bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Prospects of Exon Skipping for Epidermolysis Bullosa
Authors: Vermeer Franciscus , Bremer Jeroen , Sietsma Robert , Sandilands Aileen , Hickerson Robyn , Bolling Marieke , Pasmooij Anna , Lemmink Henny , Swertz Morris , Knoers Nine , van der Velde K. , van den Akker Peter
Published: November 2021

Epidermolysis bullosa is a group of genetic skin conditions characterized by abnormal skin (and mucosal) fragility caused by pathogenic variants in various genes. The disease severity ranges from early childhood mortality in the most severe types to occasional acral blistering in the mildest types. The subtype and severity of EB is linked to the gene involved and the specific variants in that gene, which also determine its mode of inheritance. Current treatment is mainly focused on symptomatic relief such as wound care and blister prevention, because truly curative treatment options are still at the preclinical stage. Given the current level of understanding, the broad spectrum of genes and variants underlying EB makes it impossible to develop a single treatment strategy for all patients. It is likely that many different variant-specific treatment strategies will be needed to ultimately treat all patients. Antisense-oligonucleotide (ASO)-mediated exon skipping aims to counteract pathogenic sequence variants by restoring the open reading frame through the removal of the mutant exon from the pre-messenger RNA. This should lead to the restored production of the protein absent in the affected skin and, consequently, improvement of the phenotype. Several preclinical studies have demonstrated that exon skipping can restore protein production in vitro, in skin equivalents, and in skin grafts derived from EB-patient skin cells, indicating that ASO-mediated exon skipping could be a viable strategy as a topical or systemic treatment. The potential value of exon skipping for EB is supported by a study showing reduced phenotypic severity in patients who carry variants that result in natural exon skipping. In this article, we review the substantial progress made on exon skipping for EB in the past 15 years and highlight the opportunities and current challenges of this RNA-based therapy approach. In addition, we present a prioritization strategy for the development of exon skipping based on genomic information of all EB-involved genes.
A Yeast-Based Repurposing Approach for the Treatment of Mitochondrial DNA Depletion Syndromes Led to the Identification of Molecules Able to Modulate the dNTP Pool
Authors: di Punzio Giulia , Gilberti Micol , Baruffini Enrico , Lodi Tiziana , Donnini Claudia , Dallabona Cristina
Published: November 2021

Mitochondrial DNA depletion syndromes (MDS) are clinically heterogenous and often severe diseases, characterized by a reduction of the number of copies of mitochondrial DNA (mtDNA) in affected tissues. In the context of MDS, yeast has proved to be both an excellent model for the study of the mechanisms underlying mitochondrial pathologies and for the discovery of new therapies via high-throughput assays. Among the several genes involved in MDS, it has been shown that recessive mutations in MPV17 cause a hepatocerebral form of MDS and Navajo neurohepatopathy. MPV17 encodes a non selective channel in the inner mitochondrial membrane, but its physiological role and the nature of its cargo remains elusive. In this study we identify ten drugs active against MPV17 disorder, modelled in yeast using the homologous gene SYM1. All ten of the identified molecules cause a concomitant increase of both the mitochondrial deoxyribonucleoside triphosphate (mtdNTP) pool and mtDNA stability, which suggests that the reduced availability of DNA synthesis precursors is the cause for the mtDNA deletion and depletion associated with Sym1 deficiency. We finally evaluated the effect of these molecules on mtDNA stability in two other MDS yeast models, extending the potential use of these drugs to a wider range of MDS patients.
CTI-2 Inhibits Metastasis and Epithelial-Mesenchymal Transition of Breast Cancer Cells by Modulating MAPK Signaling Pathway
Authors: Ke Junfeng , Han Wenzhao , Meng Fanwei , Guo Feng , Wang Yuhong , Wang Liping
Published: November 2021

Although some breast cancer patients die due to tumor metastasis rather than from the primary tumor, the molecular mechanism of metastasis remains unclear. Therefore, it is necessary to inhibit breast cancer metastasis during cancer treatment. In this case, after designing and synthesizing CTI-2, we found that CTI-2 treatment significantly reduced breast cancer cell metastasis in vivo and in vitro. Notably, with the treatment of CTI-2 in breast cancer cells, the expression level of E-cadherin increased, while the expression level of N-cadherin and vimentin decreased. In addition, after CTI-2 treatment, those outflow levels for p-ERK, p-p38, and p-JNK diminished, while no significant changes in the expression levels of ERK, JNK, or p38 were observed. Our conclusion suggested that CTI-2 inhibits the epithelial-mesenchymal transition (EMT) of breast carcinoma cells by inhibiting the activation of the mitogen-activated protein kinase (MAPK) signaling pathway, thereby inhibiting the metastasis of breast tumor cells. Therefore, we believe that CTI-2 is another candidate for breast tumor medication.
BP180/Collagen XVII: A Molecular View
Authors: Tuusa Jussi , Kokkonen Nina , Tasanen Kaisa
Published: November 2021

