3 samples. The resulting predictive model (Cancer Grade Model, CGM) was applied on samples of grade-2 and unknown-grade (3029) for prognostic risk classification.

Results
A 70-gene signature for assessing clinical risk was identified and was shown to be 90% accurate when tested on known histological-grade samples. The predictive framework was validated through survival analysis and showed robust prognostic performance. CGM was cross-referenced with existing genomic tests and demonstrated the competitive predictive power of tumour risk.

Conclusions
CGM is able to classify tumours into better-defined prognostic categories without employing information on tumour size, stage, or subgroups. The model offers means to improve prognosis and support the clinical decision and precision treatments, thereby potentially contributing to preventing underdiagnosis of high-risk tumours and minimising over-treatment of low-risk disease.
TAM kinase signaling is indispensable for proper skeletal muscle regeneration in mice
Authors: Al-Zaeed Nour , Budai Zsófia , Szondy Zsuzsa , Sarang Zsolt 
Published: June 2021

AbstractSkeletal muscle regeneration following injury results from the proliferation and differentiation of myogenic stem cells, called satellite cells, located beneath the basal lamina of the muscle fibers. Infiltrating macrophages play an essential role in the process partly by clearing the necrotic cell debris, partly by producing cytokines that guide myogenesis. Infiltrating macrophages are at the beginning pro-inflammatory, but phagocytosis of dead cells induces a phenotypic change to become healing macrophages that regulate inflammation, myoblast fusion and growth, fibrosis, vascularization and return to homeostasis. The TAM receptor kinases Mer and Axl are known efferocytosis receptors in macrophages functioning in tolerogenic or inflammatory conditions, respectively. Here we investigated their involvement in the muscle regeneration process by studying the muscle repair following cardiotoxin-induced injury in Mer−/− mice. We found that Axl was the only TAM kinase receptor expressed on the protein level by skeletal muscle and C2C12 myoblast cells, while Mer was the dominant TAM kinase receptor in the CD45+ cells, and its expression significantly increased during repair. Mer ablation did not affect the skeletal muscle weight or structure, but following injury it resulted in a delay in the clearance of necrotic muscle cell debris, in the healing phenotype conversion of macrophages and consequently in a significant delay in the full muscle regeneration. Administration of the TAM kinase inhibitor BMS-777607 to wild type mice mimicked the effect of Mer ablation on the muscle regeneration process, but in addition, it resulted in a long-persisting necrotic area. Finally, in vitro inhibition of TAM kinase signaling in C2C12 myoblasts resulted in decreased viability and in impaired myotube growth. Our work identifies Axl as a survival and growth receptor in the mouse myoblasts, and reveals the contribution of TAM kinase-mediated signaling to the skeletal muscle regeneration both in macrophages and in myoblasts.
Hypoxic TAM-derived exosomal miR-155-5p promotes RCC progression through HuR-dependent IGF1R/AKT/PI3K pathway
Authors: Gu Wenyu , Gong Linjing , Wu Xu , Yao Xudong 
Published: June 2021

AbstractHypoxic tumor-associated macrophages (TAMs) are related to poor prognosis of patients with clear cell renal cell carcinoma (ccRCC). Exosomes are small lipid-bilayer vesicles that implicated in tumor progression and metastasis. However, whether hypoxic TAM-derived exosomes affect RCC progression within the hypoxic tumor microenvironment has not been elucidated. GSE analysis identified miR-155-5p was upregulated in RCC. Moreover, we quantified levels of miR-155-5p using RT-qPCR, performed immunohistochemical staining in 79 pairs of primary RCC specimens and related them to clinicopathological parameters. Higher miR-155-5p levels were related to more CD163 + TAM infiltration and elevated HIF-1a expression in our cohort. In the in vitro studies, we initially purified and characterized the exosomes from the supernatant of TAMs subjected to normoxia or hypoxia, and then transfected antagomiR-155-5p or control into these TAMs to produce corresponding exosomes. Gain and loss-of-function studies further investigated the effect of transferred hypoxic exosomal miR-155-5p on the cross-talk between TAMs and RCC cells in xenograft model and in vitro co-culture experiments. The results of RNA immunoprecipitation analyses elucidated that miR-155-5p could directly interact with human antigen R (HuR), thus increasing IGF1R mRNA stability. Mechanistically, hypoxic TAM-Exo transferred miR-155-5p promoted RCC progression partially through activating IGF1R/PI3K/AKT cascades. Taken together, transfer of miR-155-5p from hypoxic TAMs by exosomes to renal cancer cells explains the oncogenic manner, in which M2 macrophages confer the malignant phenotype to RCC cells by enhancing HuR-mediated mRNA stability of IGF1R.
MicroRNA-326 attenuates immune escape and prevents metastasis in lung adenocarcinoma by targeting PD-L1 and B7-H3
Authors: Shao Lijuan , He Qian , Wang Jingbo , He Fei , Lin Shengcheng , Wu Liujing , Gao Yubiao , Ma Wei , Dong Jun , Yang Xiaofei , Li Furong 
Published: June 2021

