bluuebunny/crossref_metadata_2025 huggingface dataset:
Study of Discharge Characteristics on Ignition Performance via High-Speed Imaging in a CVCC
Authors: Chen Qingchu , Kuboyama Tatsuya , Moriyoshi Yasuo , Oryoji Kazuhiro
Published: March 2022

Advanced combustion technologies, like highly boosted and lean or dilute combustion, have been employed to meet the demands of high efficiency and low emissions in SI engines, which have increased the challenges of ignition control. It is essential to find a suitable ignition strategy due to the need to develop a next-generation spark ignition system. In this study, simultaneous visualization by a high-speed infrared camera (FLIR X6900sc) and a conventional high-speed camera (FASTCAM SA-X) is carried out to obtain deeper insights into the ignition process in a constant volume combustion chamber (CVCC). Infrared images have provided a more accurate way of measuring the initial flame and are able to analyze quantitatively. Ignition performance is studied with various mixture dilutions, flow conditions, and discharge characteristics. Two types of ignition coils that have the same discharge energy were analyzed in particular. The results show that extending the discharge duration is more helpful in improving the ignition performance under the increasing dilution ratio, compared to the enhanced discharge current at the same discharge energy. However, the discharge current plays a more vital role in perfecting the ignition performance under the increasing local flow velocity than the discharge duration.
A Sun-Tracking Algorithm for Satellite-Borne Spectrometers Based on the Orbital Motion Model
Authors: Guo Xu , Yan Changxiang , Guo Yongfei , Qi Xinda , Huang Bin , Che Xin
Published: March 2022

To guarantee that a spectrometer can obtain effective solar spectral data, it is important that the two-dimensional turntable that carries the spectrometer tracks the sun with high accuracy for long time periods, such that the sun is always near the center of the field of view of the spectrometer. However, there is an offset lag problem for the tracking sensor, leading to an increase in the sun-tracking error and inaccuracies in solar spectrum data. To mitigate this problem, an on-axis tracking control algorithm—based on the orbital motion model—is proposed in this paper. First, the sun-tracking model of the spectrometer is established based on the coordinate transformation method, and the analytical relationship between the adjustment angle of the turntable and the solar vector in the orbit system is given by means of the inverse kinematics solution of the target model. Then, the predictive filtering algorithm of the target model is derived to acquire the target position, based on which, the on-axis tracking control algorithm of the spectrometer system is realized to compensate the offset lag and increase the sun-tracking accuracy. Finally, the simulation analysis and experimental verification were performed under the actual working conditions of an orbit. The simulation results demonstrate that the root-mean-square (RMS) of the target position deviation decreased from 2.08″ to 0.77″ after prediction filtering, and the RMS of the tracking error decreased from 7.14″ to 0.97″. The RMS of an orbit’s sun-tracking error decreased from 5.72″ to 1.43″ in the ground test. The simulation and experimental results verify that the algorithm proposed in this paper can improve the tracking accuracy of the spectrometer, providing a reference for the design of a spectrometer in orbit.
Simulated Methane Emission Detection Capabilities of Continuous Monitoring Networks in an Oil and Gas Production Region
Authors: Chen Qining , Modi Mrinali , McGaughey Gary , Kimura Yosuke , McDonald-Buller Elena , Allen David T.
Published: March 2022

Simulations of the atmospheric dispersion of methane emissions were created for a region containing 26 oil and gas production sites in the Permian Basin in Texas. Virtual methane sensors were placed at 24 of the 26 sites, with at most 1 sensor per site. Continuous and intermittent emissions from each of the 26 oil and gas production sites, over 4 week-long meteorological episodes, representative of winter, spring, summer, and fall meteorology, were simulated. The trade-offs between numbers of sensors and precision of sensors required to reliably detect methane emissions of 1 to 10 kg/h were characterized. A total of 15 sensors, able to detect concentration enhancements of 1 ppm, were capable of identifying emissions at all 26 sites in all 4 week-long meteorological episodes, if emissions were continuous at a rate of 10 kg/h. More sensors or sensors with lower detection thresholds were required if emissions were intermittent or if emission rates were lower. The sensitivity of the required number of sensors to site densities in the region, emission dispersion calculation approaches, meteorological conditions, intermittency of the emissions, and emission rates, were examined. The results consistently indicated that, for the conditions in the Permian Basin, a fixed monitoring network with approximately one continuous monitor per site is likely to be capable of consistently detecting site-level methane emissions in the range of 5–10 kg/h.
Atrial Fibrillation: Focus on Myocardial Connexins and Gap Junctions
Authors: Guo Yu-Han , Yang Yi-Qing
Published: March 2022

Atrial fibrillation (AF) represents the most common type of clinical cardiac arrhythmia worldwide and contributes to substantial morbidity, mortality and socioeconomic burden. Aggregating evidence highlights the strong genetic basis of AF. In addition to chromosomal abnormalities, pathogenic mutations in over 50 genes have been causally linked to AF, of which the majority encode ion channels, cardiac structural proteins, transcription factors and gap junction channels. In the heart, gap junctions comprised of connexins (Cxs) form intercellular pathways responsible for electrical coupling and rapid coordinated action potential propagation between adjacent cardiomyocytes. Among the 21 isoforms of connexins already identified in the mammal genomes, 5 isoforms (Cx37, Cx40, Cx43, Cx45 and Cx46) are expressed in human heart. Abnormal electrical coupling between cardiomyocytes caused by structural remodeling of gap junction channels (alterations in connexin distribution and protein levels) has been associated with enhanced susceptibility to AF and recent studies have revealed multiple causative mutations or polymorphisms in 4 isoforms of connexins predisposing to AF. In this review, an overview of the genetics of AF is made, with a focus on the roles of mutant myocardial connexins and gap junctions in the pathogenesis of AF, to underscore the hypothesis that cardiac connexins are a major molecular target in the management of AF.
Determining Carina and Clavicular Distance-Dependent Positioning of Endotracheal Tube in Critically Ill Patients: An Artificial Intelligence-Based Approach
Authors: Tsai Lung-Wen , Yuan Kuo-Ching , Hou Sen-Kuang , Wu Wei-Lin , Hsu Chen-Hao , Liu Tyng-Luh , Lee Kuang-Min , Li Chiao-Hsuan , Chen Hann-Chyun , Tu Ethan , Dubey Rajni , Yeh Chun-Fu , Chen Ray-Jade
Published: March 2022

