bluuebunny/crossref_metadata_2025 huggingface dataset:
Oral Capsaicinoid Administration Alters the Plasma Endocannabinoidome and Fecal Microbiota of Reproductive-Aged Women Living with Overweight and Obesity
Authors: Manca Claudia , Lacroix Sébastien , Pérusse Francine , Flamand Nicolas , Chagnon Yvon , Drapeau Vicky , Tremblay Angelo , Di Marzo Vincenzo , Silvestri Cristoforo
Published: September 2021

Capsaicinoids, the pungent principles of chili peppers and prototypical activators of the transient receptor potential of the vanilloid type-1 (TRPV1) channel, which is a member of the expanded endocannabinoid system known as the endocannabinoidome (eCBome), counteract food intake and obesity. In this exploratory study, we examined the blood and stools from a subset of the participants in a cohort of reproductive-aged women with overweight/obesity who underwent a 12-week caloric restriction of 500 kcal/day with the administration of capsaicinoids (two capsules containing 100 mg of a capsicum annuum extract (CAE) each for a daily dose of 4 mg of capsaicinoids) or a placebo. Samples were collected immediately before and after the intervention, and plasma eCBome mediator levels (from 23 participants in total, 13 placebo and 10 CAE) and fecal microbiota taxa (from 15 participants in total, 9 placebo and 6 CAE) were profiled using LC–MS/MS and 16S metagenomic sequencing, respectively. CAE prevented the reduced caloric-intake-induced decrease in beneficial eCBome mediators, i.e., the TRPV1, GPR119 and/or PPARα agonists, N-oleoyl-ethanolamine, N-linoleoyl-ethanolamine and 2-oleoyl-glycerol, as well as the anti-inflammatory N-acyl-ethanolamines N-docosapentaenyl-ethanolamine and N-docosahexaenoyl-ethanolamine. CAE produced few but important alterations in the fecal microbiota, such as an increased relative abundance of the genus Flavonifractor, which is known to be inversely associated with obesity. Correlations between eCBome mediators and other potentially beneficial taxa were also observed, thus reinforcing the hypothesis of the existence of a link between the eCBome and the gut microbiome in obesity.
Clinical Significance of HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA Panel in NAFLD/NASH Diagnosis: Egyptian Pilot Study
Authors: Albadawy Reda , Agwa Sara H. A. , Khairy Eman , Saad Maha , El Touchy Naglaa , Othman Mohamed , Matboli Marwa
Published: September 2021

Background: Non-alcoholic steatohepatitis ((NASH) is the progressive form of (non-alcoholic fatty liver disease) (NAFLD), which can progress to liver cirrhosis and hepatocellular carcinoma. There is no available reliable non-invasive diagnostic tool to diagnose NASH, and still the liver biopsy is the gold standard in diagnosis. In this pilot study, we aimed to evaluate the Nod-like receptor (NLR) signaling pathway related RNA panel in the diagnosis of NASH. Methods: Bioinformatics analysis was done, with retrieval of the HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 RNA panel based on the relation to the NLR-signaling pathway. Hepatitis serum markers, lipid profile, NAFLD score and fibrosis score were assessed in the patients’ sera. Reverse transcriptase real time polymerase chain reaction (RT-PCR) was done to assess the relative expression of the RNA panel among patients who had NAFLD without steatosis, NAFLD with simple steatosis, NASH and healthy controls. Results: We observed up-regulation of Lnc-SPARCL1-1:2 lncRNA that led to upregulation of miR-6881-5P with a subsequent increase in levels of HSPD1, MMP14, and ITGB1 mRNAs. In addition, ROC curve analysis was done, with discriminative cutoff values that aided discrimination between NASH cases and control, and also between NAFLD, simple steatosis and NASH. Conclusion: This pilot study concluded that HSPD1/MMP14/ITGB1/miR-6881-5P/Lnc-SPARCL1-1:2 panel expression has potential in the diagnosis of NASH, and also differentiation between NAFLD, simple steatosis and NASH cases.
The AST-120 Recovers Uremic Toxin-Induced Cognitive Deficit via NLRP3 Inflammasome Pathway in Astrocytes and Microglia
Authors: Li Lung-Chih , Chen Wei-Yu , Chen Jin-Bor , Lee Wen-Chin , Chang Chiung-Chih , Tzeng Hong-Tai , Huang Chiang-Chi , Chang Ya-Jen , Yang Jenq-Lin
Published: September 2021