BP180 is a type II collagenous transmembrane protein and is best known as the major autoantigen in the blistering skin disease bullous pemphigoid (BP). The BP180 trimer is a central component in type I hemidesmosomes (HD), which cause the adhesion between epidermal keratinocytes and the basal lamina, but BP180 is also expressed in several non-HD locations, where its functions are poorly characterized. The immunological roles of intact and proteolytically processed BP180, relevant in BP, have been subject to intensive research, but novel functions in cell proliferation, differentiation, and aging have also recently been described. To better understand the multiple physiological functions of BP180, the focus should return to the protein itself. Here, we comprehensively review the properties of the BP180 molecule, present new data on the biochemical features of its intracellular domain, and discuss their significance with regard to BP180 folding and protein–protein interactions.
Genome-Wide Characterization of Salt-Responsive miRNAs, circRNAs and Associated ceRNA Networks in Tomatoes
Authors: Wang Zhongyu , Li Ning , Yu Qinghui , Wang Huan
Published: November 2021

Soil salinization is a major environmental stress that causes crop yield reductions worldwide. Therefore, the cultivation of salt-tolerant crops is an effective way to sustain crop yield. Tomatoes are one of the vegetable crops that are moderately sensitive to salt stress. Global market demand for tomatoes is huge and growing. In recent years, the mechanisms of salt tolerance in tomatoes have been extensively investigated; however, the molecular mechanism through which non-coding RNAs (ncRNAs) respond to salt stress is not well understood. In this study, we utilized small RNA sequencing and whole transcriptome sequencing technology to identify salt-responsive microRNAs (miRNAs), messenger RNAs (mRNAs), and circular RNAs (circRNAs) in roots of M82 cultivated tomato and Solanum pennellii (S. pennellii) wild tomato under salt stress. Based on the theory of competitive endogenous RNA (ceRNA), we also established several salt-responsive ceRNA networks. The results showed that circRNAs could act as miRNA sponges in the regulation of target mRNAs of miRNAs, thus participating in the response to salt stress. This study provides insights into the mechanisms of salt tolerance in tomatoes and serves as an effective reference for improving the salt tolerance of salt-sensitive cultivars.
Morphophysiological and Proteomic Responses on Plants of Irradiation with Electromagnetic Waves
Authors: Zhong Zhuoheng , Wang Xin , Yin Xiaojian , Tian Jingkui , Komatsu Setsuko
Published: November 2021

Electromagnetic energy is the backbone of wireless communication systems, and its progressive use has resulted in impacts on a wide range of biological systems. The consequences of electromagnetic energy absorption on plants are insufficiently addressed. In the agricultural area, electromagnetic-wave irradiation has been used to develop crop varieties, manage insect pests, monitor fertilizer efficiency, and preserve agricultural produce. According to different frequencies and wavelengths, electromagnetic waves are typically divided into eight spectral bands, including audio waves, radio waves, microwaves, infrared, visible light, ultraviolet, X-rays, and gamma rays. In this review, among these electromagnetic waves, effects of millimeter waves, ultraviolet, and gamma rays on plants are outlined, and their response mechanisms in plants through proteomic approaches are summarized. Furthermore, remarkable advancements of irradiating plants with electromagnetic waves, especially ultraviolet, are addressed, which shed light on future research in the electromagnetic field.
HATMSC Secreted Factors in the Hydrogel as a Potential Treatment for Chronic Wounds—In Vitro Study
Authors: Kraskiewicz Honorata , Hinc Piotr , Krawczenko Agnieszka , Bielawska-Pohl Aleksandra , Paprocka Maria , Witkowska Danuta , Mohd Isa Isma Liza , Pandit Abhay , Klimczak Aleksandra
Published: November 2021

Mesenchymal stem cells (MSCs) can improve chronic wound healing; however, recent studies suggest that the therapeutic effect of MSCs is mediated mainly through the growth factors and cytokines secreted by these cells, referred to as the MSC secretome. To overcome difficulties related to the translation of cell therapy into clinical use such as efficacy, safety and cost, we propose a hydrogel loaded with a secretome from the recently established human adipose tissue mesenchymal stem cell line (HATMSC2) as a potential treatment for chronic wounds. Biocompatibility and biological activity of hydrogel-released HATMSC2 supernatant were investigated in vitro by assessing the proliferation and metabolic activity of human fibroblast, endothelial cells and keratinocytes. Hydrogel degradation was measured using hydroxyproline assay while protein released from the hydrogel was assessed by interleukin-8 (IL-8) and macrophage chemoattractant protein-1 (MCP-1) ELISAs. Pro-angiogenic activity of the developed treatment was assessed by tube formation assay while the presence of pro-angiogenic miRNAs in the HATMSC2 supernatant was investigated using real-time RT-PCR. The results demonstrated that the therapeutic effect of the HATMSC2-produced factors is maintained following incorporation into collagen hydrogel as confirmed by increased proliferation of skin-origin cells and improved angiogenic properties of endothelial cells. In addition, HATMSC2 supernatant revealed antimicrobial activity, and which therefore, in combination with the hydrogel has a potential to be used as advanced wound-healing dressing.
Safety of Surgery after Neoadjuvant Targeted Therapies in Non-Small Cell Lung Cancer: A Narrative Review
Authors: Marjanski Tomasz , Dziedzic Robert , Kowalczyk Anna , Rzyman Witold
Published: November 2021

