bluuebunny/crossref_metadata_2025 huggingface dataset:
CRISPR Approaches for the Diagnosis of Human Diseases
Authors: Puig-Serra Pilar , Casado-Rosas Maria Cruz , Martinez-Lage Marta , Olalla-Sastre Beatriz , Alonso-Yanez Alejandro , Torres-Ruiz Raul , Rodriguez-Perales Sandra
Published: February 2022

CRISPR/Cas is a prokaryotic self-defense system, widely known for its use as a gene-editing tool. Because of their high specificity to detect DNA and RNA sequences, different CRISPR systems have been adapted for nucleic acid detection. CRISPR detection technologies differ highly among them, since they are based on four of the six major subtypes of CRISPR systems. In just 5 years, the CRISPR diagnostic field has rapidly expanded, growing from a set of specific molecular biology discoveries to multiple FDA-authorized COVID-19 tests and the establishment of several companies. CRISPR-based detection methods are coupled with pre-existing preamplification and readout technologies, achieving sensitivity and reproducibility comparable to the current gold standard nucleic acid detection methods. Moreover, they are very versatile, can be easily implemented to detect emerging pathogens and new clinically relevant mutations, and offer multiplexing capability. The advantages of the CRISPR-based diagnostic approaches are a short sample-to-answer time and no requirement of laboratory settings; they are also much more affordable than current nucleic acid detection procedures. In this review, we summarize the applications and development trends of the CRISPR/Cas13 system in the identification of particular pathogens and mutations and discuss the challenges and future prospects of CRISPR-based diagnostic platforms in biomedicine.
Epigenetics and Helicobacter pylori
Authors: Capparelli Rosanna , Iannelli Domenico
Published: February 2022

Epigenetics regulates gene expression, cell type development during differentiation, and the cell response to environmental stimuli. To survive, bacteria need to evade the host immune response. Bacteria, including Helicobacter pylori (Hp), reach this target epigenetically, altering the chromatin of the host cells, in addition to several more approaches, such as DNA mutation and recombination. This review shows that Hp prevalently silences the genes of the human gastric mucosa by DNA methylation. Epigenetics includes different mechanisms. However, DNA methylation persists after DNA replication and therefore is frequently associated with the inheritance of repressed genes. Chromatin modification can be transmitted to daughter cells leading to heritable changes in gene expression. Aberrant epigenetic alteration of the gastric mucosa DNA remains the principal cause of gastric cancer. Numerous methylated genes have been found in cancer as well as in precancerous lesions of Hp-infected patients. These methylated genes inactivate tumor-suppressor genes. It is time for us to complain about our genetic and epigenetic makeups for our diseases.
Synthesis and In Vitro Activity of Novel Melphalan Analogs in Hematological Malignancy Cells
Authors: Poczta Anastazja , Krzeczyński Piotr , Tobiasz Joanna , Rogalska Aneta , Gajek Arkadiusz , Marczak Agnieszka
Published: February 2022

Despite the continuous developments in pharmacology and the high therapeutic effect of new treatment options for patients with hematological malignancies, these diseases remain a major health issue. Our study aimed to synthesize, analyze in silico, and determine the biological properties of new melphalan derivatives. We obtained three methyl esters of melphalan having in their structures amidine moieties substituted with thiomorpholine (EM–T–MEL), indoline (EM–I–MEL), or 4-(4-morpholinyl) piperidine (EM–MORPIP–MEL). These have not yet been described in the literature. The in vitro anticancer properties of the analogs were determined against THP1, HL60, and RPMI8226 cells. Melphalan derivatives were evaluated for cytotoxicity (resazurin viability assay), genotoxicity (alkaline comet assay), and their ability to induce apoptosis (Hoechst33342/propidium iodide double staining method; phosphatidylserine translocation; and caspase 3/7, 8, and 9 activity measurements). Changes in mitochondrial membrane potential were examined using the specific fluorescence probe JC–1 (5,5′,6,6′-tetrachloro-1,1′,3,3′–tetraethylbenzimidazol carbocyanine). The EM–T–MEL derivative had the highest biological activity, showing higher cytotoxic and genotoxic properties than the parent drug. Moreover, it showed a high ability to induce apoptosis in the tested cancer cells. This compound also had a beneficial effect in peripheral blood mononuclear cells (PBMC). In conclusion, we verified and confirmed the hypothesis that chemical modifications of the melphalan structure improved its anticancer properties. The conducted study allowed the selection of the compound with the highest biological activity and provided a basis for chemical structure-biological activity analyses.
Neuron Compatibility and Antioxidant Activity of Barium Titanate and Lithium Niobate Nanoparticles
Authors: Candito Mariarita , Simoni Edi , Gentilin Erica , Martini Alessandro , Marioni Gino , Danti Serena , Astolfi Laura
Published: February 2022

The biocompatibility and the antioxidant activity of barium titanate (BaTiO3) and lithium niobate (LiNbO3) were investigated on a neuronal cell line, the PC12, to explore the possibility of using piezoelectric nanoparticles in the treatment of inner ear diseases, avoiding damage to neurons, the most delicate and sensitive human cells. The cytocompatibility of the compounds was verified by analysing cell viability, cell morphology, apoptotic markers, oxidative stress and neurite outgrowth. The results showed that BaTiO3 and LiNbO3 nanoparticles do not affect the viability, morphological features, cytochrome c distribution and production of reactive oxygen species (ROS) by PC12 cells, and stimulate neurite branching. These data suggest the biocompatibility of BaTiO3 and LiNbO3 nanoparticles, and that they could be suitable candidates to improve the efficiency of new implantable hearing devices without damaging the neuronal cells.
A Major Intestinal Catabolite of Quercetin Glycosides, 3-Hydroxyphenylacetic Acid, Protects the Hepatocytes from the Acetaldehyde-Induced Cytotoxicity through the Enhancement of the Total Aldehyde Dehydrogenase Activity
Authors: Liu Yujia , Myojin Takumi , Li Kexin , Kurita Ayuki , Seto Masayuki , Motoyama Ayano , Liu Xiaoyang , Satoh Ayano , Munemasa Shintaro , Murata Yoshiyuki , Nakamura Toshiyuki , Nakamura Yoshimasa
Published: February 2022