Chronic kidney disease (CKD) is characterized by the progressive loss of renal function; moreover, CKD progression commonly leads to multiple comorbidities, including neurological dysfunction and immune disorders. CKD-triggered neuroinflammation significantly contributes to cognitive impairment. This study aimed to investigate the contribution of uremic toxins to cognitive impairment. Serum creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS), and p-cresol sulfate (PCS) levels were measured using an enzyme-linked immunosorbent assay and high-performance liquid chromatography. The creatinine, BUN, IS, and PCS levels were increased from 4 weeks after 5/6-nephrectomy in mice, which suggested that 5/6-nephrectomy could yield a CKD animal model. Further, CKD mice showed significantly increased brain and serum indoxyl sulfate levels. Immunohistochemistry analysis revealed hippocampal inflammation and NLRP3-inflammasomes in astrocytes. Further, the Y-maze and Morris water maze tests revealed learning and memory defects in CKD mice. AST-120, which is also an IS absorbent, effectively reduced serum and hippocampal IS levels as well as reversed the cognitive impairment in CKD mice. Additionally, NLRP3-knockout mice that underwent 5/6-nephrectomy showed no change in cognitive function. These findings suggested that IS is an important uremic toxin that induces NLRP3 inflammasome-mediated not only in microglia, but it also occurred in astrocytic inflammation, which subsequently causes cognitive impairment.
Alterations in Circulating Monocytes Predict COVID-19 Severity and Include Chromatin Modifications Still Detectable Six Months after Recovery
Authors: Utrero-Rico Alberto , González-Cuadrado Cecilia , Chivite-Lacaba Marta , Cabrera-Marante Oscar , Laguna-Goya Rocío , Almendro-Vazquez Patricia , Díaz-Pedroche Carmen , Ruiz-Ruigómez María , Lalueza Antonio , Folgueira María Dolores , Vázquez Enrique , Quintas Ana , Berges-Buxeda Marcos J. , Martín-Rodriguez Moisés , Dopazo Ana , Serrano-Hernández Antonio , Aguado José María , Paz-Artal Estela
Published: September 2021

An early analysis of circulating monocytes may be critical for predicting COVID-19 course and its sequelae. In 131 untreated, acute COVID-19 patients at emergency room arrival, monocytes showed decreased surface molecule expression, including low HLA-DR, in association with an inflammatory cytokine status and limited anti-SARS-CoV-2-specific T cell response. Most of these alterations had normalized in post-COVID-19 patients 6 months after discharge. Acute COVID-19 monocytes transcriptome showed upregulation of anti-inflammatory tissue repair genes such as BCL6, AREG and IL-10 and increased accessibility of chromatin. Some of these transcriptomic and epigenetic features still remained in post-COVID-19 monocytes. Importantly, a poorer expression of surface molecules and low IRF1 gene transcription in circulating monocytes at admission defined a COVID-19 patient group with impaired SARS-CoV-2-specific T cell response and increased risk of requiring intensive care or dying. An early analysis of monocytes may be useful for COVID-19 patient stratification and for designing innate immunity-focused therapies.
When Activator and Inhibitor of PPARα Do the Same: Consequence for Differentiation of Human Intestinal Cells
Authors: Cizkova Katerina , Foltynkova Tereza , Hanyk Jiri , Kamencak Zbynek , Tauber Zdenek
Published: September 2021

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor that plays a role in various processes including differentiation of several cell types. We investigated the role of PPARα in the differentiation of intestinal cells using HT-29 and Caco2 cell lines as a model as well as human normal colon and colorectal carcinoma tissues. We detected a significant increase in PPARα expression in differentiated HT-29 cells as well as in normal surface colon epithelium where differentiated cells are localised. Thus, it seems that PPARα may play a role in differentiation of intestinal cells. Interestingly, we found that both PPARα activators (fenofibrate and WY-14643) as well as its inhibitor (GW6471) regulated proliferation and differentiation of HT-29 cells in vitro in the same way. Both compounds led to a decrease in proliferation accompanied by a significant increase in expression of villin, intestinal alkaline phosphatase (differentiation markers). Moreover, the same trend in villin expression was observed in Caco2 cells. Furthermore, villin expression was independent of subcellular localisation of PPARα. In addition, we found similar levels of PPARα expression in colorectal carcinomas in comparison to adjacent normal epithelium. All these findings support the hypothesis that differentiation of intestinal epithelium is PPARα-independent.
Design of a Wearable Eye-Movement Detection System Based on Electrooculography Signals and Its Experimental Validation
Authors: Lin Chin-Teng , Jiang Wei-Ling , Chen Sheng-Fu , Huang Kuan-Chih , Liao Lun-De
Published: September 2021

In the assistive research area, human–computer interface (HCI) technology is used to help people with disabilities by conveying their intentions and thoughts to the outside world. Many HCI systems based on eye movement have been proposed to assist people with disabilities. However, due to the complexity of the necessary algorithms and the difficulty of hardware implementation, there are few general-purpose designs that consider practicality and stability in real life. Therefore, to solve these limitations and problems, an HCI system based on electrooculography (EOG) is proposed in this study. The proposed classification algorithm provides eye-state detection, including the fixation, saccade, and blinking states. Moreover, this algorithm can distinguish among ten kinds of saccade movements (i.e., up, down, left, right, farther left, farther right, up-left, down-left, up-right, and down-right). In addition, we developed an HCI system based on an eye-movement classification algorithm. This system provides an eye-dialing interface that can be used to improve the lives of people with disabilities. The results illustrate the good performance of the proposed classification algorithm. Moreover, the EOG-based system, which can detect ten different eye-movement features, can be utilized in real-life applications.
Altered Effective Connectivity within an Oculomotor Control Network in Unaffected Relatives of Individuals with Schizophrenia
Authors: Lehet Matthew , Tso Ivy F. , Park Sohee , Neggers Sebastiaan F. W. , Thompson Ilse A. , Kahn Rene S. , Thakkar Katharine N.
Published: September 2021