AbstractTumor-infiltrating T cells are highly expressive of inhibitory receptor/immune checkpoint molecules that bind to ligand expressed by tumor cells and antigen-presenting cells, and eventually lead to T cell dysfunction. It is a hot topic to restore T cell function by targeting immune checkpoint. In recent years, immunotherapy of blocking immune checkpoint and its receptor, such as PD-L1/PD-1 targeted therapy, has made effective progress, which brings hope for patients with advanced malignant tumor. However, only a few patients benefit from directly targeting these checkpoints or their receptors by small compounds or antibodies. Since the complexity of the regulation of immune checkpoints in tumor cells, further research is needed to identify the novel endogenous regulators of immune checkpoints which can help for developing effective drug target to improve the effect of immunotherapy. Here, we verified that microRNA-326 (miR-326) repressed the gene expression of immune checkpoint molecules PD-L1 and B7-H3 in lung adenocarcinoma (LUAD). We detected that the expression of miR-326 in LUAD tissue was negatively correlated with PD-L1/B7-H3. The repression of PD-L1 and B7-H3 expression through miR-326 overexpression leads to the modification the cytokine profile of CD8+ T cells and decreased migration capability of tumor cells. Meanwhile, the downregulation of miR-326 promoted tumor cell migration. Moreover, blocking PD-L1 and B7-H3 attenuated the tumor-promoting effect induced by miR-326 inhibitor. In tumor-bearing mice, the infiltration of CD8+ T cells was significantly increased and the expression of TNF-α, and IFN-γ was significantly enhanced which contributed to tumor progression after miR-326 overexpression. Collectively, miR-326 restrained tumor progression by downregulating PD-L1 and B7-H3 expression and increasing T cell cytotoxic function in LUAD. Our findings revealed a novel perspective on the complex regulation of immune checkpoint molecules. A new strategy of using miR-326 in tumor immunotherapy is proposed.
Potential transmission chains of variant B.1.1.7 and co-mutations of SARS-CoV-2
Authors: Zhang Jingsong , Zhang Yang , Kang Jun-Yan , Chen Shuiye , He Yongqun , Han Benhao , Liu Mo-Fang , Lu Lina , Li Li , Yi Zhigang , Chen Luonan 
Published: June 2021