Early and accurate prediction of endotracheal tube (ETT) location is pivotal for critically ill patients. Automatic and timely detection of faulty ETT locations from chest X-ray images may avert patients’ morbidity and mortality. Therefore, we designed convolutional neural network (CNN)-based algorithms to evaluate ETT position appropriateness relative to four detected key points, including tracheal tube end, carina, and left/right clavicular heads on chest radiographs. We estimated distances from the tube end to tracheal carina and the midpoint of clavicular heads. A DenseNet121 encoder transformed images into embedding features, and a CNN-based decoder generated the probability distributions. Based on four sets of tube-to-carina distance-dependent parameters (i.e., (i) 30–70 mm, (ii) 30–60 mm, (iii) 20–60 mm, and (iv) 20–55 mm), corresponding models were generated, and their accuracy was evaluated through the predicted L1 distance to ground-truth coordinates. Based on tube-to-carina and tube-to-clavicle distances, the highest sensitivity, and specificity of 92.85% and 84.62% respectively, were revealed for 20–55 mm. This implies that tube-to-carina distance between 20 and 55 mm is optimal for an AI-based key point appropriateness detection system and is empirically comparable to physicians’ consensus.
A Cross-Cultural Analysis of Plant Resources among Five Ethnic Groups in the Western Himalayan Region of Jammu and Kashmir
Authors: Haq Shiekh Marifatul , Hassan Musheerul , Bussmann Rainer W. , Calixto Eduardo Soares , Rahman Inayat Ur , Sakhi Shazia , Ijaz Farhana , Hashem Abeer , Al-Arjani Al-Bandari Fahad , Almutairi Khalid F. , Abd_Allah Elsayed Fathi , Aziz Muhammad Abdul , Ali Niaz
Published: March 2022

Plant resources have always been valuable in human life, and many plant species are used in medicine, food, and ritual, and resource utilization is closely related to cultural diversity. Our study was conducted from June 2019 to April 2021, during which we aimed to document the local knowledge of plant resources of five ethnic groups, i.e., the Gujjar, Bakarwal, Kashmiri, Pahari, and Dogra communities of the Jammu and Kashmir (J&K) region, Western Himalayas. Through semi-structured interviews (N = 342) and group discussions (N = 38), we collected data on the ethnobotanical uses of plant resources. The data was subjected to hierarchical cluster analysis and ordination techniques (Principal Component Analysis) via, R software of version 4.0.0. Traditional uses were classified into three groups, i.e., single-, double-, and multi-use groups. The study recorded a total of 127 plant species, belonging to 113 genera and distributed among 64 botanical families. The dominant plant families were the Asteraceae, with 8% of all species, followed by Lamiaceae (6%), Polygonaceae (5%) and Ranunculaceae (4%). The recorded plant taxa were frequently used for medicine (51.4% responses), followed by food (14.9%), and fodder (9.5%). Principal component analysis (PCA) separated three groups of provisioning services depending on plant consumption preference levels. Comparative analysis showed remarkable similarities in plant uses (food, medicinal) among the Gujjar and Bakarwal ethnic groups, as both groups share a common culture. Some plants like Azadirachta indica, Brassica campestris, Ulmus wallichiana, Amaranthus blitum, and Celtis australis were also used for magico-religious purposes. We also recorded some medicinal uses that are new to the ethnobotanical literature of the J&K Himalayas, such as for Betula utilis, Sambucus wightiana, and Dolomiaea macrocephala, in our case for example local medicinal recipe, which is derived from Dolomiaea macrocephala, often known as Nashasta, used to treat weakness, back pain, and joint pain. Similarly, we also recorded new food uses for Eremurus himalaicus. Moreover, we also observed some plants for instance, Fragaria nubicola, Betula utilis and Juniperus communis have spiritual significance (i.e., amulets and scrolls) for this part of the Himalayan region. The present study provides a useful tool for resource management and can help in developing scientifically informed strategies for the conservation of plant resources.
Glycotherapy: A New Paradigm in Breast Cancer Research
Authors: Banerjee Dipak K. , Seijo Lebrón Arelis , Baksi Krishna
Published: March 2022