Aldehyde dehydrogenases (ALDHs) are the major enzyme superfamily for the aldehyde metabolism. Since the ALDH polymorphism leads to the accumulation of acetaldehyde, we considered that the enhancement of the liver ALDH activity by certain food ingredients could help prevent alcohol-induced chronic diseases. Here, we evaluated the modulating effects of 3-hydroxyphenylacetic acid (OPAC), the major metabolite of quercetin glycosides, on the ALDH activity and acetaldehyde-induced cytotoxicity in the cultured cell models. OPAC significantly enhanced the total ALDH activity not only in mouse hepatoma Hepa1c1c7 cells, but also in human hepatoma HepG2 cells. OPAC significantly increased not only the nuclear level of aryl hydrocarbon receptor (AhR), but also the AhR-dependent reporter gene expression, though not the nuclear factor erythroid-2-related factor 2 (Nrf2)-dependent one. The pretreatment of OPAC at the concentration required for the ALDH upregulation completely inhibited the acetaldehyde-induced cytotoxicity. Silencing AhR impaired the resistant effect of OPAC against acetaldehyde. These results strongly suggested that OPAC protects the cells from the acetaldehyde-induced cytotoxicity, mainly through the AhR-dependent and Nrf2-independent enhancement of the total ALDH activity. Our findings suggest that OPAC has a protective potential in hepatocyte models and could offer a new preventive possibility of quercetin glycosides for targeting alcohol-induced chronic diseases.
A Case Study of the Morphological and Molecular Variation within a Ciliate Genus: Taxonomic Descriptions of Three Dysteria Species (Ciliophora, Cyrtophoria), with the Establishment of a New Species
Authors: Zhao Xuetong , Zhang Hui , Zhang Qianqian , Qu Zhishuai , Warren Alan , Wu Di , Chen Xiangrui
Published: February 2022

Three Dysteria species, D. crassipes Claparède & Lachmann, 1859; D. brasiliensis Faria et al., 1922; and D. paracrassipes n. sp., were collected from subtropical coastal waters of the East China Sea, near Ningbo, China. The three species were studied based on their living morphology, infraciliature, and molecular data. The new species D. paracrassipes n. sp. is very similar to D. crassipes in most morphological features except the preoral kinety, which is double-rowed in the new species (vs. single-rowed in D. crassipes). The difference in the small ribosomal subunit sequences (SSU rDNA) between these two species is 56 bases, supporting the establishment of the new species. The Ningbo population of D. crassipes is highly similar in morphology to other known populations. Nevertheless, the SSU rDNA sequences of these populations are very different, indicating high genetic diversity and potentially cryptic species. Dysteria brasiliensis is cosmopolitan with many described populations worldwide and four deposited SSU rDNA sequences. The present work supplies morphological and molecular information from five subtropical populations of D. brasiliensis that bear identical molecular sequences but show significant morphological differences. The findings of this study provide an opportunity to improve understanding of the morphological and genetic diversity of ciliates.
Bioengineered Living Bone Grafts—A Concise Review on Bioreactors and Production Techniques In Vitro
Authors: Kazimierczak Paulina , Przekora Agata
Published: February 2022

It has been observed that bone fractures carry a risk of high mortality and morbidity. The deployment of a proper bone healing method is essential to achieve the desired success. Over the years, bone tissue engineering (BTE) has appeared to be a very promising approach aimed at restoring bone defects. The main role of the BTE is to apply new, efficient, and functional bone regeneration therapy via a combination of bone scaffolds with cells and/or healing promotive factors (e.g., growth factors and bioactive agents). The modern approach involves also the production of living bone grafts in vitro by long-term culture of cell-seeded biomaterials, often with the use of bioreactors. This review presents the most recent findings concerning biomaterials, cells, and techniques used for the production of living bone grafts under in vitro conditions. Particular attention has been given to features of known bioreactor systems currently used in BTE: perfusion bioreactors, rotating bioreactors, and spinner flask bioreactors. Although bioreactor systems are still characterized by some limitations, they are excellent platforms to form bioengineered living bone grafts in vitro for bone fracture regeneration. Moreover, the review article also describes the types of biomaterials and sources of cells that can be used in BTE as well as the role of three-dimensional bioprinting and pulsed electromagnetic fields in both bone healing and BTE.
Chronic Inflammation as the Underlying Mechanism of the Development of Lung Diseases in Psoriasis: A Systematic Review
Authors: Mleczko Mateusz , Gerkowicz Agnieszka , Krasowska Dorota
Published: February 2022

