bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of Germination Black Soy Milk Fermented with Lactobacillus plantarum TWK10 on Anti-Oxidative and Anti-Melanogenesis
Authors: Liu Te-Hua , Chiang Wei-Ting , Cheng Meng-Chun , Tsai Tsung-Yu
Published: December 2021

Black soybean germination or fermentation increases active ingredient bioavailability and anti-oxidative activity. This study investigated the effects of fermented and germinated black soy milk on anti-oxidation and melanogenesis inhibition. The total phenolic content (TPC; 42.66 ± 1.65 mg gallic acid equivalent/g) and total flavonoid content (TFC; 5.43 ± 0.54 mg quercetin equivalent (QE)/g) in ethanol extracts from Lactobacillus plantarum TWK10 (TWK10)-fermented nongermination black soy milk (FNGB) were significantly (p < 0.05) higher than those in ethanol extracts from nonfermented-nongermination black soy milk (NNGB). Although the TPC of ethanol extracts from nonfermented-germination black soy milk (NGB) and fermented-germination black soy milk (FGB) were not significantly different (p > 0.05), the TFC of FGB (1.79 ± 0.08 mg QE/g) was significantly higher than that of NGB (p < 0.05). The 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity of ethanol extracts from NNGB, FNGB, NGB, and FGB was significantly higher than that of water extracts at 10 mg/mL (p < 0.05). Furthermore, ethanol extracts from both FNGB and FGB significantly reduced the melanin content in zebrafish embryos at 100 µg/mL (p < 0.05) without causing death, malformation or bradycardia. Overall, the antioxidant activity of black soy milk significantly increased after TWK10 fermentation; moreover, ethanol extracts from FNGB and FGB could inhibit melanogenesis, indicating their potential as whitening ingredients.
Review of Long-Term Trends in the Equatorial Ionosphere Due the Geomagnetic Field Secular Variations and Its Relevance to Space Weather
Authors: Elias Ana G. , de Haro Barbas Blas F. , Zossi Bruno S. , Medina Franco D. , Fagre Mariano , Venchiarutti Jose V.
Published: December 2021

The Earth’s ionosphere presents long-term trends that have been of interest since a pioneering study in 1989 suggesting that greenhouse gases increasing due to anthropogenic activity will produce not only a troposphere global warming, but a cooling in the upper atmosphere as well. Since then, long-term changes in the upper atmosphere, and particularly in the ionosphere, have become a significant topic in global change studies with many results already published. There are also other ionospheric long-term change forcings of natural origin, such as the Earth’s magnetic field secular variation with very special characteristics at equatorial and low latitudes. The ionosphere, as a part of the space weather environment, plays a crucial role to the point that it could certainly be said that space weather cannot be understood without reference to it. In this work, theoretical and experimental results on equatorial and low-latitude ionospheric trends linked to the geomagnetic field secular variation are reviewed and analyzed. Controversies and gaps in existing knowledge are identified together with important areas for future study. These trends, although weak when compared to other ionospheric variations, are steady and may become significant in the future and important even now for long-term space weather forecasts.
Projected Changes in Terrestrial Vegetation and Carbon Fluxes under 1.5 °C and 2.0 °C Global Warming
Authors: Peng Xiaobin , Yu Miao , Chen Haishan
Published: December 2021

The terrestrial ecosystem plays a vital role in regulating the exchange of carbon between land and atmosphere. This study investigates how terrestrial vegetation coverage and carbon fluxes change in a world stabilizing at 1.5 °C and 2 °C warmer than pre-industrial level. Model results derived from 20 Earth System Models (ESMs) under low, middle, and high greenhouse emission scenarios from CMIP5 and CMIP6 are employed to supply the projected results. Although the ESMs show a large spread of uncertainties, the ensemble means of global LAI are projected to increase by 0.04 ± 0.02 and 0.08 ± 0.04 in the 1.5 and 2.0 °C warming worlds, respectively. Vegetation density is projected to decrease only in the Brazilian Highlands due to the decrease of precipitation there. The high latitudes in Eurasia are projected to have stronger increase of LAI in the 2.0 °C warming world compared to that in 1.5 °C warming level caused by the increase of tree coverage. The largest zonal LAI is projected around 70° N while the largest zonal NPP is projected around 60° N and equator. The zonally inhomogeneous increase of vegetation density and productivity relates to the zonally inhomogeneous increase of temperature, which in turn could amplify the latitudinal gradient of temperature with additional warming. Most of the ESMs show uniform increases of global averaged NPP by 10.68 ± 8.60 and 15.42 ± 10.90 PgC year−1 under 1.5 °C and 2.0 °C warming levels, respectively, except in some sparse vegetation areas. The ensemble averaged NEE is projected to increase by 3.80 ± 7.72 and 4.83 ± 10.13 PgC year−1 in the two warming worlds. The terrestrial ecosystem over most of the world could be a stronger carbon sink than at present. However, some dry areas in Amazon and Central Africa may convert to carbon sources in a world with additional 0.5 °C warming. The start of the growing season in the northern high latitudes is projected to advance by less than one month earlier. Five out of 10 CMIP6 ESMs, which use the Land Use Harmonization Project (LUH2) dataset or a prescribed potential vegetation distribution to constrain the future change of vegetation types, do not reduce the model uncertainties in projected LAI and terrestrial carbon fluxes. This may suggest the challenge in optimizing the carbon fluxes modeling in the future.
Simulation of Carbon Exchange from a Permafrost Peatland in the Great Hing’an Mountains Based on CoupModel
Authors: Li Yue , Wan Zhongmei , Sun Li
Published: December 2021

