bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Nature and Origin of Atmospheric Annual and Semi-Annual Oscillations
Authors: Courtillot Vincent , Le Mouël Jean-Louis , Lopes Fernando , Gibert Dominique
Published: November 2022

This paper proposes a joint analysis of variations of global sea-level pressure (SLP) and of Earth’s rotation (RP), expressed as the coordinates of the rotation pole (m1, m2) and length of day (lod). We retain iterative singular spectrum analysis (iSSA) as the main tool to extract the trend, periods, and quasi periods in the data time series. SLP components are a weak trend, seven quasi-periodic or periodic components (∼130, 90, 50, 22, 15, 4, 1.8 years), an annual cycle, and its first three harmonics. These periods are characteristic of the space-time evolution of the Earth’s rotation axis and are present in many characteristic features of solar and terrestrial physics. The amplitudes of the annual SLP component and its three first harmonics decrease from 93 hPa for the annual to 21 hPa for the third harmonic. In contrast, the components with pseudo-periods longer than a year range between 0.2 and 0.5 hPa. We focus mainly on the annual and, to a lesser extent, the semi-annual components. The annual RP and SLP components have a phase lag of 152 days (half the Euler period). Maps of the first three components of SLP (that together comprise 85% of the data variance) reveal interesting symmetries. The trend is very stable and forms a triskeles structure that can be modeled as Taylor–Couette flow of mode 3. The annual component is characterized by a large negative anomaly extending over Eurasia in the NH summer (and the opposite in the NH winter) and three large positive anomalies over Australia and the southern tips of South America and South Africa in the SH spring (and the opposite in the SH autumn), forming a triskeles. The semi-annual component is characterized by three positive anomalies (an irregular triskeles) in the NH spring and autumn (and the opposite in the NH summer and winter), and in the SH spring and autumn by a strong stable pattern consisting of three large negative anomalies forming a clear triskeles within the 40–60∘ annulus formed by the southern oceans. A large positive anomaly centered over Antarctica, with its maximum displaced toward Australia, and a smaller one centered over Southern Africa, complement the pattern. Analysis of iSSA components of global sea level pressure shows a rather simple spatial distribution with the principal forcing factor being changes in parameters of the Earth’s rotation pole and velocity. The flow can probably best be modeled as a set of coaxial cylinders arranged in groups of three (triskeles) or four and controlled by Earth topography and continent/ocean boundaries. Flow patterns suggested by maps of the three main iSSA components of SLP (trend, annual, and semi-annual) are suggestive of Taylor–Couette flow. The envelopes of the annual components of SLP and RP are offset by four decades, and there are indications that causality is present in that changes in Earth rotation axis lead force pressure variations.
Extreme Months: Multidimensional Studies in the Carpathian Basin
Authors: Izsák Beatrix , Szentimrey Tamás , Lakatos Mónika , Pongrácz Rita
Published: November 2022

In addition to the one-dimensional mathematical statistical methods used to study the climate and its possible variations, the study of several elements together is also worthwhile. Here, a combined analysis of precipitation and temperature time series was performed using the norm method based on the probability distribution of the elements. This means, schematically speaking, that each component was transformed into a standard normal distribution so that no element was dominant. The transformed components were sorted into a vector, the inverse of the correlation matrix was determined and the resulting norm was calculated. Where this norm was at the maximum, the extreme vector, in this case the extreme month, was found. In this paper, we presented the results obtained from a joint analysis of the monthly precipitation and temperature time series for the whole territory of Hungary over the period 1871–2020. To do this, multidimensional statistical tests that allowed the detection of climate change were defined. In the present analysis, we restricted ourselves to two-dimensional analyses. The results showed that none of the tests could detect two-dimensional climate change on a spatial average for the months of January, April, July and December, while all the statistical tests used indicated a clear change in the months of March and August. As for the other months, one or two, but not necessarily all tests, showed climate change in two dimensions.
The Pattern of Tooth Loss for Periodontally Favorable Teeth: A Retrospective Study
Authors: Yanni Peter , Curtis Donald A. , Kao Richard T. , Lin Guo-Hao
Published: November 2022

To retrospectively analyze local and systemic factors that resulted in the short-term tooth loss of teeth that were previously assigned a favorable prognosis in patients who were seen and treated over an observational five-year period. This retrospective study included the records of patients who had a minimum of two dental exams at least twelve months apart over a 5-year period. This study investigated extracted teeth with an initially favorable periodontal prognosis that were then divided into one of four categories based on the reason for extraction: caries, periodontal disease, endodontic reasons, or fracture. Patient- and tooth-related factors associated with the extracted teeth were recorded: crown-to-root ratio, initial pocket depth, initial periodontal diagnosis, maintenance interval, presence of existing restoration, furcation involvement, and systemic conditions. Data analysis was performed using a linear mixed model. A total of 50 patients with 111 teeth met the inclusion criteria for this study. A higher odds ratio (OR) for tooth loss due to caries, endodontic reasons, and fracture were found in teeth with a history of root canal treatment with an OR of 3.61, 3.86, and 2.52, respectively. For tooth loss due to periodontal disease, higher ORs were found in patients who were on anti-depressants (OR = 4.28) and patients who had an initial diagnosis of Stage III/IV periodontitis (OR = 2.66). In addition, teeth with initial probing depths ≥5 mm (OR = 4.32) and with furcation involvement (OR = 1.93) showed a higher OR for tooth loss due to periodontal disease. Within the limitations of this study, previously root-canal-treated teeth present a higher OR for early loss due to caries, recurrent endodontic lesions, or fracture. In addition, patients with anti-depressant medication use, sporadic maintenance, initial probing depths ≥5 mm, and furcation involvement represent a significantly higher OR of tooth loss due to periodontal disease even for initially favorable teeth.
The Effect of Date Palm Genotypes on Rhizobacterial Community Structures under Saline Environments
Authors: Al-Busaidi Aya , Glick Bernard R. , Yaish Mahmoud W.
Published: November 2022