Psoriasis is a systemic inflammatory disease caused by dysfunctional interactions between the innate and adaptive immune responses. The systemic inflammation in psoriasis may be associated with the development of comorbidities, including lung diseases. In this review, we aimed to provide a summary of the evidence regarding the prevalence of lung diseases in patients with psoriasis and the potential underlying mechanisms. Twenty-three articles published between March 2010 and June 2021 were selected from 195 initially identified records. The findings are discussed in terms of the prevalence of asthma, chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea, pulmonary hypertension, and sarcoidosis in psoriasis. A higher prevalence of lung diseases in psoriasis has been confirmed in asthma, chronic obstructive pulmonary disease, obstructive sleep apnea, and pulmonary hypertension. These conditions are important as they are previously unrecognized causes of morbidity and mortality in psoriasis. The development of lung diseases in patients with psoriasis can be explained by several mechanisms, including common risk factors, shared immune and molecular characteristics associated with chronic inflammation, as well as other mechanisms. Understanding the prevalence of lung diseases in psoriasis and their underlying mechanisms can help implement appropriate preventative and therapeutic strategies to address respiratory diseases in patients with psoriasis.
Is Cadmium Toxicity Tissue-Specific? Toxicogenomics Studies Reveal Common and Specific Pathways in Pulmonary, Hepatic, and Neuronal Cell Models
Authors: Forcella Matilde , Lau Pierre , Fabbri Marco , Fusi Paola , Oldani Monica , Melchioretto Pasquale , Gribaldo Laura , Urani Chiara
Published: February 2022

Several harmful modifications in different tissues-organs, leading to relevant diseases (e.g., liver and lung diseases, neurodegeneration) are reported after exposure to cadmium (Cd), a wide environmental contaminant. This arises the question whether any common molecular signatures and/or Cd-induced modifications might represent the building block in initiating or contributing to address the cells towards different pathological conditions. To unravel possible mechanisms of Cd tissue-specificity, we have analyzed transcriptomics data from cell models representative of three major Cd targets: pulmonary (A549), hepatic (HepG2), and neuronal (SH-SY-5Y) cells. Further, we compared common features to identify any non-specific molecular signatures. The functional analysis of dysregulated genes (gene ontology and KEGG) shows GO terms related to metabolic processes significantly enriched only in HepG2 cells. GO terms in common in the three cell models are related to metal ions stress response and detoxification processes. Results from KEGG analysis show that only one specific pathway is dysregulated in a significant way in all cell models: the mineral absorption pathway. Our data clearly indicate how the molecular mimicry of Cd and its ability to cause a general metal ions dyshomeostasis represent the initial common feature leading to different molecular signatures and alterations, possibly responsible for different pathological conditions.
Extracellular Vesicles and Thrombogenicity in Atrial Fibrillation
Authors: Berezin Alexander E. , Berezin Alexander A.
Published: February 2022

Extracellular vesicles (EVs) are defined as a heterogenic group of lipid bilayer vesicular structures with a size in the range of 30–4000 nm that are released by all types of cultured cells. EVs derived from platelets, mononuclears, endothelial cells, and adipose tissue cells significantly increase in several cardiovascular diseases, including in atrial fibrillation (AF). EVs are engaged in cell-to-cell cooperation, endothelium integrity, inflammation, and immune response and are a cargo for several active molecules, such as regulatory peptides, receptors, growth factors, hormones, and lipids. Being transductors of the intercellular communication, EVs regulate angiogenesis, neovascularization, coagulation, and maintain tissue reparation. There is a large amount of evidence regarding the fact that AF is associated with elevated levels of EVs derived from platelets and mononuclears and a decreased number of EVs produced by endothelial cells. Moreover, some invasive procedures that are generally performed for the treatment of AF, i.e., pulmonary vein isolation, were found to be triggers for elevated levels of platelet and mononuclear EVs and, in turn, mediated the transient activation of the coagulation cascade. The review depicts the role of EVs in thrombogenicity in connection with a risk of thromboembolic complications, including ischemic stroke and systemic thromboembolism, in patients with various forms of AF.
Quinagolide Treatment Reduces Invasive and Angiogenic Properties of Endometrial Mesenchymal Stromal Cells
Authors: Iampietro Corinne , Brossa Alessia , Canosa Stefano , Tritta Stefania , Croston Glenn E. , Reinheimer Torsten Michael , Bonelli Filippo , Carosso Andrea Roberto , Gennarelli Gianluca , Cosma Stefano , Benedetto Chiara , Revelli Alberto , Bussolati Benedetta
Published: February 2022

Endometrial mesenchymal stromal cells (E-MSCs) extensively contribute to the establishment and progression of endometrial ectopic lesions through formation of the stromal vascular tissue, and support to its growth and vascularization. As E-MSCs lack oestrogen receptors, endometriosis eradication cannot be achieved by hormone-based pharmacological approaches. Quinagolide is a non-ergot-derived dopamine receptor 2 agonist reported to display therapeutic effects in in vivo models of endometriosis. In the present study, we isolated E-MSCs from eutopic endometrial tissue and from ovarian and peritoneal endometriotic lesions, and we tested the effect of quinagolide on their proliferation and matrix invasion ability. Moreover, the effect of quinagolide on E-MSC endothelial differentiation was assessed in an endothelial co-culture model of angiogenesis. E-MSC lines expressed dopamine receptor 2, with higher expression in ectopic than eutopic ones. Quinagolide inhibited the invasive properties of E-MSCs, but not their proliferation, and limited their endothelial differentiation. The abrogation of the observed effects by spiperone, a dopamine receptor antagonist, confirmed specific dopamine receptor activation. At variance, no involvement of VEGFR2 inhibition was observed. Moreover, dopamine receptor 2 activation led to downregulation of AKT and its phosphorylation. Of interest, several effects were more prominent on ectopic E-MSCs with respect to eutopic lines. Together with the reported effects on endometrial and endothelial cells, the observed inhibition of E-MSCs may increase the rationale for quinagolide in endometriosis treatment.
Neuronal Phenotype of col4a1 and col25a1: An Intriguing Hypothesis in Vertebrates Brain Aging
Authors: Leggieri Adele , Attanasio Chiara , Palladino Antonio , de Girolamo Paolo , Lucini Carla , D’Angelo Livia
Published: February 2022