Climate change is accelerating its impact on northern ecosystems. Northern peatlands store a considerable amount of C, but their response to climate change remains highly uncertain. In order to explore the feedback of a peatland in the Great Hing’an Mountains to future climate change, we simulated the response of the overall net ecosystem exchange (NEE), ecosystem respiration (ER), and gross primary production (GPP) during 2020–2100 under three representative concentration pathways (RCP2.6, RCP6.0, and RCP8.5). Under the RCP2.6 and RCP6.0 scenarios, the carbon sink will increase slightly until 2100. Under the RCP8.5 scenario, the carbon sink will follow a trend of gradual decrease after 2053. These results show that when meteorological factors, especially temperature, reach a certain degree, the carbon source/sink of the peatland ecosystem will be converted. In general, although the peatland will remain a carbon sink until the end of the 21st century, carbon sinks will decrease under the influence of climate change. Our results indicate that in the case of future climate warming, with the growing seasons experiencing overall dryer and warmer environments and changes in vegetation communities, peatland NEE, ER, and GPP will increase and lead to the increase in ecosystem carbon accumulation.
Chemical Composition and Polyphenolic Compounds of Red Wines: Their Antioxidant Activities and Effects on Human Health—A Review
Authors: Nemzer Boris , Kalita Diganta , Yashin Alexander Y. , Yashin Yakov I.
Published: December 2021

Red wine, an alcoholic beverage is composed of a spectrum of complex compounds such as water, alcohol, glycerol, organic acid, carbohydrates, polyphenols, and minerals as well as volatile compounds. Major factors that affect the levels of phenolic compounds in red wines are the variety of grapes and the storage of the wines. Among the constituents of red wine, phenolic compounds play a crucial role in attributes including color and mouthfeel and confer beneficial properties on health. Most importantly, phenolic compounds such as flavanols, flavonols, flavanones, flavones, tannins, anthocyanins, hydroxycinnamic acids, hydroxybenzoic acids, and resveratrol can prevent the development of cardiovascular diseases, cancers, diabetes, inflammation, and some other chronic diseases.
A Novel Hybrid Parametric and Non-Parametric Optimisation Model for Average Technical Efficiency Assessment in Public Hospitals during and Post-COVID-19 Pandemic
Authors: Mirmozaffari Mirpouya , Yazdani Reza , Shadkam Elham , Khalili Seyed Mohammad , Tavassoli Leyla Sadat , Boskabadi Azam
Published: December 2021

The COVID-19 pandemic has had a significant impact on hospitals and healthcare systems around the world. The cost of business disruption combined with lingering COVID-19 costs has placed many public hospitals on a course to insolvency. To quickly return to financial stability, hospitals should implement efficiency measure. An average technical efficiency (ATE) model made up of data envelopment analysis (DEA) and stochastic frontier analysis (SFA) for assessing efficiency in public hospitals during and after the COVID-19 pandemic is offered. The DEA method is a non-parametric method that requires no information other than the input and output quantities. SFA is a parametric method that considers stochastic noise in data and allows statistical testing of hypotheses about production structure and degree of inefficiency. The rationale for using these two competing approaches is to balance each method’s strengths, weaknesses and introduce a novel integrated approach. To show the applicability and efficacy of the proposed hybrid VRS-CRS-SFA (VCS) model, a case study is presented.
CGENet: A Deep Graph Model for COVID-19 Detection Based on Chest CT
Authors: Lu Si-Yuan , Zhang Zheng , Zhang Yu-Dong , Wang Shui-Hua
Published: December 2021

Accurate and timely diagnosis of COVID-19 is indispensable to control its spread. This study proposes a novel explainable COVID-19 diagnosis system called CGENet based on graph embedding and an extreme learning machine for chest CT images. We put forward an optimal backbone selection algorithm to select the best backbone for the CGENet based on transfer learning. Then, we introduced graph theory into the ResNet-18 based on the k-nearest neighbors. Finally, an extreme learning machine was trained as the classifier of the CGENet. The proposed CGENet was evaluated on a large publicly-available COVID-19 dataset and produced an average accuracy of 97.78% based on 5-fold cross-validation. In addition, we utilized the Grad-CAM maps to present a visual explanation of the CGENet based on COVID-19 samples. In all, the proposed CGENet can be an effective and efficient tool to assist COVID-19 diagnosis.
Insight on Polyunsaturated Fatty Acids in Endometrial Receptivity
Authors: Chen Min , Zheng Zimeng , Shi Jialu , Shao Jun
Published: December 2021