Some genotypes of date palms (Phoenix dactylifera L.) are salt-tolerant; however, salinity significantly affects others. This study aimed to determine the root epiphytic bacterial contributions to the salt tolerance mechanism in the date palm and to verify if the salt-tolerant “Umsila” and the salt-susceptible “Zabad” cultivars have different bacterial communities. Therefore, the epiphytic bacterial community structures were investigated in both cultivars when grown under control and salinity conditions. The proximal soils of the roots were collected, the DNA was extracted, and a culture-independent approach using Illumina® MiSeq™ sequence analysis was carried out to identify the changes in the bacterial community structures in the soil samples due to the changes in salinity and the genotypes of the plants based on 16S rRNA gene sequencing. While salt tolerance response differences were evident between the two cultivars, the 16S rRNA gene sequencing results revealed 771 operational taxonomic units (OTUs), including 62 that were differentially accumulated in response to salinity. The ordination analysis showed significant (p = 0.001) changes among the communities in response to salinity in both cultivars. However, the results showed that the two cultivars had distinct bacterial communities when grown under controlled conditions, whereas they had a more similar bacterial community structure when grown under salinity conditions. The plant genotype does not affect the epiphyte bacterial community structure under salinity, probably because salinity affects the plant-microbe interaction similarly in both cultivars. Also, the identified rhizospheric bacteria are not directly associated with the root’s physiological processes in response to salinity.
Stk10 Deficiency in Mice Promotes Tumor Growth by Dysregulating the Tumor Microenvironment
Authors: Ma Jin-Xia , Xu Dan-Dan , Lu Shun-Yuan , Wang Qian-Lan , Zhang Lu , Guo Rui , Tang Ling-Yun , Shen Yan , Shen Chun-Ling , Wang Jin-Jin , Lu Li-Ming , Wang Zhu-Gang , Zhang Hong-Xin
Published: November 2022

Serine-threonine kinase 10 (STK10) is a member of the STE20/p21-activated kinase (PAK) family and is predominantly expressed in immune organs. Our previous reports suggested that STK10 participates in the growth and metastasis of prostate cancer via in vitro and in vivo data. However, the correlation between STK10 and the tumor microenvironment (TME) remains unclear. In this study, we assessed the relationship between STK10 and the immune cells in the tumor microenvironment of prostate cancer through bioinformatic analysis, and investigated the role of Stk10 in tumor growth using an Stk10 knockout mouse model. The results showed that STK10 is significantly associated with the tumor-infiltrating immune cells including lymphocytes, neutrophils, macrophages and dendritic cells. The target deletion of host Stk10 results in increased tumor growth, due to decreased activated/effector cytotoxic T lymphocytes (CTLs) and increased vessel density in the TME. In conclusion, we demonstrate that host Stk10 is involved in the host anti-tumor response by modulating the activated tumor-infiltrated CTLs and angiogenesis.
An Evolutionary Perspective on the Origin, Conservation and Binding Partner Acquisition of Tankyrases
Authors: Sowa Sven T. , Bosetti Chiara , Galera-Prat Albert , Johnson Mark S. , Lehtiö Lari
Published: November 2022

Tankyrases are poly-ADP-ribosyltransferases that regulate many crucial and diverse cellular processes in humans such as Wnt signaling, telomere homeostasis, mitotic spindle formation and glucose metabolism. While tankyrases are present in most animals, functional differences across species may exist. In this work, we confirm the widespread distribution of tankyrases throughout the branches of multicellular animal life and identify the single-celled choanoflagellates as earliest origin of tankyrases. We further show that the sequences and structural aspects of TNKSs are well-conserved even between distantly related species. We also experimentally characterized an anciently diverged tankyrase homolog from the sponge Amphimedon queenslandica and show that the basic functional aspects, such as poly-ADP-ribosylation activity and interaction with the canonical tankyrase binding peptide motif, are conserved. Conversely, the presence of tankyrase binding motifs in orthologs of confirmed interaction partners varies greatly between species, indicating that tankyrases may have different sets of interaction partners depending on the animal lineage. Overall, our analysis suggests a remarkable degree of conservation for tankyrases, and that their regulatory functions in cells have likely changed considerably throughout evolution.
Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-β1: Relevance to Pseudoexfoliation Glaucoma
Authors: Roodnat Anton W. , Callaghan Breedge , Doyle Chelsey , Henry Megan , Goljanek-Whysall Katarzyna , Simpson David A. , Sheridan Carl , Atkinson Sarah D. , Willoughby Colin E.
Published: November 2022