AbstractThe presence of SARS-CoV-2 mutants, including the emerging variant B.1.1.7, has raised great concerns in terms of pathogenesis, transmission, and immune escape. Characterizing SARS-CoV-2 mutations, evolution, and effects on infectivity and pathogenicity is crucial to the design of antibody therapies and surveillance strategies. Here, we analyzed 454,443 SARS-CoV-2 spike genes/proteins and 14,427 whole-genome sequences. We demonstrated that the early variant B.1.1.7 may not have evolved spontaneously in the United Kingdom or within human populations. Our extensive analyses suggested that Canidae, Mustelidae or Felidae, especially the Canidae family (for example, dog) could be a possible host of the direct progenitor of variant B.1.1.7. An alternative hypothesis is that the variant was simply yet to be sampled. Notably, the SARS-CoV-2 whole-genome represents a large number of potential co-mutations. In addition, we used an experimental SARS-CoV-2 reporter replicon system to introduce the dominant co-mutations NSP12_c14408t, 5′UTR_c241t, and NSP3_c3037t into the viral genome, and to monitor the effect of the mutations on viral replication. Our experimental results demonstrated that the co-mutations significantly attenuated the viral replication. The study provides valuable clues for discovering the transmission chains of variant B.1.1.7 and understanding the evolutionary process of SARS-CoV-2.
Shortwave infrared otoscopy for diagnosis of middle ear effusions: a machine-learning-based approach
Authors: Kashani Rustin G. , Młyńczak Marcel C. , Zarabanda David , Solis-Pazmino Paola , Huland David M. , Ahmad Iram N. , Singh Surya P. , Valdez Tulio A. 
Published: June 2021

AbstractOtitis media, a common disease marked by the presence of fluid within the middle ear space, imparts a significant global health and economic burden. Identifying an effusion through the tympanic membrane is critical to diagnostic success but remains challenging due to the inherent limitations of visible light otoscopy and user interpretation. Here we describe a powerful diagnostic approach to otitis media utilizing advancements in otoscopy and machine learning. We developed an otoscope that visualizes middle ear structures and fluid in the shortwave infrared region, holding several advantages over traditional approaches. Images were captured in vivo and then processed by a novel machine learning based algorithm. The model predicts the presence of effusions with greater accuracy than current techniques, offering specificity and sensitivity over 90%. This platform has the potential to reduce costs and resources associated with otitis media, especially as improvements are made in shortwave imaging and machine learning.
Serotonin signaling modulates aging-associated metabolic network integrity in response to nutrient choice in Drosophila melanogaster
Authors: Lyu Yang , Promislow Daniel E. L. , Pletcher Scott D. 
Published: June 2021

AbstractAging arises from complex interactions among multiple biochemical products. Systems-level analyses of biological networks may provide insights into the causes and consequences of aging that evade single-gene studies. We have previously found that dietary choice is sufficient to modulate aging in the vinegar fly,Drosophila melanogaster. Here we show that nutrient choice influenced several measures of metabolic network integrity, including connectivity, community structure, and robustness. Importantly, these effects are mediated by serotonin signaling, as a mutation in serotonin receptor 2A (5-HT2A) eliminated the effects of nutrient choice. Changes in network structure were associated with organism resilience and increased susceptibility to genetic perturbation. Our data suggest that the behavioral or perceptual consequences of exposure to individual macronutrients, involving serotonin signaling through 5-HT2A, qualitatively change the state of metabolic networks throughout the organism from one that is highly connected and robust to one that is fragmented, fragile, and vulnerable to perturbations.
General theory and observation of Cherenkov radiation induced by multimode solitons
Authors: Eftekhar M. A. , Lopez-Aviles H. , Wise F. W. , Amezcua-Correa R. , Christodoulides D. N. 
Published: June 2021

AbstractAdvancements in computational capabilities along with the possibility of accessing high power levels have stimulated a reconsideration of multimode fibers. Multimode fibers are nowadays intensely pursued in terms of addressing longstanding issues related to information bandwidth and implementing new classes of high-power laser sources. In addition, the multifaceted nature of this platform, arising from the complexity associated with hundreds and thousands of interacting modes, has provided a fertile ground for observing novel physical effects. However, this same complexity has introduced a formidable challenge in understanding these newly emerging physical phenomena. Here, we provide a comprehensive theory capable of explaining the distinct Cherenkov radiation lines produced during multimode soliton fission events taking place in nonlinear multimode optical fibers. Our analysis reveals that this broadband dispersive wave emission is a direct byproduct of the nonlinear merging of the constituent modes comprising the resulting multimode soliton entities, and is possible in both the normal and anomalous dispersive regions. These theoretical predictions are experimentally and numerically corroborated in both parabolic and step-index multimode silica waveguides. Effects arising from different soliton modal compositions can also be accounted for, using this model. At a more fundamental level, our results are expected to further facilitate our understanding of the underlying physics associated with these complex “many-body” nonlinear processes.
Japanese carbon emissions patterns shifted following the 2008 financial crisis and the 2011 Tohoku earthquake
Authors: Long Yin , Yoshida Yoshikuni , Liu Qiaoling , Guan Dabo , Zheng Heran , Li Yuan , Gasparatos Alexandros 
Published: June 2021