Endometrial receptivity plays a crucial role in fertilization as well as pregnancy outcome in patients faced with fertility challenges. The optimization of endometrial receptivity may help with normal implantation of the embryo, and endometrial receptivity may be affected by numerous factors. Recently, the role of lipids in pregnancy has been increasingly recognized. Fatty acids and their metabolites may be involved in all stages of pregnancy and play a role in supporting cell proliferation and development, participating in cell signaling and regulating cell function. Polyunsaturated fatty acids, in particular, are essential fatty acids for the human body that can affect the receptivity of the endometrium through in a variety of methods, such as producing prostaglandins, estrogen and progesterone, among others. Additionally, polyunsaturated fatty acids are also involved in immunity and the regulation of endometrial decidualization. Fatty acids are essential for fetal placental growth and development. The interrelationship of polyunsaturated fatty acids with these substances and how they may affect endometrial receptivity will be reviewed in this article.
Metabolomics Coupled with Pathway Analysis Provides Insights into Sarco-Osteoporosis Metabolic Alterations and Estrogen Therapeutic Effects in Mice
Authors: Wei Ziheng , Ge Fei , Che Yanting , Wu Si , Dong Xin , Song Dianwen
Published: December 2021

Postmenopausal osteoporosis (PMOP) and sarcopenia are common diseases that predominantly affect postmenopausal women. In the occurrence and development of these two diseases, they are potentially pathologically connected with each other at various molecular levels. However, the application of metabolomics in sarco-osteoporosis and the metabolic rewiring happening throughout the estrogen loss-replenish process have not been reported. To investigate the metabolic alteration of sarco-osteoporosis and the possible therapeutical effects of estradiol, 24 mice were randomly divided into sham surgery, ovariectomy (OVX), and estradiol-treated groups. Three-dimensional reconstructions and histopathology examination showed significant bone loss after ovariectomy. Estrogen can well protect against OVX-induced bone loss deterioration. UHPLC-Q-TOF/MS was preformed to profile semi- polar metabolites of skeletal muscle samples from all groups. Metabolomics analysis revealed metabolic rewiring occurred in OVX group, most of which can be reversed by estrogen supplementation. In total, 65 differential metabolites were identified, and pathway analysis revealed that sarco-osteoporosis was related to the alterations in purine metabolism, glycerophospholipid metabolism, arginine biosynthesis, tryptophan metabolism, histidine metabolism, oxidative phosphorylation, and thermogenesis, which provided possible explanations for the metabolic mechanism of sarco-osteoporosis. This study indicates that an UHPLC-Q-TOF/MS-based metabolomics approach can elucidate the metabolic reprogramming mechanisms of sarco-osteoporosis and provide biological evidence of the therapeutical effects of estrogen on sarco-osteoporosis.
Curcumin Analogues as a Potential Drug against Antibiotic Resistant Protein, β-Lactamases and L, D-Transpeptidases Involved in Toxin Secretion in Salmonella typhi: A Computational Approach
Authors: Akter Tanzina , Chakma Mahim , Tanzina Afsana Yeasmin , Rumi Meheadi Hasan , Shimu Mst. Sharmin Sultana , Saleh Md. Abu , Mahmud Shafi , Sami Saad Ahmed , Emran Talha Bin
Published: December 2021

Typhoid fever caused by the bacteria Salmonella typhi gained resistance through multidrug-resistant S. typhi strains. One of the reasons behind β-lactam antibiotic resistance is -lactamase. L, D-Transpeptidases is responsible for typhoid fever as it is involved in toxin release that results in typhoid fever in humans. A molecular modeling study of these targeted proteins was carried out by various methods, such as homology modeling, active site prediction, prediction of disease-causing regions, and by analyzing the potential inhibitory activities of curcumin analogs by targeting these proteins to overcome the antibiotic resistance. The five potent drug candidate compounds were identified to be natural ligands that can inhibit those enzymes compared to controls in our research. The binding affinity of both the Go-Y032 and NSC-43319 were found against β-lactamase was −7.8 Kcal/mol in AutoDock, whereas, in SwissDock, the binding energy was −8.15 and −8.04 Kcal/mol, respectively. On the other hand, the Cyclovalone and NSC-43319 had an equal energy of −7.60 Kcal/mol in AutoDock, whereas −7.90 and −8.01 Kcal/mol in SwissDock against L, D-Transpeptidases. After the identification of proteins, the determination of primary and secondary structures, as well as the gene producing area and homology modeling, was accomplished. The screened drug candidates were further evaluated in ADMET, and pharmacological properties along with positive drug-likeness properties were observed for these ligand molecules. However, further in vitro and in vivo experiments are required to validate these in silico data to develop novel therapeutics against antibiotic resistance.
Multisession Anodal tDCS on the Right Temporo-Parietal Junction Improves Mentalizing Processes in Adults with Autistic Traits
Authors: Padrón Iván , García-Marco Enrique , Moreno Iván , Birba Agustina , Silvestri Valentina , León Inmaculada , Álvarez Carlos , López Joana , de Vega Manuel
Published: December 2021