Pseudoexfoliation glaucoma (XFG) is an aggressive form of secondary open angle glaucoma, characterised by the production of exfoliation material and is estimated to affect 30 million people worldwide. Activation of the TGF-β pathway by TGF-β1 has been implicated in the pathogenesis of pseudoexfoliation glaucoma. To further investigate the role of TGF-β1 in glaucomatous changes in the trabecular meshwork (TM), we used RNA-Seq to determine TGF-β1 induced changes in the transcriptome of normal human trabecular meshwork (HTM) cells. The main purpose of this study was to perform a hypothesis-independent RNA sequencing analysis to investigate genome-wide alterations in the transcriptome of normal HTMs stimulated with TGF-β1 and investigate possible pathophysiological mechanisms driving XFG. Our results identified multiple differentially expressed genes including several genes known to be present in exfoliation material. Significantly altered pathways, biological processes and molecular functions included extracellular matrix remodelling, Hippo and Wnt pathways, the unfolded protein response, oxidative stress, and the antioxidant system. This cellular model of pseudoexfoliation glaucoma can provide insight into disease pathogenesis and support the development of novel therapeutic interventions.
Use of Hypoxic Respiratory Challenge for Differentiating Alzheimer’s Disease and Wild-Type Mice Non-Invasively: A Diffuse Optical Spectroscopy Study
Authors: Seong Myeongsu , Oh Yoonho , Park Hyung Joon , Choi Won-Seok , Kim Jae Gwan
Published: November 2022

Alzheimer’s disease is one of the most critical brain diseases. The prevalence of the disease keeps rising due to increasing life spans. This study aims to examine the use of hemodynamic signals during hypoxic respiratory challenge for the differentiation of Alzheimer’s disease (AD) and wild-type (WT) mice. Diffuse optical spectroscopy, an optical system that can non-invasively monitor transient changes in deoxygenated (ΔRHb) and oxygenated (ΔOHb) hemoglobin concentrations, was used to monitor hemodynamic reactivity during hypoxic respiratory challenges in an animal model. From the acquired signals, 13 hemodynamic features were extracted from each of ΔRHb and −ΔOHb (26 features total) for more in-depth analyses of the differences between AD and WT. The hemodynamic features were statistically analyzed and tested to explore the possibility of using machine learning (ML) to differentiate AD and WT. Among the twenty-six features, two features of ΔRHb and one feature of −ΔOHb showed statistically significant differences between AD and WT. Among ML techniques, a naive Bayes algorithm achieved the best accuracy of 84.3% when whole hemodynamic features were used for differentiation. While further works are required to improve the approach, the suggested approach has the potential to be an alternative method for the differentiation of AD and WT.
Recent Advances in Biosensor Technologies for Point-of-Care Urinalysis
Authors: Hwang Chuljin , Lee Won-June , Kim Su Dong , Park Sungjun , Kim Joo Hee
Published: November 2022

Human urine samples are non-invasive, readily available, and contain several components that can provide useful indicators of the health status of patients. Hence, urine is a desirable and important template to aid in the diagnosis of common clinical conditions. Conventional methods such as dipstick tests, urine culture, and urine microscopy are commonly used for urinalysis. Among them, the dipstick test is undoubtedly the most popular owing to its ease of use, low cost, and quick response. Despite these advantages, the dipstick test has limitations in terms of sensitivity, selectivity, reusability, and quantitative evaluation of diseases. Various biosensor technologies give it the potential for being developed into point-of-care (POC) applications by overcoming these limitations of the dipstick test. Here, we present a review of the biosensor technologies available to identify urine-based biomarkers that are typically detected by the dipstick test and discuss the present limitations and challenges that future development for their translation into POC applications for urinalysis.
Virtual Intelligence: A Systematic Review of the Development of Neural Networks in Brain Simulation Units
Authors: Zavala Hernández Jesús Gerardo , Barbosa-Santillán Liliana Ibeth
Published: November 2022

The functioning of the brain has been a complex and enigmatic phenomenon. From the first approaches made by Descartes about this organism as the vehicle of the mind to contemporary studies that consider the brain as an organism with emergent activities of primary and higher order, this organism has been the object of continuous exploration. It has been possible to develop a more profound study of brain functions through imaging techniques, the implementation of digital platforms or simulators through different programming languages and the use of multiple processors to emulate the speed at which synaptic processes are executed in the brain. The use of various computational architectures raises innumerable questions about the possible scope of disciplines such as computational neurosciences in the study of the brain and the possibility of deep knowledge into different devices with the support that information technology (IT) brings. One of the main interests of cognitive science is the opportunity to develop human intelligence in a system or mechanism. This paper takes the principal articles of three databases oriented to computational sciences (EbscoHost Web, IEEE Xplore and Compendex Engineering Village) to understand the current objectives of neural networks in studying the brain. The possible use of this kind of technology is to develop artificial intelligence (AI) systems that can replicate more complex human brain tasks (such as those involving consciousness). The results show the principal findings in research and topics in developing studies about neural networks in computational neurosciences. One of the principal developments is the use of neural networks as the basis of much computational architecture using multiple techniques such as computational neuromorphic chips, MRI images and brain–computer interfaces (BCI) to enhance the capacity to simulate brain activities. This article aims to review and analyze those studies carried out on the development of different computational architectures that focus on affecting various brain activities through neural networks. The aim is to determine the orientation and the main lines of research on this topic and work in routes that allow interdisciplinary collaboration.
A Potential Prognosis Indicator Based on P300 Brain–Computer Interface for Patients with Disorder of Consciousness
Authors: Li Jingcong , Huang Biao , Wang Fei , Xie Qiuyou , Xu Chengwei , Huang Haiyun , Pan Jiahui
Published: November 2022