New drugs, including immune checkpoint inhibitors and targeted therapy, have changed the prognosis in a subset of patients with advanced lung cancer, and are now actively investigated in a number of trials with neoadjuvant and adjuvant regimens. However, no phase III randomized studies were published yet. The current narrative review proves that targeted therapies are safe in neoadjuvant approach. Unsurprisingly, administration of therapy is related to an acceptable toxicity profile. Severe adverse events’ rate that rarely compromises outcomes of patients with advanced lung cancer is not that commonly accepted in early lung cancer as it may lead to missing the chance of curative surgery. Among those complications, the most important factors that may limit the use of targeted therapies are severe respiratory adverse events precluding the resection occurring after treatment with some anaplastic lymphoma kinase and rarely after epidermal growth factor receptor tyrosine kinase inhibitors. At this point, in the presented literature assessing the feasibility of neoadjuvant therapies with anaplastic lymphoma kinase and epidermal growth factor receptor tyrosine kinase inhibitors, we did not find any unexpected intraoperative events that would be of special interest to a thoracic surgeon. Moreover, the postoperative course was associated with typical rate of complications.
Revisiting the Hybridization Processes in the Triatoma brasiliensis Complex (Hemiptera, Triatominae): Reproductive Isolation between Triatoma petrocchiae and T. b. brasiliensis and T. lenti
Authors: Delgado Luiza Maria Grzyb , Oliveira Jader de , Ravazi Amanda , Madeira Fernanda Fernandez , Reis Yago Visinho dos , Pinotti Heloisa , Oliveira Ana Beatriz Bortolozo de , Masarin Isabella da Silva , Lilioso Maurício , Folly-Ramos Elaine , Galvão Cleber , Azeredo-Oliveira Maria Tercília Vilela de , Rosa João Aristeu da , Alevi Kaio Cesar Chaboli
Published: November 2021

Triatoma petrocchiae is a species morphologically similar to T. b. brasiliensis (which resulted in a synonymization event); despite this similarity, genetic, morphological, and experimental crossbreeding studies confirmed the specific status of T. petrocchiae. Considering that both species have been reported living in sympatry and that, for a long time, most species of the T. brasiliensis complex were considered only chromatic variants of T. b. brasiliensis, we carried out experimental crosses between T. b. brasiliensis and T. petrocchiae (to confirm whether these species are reproductively isolated) and between T. lenti and T. petrocchiae (to assess whether T. petrocchiae also presents prezygotic isolation with the other species of the T. brasiliensis complex). Reciprocal experimental crosses were conducted, and weekly, the eggs were collected, counted, and separated in new containers to assess the hatch rate. Neither cross resulted in hybrids, demonstrating that there are pre-zygotic reproductive barriers installed between T. petrocchiae and the other species of the T. brasiliensis complex. On the basis of the results above, we demonstrated that T. petrocchiae is reproductively isolated from T. b. brasiliensis and T. lenti. Furthermore, we suggest that T. petrocchiae is the species most derived from the T. brasiliensis complex.
Insecticidal Effect of Zinc Oxide Nanoparticles against Spodoptera frugiperda under Laboratory Conditions
Authors: Pittarate Sarayut , Rajula Julius , Rahman Afroja , Vivekanandhan Perumal , Thungrabeab Malee , Mekchay Supamit , Krutmuang Patcharin
Published: November 2021

Fall armyworm Spodoptera frugiperda is a major pest of corn, rice, and sorghum among other crops usually controlled using synthetic or biological insecticides. Currently, the new invention of nanotechnology is taking root in the agricultural industry as an alternative source of pest management that is target-specific, safe, and efficient. This study sought to determine the efficacy of commercial Zinc Oxide (ZnO) nanoparticles (NPs) towards S. frugiperda under laboratory conditions. ZnO NPs were diluted into different concentrations (100–500 ppm), where the baby corn used to feed the S. frugiperda larvae was dipped. The development of the insect feeding on food dipped in ZnO solution was significantly (p < 0.05) affected, and the number of days that the insect took to complete its life cycle had a significant difference compared to the control. There was a significant difference in the adults’ emergence in all the concentrations of ZnO NPs compared to the control, with over 90% of the eggs successfully going through the life cycle until adult emergence. Additionally, several body malformations were observed throughout the lifecycle of the insect. Also, the fecundity of the females was greatly affected. The findings of this study suggest the possibility of exploitation of ZnO nanoparticles not only to manage S. frugiperda but to significantly reduce their population in the ecosystem through body deformations, reduced fecundity, reduced oviposition, and hatchability of eggs. It will be a valuable tool in integrated pest management regimens.
Anaphylactic Reactions Due to Triatoma protracta (Hemiptera, Reduviidae, Triatominae) and Invasion into a Home in Northern California, USA
Authors: Beatty Norman L. , White Zoe S. , Bhosale Chanakya R. , Wilson Kristen , Cannella Anthony P. , Stenn Tanise , Burkett-Cadena Nathan , Wisely Samantha M.
Published: November 2021