Persons with autism spectrum disorder (ASD) have impaired mentalizing skills. In this study, a group of persons with ASD traits (high-AQ scores) initially received sham tDCS before completing a pre-test in two mentalizing tasks: false belief and self-other judgments. Over the next week, on four consecutive days, they received sessions of anodal electrical stimulation (a-tDCS) over the right temporo-parietal junction (rTPJ), a region frequently associated with the theory of mind. On the last day, after the stimulation session, they completed a new set of mentalizing tasks. A control group (with low-AQ scores) matched in age, education and intelligence received just sham stimulation and completed the same pre-test and post-test. The results showed that the high-AQ group improved their performance (faster responses), after a-tDCS, in the false belief and in the self-other judgments of mental features, whereas they did not change performance in the false photographs or the self-other judgments of physical features. These selective improvements cannot be attributed to increased familiarity with the tasks, because the performance of the low-AQ control group remained stable about one week later. Therefore, our study provides initial proof that tDCS could be used to improve mentalizing skills in persons with ASD traits.
Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories
Authors: East Brett S. , Brady Lauren R. , Quinn Jennifer J.
Published: December 2021

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.
Cyclic Responses of Two-Side-Connected Precast-Reinforced Concrete Infill Panels with Different Slit Types
Authors: Sun Guohua , Li Fei , Zhou Qiyou
Published: December 2021

This study aimed to study the cyclic behavior of two-side-connected precast-reinforced concrete infill panel (RCIP). A total of four RCIP specimens with different slit types and height-to-span ratios modeled at a one-third scale were tested subjected to cyclic lateral loads. The failure mode, hysteretic behavior, lateral strength, stiffness degradation, ductility, and energy dissipation capacity of each RCIP specimen were determined and analyzed. The specimens experienced a similar damage process, which involved concrete cracking, steel rebar yielding, concrete crushing, and plastic hinge formation. All the specimens showed pinched hysteretic curves, resulting in a small energy dissipation capacity and a maximum equivalent viscous damping ratio lower than 0.2. The specimens with penetrated slits experienced ductile failure, in which flexural hinges developed at both slit wall ends. The application of penetrated slits decreased the initial stiffness and lateral load-bearing capacity of the RC panel but increased the deformation capacity, the average ultimate drift ratios ranged from 1.41% to 1.99%, and the lowest average ductility ratio reached 2.48. The specimens with high-strength concrete resulted in a small slip no more than 1 mm between the RC panel and steel beam, and the channel shear connectors ensured that the RC infill panel developed a reliable assembly with the surrounding steel components. However, specimens with concealed vertical slits (CVSs) and concealed hollow slits (CHSs) achieved significantly higher lateral stiffness and lateral strength values. Generally, the specimens exhibited two-stage mechanical features. The concrete in the CVSs and CHSs was crushed, and flexural plastic hinges developed at both ends of the slit walls during the second stage. With increasing concrete strength, the initial lateral stiffness and lateral strength values of the RCIP specimens increased. With an increasing height-to-span ratio, the lateral stiffness and strength of the RC panels with slits decreased, but the failure mode remained unchanged.
Recycling Cigarette Butts in Ceramic Tiles
Authors: Yuan Qibin , Mohajerani Abbas , Kristoforus Adrian , Kurmus Halenur , Chowdhury Urmila , Robert Dilan , Pramanik Biplob , Tran Phuong
Published: December 2021

Cigarettes are one of the favoured commodities on our planet. However, the annual consumption of 5.7 trillion cigarettes and 75% littering rate results in cigarette butts (CBs) being one of the most critical environmental issues. The leachate of heavy metals and toxic chemicals is polluting our ecosystem and threatening the wildlife species. Therefore, it is crucial to find effective and efficient recycling methods to solve the growing CB waste issue. In this study, unglazed fired ceramic tiles were manufactured with 0%, 0.5%, 1.0%, and 1.5% shredded CBs by dry mass to investigate the feasibility of the proposed sustainable recycling method. The chemical and mineralogical characterisation, density, shrinkage, bulk density, breaking strength, water absorption, and modulus of rupture were investigated and compared with the Australian Standards for ceramic tiles (AS 4459). The results revealed that tiles incorporating 0.5% CBs by mass demonstrated the greatest performance compared to the other mixtures. The water absorption for all tile–CB mixtures was found to be greater than 10%, with a positive growth tendency. The addition of 0.5% CBs by mass slightly improved flexural strength from 15.56 MPa for control samples to 16.63 MPa. Tiles containing 0.5% CBs by mass satisfied the modulus of rupture and water absorption limits for group III class according to the Australian Standards (AS 13006), and they may be suitable to be used as wall tiles. The result of a simulation equation predicts that an energy savings of up to 7.79% is achievable during the firing process for ceramic tiles incorporating 1% CBs by mass.
Immune-Based Therapeutic Strategies for Acute Myeloid Leukemia
Authors: Böhme Matthias , Kayser Sabine
Published: December 2021