The ability to rapidly stop or change a planned action is a critical cognitive process that is impaired in schizophrenia. The current study aimed to examine whether this impairment reflects familial vulnerability to schizophrenia across two experiments comparing unaffected first-degree relatives to healthy controls. First, we examined performance on a saccadic stop-signal task that required rapid inhibition of an eye movement. Then, in a different sample, we investigated behavioral and neural responses (using fMRI) during a stop-signal task variant that required rapid modification of a prepared eye movement. Here, we examined differences between relatives and healthy controls in terms of activation and effective connectivity within an oculomotor control network during task performance. Like individuals with schizophrenia, the unaffected relatives showed behavioral evidence for more inefficient inhibitory processes. Unlike previous findings in individuals with schizophrenia, however, the relatives showed evidence for a compensatory waiting strategy. Behavioral differences were accompanied by more activation among the relatives in task-relevant regions across conditions and group differences in effective connectivity across the task that were modulated differently by the instruction to exert control over a planned saccade. Effective connectivity parameters were related to behavioral measures of inhibition efficiency. The results suggest that individuals at familial risk for schizophrenia were engaging an oculomotor control network differently than controls and in a way that compromises inhibition efficiency.
Understanding of Numerical Information during the COVID-19 Pandemic
Authors: Zamarian Laura , Fürstenberg Katharina M. -A. , Gamboz Nadia , Delazer Margarete
Published: September 2021

Media news during the Coronavirus Disease 2019 (COVID-19) pandemic often entail complex numerical concepts such as exponential increase or reproduction number. This study investigated whether people have difficulties in understanding such information and whether these difficulties are related to numerical competence, reflective thinking, and risk proneness. One hundred sixty-three participants provided answers to a numeracy scale focusing on complex numerical concepts relevant to COVID-19 (COV Numeracy Scale). They also provided responses to well-established objective and subjective scales, questions about affective states, and questions about the COVID-19 pandemic. Higher scores on the COV Numeracy Scale correlated with higher scores on the Health Numeracy Scale, in the Cognitive Reflection Test (CRT), and in self-assessments of verbal comprehension, mathematical intelligence, and subjective numeracy. Interestingly, scores on the COV Numeracy Scale also positively correlated with the number of consulted information sources about COVID-19. Accuracy in the CRT emerged as a significant predictor, explaining ca. 14% of variance on the COV Numeracy Scale. The results suggest that people with lower reflective thinking skills and lower subjective and objective numerical competence can be more at disadvantage when confronted with COVID-related numerical information in everyday life. These findings advise caution in the communication of relevant public health information that entails complex numerical concepts.
What Is the Role of Resilience and Coping Strategies on the Mental Health of the General Population during the COVID-19 Pandemic? Results from the Italian Multicentric COMET Study
Authors: Sampogna Gaia , Del Vecchio Valeria , Giallonardo Vincenzo , Luciano Mario , Albert Umberto , Carmassi Claudia , Carrà Giuseppe , Cirulli Francesca , Dell’Osso Bernardo , Menculini Giulia , Nanni Mariagiulia , Pompili Maurizio , Sani Gabriele , Volpe Umberto , Bianchini Valeria , Fiorillo Andrea
Published: September 2021

The effects of the COVID-19 pandemic on mental health are now well documented, however, few studies have been focused on the role of coping strategies and resilience in counterbalancing these detrimental effects. Data are derived from the COvid Mental hEalth Trial (COMET), a national multicentric trial carried out in the Italian general population. The final sample consisted of 20,720 participants, 53.1% (n = 11,000) of the sample reported low levels of resilience. Adaptive coping strategies and resilience levels did not have any significant protective impact on the levels of depressive, anxiety, and stress symptoms. Only self-distraction was a risk factor for poor mental health (Beta Coefficient, B = 0.1, 95% Confidence Interval, CI: 0.003 to 0.267 for stress symptoms; B = 0.2; 95% CI: 0.077 to 0.324 for anxiety symptoms and B = 0.2, 95% CI: 0.105 to 0.382 for depressive symptoms). High levels of resilience were predicted by adaptive coping strategies, such as acceptance (B = 1.8, CI 95% = 1.4–2.7). Exposure to the different weeks of lockdown, being infected by COVID-19, and being a healthcare professional did not influence the levels of resilience. Our findings should be carefully considered, since the low levels of resilience may represent the missing link between the pandemic and the current increase in mental health problems.
Transport Properties and Resistance Improvement of Ultra-High Performance Concrete (UHPC) after Exposure to Elevated Temperatures
Authors: Qian Yunfeng , Yang Dingyi , Xia Yanghao , Gao Han , Ma Zhiming
Published: September 2021

Ultra-high performance concrete (UHPC) has a high self-healing capacity and is prone to bursting after exposure to high temperatures due to its characteristics. This work evaluates the damage and improvement of UHPC with coarse aggregates through mechanical properties (compressive strength and ultrasonic pulse velocity), transport properties (water absorption and a chloride diffusion test), and micro-properties such as X-ray diffraction (XRD), Mercury intrusion porosimetry (MIP), and Scanning electronic microscopy (SEM). The result demonstrates that polypropylene (PP) fibers are more suitable for high temperature tests than polyacrylonitrile (PAN) fibers. The result shows that 400 °C is the critical temperature point. With the increase in temperature, the hydration becomes significant, and the internal material phase changes accordingly. Although the total pore volume increased, the percentage of various types of pores was optimized within 400 °C. The mass loss gradually increased and the ultrasonic pulse velocity gradually decreased. While the compressive strength first increased and then decreased, and the increase occurred within 25–400 °C. As for the transport properties, the chloride migration coefficient and capillary absorption coefficient both increased dramatically due to the higher sensitivity to temperature changes. The results of the property improvement test showed that at temperatures above 800 °C, the compressive strength recovered by more than 65% and the ultrasonic pulse velocity recovered by more than 75%. In terms of transport properties, compared to the results before self-healing, the chloride migration coefficient decreased by up to 59%, compared with 89% for the capillary absorption coefficient, after self-healing at 800 °C. With respect to the enhancement effect after exposure to high temperatures, the environment of a 5% Na2SO4 solution was not as good as the clean water environment. The corresponding changes in microstructure during the high temperatures and the self-healing process can explain the change in the pattern of macroscopic properties more precisely.
MiR-137 Targets the 3′ Untranslated Region of MSH2: Potential Implications in Lynch Syndrome-Related Colorectal Cancer
Authors: Liccardo Raffaella , Sessa Raffaele , Trombetti Silvia , De Rosa Marina , Izzo Paola , Grosso Michela , Duraturo Francesca
Published: September 2021