Background: Triatoma protracta is a triatomine found naturally throughout many regions of California and has been shown to invade human dwellings and bite residents. A man living in Mendocino County, California, reported developing anaphylactic reactions due to the bite of an “unusual bug”, which he had found in his home for several years. Methods: We conducted environmental, entomological, and clinical investigations to examine the risk for kissing bug invasion, presence of Trypanosoma cruzi, and concerns for Chagas disease at this human dwelling with triatomine invasion. Results: Home assessment revealed several risk factors for triatomine invasion, which includes pack rat infestation, above-ground wooden plank floor without a concrete foundation, canine living in the home, and lack of residual insecticide use. Triatomines were all identified as Triatoma protracta. Midgut molecular analysis of the collected triatomines revealed the detection of T. cruzi discrete typing unit I among one of the kissing bugs. Blood meal PCR-based analysis showed these triatomines had bitten humans, canine and unidentified snake species. The patient was tested for chronic Chagas disease utilizing rapid diagnostic testing and laboratory serological testing, and all were negative. Conclusions: Triatoma protracta is known to invade human dwellings in the western portions of the United States. This is the first report of T. cruzi-infected triatomines invading homes in Mendocino County, California. Triatoma protracta is a known vector responsible for autochthonous Chagas disease within the United States, and their bites can also trigger serious systemic allergic reactions, such as anaphylaxis.
Temporal Variation Dominates in Local Carabid Beetle Communities in Korean Mountains
Authors: Park Yonghwan , Jang Taewoong , Kim Jongkuk , Kim Su-Kyung , Kim Il-Kwon , Kim Chang-Jun , Takami Yasuoki
Published: November 2021

Spatial and temporal variation in ecological environments may result in spatial and temporal variation in communities. Temporal studies of biodiversity are essential for forecasting future changes in community structure and ecosystem function. Therefore, determining the mechanisms that drive temporal change in communities remains an important and interesting challenge in ecology. We quantified spatial and temporal variations in carabid beetle communities and site-specific environmental factors for 5 years at nine study sites on three mountains in the Baekdudaegan Mountain Range, Korea. Carabid beetle communities exhibited significant temporal variation, which was larger than spatial variations between and within mountains. Environmental factors mostly varied between sites within mountains. Community variation was only weakly associated with environmental factors at wide scales, i.e., between sites on three mountains, but was strongly associated at narrow spatial scales, i.e., between sites within one mountain. Our results indicate that temporal variation in communities occurs in response to variations in the local climate, and that the patterns of temporal variation differ between mountains. Thus, temporal surveys of insect communities and climates at local scales are important for predicting temporal changes in the communities.
Carotid Artery Stenting in Patients with Atrial Fibrillation: Direct Oral Anticoagulants, Brief Double Antiplatelets, and Testing Strategy
Authors: Cohen José E. , Gomori John Moshe , Honig Asaf , Leker Ronen R.
Published: November 2021

Carotid endarterectomy is usually preferred over carotid artery stenting (CAS) for patients with atrial fibrillation (AF). We present our experience with short-course periprocedural triple antithrombotic therapy in 32 patients aged >18 years with nonvalvular AF undergoing CAS. There were no deaths, cardiac events, embolic strokes, hyperperfusion syndrome, intracranial hemorrhage, or stent thrombosis within 30 days. Transient intraprocedural hemodynamic instability in 15/32 (47%) and prolonged instability in 4/32 (13%) was managed conservatively. At a mean 16-month follow-up, there were no new neurological events or deterioration. Mean stenosis was reduced from 78.0% ± 9.7% to 17.3% ± 12.2%. This retrospective study included patients AF who were symptomatic (minor stroke (NIHSS ≤ 5)/TIA) with ICA stenosis >50%, or asymptomatic under DOAC therapy with carotid stenosis >80%, who underwent CAS from 6/2014–10/2020. Patients received double antiplatelets and statins. Antiplatelet therapy effectiveness was monitored. Stenting was performed when P2Y12 reaction units (PRU) were <150. DOACs were discontinued 48 h before angioplasty; one 60 mg dose of subcutaneous enoxaparin was administered in lieu. DOAC was restarted 12–24 h after intervention. Patients were discharged under DOAC and one nonaspirin antiplatelet. 32 patients on DOAC were included (26 male, mean age 71). 19 (59.4%) presented with stroke (ICA stenosis-related in 14); 13 (40.6%) were asymptomatic. Stents were deployed under filter protection following pre-angioplasty; post-angioplasty was performed at least once in 12 patients (37.5%). Our experience suggests that CAS can be safely performed in selected patients with CAS and AF requiring DOAC. The role of CAS in AF patients under DOAC warrants study in rigorous trials.
Clinical and Epidemiological Analysis of Children’s Urinary Tract Infections in Accordance with Antibiotic Resistance Patterns of Pathogens
Authors: Werbel Katarzyna , Jankowska Dorota , Wasilewska Anna , Taranta-Janusz Katarzyna
Published: November 2021

The study was conducted to analyze urinary tract infections (UTI) in children by considering epidemiology and antibiotic resistance patterns of pathogens in accordance with inflammatory parameters. The research included 525 patients who demonstrated 627 episodes of UTI. The increasing resistance of bacteria was observed over the years covered by the study (p < 0.001). There was a significant increase of resistance to amoxicillin with clavulanic acid (p = 0.001), gentamicin (p = 0.017) and ceftazidime (p = 0.0005). According to the CART method, we managed to estimate C-reactive protein (CRP), procalcitonin (PCT) and white blood cell (WBC) values, in which antibiotic sensitivity was observed. In children with CRP > 97.91 mg/L, there was a high percentage of sensitive cases to amoxicillin with clavulanic acid (87.5%). Values of WBC above 14.45 K/µL were associated with E. coli more sensitivity to ampicillin. 100% of children with CRP > 0.42 mg/L and PCT ≤ 6.92 ng/mL had confirmed sensitivity to cefuroxime. Concerning sensitivity to gentamicin, the most optimal cut-off point of WBC was >7.80 K/µL, while in the case of nitrofurantoin, it was CRP value > 0.11 mg/L (which was presented in 98.50% of children). These results may guide us with antibiotic therapy and help to inhibit increasing antibiotic resistance.
Esophageal Pressure and Clinical Assessments in the Gastroesophageal Reflux Disease Patients with Laryngopharyngeal Reflux Disease
Authors: Tsou Yung-An , Chen Sheng-Hwa , Wu Wen-Chieh , Tsai Ming-Hsui , Bassa David , Shih Liang-Chun , Chang Wen-Dien
Published: November 2021