The development and design of immune-based strategies have become an increasingly important topic during the last few years in acute myeloid leukemia (AML), based on successful immunotherapies in solid cancer. The spectrum ranges from antibody drug conjugates, immune checkpoint inhibitors blocking programmed cell death protein 1 (PD1), cytotoxic T lymphocyte antigen 4 (CTLA4) or T cell immunoglobulin and mucin domain containing-3 (TIM3), to T-cell based monoclonal and bispecific T-cell engager antibodies, chimeric antigen receptor-T-cell (CAR-T) approaches and leukemia vaccines. Currently, there are many substances in development and multiple phase I/II studies are ongoing. These trials will help us to deepen our understanding of the pathogenesis of AML and facilitate the best immunotherapeutic strategy in AML. We discuss here the mode of action of immune-based therapies and provide an overview of the available data.
Radiotherapy in the Management of Non-Metastatic Inflammatory Breast Cancers: A Retrospective Observational Study
Authors: Nicaise Benjamin , Loap Pierre , Loirat Delphine , Laki Fatima , Pierga Jean-Yves , Fourquet Alain , Kirova Youlia
Published: December 2021

(1) Background: Inflammatory breast cancers (IBC) are characterized by a poor prognosis. This retrospective study aims to describe the clinical outcomes of non-metastatic IBC patients treated with a multidisciplinary approach with neo-adjuvant chemotherapy, surgery, and radiotherapy. (2) Methods: This single-center retrospective study included all women patients diagnosed with non-metastatic IBC between January 2010 and January 2018 at the Institut Curie (Paris, France) and treated with neoadjuvant chemotherapy, surgery, and radiotherapy. Overall survival (OS), disease-free survival (DFS), and locoregional free survival (LRRFS) were calculated from the time of diagnosis. Prognostic factors for patient survival were analyzed based on univariate and multivariate regressions. (3) Results: We identified 113 patients with a median age of 51 years. 79.7% had node-positive tumors; triple-negative breast cancers (TNBC) represented 34.6% of the cases. A large majority of patients (91.2%) received adjuvant post-mastectomy while ten patients (8.8%) received preoperative radiotherapy. Non-pathological complete response (non-pCR) was observed in 67.3% of patients. Radiotherapy delivered a median dose of 50 Gy to the breast or the chest wall in 25 fractions. With a median follow-up of 54 months, 5-year OS, DFS and LRRFS were 78% (CI: 70.1–86.8%), 68.1% (59.6–77.7%), and 85.2% (78.4–92.7%), respectively. In multivariate analysis, non-pCR was an adverse prognosis factor for OS, DFS, and LRRFS; pre-operative radiotherapy was an adverse prognosis factor for OS and DFS. Radiation-related adverse events were limited to acute skin toxicity (22% of Grade 2 and 2% of grade 3 dermatitis); no late radiation-induced toxicity was reported. (4) Conclusions: High locoregional control could be achieved with multidisciplinary management of non-metastatic IBC, suggesting the anti-tumor efficacy of radiotherapy in this rare but pejorative clinicopathological presentation. While comparing favorably with historical cohorts, OS and DFS could be potentially improved in the future with the use of new systemic treatments, such as PARP-inhibitors or immunotherapy.
BRCA1 and Metastasis: Outcome of Defective DNA Repair
Authors: Krishnan Rehna , Patel Parasvi S. , Hakem Razqallah
Published: December 2021

Heritable mutations in BRCA1 and BRCA2 genes are a major risk factor for breast and ovarian cancer. Inherited mutations in BRCA1 increase the risk of developing breast cancers by up to 72% and ovarian cancers by up to 69%, when compared to individuals with wild-type BRCA1. BRCA1 and BRCA2 (BRCA1/2) are both important for homologous recombination-mediated DNA repair. The link between BRCA1/2 mutations and high susceptibility to breast cancer is well established. However, the potential impact of BRCA1 mutation on the individual cell populations within a tumor microenvironment, and its relation to increased aggressiveness of cancer is not well understood. The objective of this review is to provide significant insights into the mechanisms by which BRCA1 mutations contribute to the metastatic and aggressive nature of the tumor cells.
Sarcopenia and Ghrelin System in the Clinical Outcome and Prognosis of Gastroenteropancreatic Neuroendocrine Neoplasms
Authors: Herrera-Martínez Yiraldine , Alzas Teomiro Carlos , León Idougourram Soraya , Molina Puertas María José , Calañas Continente Alfonso , Serrano Blanch Raquel , Castaño Justo P. , Gálvez Moreno María Ángeles , Gahete Manuel D. , Luque Raúl M. , Herrera-Martínez Aura D.
Published: December 2021

Background: Malnutrition and sarcopenia affect clinical outcomes and treatment response in cancer patients. Patients with neuroendocrine neoplasms (NENs) may present with additional symptoms related to tumor localization in the gastrointestinal tract and hormone secretion, increasing the risk and effects of sarcopenia. Aim: To explore the presence of malnutrition and sarcopenia in gastroenteropancreatic (GEP)-NEN patients, their relation to tumor characteristics, patient outcomes, survival and the molecular expression of ghrelin system components in the tumor. Patients and methods: One-hundred-and-four patients were included. Anthropometric, biochemical and CT-scans at diagnosis were evaluated. The expression levels of key ghrelin system components were assessed in 63 tumor samples. Results: Nutritional parameters were similar in GEP-NEN tumors of different origin. Relapsed disease was associated with decreased BMI. Patients who presented with weight loss at diagnosis had significantly lower overall survival (108 (25–302) vs. 263 (79–136) months). Ghrelin O-acyltransferase (GOAT) enzyme expression was higher in these patients. The prevalence of sarcopenia using CT images reached 87.2%. Mortality was observed only in patients with sarcopenia. Muscle evaluation was correlated with biochemical parameters but not with the expression of ghrelin system components. Conclusion: Survival is related to the nutritional status of patients with GEP-NENs and also to the molecular expression of some relevant ghrelin system components. Routine nutritional evaluation should be performed in these patients, in order to prescribe appropriate nutritional support, when necessary, for increasing quality of life and improving clinical outcomes.
Checkpoint Inhibitors in Multiple Myeloma: Intriguing Potential and Unfulfilled Promises
Authors: Alkharabsheh Omar , Trisel Zachary , Badami Sunil , Aljama Mohammed A. , Sidiqi M. Hasib
Published: December 2021