Mismatch Repair (MMR) gene dysregulation plays a fundamental role in Lynch Syndrome (LS) pathogenesis, a form of hereditary colorectal cancer. Loss or overexpression of key MMR genes leads to genome instability and tumorigenesis; however, the mechanisms controlling MMR gene expression are unknown. One such gene, MSH2, exerts an important role, not only in MMR, but also in cell proliferation, apoptosis, and cell cycle control. In this study, we explored the functions and underlying molecular mechanisms of increased MSH2 expression related to a c.*226A>G variant in the 3′untranslated (UTR) region of MSH2 that had been previously identified in a subject clinically suspected of LS. Bioinformatics identified a putative binding site for miR-137 in this region. To verify miRNA targeting specificity, we performed luciferase gene reporter assays using a MSH2 3′UTR psiCHECK-2 vector in human SW480 cells over-expressing miR-137, which showed a drastic reduction in luciferase activity (p > 0.0001). This effect was abolished by site-directed mutagenesis of the putative miR-137 seed site. Moreover, in these cells we observed that miR-137 levels were inversely correlated with MSH2 expression levels. These results were confirmed by results in normal and tumoral tissues from the patient carrying the 3′UTR c.*226A>G variant in MSH2. Finally, miR-137 overexpression in SW480 cells significantly suppressed cell proliferation in a time- and dose-dependent manner (p < 0.0001), supporting a role for MSH2 in apoptosis and cell proliferation processes. Our findings suggest miR-137 helps control MSH2 expression via its 3′UTR and that dysregulation of this mechanism appears to promote tumorigenesis in colon cells.
A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest Plasticity
Authors: Schmidtlein Paula M. , Volz Clara , Braun Rüdiger , Thürling Isabel , Lapshyna Olha , Wellner Ulrich F. , Konukiewitz Björn , Lehnert Hendrik , Marquardt Jens-Uwe , Ungefroren Hendrik
Published: September 2021

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial–mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or β cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5′-aza-2′-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic β cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells.
ALK-Negative Anaplastic Large Cell Lymphoma: Current Concepts and Molecular Pathogenesis of a Heterogeneous Group of Large T-Cell Lymphomas
Authors: Pina-Oviedo Sergio , Ortiz-Hidalgo Carlos , Carballo-Zarate Adrian Alejandro , Zarate-Osorno Alejandra
Published: September 2021

Anaplastic large cell lymphoma (ALCL) is a subtype of CD30+ large T-cell lymphoma (TCL) that comprises ~2% of all adult non-Hodgkin lymphomas. Based on the presence/absence of the rearrangement and expression of anaplastic lymphoma kinase (ALK), ALCL is divided into ALK+ and ALK-, and both differ clinically and prognostically. This review focuses on the historical points, clinical features, histopathology, differential diagnosis, and relevant cytogenetic and molecular alterations of ALK- ALCL and its subtypes: systemic, primary cutaneous (pc-ALCL), and breast implant-associated (BIA-ALCL). Recent studies have identified recurrent genetic alterations in this TCL. In systemic ALK- ALCL, rearrangements in DUSP22 and TP63 are detected in 30% and 8% of cases, respectively, while the remaining cases are negative for these rearrangements. A similar distribution of these rearrangements is seen in pc-ALCL, whereas none have been detected in BIA-ALCL. Additionally, systemic ALK- ALCL—apart from DUSP22-rearranged cases—harbors JAK1 and/or STAT3 mutations that result in the activation of the JAK/STAT signaling pathway. The JAK1/3 and STAT3 mutations have also been identified in BIA-ALCL but not in pc-ALCL. Although the pathogenesis of these alterations is not fully understood, most of them have prognostic value and open the door to the use of potential targeted therapies for this subtype of TCL.
Long-Term Outcomes and Causes of Death among Medullary Thyroid Carcinoma Patients with Distant Metastases
Authors: Park Hyunju , Yang Heera , Heo Jung , Kim Tae Hyuk , Kim Sun Wook , Chung Jae Hoon
Published: September 2021