Breast cancer is an ancient disease recognized first by the Egyptians as early as 1600 BC. The first cancer-causing gene in a chicken tumor virus was found in 1970. The United States signed the National Cancer Act in 1971, authorizing federal funding for cancer research. Irrespective of multi-disciplinary approaches, diverting a great deal of public and private resources, breast cancer remains at the forefront of human diseases, affecting as many as one in eight women during their lifetime. Because of overarching challenges and changes in the breast cancer landscape, five-year disease-free survival is no longer considered adequate. The absence of a cure, and the presence of drug resistance, severe side effects, and destruction of the patient’s quality of life, as well as the fact that therapy is often expensive, making it unaffordable to many, have created anxiety among patients, families, and friends. One of the reasons for the failure of cancer therapeutics is that the approaches do not consider cancer holistically. Characteristically, all breast cancer cells and their microenvironmental capillary endothelial cells express asparagine-linked (N-linked) glycoproteins with diverse structures. We tested a small biological molecule, Tunicamycin, that blocks a specific step of the protein N-glycosylation pathway in the endoplasmic reticulum (ER), i.e., the catalytic activity of N-acetylglusosaminyl 1-phosphate transferase (GPT). The outcome was overwhelmingly exciting. Tunicamycin quantitatively inhibits angiogenesis in vitro and in vivo, and inhibits the breast tumor progression of multiple subtypes in pre-clinical mouse models with “zero” toxicity. Mechanistic details support ER stress-induced unfolded protein response (upr) signaling as the cause for the apoptotic death of both cancer and the microvascular endothelial cells. Additionally, it interferes with Wnt signaling. We therefore conclude that Tunicamycin can be expected to supersede the current therapeutics to become a glycotherapy for treating breast cancer of all subtypes.
The Sarcoplasmic Reticulum of Skeletal Muscle Cells: A Labyrinth of Membrane Contact Sites
Authors: Rossi Daniela , Pierantozzi Enrico , Amadsun David Osamwonuyi , Buonocore Sara , Rubino Egidio Maria , Sorrentino Vincenzo
Published: March 2022

The sarcoplasmic reticulum of skeletal muscle cells is a highly ordered structure consisting of an intricate network of tubules and cisternae specialized for regulating Ca2+ homeostasis in the context of muscle contraction. The sarcoplasmic reticulum contains several proteins, some of which support Ca2+ storage and release, while others regulate the formation and maintenance of this highly convoluted organelle and mediate the interaction with other components of the muscle fiber. In this review, some of the main issues concerning the biology of the sarcoplasmic reticulum will be described and discussed; particular attention will be addressed to the structure and function of the two domains of the sarcoplasmic reticulum supporting the excitation–contraction coupling and Ca2+-uptake mechanisms.
Exploring the Distinct Distribution of Archaeal Communities in Sites Contaminated with Explosives
Authors: Pal Yash , Mayilraj Shanmugam , Krishnamurthi Srinivasan
Published: March 2022

Most of the research on bioremediation and estimation of microbial diversity in waste contaminated sites is focused on the domain Bacteria, whereas details on the relevance of Archaea are still lacking. The present study examined the archaeal diversity and predicted metabolic pathways in two discrete sites (SITE1 and SITE2) contaminated with explosives (RDX and HMX) by amplicon-targeted sequencing of 16S rRNA genes. In total, 14 soil samples were processed, and 35,758 OTUs were observed, among which 981 OTUs were classified as Archaea, representing ~2.7% of the total microbial diversity in our samples. The majority of OTUs belonged to phyla Euryarchaeota (~49%), Crenarchaeota (~24%), and Thaumarchaeota (~23%), while the remaining (~4%) OTUs were affiliated to Candidatus Parvarchaeota, Candidatus Aenigmarchaeota, and Candidatus Diapherotrites. The comparative studies between explosives contaminated and agricultural soil samples (with no history of explosives contamination) displayed significant differences between the compositions of the archaeal communities. Further, the metabolic pathways pertaining to xenobiotic degradation were presumably more abundant in the contaminated sites. Our data provide a first comprehensive report of archaeal communities in explosives contaminated sites and their putative degradation role in such ecosystems which have been as yet unexplored.
Proof of Concept in Artificial-Intelligence-Based Wearable Gait Monitoring for Parkinson’s Disease Management Optimization
Authors: Ileșan Robert Radu , Cordoș Claudia-Georgiana , Mihăilă Laura-Ioana , Fleșar Radu , Popescu Ana-Sorina , Perju-Dumbravă Lăcrămioara , Faragó Paul
Published: March 2022

Parkinson’s disease (PD) is the second most common progressive neurodegenerative disorder, affecting 6.2 million patients and causing disability and decreased quality of life. The research is oriented nowadays toward artificial intelligence (AI)-based wearables for early diagnosis and long-term PD monitoring. Our primary objective is the monitoring and assessment of gait in PD patients. We propose a wearable physiograph for qualitative and quantitative gait assessment, which performs bilateral tracking of the foot biomechanics and unilateral tracking of arm balance. Gait patterns are assessed by means of correlation. The surface plot of a correlation coefficient matrix, generated from the recorded signals, is classified using convolutional neural networks into physiological or PD-specific gait. The novelty is given by the proposed AI-based decisional support procedure for gait assessment. A proof of concept of the proposed physiograph is validated in a clinical environment on five patients and five healthy controls, proving to be a feasible solution for ubiquitous gait monitoring and assessment in PD. PD management demonstrates the complexity of the human body. A platform empowering multidisciplinary, AI-evidence-based decision support assessments for optimal dosing between drug and non-drug therapy could lay the foundation for affordable precision medicine.
Phonetic Effects in the Perception of VOT in a Prevoicing Language
Authors: Kharlamov Viktor
Published: March 2022

Previous production studies have reported differential amounts of closure voicing in plosives depending on the location of the oral constriction (anterior vs. posterior), vocalic context (high vs. low vowels), and speaker sex. Such differences have been attributed to the aerodynamic factors related to the configuration of the cavity behind the oral constriction, with certain articulations and physiological characteristics of the speaker facilitating vocal fold vibration during closure. The current study used perceptual identification tasks to examine whether similar effects of consonantal posteriority, adjacent vowel height, and speaker sex exist in the perception of voicing. The language of investigation was Russian, a prevoicing language that uses negative VOT to signal the voicing contrast in plosives. The study used both original and resynthesized tokens for speaker sex, which allowed it to focus on the role of differences in VOT specifically. Results indicated that listeners’ judgments were significantly affected by consonantal place of articulation, with listeners accepting less voicing in velar plosives. Speaker sex showed only a marginally significant difference in the expected direction, and vowel height had no effect on perceptual responses. These findings suggest that certain phonetic factors can affect both the initial production and subsequent perception of closure voicing.
Ultrasonic Deep Brain Neuromodulation in Acute Disorders of Consciousness: A Proof-of-Concept
Authors: Cain Josh A. , Spivak Norman M. , Coetzee John P. , Crone Julia S. , Johnson Micah A. , Lutkenhoff Evan S. , Real Courtney , Buitrago-Blanco Manuel , Vespa Paul M. , Schnakers Caroline , Monti Martin M.
Published: March 2022