Immune dysregulation and alteration of the bone marrow microenvironment allowing plasma cells to escape immune surveillance are well-known factors associated with the proliferation of clonal plasma cells and development of multiple myeloma (MM). Whilst immunotherapeutic approaches are now commonplace in a wide spectrum of malignancies, this aberration of myeloma development gives rise to the biological rationale for the use of immune checkpoint inhibitors (ICIs) in MM. However, the initial experience with these agents has been challenging with limited single agent efficacy, significant toxicity, and side effects. Herein, we review the biological and immunological aspects of MM and ICIs. We discuss the basic biology of immune checkpoint inhibitors, mechanisms of resistance, and drug failure patterns, review the published clinical trial data for ICIs in MM, and look towards the future of ICIs for MM treatment.
Neutrophil Extracellular Traps Are Increased in Chronic Myeloid Leukemia and Are Differentially Affected by Tyrosine Kinase Inhibitors
Authors: Telerman Alona , Granot Galit , Leibovitch Chiya , Yarchovsky-Dolberg Osnat , Shacham-Abulafia Adi , Partouche Shirly , Yeshurun Moshe , Ellis Martin H. , Raanani Pia , Wolach Ofir
Published: December 2021

Cardiovascular complications are increasingly reported with the use of certain tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML). We studied neutrophil extracellular trap (NET) formation in CML and evaluated the effect of TKIs on NET formation. Neutrophils isolated from treatment-naïve patients with CML showed a significant increase in NET formation compared to matched controls at baseline and after stimulation with ionomycin (IO) and phorbol 12-myristate 13-acetate (PMA). Expression of citrullinated histone H3 (H3cit), peptidyl arginine deiminase 4 (PAD4) and reactive oxygen species (ROS) was significantly higher in CML samples compared to controls. Pre-treatment of neutrophils with TKIs was associated with a differential effect on NET formation, and ponatinib significantly augmented NET-associated elastase and ROS levels as compared to controls and other TKIs. BCR-ABL1 retroviral transduced HoxB8-immortalized mouse hematopoietic progenitors, which differentiate into neutrophils in-vitro, demonstrated increased H3cit & myeloperoxidase (MPO) expression consistent with excess NET formation. This was inhibited by Cl-amidine, a PAD4 inhibitor, but not by the NADPH inhibitor diphenyleneiodonium (DPI). Ponatinib pre-exposure significantly increased H3cit expression in HoxB8-BCR-ABL1 cells after stimulation with IO. In summary, CML is associated with increased NET formation, which is augmented by ponatinib, suggesting a possible role for NETs in promoting vascular toxicity in CML.
Peptide Receptor Radionuclide Therapy Targeting the Somatostatin Receptor: Basic Principles, Clinical Applications and Optimization Strategies
Authors: Ahmadi Bidakhvidi Niloefar , Goffin Karolien , Dekervel Jeroen , Baete Kristof , Nackaerts Kristiaan , Clement Paul , Van Cutsem Eric , Verslype Chris , Deroose Christophe M.
Published: December 2021

Peptide receptor radionuclide therapy (PRRT) consists of the administration of a tumor-targeting radiopharmaceutical into the circulation of a patient. The radiopharmaceutical will bind to a specific peptide receptor leading to tumor-specific binding and retention. The only target that is currently used in clinical practice is the somatostatin receptor (SSTR), which is overexpressed on a range of tumor cells, including neuroendocrine tumors and neural-crest derived tumors. Academia played an important role in the development of PRRT, which has led to heterogeneous literature over the last two decades, as no standard radiopharmaceutical or regimen has been available for a long time. This review provides a summary of the treatment efficacy (e.g., response rates and symptom-relief), impact on patient outcome and toxicity profile of PRRT performed with different generations of SSTR-targeting radiopharmaceuticals, including the landmark randomized-controlled trial NETTER-1. In addition, multiple optimization strategies for PRRT are discussed, i.e., the dose–effect concept, dosimetry, combination therapies (i.e., tandem/duo PRRT, chemoPRRT, targeted molecular therapy, somatostatin analogues and radiosensitizers), new radiopharmaceuticals (i.e., SSTR-antagonists, Evans-blue containing vector molecules and alpha-emitters), administration route (intra-arterial versus intravenous) and response prediction via molecular testing or imaging. The evolution and continuous refinement of PRRT resulted in many lessons for the future development of radionuclide therapy aimed at other targets and tumor types.
Decreasing Postoperative Pulmonary Complication Following Laparoscopic Surgery in Elderly Individuals with Colorectal Cancer: A Competing Risk Analysis in a Propensity Score–Weighted Cohort Study
Authors: Chern Yih-Jong , You Jeng-Fu , Cheng Ching-Chung , Jhuang Jing-Rong , Yeh Chien-Yuh , Hsieh Pao-Shiu , Tsai Wen-Sy , Liao Chun-Kai , Hsu Yu-Jen
Published: December 2021