Laryngopharyngeal reflux disease (LPRD) might be associated with reflux symptoms, and its severity is correlated with the Reflux Symptoms Index. Diagnosis is often challenging because of a lack of accurate diagnostic tools. Although an association between LPRD and gastroesophageal reflux disease (GERD) exists, the extent to which esophageal pressure changes in patients with LPRD with GERD has been unknown. Therefore, this study surveys the clinical assessments and extent of esophageal pressure changes in LRPD patients with various GERD severities, and compares esophageal sphincter pressures between ages, genders, and body mass index (BMI). This observational study assessed patients with LPRD and GERD. High-resolution esophageal manometry was used to gather data pertaining to the area pressure on the upper esophageal sphincter (UES) and lower esophageal sphincter (LES), and the correlation between such pressure and symptom severity was determined. We compared the esophageal pressure of different UES and LES levels in the following categories: gender, age, BMI, and GERD severity. We analyzed correlations between esophageal pressure and clinical assessments among 90 patients with throat globus with laryngitis with LPRD. LPRD was measured using laryngoscopy, and GERD was measured using esophagoscopy and 24 h PH monitoring. There were no significant differences in the clinical assessments among the four grades of GERD. The LPRD patients with serious GERD had a lower UES and LES pressure. The lowest pressure and longer duration of LES and UES were also observed among patients with LPRD of grade D GERD. No significant differences in UES and LES pressures among ages, genders, or BMIs were noted.
Physically Crosslinked Chitosan/PVA Hydrogels Containing Honey and Allantoin with Long-Term Biocompatibility for Skin Wound Repair: An In Vitro and In Vivo Study
Authors: Koosha Mojtaba , Aalipour Hadis , Sarraf Shirazi Mohammad Javad , Jebali Ali , Chi Hong , Hamedi Sepideh , Wang Nianxing , Li Tianduo , Moravvej Hamideh
Published: November 2021

Chitosan/PVA hydrogel films crosslinked by the freeze–thaw method and containing honey and allantoin were prepared for application as wound dressing materials. The effects of the freeze–thaw process and the addition of honey and allantoin on the swelling, the gel content and the mechanical properties of the samples were evaluated. The physicochemical properties of the samples, with and without the freeze–thaw process, were compared using FTIR, DSC and XRD. The results showed that the freeze–thaw process can increase the crystallinity and thermal stability of chitosan/PVA films. The freeze–thaw process increased the gel content but did not have a significant effect on the tensile strength. The presence of honey reduced the swelling and the tensile strength of the hydrogels due to hydrogen bonding interactions with PVA and chitosan chains. Long-term cell culture experiments using normal human dermal fibroblast (NHDF) cells showed that the hydrogels maintained their biocompatibility, and the cells showed extended morphology on the surface of the hydrogels for more than 30 days. The presence of honey significantly increased the biocompatibility of the hydrogels. The release of allantoin from the hydrogel was studied and, according to the Korsmeyer–Peppas and Weibull models, the mechanism was mainly diffusional. The results for the antimicrobial activity against E. coli and S. aureus bacteria showed that the allantoin-containing samples had a more remarkable antibacterial activity against S. aureus. According to the wound healing experiments, 98% of the wound area treated by the chitosan/PVA/honey hydrogel was closed, compared to 89% for the control. The results of this study suggest that the freeze–thaw process is a non-toxic crosslinking method for the preparation of chitosan/PVA hydrogels with long term biocompatibility that can be applied for wound healing and skin tissue engineering.
Use of Drug Claims Data and a Medication Risk Score to Assess the Impact of CYP2D6 Drug Interactions among Opioid Users on Healthcare Costs
Authors: Michaud Veronique , Bikmetov Ravil , Smith Matt K. , Dow Pamela , Darakjian Lucy I. , Deodhar Malavika , Cicali Brian , Bain Kevin T. , Turgeon Jacques
Published: November 2021