The promotion of recovery in patients who have entered a disorder of consciousness (DOC; e.g., coma or vegetative states) following severe brain injury remains an enduring medical challenge despite an ever-growing scientific understanding of these conditions. Indeed, recent work has consistently implicated altered cortical modulation by deep brain structures (e.g., the thalamus and the basal ganglia) following brain damage in the arising of, and recovery from, DOCs. The (re)emergence of low-intensity focused ultrasound (LIFU) neuromodulation may provide a means to selectively modulate the activity of deep brain structures noninvasively for the study and treatment of DOCs. This technique is unique in its combination of relatively high spatial precision and noninvasive implementation. Given the consistent implication of the thalamus in DOCs and prior results inducing behavioral recovery through invasive thalamic stimulation, here we applied ultrasound to the central thalamus in 11 acute DOC patients, measured behavioral responsiveness before and after sonication, and applied functional MRI during sonication. With respect to behavioral responsiveness, we observed significant recovery in the week following thalamic LIFU compared with baseline. With respect to functional imaging, we found decreased BOLD signals in the frontal cortex and basal ganglia during LIFU compared with baseline. In addition, we also found a relationship between altered connectivity of the sonicated thalamus and the degree of recovery observed post-LIFU.
The Prognostic Value of PI-RADS Score in CyberKnife Ultra-Hypofractionated Radiotherapy for Localized Prostate Cancer
Authors: Miszczyk Marcin , Rembak-Szynkiewicz Justyna , Magrowski Łukasz , Stawiski Konrad , Namysł-Kaletka Agnieszka , Napieralska Aleksandra , Kraszkiewicz Małgorzata , Woźniak Grzegorz , Stąpór-Fudzińska Małgorzata , Głowacki Grzegorz , Pradere Benjamin , Laukhtina Ekaterina , Rajwa Paweł , Majewski Wojciech
Published: March 2022

Prostate Imaging-Reporting and Data System (PI-RADS) has been widely implemented as a diagnostic tool for significant prostate cancer (PCa); less is known about its prognostic value, especially in the setting of primary radiotherapy. We aimed to analyze the association between PI-RADS v. 2.1 classification and risk of metastases, based on a group of 152 patients treated with ultra-hypofractionated stereotactic CyberKnife radiotherapy for localized low or intermediate risk-group prostate cancer. We found that all distant failures (n = 5) occurred in patients diagnosed with a PI-RADS score of 5, and axial measurements of the target lesion were associated with the risk of developing metastases (p < 0.001). The best risk stratification model (based on a combination of greatest dimension, the product of multiplication of PI-RADS target lesion axial measurements, and age) achieved a c-index of 0.903 (bootstrap-validated bias-corrected 95% CI: 0.848–0.901). This creates a hypothesis that PI-RADS 5 and the size of the target lesion are important prognostic factors in early-stage PCa patients and should be considered as an adverse prognostic measure for patients undergoing early treatment such as radiation or focal therapy.
Spherical Nucleic Acids as Precision Therapeutics for the Treatment of Cancer—From Bench to Bedside
Authors: Mahajan Akanksha S. , Stegh Alexander H.
Published: March 2022

Spherical Nucleic Acids (SNAs) emerged as a new class of nanotherapeutics consisting of a nanoparticle core densely functionalized with a shell of radially oriented synthetic oligonucleotides. The unique three-dimensional architecture of SNAs protects the oligonucleotides from nuclease-mediated degradation, increases oligonucleotide bioavailability, and in the absence of auxiliary transfection agents, enables robust uptake into tumor and immune cells through polyvalent association with cell surface pattern recognition receptors. When composed of gene-regulatory small interfering (si)RNA or immunostimulatory DNA or RNA oligonucleotides, SNAs silence gene expression and induce immune responses superior to those raised by the oligonucleotides in their “free” form. Early phase clinical trials of gene-regulatory siRNA-based SNAs in glioblastoma (NCT03020017) and immunostimulatory Toll-like receptor 9 (TLR9)-agonistic SNAs carrying unmethylated CpG-rich oligonucleotides in solid tumors (NCT03086278) have shown that SNAs represent a safe, brain-penetrant therapy for inhibiting oncogene expression and stimulating immune responses against tumors. This review focuses on the application of SNAs as precision cancer therapeutics, summarizes the findings from first-in-human clinical trials of SNAs in solid tumors, describes the most recent preclinical efforts to rationally design next-generation multimodal SNA architectures, and provides an outlook on future efforts to maximize the anti-neoplastic activity of the SNA platform.
Proton Beam Therapy in Managing Unresectable Hepatocellular Carcinoma with Bile Duct Invasion
Authors: Lee Ching-Hsin , Chen An-Hsin , Hung Sheng-Ping , Hsieh Cheng-En , Tseng Jeng-Hwei , Chen Po-Jui , Cheng Jen-Yu , Chang Joseph Tung-Chieh , Chan Kun-Ming , Lin Shi-Ming , Lin Chen-Chun , Chen Wei-Ting , Chen Wan-Yu , Huang Bing-Shen
Published: March 2022