Distant metastasis is a poor prognostic factor in medullary thyroid carcinoma (MTC), but the significance of differentiating the characteristics according to the site of distant metastasis remains unclear. This study aimed to evaluate the clinical characteristics and long-term oncologic outcomes in MTC patients with distant metastasis. We identified 46 MTC patients with distant metastasis between 1994 and 2019. Clinical characteristics were compared based on the timing of the detection of distant metastasis. Additionally, survival rates following the detection of distant metastasis were evaluated to compare the clinical significance of metastatic site. The detailed causes of death were also investigated. Of the 46 patients, 15 patients (32.6%) had synchronous distant metastasis and 31 patients (67.4%) had metachronous distant metastasis. There was no clinical difference between these two groups except regarding initial surgical extent. The lung (52.2%) was the most common metastatic site, followed by the bone (28.3%), mediastinum (19.6%), liver (17.4%), adrenal gland (4.3%), brain (4.3%), kidney (2.2%), and pancreas (2.2%). Patients with bone metastasis and multisite metastasis had significantly worse prognoses than those with lung metastasis (hazard ratio: 5.42; p = 0.044 and hazard ratio: 6.11; p = 0.006). Complications due to the progression of distant metastasis, airway obstruction due to tracheal invasion, and complications related to chemotherapy were leading causes of death. In conclusion, there was no difference in clinical characteristics according to the timing of distant metastasis. Oncological outcomes differed by metastatic site.
Identifying New Potential Biomarkers in Adrenocortical Tumors Based on mRNA Expression Data Using Machine Learning
Authors: Marquardt André , Landwehr Laura-Sophie , Ronchi Cristina L. , di Dalmazi Guido , Riester Anna , Kollmannsberger Philip , Altieri Barbara , Fassnacht Martin , Sbiera Silviu
Published: September 2021

Adrenocortical carcinoma (ACC) is a rare disease, associated with poor survival. Several “multiple-omics” studies characterizing ACC on a molecular level identified two different clusters correlating with patient survival (C1A and C1B). We here used the publicly available transcriptome data from the TCGA-ACC dataset (n = 79), applying machine learning (ML) methods to classify the ACC based on expression pattern in an unbiased manner. UMAP (uniform manifold approximation and projection)-based clustering resulted in two distinct groups, ACC-UMAP1 and ACC-UMAP2, that largely overlap with clusters C1B and C1A, respectively. However, subsequent use of random-forest-based learning revealed a set of new possible marker genes showing significant differential expression in the described clusters (e.g., SOAT1, EIF2A1). For validation purposes, we used a secondary dataset based on a previous study from our group, consisting of 4 normal adrenal glands and 52 benign and 7 malignant tumor samples. The results largely confirmed those obtained for the TCGA-ACC cohort. In addition, the ENSAT dataset showed a correlation between benign adrenocortical tumors and the good prognosis ACC cluster ACC-UMAP1/C1B. In conclusion, the use of ML approaches re-identified and redefined known prognostic ACC subgroups. On the other hand, the subsequent use of random-forest-based learning identified new possible prognostic marker genes for ACC.
Exosomes: A Forthcoming Era of Breast Cancer Therapeutics
Authors: Bondhopadhyay Banashree , Sisodiya Sandeep , Alzahrani Faisal Abdulrahman , Bakhrebah Muhammed A. , Chikara Atul , Kasherwal Vishakha , Khan Asiya , Rani Jyoti , Dar Sajad Ahmad , Akhter Naseem , Tanwar Pranay , Agrawal Usha , Hussain Showket
Published: September 2021

Despite the recent advancements in therapeutics and personalized medicine, breast cancer remains one of the most lethal cancers among women. The prognostic and diagnostic aids mainly include assessment of tumor tissues with conventional methods towards better therapeutic strategies. However, current era of gene-based research may influence the treatment outcome particularly as an adjunct to diagnostics by exploring the role of non-invasive liquid biopsies or circulating markers. The characterization of tumor milieu for physiological fluids has been central to identifying the role of exosomes or small extracellular vesicles (sEVs). These exosomes provide necessary communication between tumor cells in the tumor microenvironment (TME). The manipulation of exosomes in TME may provide promising diagnostic/therapeutic strategies, particularly in triple-negative breast cancer patients. This review has described and highlighted the role of exosomes in breast carcinogenesis and how they could be used or targeted by recent immunotherapeutics to achieve promising intervention strategies.
Glioblastoma Surgery Imaging–Reporting and Data System: Validation and Performance of the Automated Segmentation Task
Authors: Bouget David , Eijgelaar Roelant S. , Pedersen André , Kommers Ivar , Ardon Hilko , Barkhof Frederik , Bello Lorenzo , Berger Mitchel S. , Nibali Marco Conti , Furtner Julia , Fyllingen Even Hovig , Hervey-Jumper Shawn , Idema Albert J. S. , Kiesel Barbara , Kloet Alfred , Mandonnet Emmanuel , Müller Domenique M. J. , Robe Pierre A. , Rossi Marco , Sagberg Lisa M. , Sciortino Tommaso , Van den Brink Wimar A. , Wagemakers Michiel , Widhalm Georg , Witte Marnix G. , Zwinderman Aeilko H. , Reinertsen Ingerid , De Witt Hamer Philip C. , Solheim Ole
Published: September 2021