For patients with disorders of consciousness, such as unresponsive wakefulness syndrome (UWS) patients and minimally conscious state (MCS) patients, their long treatment cycle and high cost commonly put a heavy burden on the patient’s family and society. Therefore, it is vital to accurately diagnose and predict consciousness recovery for such patients. In this paper, we explored the role of the P300 signal based on an audiovisual BCI in the classification and prognosis prediction of patients with disorders of consciousness. This experiment included 18 patients: 10 UWS patients and 8 MCS- patients. At the three-month follow-up, we defined patients with an improved prognosis (from UWS to MCS-, from UWS to MCS+, or from MCS- to MCS+) as “improved patients” and those who stayed in UWS/MCS as “not improved patients”. First, we compared and analyzed different types of patients, and the results showed that the P300 detection accuracy rate of “improved” patients was significantly higher than that of “not improved” patients. Furthermore, the P300 detection accuracy of traumatic brain injury (TBI) patients was significantly higher than that of non-traumatic brain injury (NTBI, including acquired brain injury and cerebrovascular disease) patients. We also found that there was a positive linear correlation between P300 detection accuracy and CRS-R score, and patients with higher P300 detection accuracy were likely to achieve higher CRS-R scores. In addition, we found that the patients with higher P300 detection accuracies tend to have better prognosis in this audiovisual BCI. These findings indicate that the detection accuracy of P300 is significantly correlated with the level of consciousness, etiology, and prognosis of patients. P300 can be used to represent the preservation level of consciousness in clinical neurophysiology and predict the possibility of recovery in patients with disorders of consciousness.
Evacuation of Shelter in Place at Subway Transfer Stations Based on BIM and Proposal of a Strengthening Method
Authors: Kim Young-Hwi , Choi Jin-Seok , Yuan Tian-Feng , Yoon Young-Soo
Published: November 2022

Among public facilities, facilities belonging to Multi-Group (I) include high-rise buildings, tunnels, and subway stations, and the location of Shelter in Place (SIP) is an important factor in the safety of citizens. However, subway evacuation maps usually induce evacuation to ground level or the tunnel of a subway platform without considering the location of SIP. In other words, since the location of the SIP is not determined, conditions, such as ventilation, air conditioning facilities, and structural durability required for the SIP cannot be satisfied. It is difficult to suggest the location of SIP because the domestic standards limit only the time it takes to move from the outside to the facility designated as SIP during an emergency evacuation. Therefore, in this study, when there is a situation of emergency evacuation in the subway, the total allowed time to evacuate to SIP is limited to 6 min. We designate a space that can accommodate the number of evacuees at the location and compare and analyze the results of the evacuation simulation using six scenarios. Additionally, suggestions are made for improvement methods relating to evacuation as well as the proposal of reinforcement methods through an experiment to satisfy the structural requirements of SIP in subway stations.
Natural and Mechanical Ventilation Concepts for Indoor Comfort and Well-Being with a Sustainable Design Perspective: A Systematic Review
Authors: Zaniboni Luca , Albatici Rossano
Published: November 2022

Current literature and guidelines on sustainable design often debate on the advantages of natural ventilation (NV) and mechanical ventilation (MV) on indoor environment and energy consumption. The present systematic review explores the existing literature comparing NV and MV on the indoor comfort and well-being points of view. The findings emphasize that thermo-hygrometric comfort is the main driver of occupants’ ventilation behavior, while ventilation design is mainly led by indoor air quality targets. Moreover, more recent papers (especially after COVID-19 outbreak) emphasize the necessity of a health-based approach, contrasting airborne pathogens transmission. In this sense, MV is more frequently recommended in public spaces, while hybrid ventilation (HV) is often suggested as a solution to both ensure proper indoor conditions and energy savings. The concept of well-being is currently under-explored, as the present literature only refers to comfort. The same happens with topics such as visual, acoustic, and multi-domain comfort, as well as passive techniques such as night cooling, or analysis of specific environments such as healthcare facilities. Current knowledge would benefit from an expansion of future research in these directions. The choice of the best ventilation solution cannot ignore the context, type, and condition of energy efficient buildings, in order to properly take into account occupants’ well-being.
Fabrication of Metal/Graphene Composites via Cold Spray Process: State-of-the-Art and the Way Forward
Authors: Prasad Krishnamurthy , Rahman Rashid Rizwan Abdul , Hutasoit Novana , Palanisamy Suresh , Hameed Nishar
Published: November 2022

Cold spray (CS)-fabricated metal–graphene composites have applications in several fields ranging from tribology and corrosion protection to antibacterial applications. However, it is critical from a process perspective to create a viable feedstock, and to this end, there are two widely reported techniques: ball milling and in situ reduction. In this paper, the CS feedstocks prepared via these two methods are compared and contrasted with other miscellaneous techniques in the literature based on their efficacies and the end properties of the fabricated coatings. CS metal–graphene composite coatings are found to display self-healing behaviour and excellent corrosion/wear resistance and mechanical properties, but at this juncture, there is a gap in the literature as far as the CS fabrication of self-standing metal–graphene composite parts is concerned. Several future research avenues are discussed to fully comprehend the printability and functionality of metal/GNP composite cold-sprayed structures.
Antitumor Activity of Simvastatin in Preclinical Models of Mantle Cell Lymphoma
Authors: Santos Juliana Carvalho , Profitós-Pelejà Núria , Ribeiro Marcelo Lima , Roué Gaël
Published: November 2022