Hepatocellular carcinoma (HCC) with bile duct invasion is a rare and notorious subtype of HCC. This study included patients that had unresectable HCC with bile duct invasion and proton beam therapy between November 2015 and February 2021. Twenty patients fit the inclusion criteria. The median tumor size was 6.3 cm. Nine patients (45.0%) had major vascular invasions. All included patients received the radiation dose of 72.6 gray relative biological effectiveness due to the proximity of porta hepatis and tumor. The median follow-up time was 19.9 months. The median overall survival was 19.9 months among deceased patients. The 1-year cumulative local recurrence rates were 5.3%, with only two patients developing in-field failure. The 1-year and 2-year overall survival rates were 79.4% and 53.3%. The 1-year progression-free survival was 58.9%. Four patients developed radiation-induced liver disease. The 1-year cholangitis-free survival was 55.0%. Skin toxicity was the most common acute toxicity and rarely severe. Eight patients developed ≤ grade 3 gastrointestinal ulcers. Proton beam therapy offers desirable survival outcomes for unresectable HCC patients with bile duct invasion. Optimal local tumor control could also be obtained within acceptable toxicities.
Targeted Dual-Modal PET/SPECT-NIR Imaging: From Building Blocks and Construction Strategies to Applications
Authors: Usama Syed Muhammad , Marker Sierra C. , Hernandez Vargas Servando , AghaAmiri Solmaz , Ghosh Sukhen C. , Ikoma Naruhiko , Tran Cao Hop S. , Schnermann Martin J. , Azhdarinia Ali
Published: March 2022

Molecular imaging is an emerging non-invasive method to qualitatively and quantitively visualize and characterize biological processes. Among the imaging modalities, PET/SPECT and near-infrared (NIR) imaging provide synergistic properties that result in deep tissue penetration and up to cell-level resolution. Dual-modal PET/SPECT-NIR agents are commonly combined with a targeting ligand (e.g., antibody or small molecule) to engage biomolecules overexpressed in cancer, thereby enabling selective multimodal visualization of primary and metastatic tumors. The use of such agents for (i) preoperative patient selection and surgical planning and (ii) intraoperative FGS could improve surgical workflow and patient outcomes. However, the development of targeted dual-modal agents is a chemical challenge and a topic of ongoing research. In this review, we define key design considerations of targeted dual-modal imaging from a topological perspective, list targeted dual-modal probes disclosed in the last decade, review recent progress in the field of NIR fluorescent probe development, and highlight future directions in this rapidly developing field.
Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers
Authors: Lechpammer Mirna , Rao Rohan , Shah Sanjit , Mirheydari Mona , Bhattacharya Debanjan , Koehler Abigail , Toukam Donatien Kamdem , Haworth Kevin J. , Pomeranz Krummel Daniel , Sengupta Soma
Published: March 2022

Glioblastoma, or glioblastoma multiforme (GBM, WHO Grade IV), is a highly aggressive adult glioma. Despite extensive efforts to improve treatment, the current standard-of-care (SOC) regimen, which consists of maximal resection, radiotherapy, and temozolomide (TMZ), achieves only a 12–15 month survival. The clinical improvements achieved through immunotherapy in several extracranial solid tumors, including non-small-cell lung cancer, melanoma, and non-Hodgkin lymphoma, inspired investigations to pursue various immunotherapeutic interventions in adult glioblastoma patients. Despite some encouraging reports from preclinical and early-stage clinical trials, none of the tested agents have been convincing in Phase III clinical trials. One, but not the only, factor that is accountable for the slow progress is the blood–brain barrier, which prevents most antitumor drugs from reaching the target in appreciable amounts. Herein, we review the current state of immunotherapy in glioblastoma and discuss the significant challenges that prevent advancement. We also provide thoughts on steps that may be taken to remediate these challenges, including the application of ultrasound technologies.
Modified eQTL and Somatic DNA Segment Alterations in Esophageal Squamous Cell Carcinoma for Genes Related to Immunity, DNA Repair, and Inflammation
Authors: Yang Howard H. , Liu Huaitian , Hu Nan , Su Hua , Wang Chaoyu , Giffen Carol , Goldstein Alisa M. , Taylor Philip R. , Lee Maxwell P.
Published: March 2022

We integrated ESCC expression and GWAS genotyping, to investigate eQTL and somatic DNA segment alterations, including somatic copy number alteration, allelic imbalance (AI), and loss of heterozygosity (LOH) in ESCC. First, in eQTL analysis, we used a classical approach based on genotype data from GWAS and expression signals in normal tissue samples, and then used a modified approach based on fold change in the tumor vs. normal samples. We focused on the genes in three pathways: inflammation, DNA repair, and immunity. Among the significant (p < 0.05) SNP-probe pairs from classical and modified eQTL analyses, 24 genes were shared by the two approaches, including 18 genes that showed the same numbers of SNPs and probes and 6 genes that had the different numbers of SNPs and probes. For these 18 genes, we found 28 SNP–probe pairs were correlated in opposite directions in the two approaches, indicating an intriguing difference between the classical and modified eQTL approaches. Second, we analyzed the somatic DNA segment alterations. Across the 24 genes, abnormal gene expression on mRNA arrays was seen in 19–95% of cases and 26–78% showed somatic DNA segment alterations on Affymetrix GeneChip Human Mapping Arrays. The results suggested that this strategy could identify gene expression and somatic DNA segment alterations for biological markers (genes) by combining classical and modified eQTLs and somatic DNA evaluation on SNP arrays. Thus, this study approach may allow us to understand functionality indicative of potentially relevant biomarkers in ESCC.
5-Azacytidine Downregulates the Proliferation and Migration of Hepatocellular Carcinoma Cells In Vitro and In Vivo by Targeting miR-139-5p/ROCK2 Pathway
Authors: Tonon Federica , Cemazar Maja , Kamensek Urska , Zennaro Cristina , Pozzato Gabriele , Caserta Sergio , Ascione Flora , Grassi Mario , Guido Stefano , Ferrari Cinzia , Cansolino Laura , Trotta Francesco , Kuzmanov Biljana Grcar , Forte Giancarlo , Martino Fabiana , Perrone Francesca , Bomben Riccardo , Gattei Valter , Elvassore Nicola , Murano Erminio , Truong Nhung Hai , Olson Michael , Farra Rossella , Grassi Gabriele , Dapas Barbara
Published: March 2022