Collagens are the most abundant proteins in vertebrates and constitute the major components of the extracellular matrix. Collagens play an important and multifaceted role in the development and functioning of the nervous system and undergo structural remodeling and quantitative modifications during aging. Here, we investigated the age-dependent regulation of col4a1 and col25a1 in the brain of the short-lived vertebrate Nothobranchius furzeri, a powerful model organism for aging research due to its natural fast-aging process and further characterized typical hallmarks of brain aging in this species. We showed that col4a1 and col25a1 are relatively well conserved during vertebrate evolution, and their expression significantly increases in the brain of N. furzeri upon aging. Noteworthy, we report that both col4a1 and col25a1 are expressed in cells with a neuronal phenotype, unlike what has already been documented in mammalian brain, in which only col25a1 is considered a neuronal marker, whereas col4a1 seems to be expressed only in endothelial cells. Overall, our findings encourage further investigation on the role of col4a1 and col25a1 in the biology of the vertebrate brain as well as the onset of aging and neurodegenerative diseases.
Expression and Function of Nicotinic Acetylcholine Receptors in Induced Regulatory T Cells
Authors: Nakata Yuichiro , Miura Kento , Yamasaki Norimasa , Ogata Sawako , Miura Shuka , Hosomi Naohisa , Kaminuma Osamu
Published: February 2022

A contribution of the cholinergic system to immune cell function has been suggested, though the role of nicotine and its receptors in T cells, especially regulatory T (Treg) cells, is unclear. We herein investigated the expression and function of nicotinic acetylcholine receptors (nAChRs) in murine-induced Treg (iTreg) cells. Upon differentiation of naive BALB/c T cells into iTreg cells and other T-cell subsets, the effect of nicotine on cytokine production and proliferation of iTreg cells was examined. The expression of nAChRs and its regulatory mechanisms were comparatively analyzed among T-cell subsets. Stimulation-induced transforming growth factor-β1 (TGF-β1) production of iTreg cells was suppressed by nicotine, whereas interleukin (IL)-10 production and proliferation was not affected. α2-, α5-, α9-, and β2-nAChRs were differentially expressed in naive, Th1, Th2, Th9, Th17, and iTreg cells. Among these cell types, the α9-nAChR was particularly upregulated in iTreg cells via its gene promoter, but not through tri-methylation at the 4th lysine residue of the histone H3-dependent mechanisms. We conclude that the immunoregulatory role of Treg cells is modified by the cholinergic system, probably through the characteristic expression of nAChRs.
COMT Val/Met and Psychopathic Traits in Children and Adolescents: A Systematic Review and New Evidence of a Developmental Trajectory toward Psychopathy
Authors: Kant Tuana , Koyama Emiko , Zai Clement C. , Beitchman Joseph H. , Kennedy James L.
Published: February 2022

Psychopathic traits in youth may lead to adult criminal behaviors/psychopathy. The Val158Met polymorphism of catechol-O-methyltransferase (COMT) may influence the risk for psychopathy-related behaviors, while acting as a biomarker for predicting treatment response to dopaminergic medications. The literature shows inconsistent findings, making the interpretation of COMT’s role difficult. The aims of this article are (i) to conduct a systematic review to analyze the effects of COMT Val158Met on psychopathic traits in children and adolescents, and (ii) to present new evidence on the developmental trajectory of the association of Val158Met and youth psychopathic traits. For the systematic review, a literature search was conducted using PubMed, EMBASE, OVID Medline and PsychINFO with the search terms for psychopathic traits, Val158Met and age of interest. In our genotype study, the COMT Val158Met genotype of 293 youth with European ancestry was analyzed in association with the psychopathy-related behavior scores from the Child Behavior Checklist and the Psychopathy Screening Device. To examine the potential influence of developmental changes, the sample was split into at or above and below age 13, and analyses were performed in males and females separately. The literature search yielded twenty-eight articles to be included in the systematic review, which demonstrated mixed results on the association depending on environmental factors, sex ratios, age groups and behavioral disorder diagnoses. The results from our genotype study revealed that Met homozygous youth in the below age 13 group and conversely Val carrier youth in the above age 13 group were more likely to display psychopathic traits. To our knowledge, this is the first study to systematically review the effects of COMT Val158Met on psychopathic traits in childhood and adolescence, and to provide new evidence on the changing effects of Val158Met on psychopathy-related behaviors with development. Elucidating the role of the COMT genotype in conjunction with the child versus adolescent stage of development for psychopathic traits may help predict treatment response, and may lead to early intervention and prevention strategies.
Profiling of the Bacterial Microbiota along the Murine Alimentary Tract
Authors: Vilchez-Vargas Ramiro , Salm Franz , Znalesniak Eva B. , Haupenthal Katharina , Schanze Denny , Zenker Martin , Link Alexander , Hoffmann Werner
Published: February 2022