Background: Mantle cell lymphoma (MCL) is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable with standard therapy. Statins are well-tolerated, inexpensive, and widely prescribed as cholesterol-lowering agents to treat hyperlipidemia and to prevent cardiovascular diseases through the blockage of the mevalonate metabolic pathway. These drugs have also shown promising anti-cancer activity through pleiotropic effects including the induction of lymphoma cell death. However, their potential use as anti-MCL agents has not been evaluated so far. Aim: The present study aimed to investigate the activity of simvastatin on MCL cells. Methods: We evaluated the cytotoxicity of simvastatin in MCL cell lines by CellTiter-Glo and lactate dehydrogenase (LDH) release assays. Cell proliferation and mitotic index were assessed by direct cell recounting and histone H3-pSer10 immunostaining. Apoptosis induction and reactive oxygen species (ROS) generation were evaluated by flow cytometry. Cell migration and invasion properties were determined by transwell assay. The antitumoral effect of simvastatin in vivo was evaluated in a chick embryo chorioallantoic membrane (CAM) MCL xenograft model. Results: We show that treatment with simvastatin induced a 2 to 6-fold LDH release, inhibited more than 50% of cell proliferation, and enhanced the caspase-independent ROS-mediated death of MCL cells. The effective impairment of MCL cell survival was accompanied by the inhibition of AKT and mTOR phosphorylation. Moreover, simvastatin strongly decreased MCL cell migration and invasion ability, leading to a 55% tumor growth inhibition and a consistent diminution of bone marrow and spleen metastasis in vivo. Conclusion: Altogether, these data provide the first preclinical insight into the effect of simvastatin against MCL cells, suggesting that this agent might be considered for repurpose as a precise MCL therapy.
Genetic Characterization in High-Risk Individuals from a Low-Resource City of Peru
Authors: Zavaleta Elizabeth , Solis Nelly , Palacios Maria Isabel , Zevallos-Escobar Liz Elva , Corales Edison Vasquez , Bazo-Alvarez Juan Carlos , Dominguez-Barrera Constantino , Campos Anthony , Wernhoff Patrik , Ekstrøm Per Olaf , Møller Pål , Visnovska Tina , Hovig Eivind , Balazar-Palacios Janina , Alvarez-Valenzuela Karin , Nakken Sigve , Dominguez-Valentin Mev
Published: November 2022

Background: Genetic testing for hereditary cancers is inconsistently applied within the healthcare systems in Latin America. In Peru, the prevalence and spectrum of cancer-predisposing germline variants is thus poorly characterized. Purpose: To determine the spectrum and prevalence of cancer-predisposing germline variants and variants of uncertain significance (VUS) in high-risk individuals located in a Peruvian low-resource setting city. Methods: Individuals presenting clinical criteria for hereditary cancer syndromes or being unaffected with familial history of cancer were included in the study. Samples from a total of 84 individuals were subjected to a high-throughput DNA sequencing assay that targeted a panel of 94 cancer predisposition genes. The pathogenicity of detected germline variants was classified according to the established American College of Medical Genetics and Genomics (ACMG) criteria. All pathogenic variants were validated by cycling temperature capillary electrophoresis. Results: We identified a total of eight pathogenic variants, found in 19 out of 84 individuals (23%). Pathogenic variants were identified in 24% (10/42) of unaffected individuals with family history of cancer and in 21% (9/42) of individuals with a cancer diagnosis. Pathogenic variants were identified in eight genes: RET (3), BRCA1 (3), SBDS (2), SBDS/MLH1 (4), MLH1 (4), TP53 (1), FANCD2 (1), DDB2/FANCG (1). In cancer cases, all colon cancer cases were affected by pathogenic variants in MLH1 and SBDS genes, while 20% (2/10) of the thyroid cancer cases by RET c.1900T>C variants were affected. One patient with endometrial cancer (1/3) had a double heterozygous pathogenic variant in DDB2 and FANCG genes, while one breast cancer patient (1/14) had a pathogenic variant in TP53 gene. Overall, each individual presented at least 17 VUS, totaling 1926 VUS for the full study population. Conclusion: We describe the first genetic characterization in a low-resource setting population where genetic testing is not yet implemented. We identified multiple pathogenic germline variants in clinically actionable predisposition genes, that have an impact on providing an appropriate genetic counselling and clinical management for individuals and their relatives who carry these variants. We also reported a high number of VUS, which may indicate variants specific for this population and may require a determination of their clinical significance.
Machine Learning in the Classification of Pediatric Posterior Fossa Tumors: A Systematic Review
Authors: Yearley Alexander G. , Blitz Sarah E. , Patel Ruchit V. , Chan Alvin , Baird Lissa C. , Friedman Gregory K. , Arnaout Omar , Smith Timothy R. , Bernstock Joshua D.
Published: November 2022