Background: For hepatocellular carcinoma (HCC), effective therapeutic approaches are lacking. As aberrant gene methylation is a major contributor to HCC development, demethylating drugs such as 5-azacytidine (5-Aza) have been proposed. As most 5-Aza mechanisms of action are unknown, we investigated its phenotypic/molecular effects. Methods: 5-Aza effects were examined in the human HCC cell lines JHH-6/HuH-7 and in the rat cell-line N1-S1. We also employed a xenograft mouse model (HuH-7), a zebrafish model (JHH-6), and an orthotopic syngeneic rat model (N1-S1) of HCC. Results: 5-Aza downregulated cell viability/growth/migration/adhesion by upregulating miR-139-5p, which in turn downregulated ROCK2/cyclin D1/E2F1 and increased p27kip1, resulting in G1/G0 cell accumulation. Moreover, a decrease in cyclin B1 and an increase in p27kip1 led to G2/M accumulation. Finally, we observed a decrease in MMP-2 levels, a stimulator of HCC cell migration. Aza effects were confirmed in the mouse model; in the zebrafish model, we also demonstrated the downregulation of tumor neo-angiogenesis, and in the orthotopic rat model, we observed impaired N1-S1 grafting in a healthy liver. Conclusion: We demonstrate for the first time that 5-Aza can impair HCC development via upregulation of miR-139-5p, which in turn impairs the ROCK2/cyclin D1/E2F1/cyclin B1 pro-proliferative pathway and the ROCK2/MMP-2 pro-migratory pathway. Thus, we provide novel information about 5-Aza mechanisms of action and deepen the knowledge about the crosstalk among ROCK2/cyclin D1/E2F1/cyclin B1/p27kip1/MMP-2 in HCC.
Quantifying Tumor Heterogeneity from Multiparametric Magnetic Resonance Imaging of Prostate Using Texture Analysis
Authors: Alanezi Saleh T. , Sullivan Frank , Kleefeld Christoph , Greally John F. , Kraśny Marcin J. , Woulfe Peter , Sheppard Declan , Colgan Niall
Published: March 2022

(1) Background: Multiparametric MRI (mp-MRI) is used to manage patients with PCa. Tumor identification via irregular sampling or biopsy is problematic and does not allow the comprehensive detection of the phenotypic and genetic alterations in a tumor. A non-invasive technique to clinically assess tumor heterogeneity is also in demand. We aimed to identify tumor heterogeneity from multiparametric magnetic resonance images using texture analysis (TA). (2) Methods: Eighteen patients with prostate cancer underwent mp-MRI scans before prostatectomy. A single radiologist matched the histopathology report to single axial slices that best depicted tumor and non-tumor regions to generate regions of interest (ROIs). First-order statistics based on the histogram analysis, including skewness, kurtosis, and entropy, were used to quantify tumor heterogeneity. We compared non-tumor regions with significant tumors, employing the two-tailed Mann–Whitney U test. Analysis of the area under the receiver operating characteristic curve (ROC-AUC) was used to determine diagnostic accuracy. (3) Results: ADC skewness for a 6 × 6 px filter was significantly lower with an ROC-AUC of 0.82 (p = 0.001). The skewness of the ADC for a 9 × 9 px filter had the second-highest result, with an ROC-AUC of 0.66; however, this was not statistically significant (p = 0.08). Furthermore, there were no substantial distinctions between pixel filter size groups from the histogram analysis, including entropy and kurtosis. (4) Conclusions: For all filter sizes, there was poor performance in terms of entropy and kurtosis histogram analyses for cancer diagnosis. Significant prostate cancer may be distinguished using a textural feature derived from ADC skewness with a 6 × 6 px filter size.
Safety and Efficacy of Transarterial Chemoembolization in Elderly Patients with Intermediate Hepatocellular Carcinoma
Authors: Roth Gael S. , Hernandez Olivier , Daabek Najeh , Brusset Bleuenn , Teyssier Yann , Ghelfi Julien , Hilleret Marie Noelle , Sengel Christian , Bricault Ivan , Decaens Thomas , Costentin Charlotte
Published: March 2022