For patients with presumed glioblastoma, essential tumor characteristics are determined from preoperative MR images to optimize the treatment strategy. This procedure is time-consuming and subjective, if performed by crude eyeballing or manually. The standardized GSI-RADS aims to provide neurosurgeons with automatic tumor segmentations to extract tumor features rapidly and objectively. In this study, we improved automatic tumor segmentation and compared the agreement with manual raters, describe the technical details of the different components of GSI-RADS, and determined their speed. Two recent neural network architectures were considered for the segmentation task: nnU-Net and AGU-Net. Two preprocessing schemes were introduced to investigate the tradeoff between performance and processing speed. A summarized description of the tumor feature extraction and standardized reporting process is included. The trained architectures for automatic segmentation and the code for computing the standardized report are distributed as open-source and as open-access software. Validation studies were performed on a dataset of 1594 gadolinium-enhanced T1-weighted MRI volumes from 13 hospitals and 293 T1-weighted MRI volumes from the BraTS challenge. The glioblastoma tumor core segmentation reached a Dice score slightly below 90%, a patientwise F1-score close to 99%, and a 95th percentile Hausdorff distance slightly below 4.0 mm on average with either architecture and the heavy preprocessing scheme. A patient MRI volume can be segmented in less than one minute, and a standardized report can be generated in up to five minutes. The proposed GSI-RADS software showed robust performance on a large collection of MRI volumes from various hospitals and generated results within a reasonable runtime.
Naples Prognostic Score Predicts Tumor Regression Grade in Resectable Gastric Cancer Treated with Preoperative Chemotherapy
Authors: Lieto Eva , Auricchio Annamaria , Tirino Giuseppe , Pompella Luca , Panarese Iacopo , Del Sorbo Giovanni , Ferraraccio Francesca , De Vita Ferdinando , Galizia Gennaro , Cardella Francesca
Published: September 2021

Despite recent progresses, locally advanced gastric cancer remains a daunting challenge to embrace. Perioperative chemotherapy and D2-gastrectomy depict multimodal treatment of gastric cancer in Europe, shows better results than curative surgery alone in terms of downstaging, micrometastases elimination, and improved long-term survival. Unfortunately, preoperative chemotherapy is useless in about 50% of cases of non-responder patients, in which no effect is registered. Tumor regression grade (TRG) is directly related to chemotherapy effectiveness, but its understanding is achieved only after surgical operation; accordingly, preoperative chemotherapy is given indiscriminately. Conversely, Naples Prognostic Score (NPS), related to patient immune-nutritional status and easily obtained before taking any therapeutic decision, appeared an independent prognostic variable of TRG. NPS was calculated in 59 consecutive surgically treated gastric cancer patients after neoadjuvant FLOT4-based chemotherapy. 42.2% of positive responses were observed: all normal NPS and half mild/moderate NPS showed significant responses to chemotherapy with TRG 1–3; while only 20% of the worst NPS showed some related benefits. Evaluation of NPS in gastric cancer patients undergoing multimodal treatment may be useful both in selecting patients who will benefit from preoperative chemotherapy and for changing immune-nutritional conditions in order to improve patient’s reaction against the tumor.
The Catalysed Transformation of Vegetable Oils or Animal Fats to Biofuels and Bio-Lubricants: A Review
Authors: Hájek Martin , Vávra Aleš , de Paz Carmona Héctor , Kocík Jaroslav
Published: September 2021

This review paper summarizes the current state-of-the-art of the chemical transformation of oils/fats (i.e., triacylglycerols) to the use of biofuels or bio-lubricants in the means of transport, which is a novelty. The chemical transformation is necessary to obtain products that are more usable with properties corresponding to fuels synthesized from crude oil. Two types of fuels are described—biodiesel (the mixture of methyl esters produced by transesterification) and green diesel (paraffins produced by hydrogenation of oils). Moreover, three bio-lubricant synthesis methods are described. The transformation, which is usually catalysed, depends on: (i) the type and composition of the raw material, including alcohols for biodiesel production and hydrogen for green diesel; (ii) the type of the catalyst in the case of catalysed reactions; (iii) the reaction conditions; and (iv) types of final products. The most important catalysts, especially heterogeneous and including reaction conditions, for each product are described. The properties of biodiesel and green diesel and a comparison with diesel from crude oil are also discussed.
Recent Progress in Catalytic Synthesis of 1,2,3-Triazoles
Authors: De Nino Antonio , Maiuolo Loredana , Costanzo Paola , Algieri Vincenzo , Jiritano Antonio , Olivito Fabrizio , Tallarida Matteo Antonio
Published: September 2021

1,2,3-triazoles represent a functional heterocyclic core that has been at the center of modern organic chemistry since the beginning of click chemistry. Being a versatile framework, such an aromatic ring can be observed in uncountable molecules useful in medicine and photochemistry, just to name a few. This review summarizes the progress achieved in their synthesis from 2015 to today, with particular emphasis on the development of new catalytic and eco-compatible approaches. In doing so, we subdivided the report based on their degree of functionalization and, for each subparagraph, we outlined the role of the catalyst employed.
Evaluation of Effects of Ractopamine on Cardiovascular, Respiratory, and Locomotory Physiology in Animal Model Zebrafish Larvae
Authors: Abbas Kumail , Saputra Ferry , Suryanto Michael Edbert , Lai Yu-Heng , Huang Jong-Chin , Yu Wen-Hao , Chen Kelvin H.-C. , Lin Ying-Ting , Hsiao Chung-Der
Published: September 2021