Background: Posterior fossa tumors (PFTs) are a morbid group of central nervous system tumors that most often present in childhood. While early diagnosis is critical to drive appropriate treatment, definitive diagnosis is currently only achievable through invasive tissue collection and histopathological analyses. Machine learning has been investigated as an alternative means of diagnosis. In this systematic review and meta-analysis, we evaluated the primary literature to identify all machine learning algorithms developed to classify and diagnose pediatric PFTs using imaging or molecular data. Methods: Of the 433 primary papers identified in PubMed, EMBASE, and Web of Science, 25 ultimately met the inclusion criteria. The included papers were extracted for algorithm architecture, study parameters, performance, strengths, and limitations. Results: The algorithms exhibited variable performance based on sample size, classifier(s) used, and individual tumor types being investigated. Ependymoma, medulloblastoma, and pilocytic astrocytoma were the most studied tumors with algorithm accuracies ranging from 37.5% to 94.5%. A minority of studies compared the developed algorithm to a trained neuroradiologist, with three imaging-based algorithms yielding superior performance. Common algorithm and study limitations included small sample sizes, uneven representation of individual tumor types, inconsistent performance reporting, and a lack of application in the clinical environment. Conclusions: Artificial intelligence has the potential to improve the speed and accuracy of diagnosis in this field if the right algorithm is applied to the right scenario. Work is needed to standardize outcome reporting and facilitate additional trials to allow for clinical uptake.
Systemic Therapy for Patients with HER2-Positive Breast Cancer and Brain Metastases: A Systematic Review and Meta-Analysis
Authors: Werter Inge M. , Remmelzwaal Sharon , Burchell George L. , de Gruijl Tanja D. , Konings Inge R. , van der Vliet Hans J. , Menke-van der Houven van Oordt C. Willemien
Published: November 2022

Aim: Patients with HER2-positive (HER2+) metastatic breast cancer (mBC) develop brain metastases (BM) in up to 30% of cases. Treatment of patients with BM can consist of local treatment (surgery and/or radiotherapy) and/or systemic treatment. We undertook a systematic review and meta-analysis to determine the effect of different systemic therapies in patients with HER2+ mBC and BM. Methods: A systematic search was performed in the databases PubMed, Embase.com, Clarivate Analytics/Web of Science Core Collection and the Wiley/Cochrane Library. Eligible articles included prospective or retrospective studies reporting on the effect of systemic therapy on objective response rate (ORR) and/or median progression free survival (mPFS) in patients with HER2+ mBC and BM. The timeframe within the databases was from inception to 19 January 2022. Fixed-effects meta-analyses were used. Quality appraisal was performed using the ROBINS-I tool. Results: Fifty-one studies were included, involving 3118 patients. Most studies, which contained the largest patient numbers, but also often carried a moderate-serious risk of bias, investigated lapatinib and capecitabine (LC), trastuzumab-emtansine (T-DM1) or pyrotinib. The best quality data and/or highest ORR were described with tucatinib (combined with trastuzumab and capecitabine, TTC) and trastuzumab-deruxtecan (T-DXd). TTC demonstrated an ORR of 47.3% in patients with asymptomatic and/or active BM. T-DXd achieved a pooled ORR of 64% (95% CI 43–85%, I2 0%) in a heavily pretreated population with asymptomatic BM (3 studies, n = 96). Conclusions: Though our meta-analysis should be interpreted with caution due to the heterogeneity of included studies and a related serious risk of bias, this review provides a comprehensive overview of all currently available systemic treatment options. T-Dxd and TTC that appear to constitute the most effective systemic therapy in patients with HER2+ mBC and BM, while pyrotinib might be an option in Asian patients.
Chemosensitivity of 3D Pancreatic Cancer Organoids Is Not Affected by Transformation to 2D Culture or Switch to Physiological Culture Medium
Authors: Gassl Vincent , Aberle Merel R. , Boonen Bas , Vaes Rianne D. W. , Olde Damink Steven W. M. , Rensen Sander S.
Published: November 2022

Organoids are increasingly used to investigate patient-specific drug responsiveness, but organoid culture is complex and expensive, and carried out in rich, non-physiological media. We investigated reproducibility of drug-responsiveness of primary cell cultures in 2D versus 3D and in conventional versus physiological cell culture medium. 3D pancreatic ductal adenocarcinoma organoid cultures PANCO09b and PANCO11b were converted to primary cell cultures growing in 2D. Transformed 2D cultures were grown in physiological Plasmax medium or Advanced-DMEM/F12. Sensitivity towards gemcitabine, paclitaxel, SN-38, 5-fluorouacil, and oxaliplatin was investigated by cell viability assays. Growth rates of corresponding 2D and 3D cultures were comparable. PANCO09b had a shorter doubling time in physiological media. Chemosensitivity of PANCO09b and PANCO11b grown in 2D or 3D was similar, except for SN-38, to which PANCO11b cultured in 3D was more sensitive (2D: 8.2 ×10−3 ± 2.3 ×10−3 vs. 3D: 1.1 ×10−3 ± 0.6 ×10−3, p = 0.027). PANCO09b and PANCO11b showed no major differences in chemosensitivity when cultured in physiological compared to conventional media, although PANCO11b was more sensitive to SN-38 in physiological media (9.8 × 10−3 ± 0.7 × 10−3 vs. 5.2 × 10−3 ± 1.8 × 10−3, p = 0.015). Collectively, these data indicate that the chemosensitivity of organoids is not affected by culture medium composition or culture dimensions. This implies that organoid-based drug screens can be simplified to become more cost-effective.
Exosomal and Soluble Programed Death-Ligand 1 (PD-L1) Predicts Responses to Pembrolizumab in Patients with Extranodal NK/T-Cell Lymphoma
Authors: Kim Seok Jin , Ryu Kyung Ju , Park Bon , Yoon Sang Eun , Cho Junhun , Park Yoon , Kim Won Seog
Published: November 2022