Cytochrome P450 2D6 (CYP2D6) activity is highly variable due to several factors, including genetic polymorphisms and drug-drug-gene interactions. Hydrocodone, oxycodone, codeine, and tramadol the most commonly prescribed CYP2D6-activated opioids for pain. However, the co-administration of CYP2D6 interacting drugs can modulate CYP2D6-medicated activation of these opioids, affecting drug analgesia, effectiveness, and safety, and can impact healthcare costs. A retrospective, observational cohort analysis was performed in a large (n = 50,843) adult population. This study used drug claims data to derive medication risk scores and matching propensity scores to estimate the effects of opioid use and drug-drug interactions (DDIs) on medical expenditures. 4088 individuals were identified as opioid users; 95% of those were prescribed CYP2D6-activated opioids. Among those, 15% were identified as being at risk for DDIs. Opioid users had a significant increase in yearly medical expenditure compared to non-opioid users ($2457 vs. $1210). In matched individuals, average healthcare expenditures were higher for opioid users with DDIs compared to those without DDIs ($7841 vs. $5625). The derived medication risk score was higher in CYP2D6 opioid users with interacting drug(s) compared to no DDI (15 vs. 12). Higher costs associated with CYP2D6 opioid use under DDI conditions suggest inadequate CYP2D6 opioid prescribing practices. Efforts to improve chronic opioid use in adults should reduce interacting drug combinations, especially among patients using CYP2D6 activated opioids.
Radiomics and Artificial Intelligence in Uterine Sarcomas: A Systematic Review
Authors: Ravegnini Gloria , Ferioli Martina , Morganti Alessio Giuseppe , Strigari Lidia , Pantaleo Maria Abbondanza , Nannini Margherita , De Leo Antonio , De Crescenzo Eugenia , Coe Manuela , De Palma Alessandra , De Iaco Pierandrea , Rizzo Stefania , Perrone Anna Myriam
Published: November 2021

Background: Recently, artificial intelligence (AI) with computerized imaging analysis is attracting the attention of clinicians, in particular for its potential applications in improving cancer diagnosis. This review aims to investigate the contribution of radiomics and AI on the radiological preoperative assessment of patients with uterine sarcomas (USs). Methods: Our literature review involved a systematic search conducted in the last ten years about diagnosis, staging and treatments with radiomics and AI in USs. The protocol was drafted according to the systematic review and meta-analysis preferred reporting project (PRISMA-P) and was registered in the PROSPERO database (CRD42021253535). Results: The initial search identified 754 articles; of these, six papers responded to the characteristics required for the revision and were included in the final analysis. The predominant technique tested was magnetic resonance imaging. The analyzed studies revealed that even though sometimes complex models included AI-related algorithms, they are still too complex for translation into clinical practice. Furthermore, since these results are extracted by retrospective series and do not include external validations, currently it is hard to predict the chances of their application in different study groups. Conclusion: To date, insufficient evidence supports the benefit of radiomics in USs. Nevertheless, this field is promising but the quality of studies should be a priority in these new technologies.
Pharmacogenetics to Avoid Adverse Reactions in Cardiology: Ready for Implementation?
Authors: García-González Xandra , Salvador-Martín Sara
Published: November 2021

Cardiovascular Diseases (CVs) are one of the main causes of mortality and disability around the world. Advances in drug treatment have greatly improved survival and quality of life in the past decades, but associated adverse events remain a relevant problem. Pharmacogenetics can help individualize cardiovascular treatment, reducing associated toxicities and improving outcomes. Several scientific societies and working groups periodically review available studies and provide consensus recommendations for those gene-drug pairs with a sufficient level of evidence. However, these recommendations are rarely mandatory, and the indications on how to adjust treatment can vary between different guidelines, which limits their clinical applicability. The aim of this review is to compile, compare and discuss available guidelines and recommendations by the main Pharmacogenetics Consortiums (Clinical Pharmacogenetics Implementation Consortium (CPIC); Dutch Pharmacogenetics Working Group (DPWG); the French Network of Pharmacogenetics (Réseau national de pharmacogénétique (RNPGx) and The Canadian Pharmacogenomics Network for Drug Safety (CPNDS) regarding how to apply pharmacogenetic results to optimize pharmacotherapy in cardiology. Pharmacogenetic recommendations included in European or American drug labels, as well as those included in the European Society of Cardiology (ESC) and the American College of Cardiology (ACC) and the American Heart Association (AHA) treatment guidelines are also discussed.
Molecular Mechanisms of Cereblon-Interacting Small Molecules in Multiple Myeloma Therapy
Authors: Costacurta Matteo , He Jackson , Thompson Philip E. , Shortt Jake
Published: November 2021

Thalidomide analogues (or immunomodulatory imide drugs, IMiDs) are cornerstones in the treatment of multiple myeloma (MM). These drugs bind Cereblon (CRBN), a receptor for the Cullin-ring 4 ubiquitin-ligase (CRL4) complex, to modify its substrate specificity. IMiDs mediate CRBN-dependent engagement and proteasomal degradation of ‘neosubstrates’, Ikaros (IKZF1) and Aiolos (IKZF3), conveying concurrent antimyeloma activity and T-cell costimulation. There is now a greater understanding of physiological CRBN functions, including endogenous substrates and chaperone activity. CRISPR Cas9-based genome-wide screening has further elucidated the complex cellular machinery implicated in IMiD sensitivity, including IKZF1/3-independent mechanisms. New-generation IMiD derivatives with more potent anti-cancer properties—the CELMoDs (Cereblon E3 ligase modulators)—are now being evaluated. Rational drug design also allows ‘hijacking’ of CRL4CRBN utilising proteolysis targeting chimeras (PROTACs) to convey entirely distinct substrate repertoires. As all these chemotypes—thalidomide, IMiDs, CELMoDs and PROTACs—engage CRBN and modify its functions, we describe them here in aggregate as ‘CRBN-interacting small molecules’ (CISMs). In this review, we provide a contemporary summary of the biological consequences of CRBN modulation by CISMs. Detailed molecular insight into CRBN–CISM interactions now provides an opportunity to more effectively target previously elusive cancer dependencies, representing a new and powerful tool for the implementation of precision medicine.
Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity
Authors: López-Campos Fernando , Conde-Moreno Antonio , Barrado Los Arcos Marta , Gómez-Caamaño Antonio , García-Gómez Raquel , Hervás Morón Asunción
Published: November 2021

The treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) is a highly unmet medical need. The classic treatment approach for these patients—androgen deprivation therapy (ADT) alone—until metastatic progression is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival (OS)—for treatments that combine ADT with apalutamide, enzalutamide, and darolutamide. As a result, these approaches are now included in treatment guidelines and are considered a standard of care. In the present article, we discuss the changing landscape of the management of patients with nmCRPC.
A Focus Group Study of Perceptions of Genetic Risk Disclosure in Members of the Public in Sweden: “I’ll Phone the Five Closest Ones, but What Happens to the Other Ten?”
Authors: Hawranek Carolina , Hajdarevic Senada , Rosén Anna
Published: November 2021

This study explores perceptions and preferences on receiving genetic risk information about hereditary cancer risk in members of the Swedish public. We conducted qualitative content analysis of five focus group discussions with participants (n = 18) aged between 24 and 71 years, recruited from various social contexts. Two prominent phenomena surfaced around the interplay between the three stakeholders involved in risk disclosure: the individual, healthcare, and the relative at risk. First, there is a genuine will to share risk information that can benefit others, even if this is difficult and causes discomfort. Second, when the duty to inform becomes overwhelming, compromises are made, such as limiting one’s own responsibility of disclosure or projecting the main responsibility onto another party. In conclusion, our results reveal a discrepancy between public expectations and the actual services offered by clinical genetics. These expectations paired with desire for a more personalized process and shared decision-making highlight a missing link in today’s risk communication and suggest a need for developed clinical routines with stronger healthcare–patient collaboration. Future research needs to investigate the views of genetic professionals on how to address these expectations to co-create a transparent risk disclosure process which can realize the full potential of personalized prevention.
Offsetting Risk in a Neoliberal Environment: The Link between Asset-Based Welfare and NIMBYism
Authors: Record Matthew C.
Published: November 2021

Affordable housing policy in the developed world has been undergoing a systematic commodification for several decades, including a push for homeownership as the normalized tenure and a commodity unto itself. Scholars suggest this push for homeownership is part and parcel of a neoliberal asset-based welfare to supplement, or even outright replace, traditionally defined benefit pension schemes. These policies individualize risk and re-fashion individual citizens as long-term financial planners, navigating the uncertainty inherent in international financial markets and general financial management. Less deeply explored, however, are the perverse incentives this system creates for homeowners to protect their home “investment” by leveraging planning policies, zoning, and land-use restrictions to preserve the community status quo and lock in the value of their home. In a policy environment in which long-term financial risk is individualized and public social welfare and pension systems are relegated to the smallest number of individuals possible, this type of NIMBYism (Not in My Backyard) is rather rational behavior, even as it simultaneously staunches the supply of new housing and drives up prices for non-homeowners. As such, this analysis synthesizes the existing research to make a formal theoretical connection between the neoliberal push for commodified housing, asset-based welfare, and the intractable political problem of NIMBYism.
The Effects of Cryptocurrency Trading Websites on Airlines’ Advertisement Campaigns
Authors: Sakas Damianos P. , Giannakopoulos Nikolaos T. , Reklitis Dimitrios P. , Dasaklis Thomas K.
Published: November 2021

In future years, airline companies will be leaning more and more towards cryptocurrencies to implement their digital marketing strategies as leaders seek to gain an understanding of the factors affecting airlines’ visibility parameters. Cryptocurrency investment websites are currently experiencing rising demand, making them an appropriate site for paid advertisements. The above factors suggest the need for airlines to harvest cryptocurrency investment and platform users in their favour. To this end, it can be beneficial for airlines’ web promotions to link certain web analytics metrics to cryptocurrency trading site metrics. For research purposes, web analytics data were monitored and gathered for 2 consecutive years from 10 globally leading cryptocurrency trading companies and 10 airline websites. A three-stage model was adopted by the authors. In the first stage, statistical analysis was implemented using cryptocurrency and airline metrics, followed by fuzzy cognitive mapping and agent-based modelling stages. The findings of the study indicate that engagement with cryptocurrency trading websites has a positive impact on airline websites’ global ranking and visibility parameters. The outcomes of this research provide noteworthy digital marketing strategies which can be addressed by airline companies to increase their website visitors and optimise visibility parameters with the assistance of cryptocurrency trading websites.
Elevating the Value of Urban Location: A Consumer Preference-Based Approach to Valuing Local Amenity Provision
Authors: Herath Shanaka
Published: November 2021

Estimating the non-market monetary values of urban amenities has become commonplace in urban planning research, particularly following Rosen’s seminal article on hedonic theory in 1974. As a revealed preference method, the hedonic approach decouples the market price of a house into price components that are attributable to housing characteristics. Despite the potential contribution of this theory in a planning context, three main limitations exist in the conventional applications: (1) variable measurement issues, (2) model misspecification, and (3) the problematic common use of global regression. These flaws problematically skew our understanding of the urban structure and spatial distribution of amenities, leading to misinformed policy interventions and poor amenity planning decisions. In this article, we propose a coherent conceptual framework that addresses measurement, specification, and scale challenges to generate consistent economic estimates of local amenities. Finally, we argue that, by paying greater attention to the spatial equity of amenity values, governments can provide greater equality of opportunities in cities.
Global Commodity Markets, Chinese Demand for Maize, and Deforestation in Northern Myanmar
Authors: Han Enze , Huang Qiongyu
Published: November 2021