Ractopamine (RAC) is a beta-adrenoceptor agonist that is used to promote lean and increased food conversion efficiency in livestock. This compound has been considered to be causing behavioral and physiological alterations in livestock like pig. Few studies have addressed the potential non-target effect of RAC in aquatic animals. In this study, we aimed to explore the potential physiological response after acute RAC exposure in zebrafish by evaluating multiple endpoints like locomotor activity, oxygen consumption, and cardiovascular performance. Zebrafish larvae were subjected to waterborne RAC exposure at 0.1, 1, 2, 4, or 8 ppm for 24 h, and the corresponding cardiovascular, respiratory, and locomotion activities were monitored and quantified. In addition, we also performed in silico molecular docking for RAC with 10 zebrafish endogenous β-adrenergic receptors to elucidate the potential acting mechanism of RAC. Results show RAC administration can significantly boost locomotor activity, cardiac performance, oxygen consumption, and blood flow rate, but without affecting the cardiac rhythm regularity in zebrafish embryos. Based on structure-based flexible molecular docking, RAC display similar binding affinity to all ten subtypes of endogenous β-adrenergic receptors, from adra1aa to adra2db, which are equivalent to the human one. This result suggests RAC might act as high potency and broad spectrum β-adrenergic receptors agonist on boosting the locomotor activity, cardiac performance, and oxygen consumption in zebrafish. To validate our results, we co-incubated a well-known β-blocker of propranolol (PROP) with RAC. PROP exposure tends to minimize the locomotor hyperactivity, high oxygen consumption, and cardiac rate in zebrafish larvae. In silico structure-based molecular simulation and binding affinity tests show PROP has an overall lower binding affinity than RAC. Taken together, our studies provide solid in vivo evidence to support that RAC plays crucial roles on modulating cardiovascular, respiratory, and locomotory physiology in zebrafish for the first time. In addition, the versatile functions of RAC as β-agonist possibly mediated via receptor competition with PROP as β-antagonist.
Mammalian Cell-Free System Recapitulates the Early Events of Post-Fertilization Sperm Mitophagy
Authors: Song Won-Hee , Zuidema Dalen , Yi Young-Joo , Zigo Michal , Zhang Zhibing , Sutovsky Miriam , Sutovsky Peter
Published: September 2021

Propagation of paternal sperm-contributed mitochondrial genes, resulting in heteroplasmy, is seldom observed in mammals due to post-fertilization degradation of sperm mitochondria, referred to as sperm mitophagy. Whole organelle sperm mitochondrion degradation is thought to be mediated by the interplay between the ubiquitin-proteasome system (UPS) and the autophagic pathway (Song et al., Proc. Natl. Acad. Sci. USA, 2016). Both porcine and primate post-fertilization sperm mitophagy rely on the ubiquitin-binding autophagy receptor, sequestosome 1 (SQSTM1), and the proteasome-interacting ubiquitinated protein dislocase, valosin-containing protein (VCP). Consequently, we anticipated that sperm mitophagy could be reconstituted in a cell-free system consisting of permeabilized mammalian spermatozoa co-incubated with porcine oocyte extracts. We found that SQSTM1 was detected in the midpiece/mitochondrial sheath of the sperm tail after, but not before, co-incubation with oocyte extracts. VCP was prominent in the sperm mitochondrial sheath both before and after the extract co-incubation and was also detected in the acrosome and postacrosomal sheath and the subacrosomal layer of the spermatozoa co-incubated with extraction buffer as control. Such patterns are consistent with our previous observation of SQSTM1 and VCP associating with sperm mitochondria inside the porcine zygote. In addition, it was observed that sperm head expansion mimicked the early stages of paternal pronucleus development in a zygote during prolonged sperm-oocyte extract co-incubation. Treatment with anti-SQSTM1 antibody during extract co-incubation prevented ooplasmic SQSTM1 binding to sperm mitochondria. Even in an interspecific cellular environment encompassing bull spermatozoa and porcine oocyte extract, ooplasmic SQSTM1 was recruited to heterospecific sperm mitochondria. Complementary with the binding of SQSTM1 and VCP to sperm mitochondria, two sperm-borne pro-mitophagy proteins, parkin co-regulated gene product (PACRG) and spermatogenesis associated 18 (SPATA18), underwent localization changes after extract coincubation, which were consistent with their degradation observed inside fertilized porcine oocytes. These results demonstrate that the early developmental events of post-fertilization sperm mitophagy observed in porcine zygote can be reconstituted in a cell-free system, which could become a useful tool for identifying additional molecules that regulate mitochondrial inheritance in mammals.
Adipose Tissue Macrophages Modulate Obesity-Associated β Cell Adaptations through Secreted miRNA-Containing Extracellular Vesicles
Authors: Gao Hong , Luo Zhenlong , Jin Zhongmou , Ji Yudong , Ying Wei
Published: September 2021

Obesity induces an adaptive expansion of β cell mass and insulin secretion abnormality. Expansion of adipose tissue macrophages (ATMs) is a hallmark of obesity. Here, we assessed a novel role of ATMs in mediating obesity-induced β cell adaptation through the release of miRNA-containing extracellular vesicles (EVs). In both in vivo and in vitro experiments, we show that ATM EVs derived from obese mice notably suppress insulin secretion and enhance β cell proliferation. We also observed similar phenotypes from human islets after obese ATM EV treatment. Importantly, depletion of miRNAs blunts the effects of obese ATM EVs, as evidenced by minimal effects of obese DicerKO ATM EVs on β cell responses. miR-155 is a highly enriched miRNA within obese ATM EVs and miR-155 overexpressed in β cells impairs insulin secretion and enhances β cell proliferation. In contrast, knockout of miR-155 attenuates the regulation of obese ATM EVs on β cell responses. We further demonstrate that the miR-155-Mafb axis plays a critical role in controlling β cell responses. These studies show a novel mechanism by which ATM-derived EVs act as endocrine vehicles delivering miRNAs and subsequently mediating obesity-associated β cell adaptation and dysfunction.
Alpha-Synuclein and Lipids: The Elephant in the Room?
Authors: Sarchione Alessia , Marchand Antoine , Taymans Jean-Marc , Chartier-Harlin Marie-Christine
Published: September 2021