Here, the spatial distribution of the bacterial flora along the murine alimentary tract was evaluated using high throughput sequencing in wild-type and Tff3-deficient (Tff3KO) animals. Loss of Tff3 was linked to increased dextran sodium sulfate-induced colitis. This systematic study shows the results of 13 different regions from the esophagus to the rectum. The number of bacterial species (richness) increased from the esophagus to the rectum, from 50 to 200, respectively. Additionally, the bacterial community structure changed continuously; the highest changes were between the upper/middle and lower gastrointestinal compartments when comparing adjacent regions. Lactobacillus was the major colonizer in the upper/middle gastrointestinal tract, especially in the esophagus and stomach. From the caecum, a drastic diminution of Lactobacillus occurred, while members of Lachnospiraceae significantly increased. A significant change occurred in the bacterial community between the ascending and the transverse colon with Bacteroidetes being the major colonizers with relative constant abundance until the rectum. Interestingly, wild-type and Tff3KO animals did not show significant differences in their bacterial communities, suggesting that Tff3 is not involved in alterations of intraluminal or adhesive microbiota but is obviously important for mucosal protection, e.g., of the sensitive stem cells in the colonic crypts probably by a mucus plume.
Upregulation of Cathepsin X in Glioblastoma: Interplay with γ-Enolase and the Effects of Selective Cathepsin X Inhibitors
Authors: Majc Bernarda , Habič Anamarija , Novak Metka , Rotter Ana , Porčnik Andrej , Mlakar Jernej , Župunski Vera , Pečar Fonović Urša Pečar , Knez Damijan , Zidar Nace , Gobec Stanislav , Kos Janko , Lah Turnšek Tamara Lah , Pišlar Anja , Breznik Barbara
Published: February 2022

Glioblastoma (GBM) is the most common and deadly primary brain tumor in adults. Understanding GBM pathobiology and discovering novel therapeutic targets are critical to finding efficient treatments. Upregulation of the lysosomal cysteine carboxypeptidase cathepsin X has been linked to immune dysfunction and neurodegenerative diseases, but its role in cancer and particularly in GBM progression in patients is unknown. In this study, cathepsin X expression and activity were found to be upregulated in human GBM tissues compared to low-grade gliomas and nontumor brain tissues. Cathepsin X was localized in GBM cells as well as in tumor-associated macrophages and microglia. Subsequently, potent irreversible (AMS36) and reversible (Z7) selective cathepsin X inhibitors were tested in vitro. Selective cathepsin X inhibitors decreased the viability of patient-derived GBM cells as well as macrophages and microglia that were cultured in conditioned media of GBM cells. We next examined the expression pattern of neuron-specific enzyme γ-enolase, which is the target of cathepsin X. We found that there was a correlation between high proteolytic activity of cathepsin X and C-terminal cleavage of γ-enolase and that cathepsin X and γ-enolase were colocalized in GBM tissues, preferentially in GBM-associated macrophages and microglia. Taken together, our results on patient-derived material suggest that cathepsin X is involved in GBM progression and is a potential target for therapeutic approaches against GBM.
miR-196a Upregulation Contributes to Gefitinib Resistance through Inhibiting GLTP Expression
Authors: Liu Bing-Jie , Li Fang-Fang , Xie Yun-Xia , Fan Chong-Yuan , Liu Wen-Jing , Qiu Jian-Ge , Jiang Bing-Hua
Published: February 2022

Tyrosine kinase inhibitor (TKI) therapy has greatly improved lung cancer survival in patients with epidermal growth factor receptor (EGFR) mutations. However, the development of TKI-acquired resistance is the major problem to be overcome. In this study, we found that miR-196a expression was greatly induced in gefitinib-resistant lung cancer cells. To understand the role and mechanism of miR-196a in TKI resistance, we found that miR-196a-forced expression alone increased cell resistance to gefitinib treatment in vitro and in vivo by inducing cell proliferation and inhibiting cell apoptosis. We identified the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) bound to the promoter region of miR-196a and induced miR-196a expression at the transcriptional level. NRF2-forced expression also significantly increased expression levels of miR-196a, and was an upstream inducer of miR-196a to mediate gefitinib resistance. We also found that glycolipid transfer protein (GLTP) was a functional direct target of miR-196a, and downregulation of GLTP by miR-196a was responsible for gefitinib resistance. GLTP overexpression alone was sufficient to increase the sensitivity of lung cancer cells to gefitinib treatment. Our studies identified a new role and mechanism of NRF2/miR-196a/GLTP pathway in TKI resistance and lung tumor development, which may be used as a new biomarker (s) for TKI resistance or as a new therapeutic target in the future.
Interplay between Inflammation and Pathological Bone Resorption: Insights into Recent Mechanisms and Pathways in Related Diseases for Future Perspectives
Authors: Terkawi M Alaa , Matsumae Gen , Shimizu Tomohiro , Takahashi Daisuke , Kadoya Ken , Iwasaki Norimasa
Published: February 2022

Bone is a mineralized and elastic connective tissue that provides fundamental functions in the human body, including mechanical support to the muscles and joints, protection of vital organs and storage of minerals. Bone is a metabolically active organ that undergoes continuous remodeling processes to maintain its architecture, shape, and function throughout life. One of the most important medical discoveries of recent decades has been that the immune system is involved in bone remodeling. Indeed, chronic inflammation has been recognized as the most significant factor influencing bone homeostasis, causing a shift in the bone remodeling process toward pathological bone resorption. Bone osteolytic diseases typified by excessive bone resorption account for one of the greatest causes of disability worldwide, with significant economic and public health burdens. From this perspective, we discuss the recent findings and discoveries highlighting the cellular and molecular mechanisms that regulate this process in the bone microenvironment, in addition to the current therapeutic strategies for the treatment of osteolytic bone diseases.
Automatic Identification of Similar Pull-Requests in GitHub’s Repositories Using Machine Learning
Authors: Eyal Salman Hamzeh , Alshara Zakarea , Seriai Abdelhak-Djamel
Published: February 2022