AbstractUnexpected events such as economic crises and natural disasters can have profound implications for energy systems and climate change mitigation efforts at different levels. Here we explore the national and regional carbon emission patterns (and their drivers) for the main economic sectors in Japan between 2007 and 2015, a period shaped by the 2008 financial crisis and the 2011 Tohoku Earthquake. Following the 2011 earthquake the previously decreasing regional emissions patterns started increasing in practically all regions except Hokkaido. This was mainly due to growing coal use particularly in the Kyushu, Chugoku and Kansai regions. Furthermore, most regions experienced shifts in the dominance of different drivers of emissions over time, with a stronger initial impact from economic effects after the 2008 financial crisis, followed by energy structure after the 2011 earthquake, and then by economic effects and energy intensity. These results offer a more nuanced understanding of how individual events can affect emissions at different periods and levels (national vs. regional) to inform the design of climate change mitigation strategies.
A Ka‐band tunable LNA for MB‐OFDM application
Authors: Hosseini Seyed Alborz , Mohammad‐Taheri Mahmoud , Khosravi Ramin , Moradi Gholamreza 
Published: June 2021

AbstractIn this paper a novel tuneable LNA is presented. This LNA is designed with two separated structures which both of them utilize noise cancellation technique and some other approaches such as gain boosting and T‐transformer feedback. Each proposed LNA has two stages that the first stage is designed based on noise cancellation and the second stage uses common gate structure. The proposed LNA type (A) utilises the switched capacitance in the first stage to tune the centre frequency and a gain boosting in the second stage to increase the gain. The second proposed LNA type (B) has implemented the parallel networks to decrease the change in the gain values of the LNA in different channels. The T‐transformer approach is used in each parallel network to decrease the inductors value and improve the input matching. In the second stage, the negative feedback is also employed to control the bandwidth. The proposed LNA is simulated in ADS software with TSMC 130 nm CMOS technology and the layout is designed by Cadence. The LNA type (A) has 22.7 dB gain in 28.8 GHz and the noise figure of 2 dB. The IIP3 for this LNA is 0 dBm in 25.42 GHZ. For the LNA type (B), the gain and noise figure standard deviations are 0.25 and 0.057 respectively which shows minimum variations by frequency tuning. For this LNA, the maximum gain is 20.5 dB and the noise figure is 2 dB at 31.42 GHz. Finally the performances of the proposed LNAs have been compared with those of LNAs which have been recently published.
Analysis of Peripherally Inserted Central Catheter Line in Cancer Patients: A Single-Center Experience
Authors: Sapkota Sulav , Sannur Raju , Naik Radheshyam 
Published: June 2021

Abstract
Background Peripherally inserted central venous catheters are now widely used in cancer patients who require long-term treatment, for delivering multiple infusates. We aimed to evaluate the overall use of peripherally inserted central catheter (PICC) line in cancer patients, with the objective to study the demographic profile, complications, and safety related to PICC line in cancer patients.
Methods All the patients undergoing treatment for hematological and solid malignancies with PICC line inserted at the Healthcare Global Hospital during the study were evaluated prospectively. The complications related to PICC and its safety were analyzed.
Results Five hundred PICCs were inserted over a period of 2 years to 8 months for a total of 62,440 catheter days (mean of 24 days, i.e., 4.2 months, range: 1–434 days). The most common indication for PICC was for delivering chemotherapy (100%). Of these, 51 (10.2%) PICCs had complications at the rate of 0.82/1000 PICC days, and hence, 41 PICCs were removed. Hematological malignancies had more complications as compared with those with solid malignancies.
Conclusions PICCs are comparatively safe method for the central venous access in cancer patients.