Since the initial identification of alpha-synuclein (α-syn) at the synapse, numerous studies demonstrated that α-syn is a key player in the etiology of Parkinson’s disease (PD) and other synucleinopathies. Recent advances underline interactions between α-syn and lipids that also participate in α-syn misfolding and aggregation. In addition, increasing evidence demonstrates that α-syn plays a major role in different steps of synaptic exocytosis. Thus, we reviewed literature showing (1) the interplay among α-syn, lipids, and lipid membranes; (2) advances of α-syn synaptic functions in exocytosis. These data underscore a fundamental role of α-syn/lipid interplay that also contributes to synaptic defects in PD. The importance of lipids in PD is further highlighted by data showing the impact of α-syn on lipid metabolism, modulation of α-syn levels by lipids, as well as the identification of genetic determinants involved in lipid homeostasis associated with α-syn pathologies. While questions still remain, these recent developments open the way to new therapeutic strategies for PD and related disorders including some based on modulating synaptic functions.
Identifying Plectin Isoform Functions through Animal Models
Authors: Castañón Maria J. , Wiche Gerhard
Published: September 2021

Plectin, a high-molecular-weight cytoskeletal linker protein, binds with high affinity to intermediate filaments of all types and connects them to junctional complexes, organelles, and inner membrane systems. In addition, it interacts with actomyosin structures and microtubules. As a multifunctional protein, plectin has been implicated in several multisystemic diseases, the most common of which is epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). A great part of our knowledge about plectin’s functional diversity has been gained through the analysis of a unique collection of transgenic mice that includes a full (null) knockout (KO), several tissue-restricted and isoform-specific KOs, three double KOs, and two knock-in lines. The key molecular features and pathological phenotypes of these mice will be discussed in this review. In summary, the analysis of the different genetic models indicated that a functional plectin is required for the proper function of striated and simple epithelia, cardiac and skeletal muscle, the neuromuscular junction, and the vascular endothelium, recapitulating the symptoms of humans carrying plectin mutations. The plectin-null line showed severe skin and muscle phenotypes reflecting the importance of plectin for hemidesmosome and sarcomere integrity; whereas the ablation of individual isoforms caused a specific phenotype in myofibers, basal keratinocytes, or neurons. Tissue-restricted ablation of plectin rendered the targeted cells less resilient to mechanical stress. Studies based on animal models other than the mouse, such as zebrafish and C. elegans, will be discussed as well.
Heat Shock Factor 1 Prevents Age-Related Hearing Loss by Decreasing Endoplasmic Reticulum Stress
Authors: Lee Yun Yeong , Gil Eun Sol , Jeong In Hye , Kim Hantai , Jang Jeong Hun , Choung Yun-Hoon
Published: September 2021

Endoplasmic reticulum (ER) stress is a common stress factor during the aging process. Heat shock factor 1 (HSF1) plays a critical role in ER stress; however, its exact function in age-related hearing loss (ARHL) has not been fully elucidated. The purpose of the present study was to identify the role of HSF1 in ARHL. In this study, we demonstrated that the loss of inner and outer hair cells and their supporting cells was predominant in the high-frequency region (basal turn, 32 kHz) in ARHL cochleae. In the aging cochlea, levels of the ER stress marker proteins p-eIF2α and CHOP increased as HSF1 protein levels decreased. The levels of various heat shock proteins (HSPs) also decreased, including HSP70 and HSP40, which were markedly downregulated, and the expression levels of Bax and cleaved caspase-3 apoptosis-related proteins were increased. However, HSF1 overexpression showed significant hearing protection effects in the high-frequency region (basal turn, 32 kHz) by decreasing CHOP and cleaved caspase-3 and increasing the HSP40 and HSP70 proteins. These findings were confirmed by HSF1 functional studies using an auditory cell model. Therefore, we propose that HSF1 can function as a mediator to prevent ARHL by decreasing ER stress-dependent apoptosis in the aging cochlea.
Single Cell Analysis of Stored Red Blood Cells Using Ultra-High Throughput Holographic Cytometry
Authors: Park Han-Sang , Price Hillel , Ceballos Silvia , Chi Jen-Tsan , Wax Adam
Published: September 2021

Holographic cytometry is introduced as an ultra-high throughput implementation of quantitative phase imaging of single cells flowing through parallel microfluidic channels. Here, the approach was applied for characterizing the morphology of individual red blood cells during storage under regular blood bank conditions. Samples from five blood donors were examined, over 100,000 cells examined for each, at three time points. The approach allows high-throughput phase imaging of a large number of cells, greatly extending our ability to study cellular phenotypes using individual cell images. Holographic cytology images can provide measurements of multiple physical traits of the cells, including optical volume and area, which are observed to consistently change over the storage time. In addition, the large volume of cell imaging data can serve as training data for machine-learning algorithms. For the study here, logistic regression was used to classify the cells according to the storage time points. The analysis showed that at least 5000 cells are needed to ensure accuracy of the classifiers. Overall, results showed the potential of holographic cytometry as a diagnostic tool.