Context: In a social coding platform such as GitHub, a pull-request mechanism is frequently used by contributors to submit their code changes to reviewers of a given repository. In general, these code changes are either to add a new feature or to fix an existing bug. However, this mechanism is distributed and allows different contributors to submit unintentionally similar pull-requests that perform similar development activities. Similar pull-requests may be submitted to review in parallel time by different reviewers. This will cause redundant reviewing time and efforts. Moreover, it will complicate the collaboration process. Objective: Therefore, it is useful to assign similar pull-requests to the same reviewer to be able to decide which pull-request to choose in effective time and effort. In this article, we propose to group similar pull-requests together into clusters so that each cluster is assigned to the same reviewer or the same reviewing team. This proposal allows saving reviewing efforts and time. Method: To do so, we first extract descriptive textual information from pull-requests content to link similar pull-requests together. Then, we employ the extracted information to find similarities among pull-requests. Finally, machine learning algorithms (K-Means clustering and agglomeration hierarchical clustering algorithms) are used to group similar pull-requests together. Results: To validate our proposal, we have applied it to twenty popular repositories from public dataset. The experimental results show that the proposed approach achieved promising results according to the well-known metrics in this subject: precision and recall. Furthermore, it helps to save the reviewer time and effort. Conclusion: According to the obtained results, the K-Means algorithm achieves 94% and 91% average precision and recall values over all considered repositories, respectively, while agglomeration hierarchical clustering performs 93% and 98% average precision and recall values over all considered repositories, respectively. Moreover, the proposed approach saves reviewing time and effort on average between (67% and 91%) by K-Means algorithm and between (67% and 83%) by agglomeration hierarchical clustering algorithm.
Development of a Community-Driven Mosquito Surveillance Program for Vectors of La Crosse Virus to Educate, Inform, and Empower a Community
Authors: Trout Fryxell Rebecca T. , Camponovo Michael , Smith Brian , Butefish Kurt , Rosenberg Joshua M. , Andsager Julie L. , Day Corey A. , Willis Micah P.
Published: February 2022

The fields of entomology, geospatial science, and science communication are understaffed in many areas, resulting in poor community awareness and heightened risks of vector-borne diseases. This is especially true in East Tennessee, where La Crosse encephalitis (LACE) causes pediatric illness each year. In response to these problems, we created a community engagement program that includes a yearlong academy for secondary STEM educators in the 6–12 grade classroom. The objectives of this program were to support inquiry-driven classroom learning to foster student interest in STEM fields, produce community-driven mosquito surveillance, and enhance community awareness of LACE. We trained educators in medical entomology, geospatial science, and science communication, and they incorporated those skills into lesson plans for a mosquito oviposition experiment that tested hypotheses developed in the classroom. Here, we share results from the first two years of the MEGA:BITESS academy, tailored for our community by having students ask questions directly related to Aedes mosquito oviposition biology and La Crosse encephalitis. In year one, we recruited 17 educators to participate in the project, and 15 of those educators returned in year two. All participating educators completed the academy, conducted the oviposition experiment, and informed over 400 students about a variety of careers and disciplines for their students. Here, we present a community-based program that helps to address the problems associated with long-term mosquito surveillance, health and science education and communication, career opportunities, and the community needs of Appalachia, as well as the initial data on the effectiveness of two years of an educator-targeted professional-development program.
Perioperative Risk Factors for Prolonged Blood Loss and Drainage Fluid Secretion after Breast Reconstruction
Authors: Flores Tonatiuh , Jaklin Florian J. , Rohrbacher Alexander , Schrögendorfer Klaus F. , Bergmeister Konstantin D.
Published: February 2022

Background: Surgical breast reconstruction is an integral part of cancer treatment but must not compromise oncological safety. Patient-dependent risk factors (smoking, BMI, etc.) are said to influence perioperative outcomes and have often been investigated. Here, we analyzed independent perioperative risk factors for increased postoperative blood loss or drainage fluid volume loss and their possible impact. Methods: Patients undergoing breast reconstructions after breast cancer with either tissue expanders, definitive breast implants, or autologous breast reconstruction were analyzed. The collected data on patients’ characteristics, blood, and drainage fluid loss were correlated and statistically investigated. Results: Traditional patient-dependent risk factors did not influence blood loss or drainage volumes. On the contrary, patients with preoperative anemia had significantly higher drainage outputs compared to non-anemic patients (U = 2448.5; p = 0.0012). The administration of low molecular weight heparin showed a tendency of increased drainage output. Similar correlations could be seen in prolonged procedure time, all of which contributed to prolonged hospital stay (τb = 0.371; p < 0.00001). Conclusions: Preoperative anemia is one of the most critical factors influencing postoperative drainage fluid output. Previously assumed patient-dependent risk factors did not affect drainage output. Preoperative anemia must be monitored, and if possible, treated preoperatively to reduce postoperative morbidity.
Association among Disorders of Gut-Brain Interaction (DGBI) and Fibromyalgia: A Prospective Study
Authors: Settembre Carmela , D’Antonio Elvira , Moscato Paolo , Loi Gabriella , Santonicola Antonella , Iovino Paola
Published: February 2022