This paper makes a significant contribution to understanding the logic of deforestation in Northern Myanmar and connects global trends and regional political economy with local environmental changes. Methodologically, through a combination of remote sensing GIS analysis, for which we use a newly available Myanmar Forest Change dataset produced by TerraPulse and the Smithsonian Conservation Biology Institute, as well as on-the-ground field research observations and interviews with farmers, this paper examines how the expansion of maize plantations in the northern part of Myanmar has implications for deforestation in the region. It argues that a combination of global commodity price shock around 2011–2012 plus easy market access to China generated strong incentives for local farmers to increase the cultivation of maize. The paper contributes to how we understand the environmental impacts of Chinese demands for agricultural products in Southeast Asia.
Racemate Resolution of Alanine and Leucine on Homochiral Quartz, and Its Alteration by Strong Radiation Damage
Authors: Garcia Adrien D. , Meinert Cornelia , Finger Friedrich , Meierhenrich Uwe J. , Hejl Ewald
Published: November 2021

Homochiral proteins orchestrate biological functions throughout all domains of life, but the origin of the uniform l-stereochemistry of amino acids remains unknown. Here, we describe enantioselective adsorption experiments of racemic alanine and leucine onto homochiral d- and l-quartz as a possible mechanism for the abiotic emergence of biological homochirality. Substantial racemate resolution with enantiomeric excesses of up to 55% are demonstrated to potentially occur in interstitial pores, along grain boundaries or small fractures in local quartz-bearing environments. Our previous hypothesis on the enhanced enantioselectivity due to uranium-induced fission tracks could not be validated. Such capillary tubes in the near-surface structure of quartz have been proposed to increase the overall chromatographic separation of enantiomers, but no systematic positive correlation of accumulated radiation damage and enantioselective adsorption was observed in this study. In general, the natural l-quartz showed stronger enantioselective adsorption affinities than synthetic d-quartz without any significant trend in amino acid selectivity. Moreover, the l-enantiomer of both investigated amino acids alanine and leucine was preferably adsorbed regardless of the handedness of the enantiomorphic quartz sand. This lack of mirror symmetry breaking is probably due to the different crystal habitus of the synthetic z-bar of d-quartz and the natural mountain crystals of l-quartz used in our experiments.
The Behavior of Cement-Bonded Particleboard with Modified Composition under Static Load Stress
Authors: Melichar Tomas , Bydzovsky Jiri , Dvorak Richard , Topolar Libor , Keprdova Sarka
Published: November 2021

This article presents research on the behavior of cement-bonded particleboards under mechanical stress caused by the static load. The composition of the boards was modified using alternative raw materials–dust (DU) forming during the processing of cement-fibre boards and particle mixture (PM) generated in the production of cement-bonded particleboards. The particleboards (1-year-old) were subjected to an adverse environment (100 to 250 frost cycles). Mechanical parameters were tested, and the development of defects during static load of the boards by bending was analyzed using acoustic emission. Particleboards with modified compositions are slightly more resistant to adverse environments. The results of the acoustic emission showed the different types of defects occurring under stress by bending. Standard-composition particleboards showed defects located mainly under the cylindrical stress-test head. The modified boards showed larger location distribution of the occurring defects that were also concentrated further away from the cylindrical stress head. The energy during the occurrence of defects was higher in the modified boards in the location of weight application than in the reference boards.
Utilizing Artificial Intelligence to Predict the Superplasticizer Demand of Self-Consolidating Concrete Incorporating Pumice, Slag, and Fly Ash Powders
Authors: Liu Jing , Mohammadi Masoud , Zhan Yubao , Zheng Pengqiang , Rashidi Maria , Mehrabi Peyman
Published: November 2021

Self-consolidating concrete (SCC) is a well-known type of concrete, which has been employed in different structural applications due to providing desirable properties. Different studies have been performed to obtain a sustainable mix design and enhance the fresh properties of SCC. In this study, an adaptive neuro-fuzzy inference system (ANFIS) algorithm is developed to predict the superplasticizer (SP) demand and select the most significant parameter of the fresh properties of optimum mix design. For this purpose, a comprehensive database consisting of verified test results of SCC incorporating cement replacement powders including pumice, slag, and fly ash (FA) has been employed. In this regard, at first, fresh properties tests including the J-ring, V-funnel, U-box, and different time interval slump values were considered to collect the datasets. At the second stage, five models of ANFIS were adjusted and the most precise method for predicting the SP demand was identified. The correlation coefficient (R2), Pearson’s correlation coefficient (r), Nash–Sutcliffe efficiency (NSE), root mean square error (RMSE), mean absolute error (MAE), and Wilmot’s index of agreement (WI) were used as the measures of precision. Later, the most effective parameters on the prediction of SP demand were evaluated by the developed ANFIS. Based on the analytical results, the employed algorithm was successfully able to predict the SP demand of SCC with high accuracy. Finally, it was deduced that the V-funnel test is the most reliable method for estimating the SP demand value and a significant parameter for SCC mix design as it led to the lowest training root mean square error (RMSE) compared to other non-destructive testing methods.