Soluble and exosomal programed death-ligand 1 (PD-L1) can be upregulated in extranodal natural killer/T-cell lymphoma (ENKTL). However, its clinical role in predicting outcomes after pembrolizumab treatment has yet to be studied in ENKTL patients. We investigated the association between pre-treatment soluble and exosomal PD-L1 and outcomes in ENKTL patients who received pembrolizumab as a salvage treatment. The production of soluble and exosomal PD-L1 was analyzed in vitro using an etoposide-resistant ENKTL cell line. Serum levels of soluble and exosomal PD-L1 were measured in patients with relapsed or refractory ENKTL prior to treatment with pembrolizumab. Relapsed or refractory ENKTL patients who received pembrolizumab as a salvage therapy between May 2017 and March 2021 were analyzed at our institute. Soluble and exosomal PD-L1 was significantly higher in serum samples of relapsed or refractory ENKTL patients compared with healthy controls, which is consistent with increased production of soluble and exosomal PD-L1 in an etoposide-resistant ENKTL cell line (SNK6R), which was found to show increased expression of soluble and exosomal PD-L1. Serum-soluble PD-L1 levels were significantly correlated with exosomal PD-L1, and were significantly lower in responders to pembrolizumab compared with non-responders. Longitudinal analysis after pembrolizumab also revealed a relationship between PD-L1 levels and responses. Treatment outcomes and overall survival after pembrolizumab were significantly better in patients with low soluble and exosomal PD-L1. In conclusion, soluble and exosomal PD-L1 can predict responses to pembrolizumab in ENKTL patients, making it a useful pre-treatment biomarker for ENKTL patients receiving pembrolizumab.
BMN673 Is a PARP Inhibitor with Unique Radiosensitizing Properties: Mechanisms and Potential in Radiation Therapy
Authors: Soni Aashish , Lin Xixi , Mladenov Emil , Mladenova Veronika , Stuschke Martin , Iliakis George
Published: November 2022

BMN673 is a relatively new PARP inhibitor (PARPi) that exhibits superior efficacy in vitro compared to olaparib and other clinically relevant PARPi. BMN673, similar to most clinical PARPi, inhibits the catalytic activities of PARP-1 and PARP-2 and shows impressive anticancer potential as monotherapy in several pre-clinical and clinical studies. Tumor resistance to PARPi poses a significant challenge in the clinic. Thus, combining PARPi with other treatment modalities, such as radiotherapy (RT), is being actively pursued to overcome such resistance. However, the modest to intermediate radiosensitization exerted by olaparib, rucaparib, and veliparib, limits the rationale and the scope of such combinations. The recently reported strong radiosensitizing potential of BMN673 forecasts a paradigm shift on this front. Evidence accumulates that BMN673 may radiosensitize via unique mechanisms causing profound shifts in the balance among DNA double-strand break (DSB) repair pathways. According to one of the emerging models, BMN673 strongly inhibits classical non-homologous end-joining (c-NHEJ) and increases reciprocally and profoundly DSB end-resection, enhancing error-prone DSB processing that robustly potentiates cell killing. In this review, we outline and summarize the work that helped to formulate this model of BMN673 action on DSB repair, analyze the causes of radiosensitization and discuss its potential as a radiosensitizer in the clinic. Finally, we highlight strategies for combining BMN673 with other inhibitors of DNA damage response for further improvements.
The Biomass of Pig-Blood-Derived Carbon as a Novel Electrode Material for Hydrogen Peroxide Electrochemical Sensing
Authors: Liu Guolei , Li Xue , Wang Qing , Sun Kuizhao , Lee Chuping , Cao Yue , Si Weimeng , Wei Haoran , Li Zhongfang , Wang Fagang
Published: November 2022

In the work, a pig-blood-derived mesoporous carbon (BC) was prepared as a novel Fe-N-C material for the electrochemical sensor to detect hydrogen peroxide. Because of the unique nanostructure of Fe-BCs with rough surface structure, hierarchical pores, and high graphitization degree, the Fe-BCs, as a kind of advanced electrode material, exhibited remarkable performance in electrocatalysis. The sensor based on Fe-BCs exhibited an extra-long range from c and a detection limit of 0.046 μM (S/N = 3). The synthesis of low-cost, advanced carbon-based electrode materials from environmentally friendly pig blood for electrochemical sensor construction is a promising approach.
Oxiapoptophagy in Age-Related Diseases. Comment on Ouyang et al. 7-Ketocholesterol Induces Oxiapoptophagy and Inhibits Osteogenic Differentiation in MC3T3-E1 Cells. Cells 2022, 11, 2882
Authors: Ghzaiel Imen , Nury Thomas , Zarrouk Amira , Vejux Anne , Lizard Gérard
Published: November 2022

Due to the increase in life span and life expectancy, which can, however, be more or less pronounced depending on the economic, social and cultural context [...]
Depletion of R270C Mutant p53 in Osteosarcoma Attenuates Cell Growth but Does Not Prevent Invasion and Metastasis In Vivo
Authors: Shimizu Takatsune , Sugihara Eiji , Takeshima Hideyuki , Nobusue Hiroyuki , Yamaguchi Rui , Yamaguchi-Iwai Sayaka , Fukuchi Yumi , Ushijima Toshikazu , Muto Akihiro , Saya Hideyuki
Published: November 2022