The disorders of gut–brain interaction (DGBI) have been associated with Fibromyalgia (FM). However, there are no data about the relationship between FM and DGBI using Rome IV criteria. This study aimed to evaluate the prevalence of FM in patients with Irritable Bowel Syndrome (IBS) and/or Functional Dyspepsia (FD) and the prevalence of IBS and FD in FM patients using Rome IV criteria. DGBI patients and FM patients were recruited from two outpatient clinics devoted to DGBI and FM. All patients underwent a standardized gastrointestinal (GI) symptoms questionnaire. FM symptoms in DGBI patients were assessed through Fibromyalgia Rapid Screening Tool (FiRST) and Fibromyalgia Impact Questionnaire. Thereafter, the rheumatologists evaluated them. 49.0% of FM patients fulfilled the diagnostic criteria for IBS, 81.6% for FD with an overlap for both IBS/FD in 44.9%. IBS-C was the most prevalent IBS-subtype in DGBI patients, whereas IBS-M was the most prevalent in FM patients (p = 0.01). 45.3% of DGBI patients reported pathological FiRST scores. DGBI patients with FM showed the highest score at the standardized GI questionnaire followed by FM patients with DGBI and DGBI without FM. In conclusion DGBI are common in FM patients and vice versa. The presence of FD is extremely frequent in FM patients. A multidisciplinary approach should be routinely used for the management of these patients.
How Does Contraceptive Use Affect Women’s Sexuality? A Novel Look at Sexual Acceptability
Authors: Caruso Salvatore , Palermo Gaia , Caruso Giuseppe , Rapisarda Agnese Maria Chiara
Published: February 2022

Among the components of a healthy life, sexuality is essential, contributing to both the psychophysical and social well-being of women and, consequently, to their quality of life. A poorly investigated standpoint is the acceptability of contraceptive methods, both in terms of their tolerability and metabolic neutrality and in terms of their impact on sexual life. In this context, we will provide an overview of the different methods of contraception and their effects on female sexuality, from biological changes to organic, social, and psychological factors, which can all shape sexuality. A MEDLINE/PubMed review of the literature between 2010 and 2021 was conducted using the following key words and phrases: hormonal contraception, contraceptives, female sexual function, libido, sexual arousal and desire, and sexual pain. Recent studies have supported the effects of contraceptives on women’s sexuality, describing a variety of positive and negative events in several domains of sexual function (desire, arousal, orgasm, pain, enjoyment). However, satisfaction with sexual activity depends on factors that extend beyond sexual functioning alone. A more holistic approach is needed to better understand the multitude of factors linked to women’s sexuality and contraception. Contraceptive counseling must consider these important elements since they are closely related to good compliance and maximize non-contraceptive health benefits.
Could Total Neoadjuvant Therapy Followed by Surgical Resection Be the New Standard of Care in Pancreatic Cancer? A Systematic Review and Meta-Analysis
Authors: De Simoni Ottavia , Scarpa Marco , Soldà Caterina , Bergamo Francesca , Lonardi Sara , Fantin Alberto , Pilati Pierluigi , Gruppo Mario
Published: February 2022

Background. Total neoadjuvant therapy (TNT), intended as induction chemotherapy (IC) followed by radio-chemotherapy (RCT), has been taking hold in the treatment of pancreatic ductal adenocarcinoma (PDAC). The aim of this review is to summarize the available evidence on the role of TNT followed by curative surgery. Methods. Eligible studies were those reporting on patients with PDAC undergoing curative surgery after TNT. The primary endpoint was overall survival (OS). Results. A total of 1080 patients with PDAC who had undergone TNT were analyzed. The most common IC regimen was Gemcitabine (N 620, 57%). Toxicity during IC varied from 14% to 51%. Disease progression during IC varied from 3% to 25%. 607 (62%) patients underwent curative surgery after IC + CRT. In meta-analysis, the available data on lymph node metastases radicality and 2 years OS had better results in favor of TNT groups (OR 1.77, 95% CI 1.20–2.60, p = 0.004 and OR 2.03, 95% CI 1.19–3.47, p = 0.01 and OR 1.64, CI 1.09–2.47, p = 0.02, respectively). Conclusions. Despite the heterogeneity of the studies, different selection criteria, and non-negligible drop-out rate, TNT demonstrated a potential superiority to NAT without CRT in oncological and pathological outcomes, even if the main differences seem to depend on the IC regimen.
Long-Term Outcome of Corneal and Anterior Chamber Angle Parameters after Combined Laser Iridotomy and Iridoplasty Using Dual Scheimpflug Analyzer: 1 Year Results
Authors: Cho Hyun-kyung , Choae Wooseok
Published: February 2022

Background: To investigate the outcomes of corneal and anterior chamber angle (ACA) parameters after laser iridotomy (LI) combined with peripheral iridoplasty (PI) using dual Scheimpflug analyzer in the long term. Methods: Fifty-eight eyes (58 subjects) with shallow AC were included in this prospective cohort study. Images of the Dual Scheimpflug analyzer were obtained before, 1 week, and 1 year after LI and PI. Pachymetry from three zones (central, middle, and peripheral), corneal aberration, and spherical equivalent (SE) were acquired. AC depth (ACD), AC volume (ACV), ACA from four quadrants, and intraocular pressure (IOP) were also obtained. For comparison of the results, the linear mixed-effects model was employed. Results: ACD significantly increased from 2.09 ± 0.25 mm to 2.10 ± 0.23 mm at 1 year after laser (all p < 0.05). ACV and ACA increased significantly after laser at 1 year (all p < 0.05). IOP significantly decreased from 15.97 ± 4.20 mmHg to 13.73 ± 2.63 mmHg at 1 year (all p < 0.0001). No significant changes were found in the coma, trefoil, total corneal aberration, pachymetry from three zones, corneal volume, central corneal thickness, and SE after LI and PI until 1 year (all p > 0.05). Conclusions: LI plus PI ameliorated parameters of ACA efficiently and significantly reduced IOP in eyes with shallow AC until 1 year of long-term follow-up. However, parameters of the cornea and SE were not influenced by LI with PI until after 1 year.
Oncoplastic Surgery and the Clinical Features of Breast Cancer—Relevant Factors Associated with Reoperation in Breast Oncoplastic Surgery
Authors: Forma Alicja , Sitarz Robert , Baj Jacek , Sołowiej Krzysztof , Łukasiewicz Sergiusz , Stanisławek Andrzej
Published: February 2022