(1) Introduction: Transarterial chemoembolization (TACE) is the most widely used treatment for intermediate hepatocellular carcinoma (HCC), with limited data available in elderly patients. This study compares the safety and efficacy of TACE for HCC in elderly patients (≥70 years) versus younger patients (<70 years). (2) Materials and Methods: Patients treated by a first TACE for HCC at Grenoble-Alpes University Hospital from January 2012 to March 2017 were included. The primary objective was to compare the safety and predictive factors of serious adverse events between groups using univariate and multivariate analyses. Secondary objectives included tumor response and survival analyses. (3) Results: 271 patients were included: 88 elderly and 183 under 70 years. A total of 20.5% of elderly patients experienced serious adverse events versus 21.3% of patients under 70 (p = 0.87). The predictive factors of serious adverse events were Child–Pugh ≥ B7 (p < 0.0001), ECOG ≥ 1 (p = 0.0019), and MELD ≥ 9 (p = 0.0415). The serious adverse event rate was not increased with age (p = 0.87). The objective tumor response rate was 89.5% in elderly versus 78.7% in younger patients (p = 0.03). (4) Conclusion: This study showed similar safety profiles of the first TACE between elderly and younger patients, with comparable efficacy outcomes, suggesting that advanced age should not constitute a limitation in itself in treatment decision-making.
Intention to Inform Relatives, Rates of Cascade Testing, and Preference for Patient-Mediated Communication in Families Concerned with Hereditary Breast and Ovarian Cancer and Lynch Syndrome: The Swiss CASCADE Cohort
Authors: Sarki Mahesh , Ming Chang , Aissaoui Souria , Bürki Nicole , Caiata-Zufferey Maria , Erlanger Tobias Ephraim , Graffeo-Galbiati Rossella , Heinimann Karl , Heinzelmann-Schwarz Viola , Monnerat Christian , Probst-Hensch Nicole , Rabaglio Manuela , Zürrer-Härdi Ursina , Chappuis Pierre Olivier , Katapodi Maria C. ,   on behalf of the CASCADE Consortium
Published: March 2022

Cascade screening for Tier 1 cancer genetic conditions is a significant public health intervention because it identifies untested relatives of individuals known to carry pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS). The Swiss CASCADE is a family-based, open-ended cohort, including carriers of HBOC- and LS-associated pathogenic variants and their relatives. This paper describes rates of cascade screening in relatives from HBOC- and LS- harboring families, examines carriers’ preferences for communication of testing results, and describes theory-based predictors of intention to invite relatives to a cascade screening program. Information has been provided by 304 index cases and 115 relatives recruited from September 2017 to December 2021. On average, 10 relatives per index case were potentially eligible for cascade screening. Approximately 65% of respondents wanted to invite relatives to the cohort, and approximately 50% indicated a preference for patient-mediated communication of testing results, possibly with the assistance of digital technology. Intention to invite relatives was higher for first- compared to second- and third-degree relatives, but was not different between syndromes or based on relatives’ gender. The family environment and carrying pathogenic variants predicts intention to invite relatives. Information helps optimize delivery of tailored genetic services.
Sustainable Catalytic Synthesis of 2,5-Diformylfuran from Various Carbohydrates
Authors: Kim Si , Sung Kihyuk , Jang June , Bang Sohee , Son Seung , Jang Hye-Young
Published: March 2022

Versatile homogeneous and heterogeneous catalysts that convert carbohydrates to 2,5-diformylfuran (DFF) are essential for the development of sustainable processes for producing high-value chemicals from biomass-derived carbohydrates. An efficient catalytic system consisting of Br−, disulfide, and dimethylsulfoxide (DMSO) promoted the sustainable and selective synthesis of DFF in modest-to-good yields from various carbohydrates, such as fructose, glucose, mannose, galactose, and sucrose. Heterogeneous catalysts containing Br− also facilitated this reaction with recyclable high yields.
The Effect of Calcination Temperature on Various Sources of ZrO2 Supported Ni Catalyst for Dry Reforming of Methane
Authors: Ibrahim Ahmed Aidid , Fakeeha Anis Hamza , Lanre Mahmud Sofiu , Al-Awadi Abdulrhman S. , Alreshaidan Salwa Bader , Albaqmaa Yousef Abdulrahman , Adil Syed Farooq , Al-Zahrani Ateyah A. , Abasaeed Ahmed Elhag , Al-Fatesh Ahmed S.
Published: March 2022

Dry reforming of methane (DRM) over an Ni-based catalyst is an innovative research area due to the growing environmental awareness about mitigating global warming gases (CH4 and CO2) and creating a greener route of synthesis. Herein, 5% Ni supported on ZrO2 obtained from various sources was prepared by the impregnation method. The catalysts were calcined at 600, 700, and 800 °C. Furthermore, Ni-RC stabilized with MgO, SiO2, TiO2, and Y2O3 were tested. Characterization techniques employed comprise the N2 physisorption, infrared spectroscopy, Raman, thermogravimetric analysis, XRD, and TEM. The results of the present study indicated that the ZrO2 support source had a profound effect on the overall performance of the process. The best catalyst Ni-RC gave an average conversion of CH4 and CO2 of 61.5% and 63.6% and the least deactivation of 10.3%. The calcination pretreatment differently influenced the catalyst performance. When the average methane conversion was higher than 40%, increasing the calcination temperature decreased the activity. While for the low activity catalysts with an average methane conversion of less than 40% the impact of the calcination temperature did not constantly decrease with the temperature rise. The stabilization of Ni-RC denoted the preference Y2O3 stabilized catalyst with average values of CH4 and CO2 conversion of about 67% and 72%, respectively. The thorough study and fine correlation will be advantageous for technologically suitable Ni-15Y-RC catalysts for DRM.
Pyrolysis Combined with the Dry Reforming of Waste Plastics as a Potential Method for Resource Recovery—A Review of Process Parameters and Catalysts
Authors: Pawelczyk Ewelina , Wysocka Izabela , Gębicki Jacek
Published: March 2022

Emissions of greenhouse gases and growing amounts of waste plastic are serious environmental threats that need urgent attention. The current methods dedicated to waste plastic recycling are still insufficient and it is necessary to search for new technologies for waste plastic management. The pyrolysis-catalytic dry reforming (PCDR) of waste plastic is a promising pro-environmental way employed for the reduction of both CO2 and waste plastic remains. PCDR allows for resource recovery, converting carbon dioxide and waste plastics into synthetic gas. The development and optimization of this technology for the high yield of high-quality synthesis gas generation requires the full understanding of the complex influence of the process parameters on efficiency and selectivity. In this regard, this review summarizes the recent findings in the field. The effect of process parameters as well as the type of catalyst and feedstock are reviewed and discussed.
Progesterone and Inflammatory Response in the Oviduct during Physiological and Pathological Conditions
Authors: McGlade Emily A. , Miyamoto Akio , Winuthayanon Wipawee
Published: March 2022