Advanced age is a risk factor for major abdominal surgery due to a decline in physical function and increased comorbidities. Although laparoscopic surgery provides good results in most patients with colorectal cancer (CRC), its effect on elderly patients remains unclear. This study aimed to compare the short- and long-term outcomes between open and laparoscopic surgeries in elderly patients with CRC. Total 1350 patients aged ≥75 years who underwent curative resection for stage I–III primary CRC were enrolled retrospectively and were divided into open surgery (846 patients) and laparoscopy (504 patients) groups. After propensity score weighting to balance an uneven distribution, a competing risk analysis was used to analyze the short-term and long-term outcomes. Postoperative mortality rates were lower in the laparoscopy group, especially due to pulmonary complications. Postoperative hospital stay was significantly shorter in the laparoscopy group than in the open surgery group. Overall survival, disease-free survival, and competing risk analysis showed no significant differences between the two groups. Laparoscopic surgery for elderly patients with CRC significantly decreased pulmonary-related postoperative morbidity and mortality in this large cohort study. Laparoscopic surgery is a favorable method for elderly patients with CRC than open surgery in terms of less hospital stay and similar oncological outcomes.
Shift in G1-Checkpoint from ATM-Alone to a Cooperative ATM Plus ATR Regulation with Increasing Dose of Radiation
Authors: Li Fanghua , Mladenov Emil , Dueva Rositsa , Stuschke Martin , Timmermann Beate , Iliakis George
Published: December 2021

The current view of the involvement of PI3-kinases in checkpoint responses after DNA damage is that ATM is the key regulator of G1-, S- or G2-phase checkpoints, that ATR is only partly involved in the regulation of S- and G2-phase checkpoints and that DNA-PKcs is not involved in checkpoint regulation. However, further analysis of the contributions of these kinases to checkpoint responses in cells exposed to ionizing radiation (IR) recently uncovered striking integrations and interplays among ATM, ATR and DNA-PKcs that adapt not only to the phase of the cell cycle in which cells are irradiated, but also to the load of DNA double-strand breaks (DSBs), presumably to optimize their processing. Specifically, we found that low IR doses in G2-phase cells activate a G2-checkpoint that is regulated by epistatically coupled ATM and ATR. Thus, inhibition of either kinase suppresses almost fully its activation. At high IR doses, the epistatic ATM/ATR coupling relaxes, yielding to a cooperative regulation. Thus, single-kinase inhibition suppresses partly, and only combined inhibition suppresses fully G2-checkpoint activation. Interestingly, DNA-PKcs integrates with ATM/ATR in G2-checkpoint control, but functions in its recovery in a dose-independent manner. Strikingly, irradiation during S-phase activates, independently of dose, an exclusively ATR-dependent G2 checkpoint. Here, ATM couples with DNA-PKcs to regulate checkpoint recovery. In the present work, we extend these studies and investigate organization and functions of these PI3-kinases in the activation of the G1 checkpoint in cells irradiated either in the G0 or G1 phase. We report that ATM is the sole regulator of the G1 checkpoint after exposure to low IR doses. At high IR doses, ATM remains dominant, but contributions from ATR also become detectable and are associated with limited ATM/ATR-dependent end resection at DSBs. Under these conditions, only combined ATM + ATR inhibition fully abrogates checkpoint and resection. Contributions of DNA-PKcs and CHK2 to the regulation of the G1 checkpoint are not obvious in these experiments and may be masked by the endpoint employed for checkpoint analysis and perturbations in normal progression through the cell cycle of cells exposed to DNA-PKcs inhibitors. The results broaden our understanding of organization throughout the cell cycle and adaptation with increasing IR dose of the ATM/ATR/DNA-PKcs module to regulate checkpoint responses. They emphasize notable similarities and distinct differences between G1-, G2- and S-phase checkpoint regulation that may guide DSB processing decisions.
The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats
Authors: Shoji Hiroki , Yoshida Yoko , Sanada Takayuki Jujo , Naito Akira , Maruyama Junko , Zhang Erquan , Sumi Kengo , Sakao Seiichiro , Maruyama Kazuo , Hidaka Hiroyoshi , Tatsumi Koichiro
Published: December 2021

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.
Transcriptomic and Functional Evidence Show Similarities between Human Amniotic Epithelial Stem Cells and Keratinocytes
Authors: Liu Li-Ping , Zheng Dong-Xu , Xu Zheng-Fang , Zhou Hu-Cheng , Wang Yun-Cong , Zhou Hang , Ge Jian-Yun , Sako Daisuke , Li Mi , Akimoto Kazunori , Li Yu-Mei , Zheng Yun-Wen
Published: December 2021