Novel therapeutic targets are needed to better treat osteosarcoma, which is the most common bone malignancy. We previously developed mouse osteosarcoma cells, designated AX (accelerated bone formation) cells from bone marrow stromal cells. AX cells harbor both wild-type and mutant forms of p53 (R270C in the DNA-binding domain, which is equivalent to human R273C). In this study, we showed that mutant p53 did not suppress the transcriptional activation function of wild-type p53 in AX cells. Notably, AXT cells, which are cells derived from tumors originating from AX cells, lost wild-type p53 expression, were devoid of the intact transcription activation function, and were resistant to doxorubicin. ChIP-seq analyses revealed that this mutant form of p53 bound to chromatin in the vicinity of the transcription start sites of various genes but exhibited a different binding profile from wild-type p53. The knockout of mutant p53 in AX and AXT cells by CRISPR–Cas9 attenuated tumor growth but did not affect the invasion of these cells. In addition, depletion of mutant p53 did not prevent metastasis in vivo. Therefore, the therapeutic potency targeting R270C (equivalent to human R273C) mutant p53 is limited in osteosarcoma. However, considering the heterogeneous nature of osteosarcoma, it is important to further evaluate the biological and clinical significance of mutant p53 in various cases.
Cell-Free DNA Sequencing Reveals Gene Variants in DNA Damage Repair Genes Associated with Prognosis of Prostate Cancer Patients
Authors: Lieb Verena , Abdulrahman Amer , Weigelt Katrin , Hauch Siegfried , Gombert Michael , Guzman Juan , Bellut Laura , Goebell Peter J. , Stöhr Robert , Hartmann Arndt , Wullich Bernd , Taubert Helge , Wach Sven
Published: November 2022

In the present study, we further analyzed the data obtained in our previous study, where we investigated the cell-free DNA (cfDNA) of 34 progressive prostate cancer patients via targeted sequencing. Here, we studied the occurrence and prognostic impact of sequence variants according to their clinical pathological significance (CPS) or their functional impact (FI) in 23 DNA damage repair (DDR) genes with a focus on the ATM serine/threonine kinase gene (ATM). All patients had at least one DDR gene with a CPS or FI variant. Kaplan-Meier analysis indicated that the group with a higher number of CPS variants in DDR genes had a shorter time to treatment change (TTC) compared to the group with a lower number of CPS variants (p = 0.038). Analysis of each DDR gene revealed that CPS variants in the ATM gene and FI variants in the nibrin (NBN) gene showed a shorter TTC (p = 0.034 and p = 0.042). In addition, patients with CPS variants in the ATM gene had shorter overall survival (OS; p = 0.022) and disease-specific survival (DSS; p = 0.010) than patients without these variants. Interestingly, patients with CPS variants in seven DDR genes possessed a better OS (p = 0.008) and DSS (p = 0.009), and patients with FI variants in four DDR genes showed a better OS (p = 0.007) and DSS (p = 0.008). Together, these findings demonstrated that the analysis of cfDNA for gene variants in DDR genes provides prognostic information that may be helpful for future temporal and targeted treatment decisions for advanced PCa patients.
Effects and Mechanisms of Exosomes from Different Sources in Cerebral Ischemia
Authors: Xie Ruoxi , Zeng Xinbing , Yan Huan , Huang Xiaoping , Deng Changqing
Published: November 2022

Cerebral ischemia refers to the symptom of insufficient blood supply to the brain. Cells of many different origins participate in the process of repairing damage after cerebral ischemia occurs, in which exosomes secreted by the cells play important roles. For their characteristics, such as small molecular weight, low immunogenicity, and the easy penetration of the blood–brain barrier (BBB), exosomes can mediate cell-to-cell communication under pathophysiological conditions. In cerebral ischemia, exosomes can reduce neuronal damage and improve the brain microenvironment by regulating inflammation, mediating pyroptosis, promoting axonal growth, and stimulating vascular remodeling. Therefore, exosomes have an excellent application prospect for the treatment of cerebral ischemia. This article reviews the roles and mechanisms of exosomes from different sources in cerebral ischemia and provides new ideas for the prevention and treatment of cerebral ischemia.
Loss of GNE Predicts Lymph Node Metastasis in Early Gastric Cancer
Authors: Guo Xinying , Gu Jie , Xue Anwei , Song Shushu , Liu Bo , Gao Xiaodong , Gu Jianxin , Chang Lei , Ruan Yuanyuan
Published: November 2022

Endoscopic surgery is increasingly utilized for the treatment of early gastric cancer (EGC) worldwide, whereas lymph node metastasis (LNM) remains a critical risk factor for the relapse of EGC after endoscopic surgery. Therefore, identifying potential predictive factors and understanding the molecular mechanisms are urgently needed for improving the outcome of EGC patients with LNM. UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is the key enzyme in the process of biosynthesis of CMP-Neu5Ac from UDP-N-acetylglucosamine (UDP-GlcNAc), which acts as a substrate for several reactions in glycan metabolism. In this study, we found that GNE was down-regulated in EGC patients with LNM. GNE expression as well as localization, tumor size, intravascular tumor thrombi and Lauren’s classification were further identified as independent predictive factors for LNM. Combining GNE expression with traditional risk factors, including tumor size and differentiation degrees, could generate a better model for predicting LNM in EGC patients. Overall, our study implies that low GNE expression is a potential predictor of LNM in EGC.