Progesterone has been shown to be a potent suppressor of several inflammatory pathways. During pregnancy, progesterone levels increase, allowing for normal pregnancy establishment and maintenance. The dysregulation of progesterone, as well as inflammation, leads to poor pregnancy outcomes. However, it is unclear how progesterone imbalance could impact inflammatory responses in the oviduct and subsequently result in early pregnancy loss. Therefore, in this review, we describe the role of progesterone signaling in regulating the inflammatory response, with a focus on the oviduct and pathological conditions in the Fallopian tubes.
Role of Platelets in Osteoarthritis—Updated Systematic Review and Meta-Analysis on the Role of Platelet-Rich Plasma in Osteoarthritis
Authors: Tramś Ewa , Malesa Kamila , Pomianowski Stanisław , Kamiński Rafał
Published: March 2022

Platelets are an essential component of hemostasis, with an increasing role in host inflammatory processes in injured tissues. The reaction between receptors and vascular endothelial cells results in the recruitment of platelets in the immune response pathway. The aim of the present review is to describe the role of platelets in osteoarthritis. Platelets induce secretion of biological substances, many of which are key players in the inflammatory response in osteoarthritis. Molecules involved in cartilage degeneration, or being markers of inflammation in osteoarthritis, are cytokines, such as tumor necrosis factor α (TNFα), interleukins (IL), type II collagen, aggrecan, and metalloproteinases. Surprisingly, platelets may also be used as a treatment modality for osteoarthritis. Multiple randomized controlled trials included in our systematic review and meta-analyses prove the effectiveness of platelet-rich plasma (PRP) as a minimally invasive method of pain alleviation in osteoarthritis treatment.
Designing Personalized Antigen-Specific Immunotherapies for Autoimmune Diseases—The Case for Using Ignored Target Cell Antigen Determinants
Authors: Tian Jide , Song Min , Kaufman Daniel L.
Published: March 2022

We have proposed that antigen-specific immunotherapies (ASIs) for autoimmune diseases could be enhanced by administering target cell antigen epitopes (determinants) that are immunogenic but ignored by autoreactive T cells because these determinants may have large pools of naïve cognate T cells available for priming towards regulatory responses. Here, we identified an immunogenic preproinsulin determinant (PPIL4-20) that was ignored by autoimmune responses in type 1 diabetes (T1D)-prone NOD mice. The size of the PPIL4-20-specific splenic naive T cell pool gradually increased from 2–12 weeks in age and remained stable thereafter, while that of the major target determinant insulin B-chain9-23 decreased greatly after 12 weeks in age, presumably due to recruitment into the autoimmune response. In 15–16 week old mice, insulin B-chain9-23/alum immunization induced modest-low level of splenic T cell IL-10 and IL-4 responses, little or no spreading of these responses, and boosted IFNγ responses to itself and other autoantigens. In contrast, PPIL4-20/alum treatment induced robust IL-10 and IL-4 responses, which spread to other autoantigens and increased the frequency of splenic IL-10-secreting Treg and Tr-1-like cells, without boosting IFNγ responses to ß-cell autoantigens. In newly diabetic NOD mice, PPIL4-20, but not insulin B-chain9-23 administered intraperitoneally (with alum) or intradermally (as soluble antigen) supplemented with oral GABA induced long-term disease remission. We discuss the potential of personalized ASIs that are based on an individual’s naïve autoantigen-reactive T cell pools and the use of HLA-appropriate ignored autoantigen determinants to safely enhance the efficacy of ASIs.
Interactions between the Nociceptin and Toll-like Receptor Systems
Authors: Zhang Lan , Stamer Ulrike M. , Huang Melody Ying-Yu , Stüber Frank
Published: March 2022

Nociceptin and the nociceptin receptor (NOP) have been described as targets for treatment of pain and inflammation, whereas toll-like receptors (TLRs) play key roles in inflammation and impact opioid receptors and endogenous opioids expression. In this study, interactions between the nociceptin and TLR systems were investigated. Human THP-1 cells were cultured with or without phorbol myristate acetate (PMA 5 ng/mL), agonists specific for TLR2 (lipoteichoic acid, LTA 10 µg/mL), TLR4 (lipopolysaccharide, LPS 100 ng/mL), TLR7 (imiquimod, IMQ 10 µg/mL), TLR9 (oligonucleotide (ODN) 2216 1 µM), PMA+TLR agonists, or nociceptin (0.01–100 nM). Prepronociceptin (ppNOC), NOP, and TLR mRNAs were quantified by RT-qPCR. Proteins were measured using flow cytometry. PMA upregulated ppNOC mRNA, intracellular nociceptin, and cell membrane NOP proteins (all p < 0.05). LTA and LPS prevented PMA’s upregulating effects on ppNOC mRNA and nociceptin protein (both p < 0.05). IMQ and ODN 2216 attenuated PMA’s effects on ppNOC mRNA. PMA, LPS, IMQ, and ODN 2216 increased NOP protein levels (all p < 0.05). PMA+TLR agonists had no effects on NOP compared to PMA controls. Nociceptin dose-dependently suppressed TLR2, TLR4, TLR7, and TLR9 proteins (all p < 0.01). Antagonistic effects observed between the nociceptin and TLR systems suggest that the nociceptin system plays an anti-inflammatory role in monocytes under inflammatory conditions.