Oncoplastic breast surgery slowly becomes a part of routine breast cancer surgical management but evidence with regard to oncological safety remains limited. The aim of this study was to compare relevant factors associated with the particular type of breast carcinoma and the applied surgical techniques either with or without oncoplastic surgery. This retrospective study enrolled the breast cancer female patients who underwent breast-conserving therapy alone or with the oncoplastic surgery in the Department of Surgical Oncology at the Center of Oncology of the Lublin Region St. Jana from Dukli in the years 2008–2011. The study involves 679 breast cancer patients who underwent oncoplasty (n = 81) and the control group (n = 598). There is a significant relationship between the histological type of breast cancer (p = 0.00000) along with the expression of estrogen and/or progesterone receptors (p = 0.01285) and the usage of oncoplastic surgery in breast cancer patients. Interestingly, in the majority of cases, there was no need to conduct a reoperation. Oncoplastic surgery is an effective and safe strategy that might be favorable especially for those patients who are potential candidates for more invasive surgical methods. High-quality evidence to support the oncological safety and benefits of oncoplastic breast surgery is lacking.
Urinary C5b-9 as a Prognostic Marker in IgA Nephropathy
Authors: Yu Byung Chul , Park Jin Hoon , Lee Kyung Ho , Oh Young Seung , Choi Soo Jeong , Kim Jin Kuk , Park Moo Yong
Published: February 2022

C5b-9 plays an important role in the pathogenesis of immunoglobin A nephropathy (IgAN). We evaluated C5b-9 as a prognostic marker for IgAN. We prospectively enrolled 33 patients with biopsy-proven IgAN. We analyzed the correlation between baseline urinary C5b-9 levels, posttreatment changes in their levels, and clinical outcomes, including changes in proteinuria, estimated glomerular filtration rate (eGFR), and treatment response. Baseline urinary C5b-9 levels were positively correlated with proteinuria (r = 0.548, p = 0.001) at the time of diagnosis. Changes in urinary C5b-9 levels were positively correlated with changes in proteinuria (r = 0.644, p < 0.001) and inversely correlated with changes in eGFR (r = −0.410, p = 0.018) at 6 months after treatment. Changes in urinary C5b-9 levels were positively correlated with time-averaged proteinuria during the follow-up period (r = 0.461, p = 0.007) but were not correlated with the mean annual rate of eGFR decline (r = −0.282, p = 0.112). Baseline urinary C5b-9 levels were not a significant independent factor that could predict the treatment response in logistic regression analyses (odds ratio 0.997; 95% confidence interval, 0.993 to 1.000; p = 0.078). Currently, urinary C5b-9 is not a promising prognostic biomarker for IgAN, and further studies are needed.
Direct Photocoagulation for Treating Microaneurysms with Hyperreflective Ring in Eyes with Refractory Macular Edema Associated with Branch Retinal Vein Occlusion
Authors: Sasajima Hirofumi , Zako Masahiro , Ueta Yoshiki , Tate Hideo , Otaki Chisato , Murotani Kenta , Suzuki Takafumi , Ishida Hidetoshi , Hashimoto Yoshihiro , Tachi Naoko
Published: February 2022

Microaneurysms (MAs) with hyperreflective rings are sometimes detected in eyes with refractory macular edema (ME) associated with branch retinal vein occlusion (BRVO) for more than 12 months after onset when examined using optical coherence tomography (OCT). We proposed that these MAs could result in refractory ME secondary to BRVO and hypothesized that OCT-guided direct photocoagulation of MAs could result in a reduction in refractory ME. Eleven eyes (from eleven different patients) with refractory ME associated with BRVO for more than 12 months following initial treatment were included. The mean number of MAs in each eye at baseline was 3.5 ± 2.0 (range, 1–8). The mean central subfield thickness, central macular volume, and parafoveal macular volume significantly decreased 6 months following initial direct photocoagulation when compared with those at baseline (baseline = 378.7 ± 61.8 μm, post-treatment = 304.2 ± 66.7 μm, p = 0.0005; baseline = 0.3 ± 0.049 mm3, post-treatment = 0.24 ± 0.053 mm3, p = 0.001; and baseline = 2.5 ± 0.14 mm3, post-treatment = 2.28 ± 0.15 mm3, p = 0.001, respectively). Moreover, the mean best-corrected visual acuity significantly improved 6 months following initial direct photocoagulation when compared with that at baseline (baseline = 0.096 ± 0.2 logarithm of the minimum angle of resolution (logMAR), post-treatment = 0.0077 ± 0.14 logMAR, p = 0.031). Direct photocoagulation could be suggested as a treatment option for refractory ME associated with BRVO in MAs with a hyperreflective ring on OCT.