Amniotic epithelial stem cells (AESCs) are considered as potential alternatives to keratinocytes (KCs) in tissue-engineered skin substitutes used for treating skin damage. However, their clinical application is limited since similarities and distinctions between AESCs and KCs remain unclear. Herein, a transcriptomics analysis and functional evaluation were used to understand the commonalities and differences between AESCs and KCs. RNA-sequencing revealed that AESCs are involved in multiple epidermis-associated biological processes shared by KCs and show more similarity to early stage immature KCs than to adult KCs. However, AESCs were observed to be heterogeneous, and some possessed hybrid mesenchymal and epithelial features distinct from KCs. A functional evaluation revealed that AESCs can phagocytose melanosomes transported by melanocytes in both 2D and 3D co-culture systems similar to KCs, which may help reconstitute pigmented skin. The overexpression of TP63 and activation of NOTCH signaling could promote AESC stemness and improve their differentiation features, respectively, bridging the gap between AESCs and KCs. These changes induced the convergence of AESC cell fate with KCs. In future, modified reprogramming strategies, such as the use of small molecules, may facilitate the further modulation human AESCs for use in skin regeneration.
Identification of miRNA–mRNA Regulatory Modules Involved in Lipid Metabolism and Seed Development in a Woody Oil Tree (Camellia oleifera)
Authors: Wu Bo , Ruan Chengjiang , Shah Asad Hussain , Li Denghui , Li He , Ding Jian , Li Jingbin , Du Wei
Published: December 2021

Tea oil camellia (Camellia oleifera), an important woody oil tree, is a source of seed oil of high nutritional and medicinal value that is widely planted in southern China. However, there is no report on the identification of the miRNAs involved in lipid metabolism and seed development in the high- and low-oil cultivars of tea oil camellia. Thus, we explored the roles of miRNAs in the key periods of oil formation and accumulation in the seeds of tea oil camellia and identified miRNA–mRNA regulatory modules involved in lipid metabolism and seed development. Sixteen small RNA libraries for four development stages of seed oil biosynthesis in high- and low-oil cultivars were constructed. A total of 196 miRNAs, including 156 known miRNAs from 35 families, and 40 novel miRNAs were identified, and 55 significantly differentially expressed miRNAs were found, which included 34 upregulated miRNAs, and 21 downregulated miRNAs. An integrated analysis of the miRNA and mRNA transcriptome sequence data revealed that 10 miRNA–mRNA regulatory modules were related to lipid metabolism; for example, the regulatory modules of ath-miR858b–MYB82/MYB3/MYB44 repressed seed oil biosynthesis, and a regulation module of csi-miR166e-5p–S-ACP-DES6 was involved in the formation and accumulation of oleic acid. A total of 23 miRNA–mRNA regulatory modules were involved in the regulation of the seed size, such as the regulatory module of hpe-miR162a_L-2–ARF19, involved in early seed development. A total of 12 miRNA–mRNA regulatory modules regulating growth and development were identified, such as the regulatory modules of han-miR156a_L+1–SPL4/SBP2, promoting early seed development. The expression changes of six miRNAs and their target genes were validated using quantitative real-time PCR, and the targeting relationship of the cpa-miR393_R-1–AFB2 regulatory module was verified by luciferase assays. These data provide important theoretical values and a scientific basis for the genetic improvement of new cultivars of tea oil camellia in the future.
Retrotransposons Down- and Up-Regulation in Aging Somatic Tissues
Authors: Giordani Giorgia , Cavaliere Valeria , Gargiulo Giuseppe , Lattanzi Giovanna , Andrenacci Davide
Published: December 2021

The transposon theory of aging hypothesizes the activation of transposable elements (TEs) in somatic tissues with age, leading to a shortening of the lifespan. It is thought that TE activation in aging produces an increase in DNA double-strand breaks, contributing to genome instability and promoting the activation of inflammatory responses. To investigate how TE regulation changes in somatic tissues during aging, we analyzed the expression of some TEs, as well as a source of small RNAs that specifically silence the analyzed TEs; the Drosophila cluster named flamenco. We found significant variations in the expression levels of all the analyzed TEs during aging, with a trend toward reduction in middle-aged adults and reactivation in older individuals that suggests dynamic regulation during the lifespan.
Effects of High Magnetic Fields on the Diffusion of Biologically Active Molecules
Authors: Zablotskii Vitalii , Polyakova Tatyana , Dejneka Alexandr
Published: December 2021

The diffusion of biologically active molecules is a ubiquitous process, controlling many mechanisms and the characteristic time scales for pivotal processes in living cells. Here, we show how a high static magnetic field (MF) affects the diffusion of paramagnetic and diamagnetic species including oxygen, hemoglobin, and drugs. We derive and solve the equation describing diffusion of such biologically active molecules in the presence of an MF as well as reveal the underlying mechanism of the MF’s effect on diffusion. We found that a high MF accelerates diffusion of diamagnetic species while slowing the diffusion of paramagnetic molecules in cell cytoplasm. When applied to oxygen and hemoglobin diffusion in red blood cells, our results suggest that an MF may significantly alter the gas exchange in an erythrocyte and cause swelling. Our prediction that the diffusion rate and characteristic time can be controlled by an MF opens new avenues for experimental studies foreseeing numerous biomedical applications.