bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitomycin C in Homologous Recombination Deficient Metastatic Pancreatic Cancer after Disease Progression on Platinum-Based Chemotherapy and Olaparib
Authors: Botrus Gehan , Roe Denise , Jameson Gayle S. , Junior Pedro Luiz Serrano Uson , Korn Ronald Lee , Caldwell Lana , Bargenquast Taylor , Miller Max , Borazanci Erkut Hasan
Published: October 2022

Recent efforts to personalize treatment with platinum-based chemotherapy and PARP inhibitors have produced promising results in homologous recombinant deficient (HRD) metastatic pancreatic cancer (MPC). However, new strategies are necessary to overcome resistance. The below case series documents patients treated at the HonorHealth Research Institute with a diagnosis of HRD MPC who received Mitomycin C (MMC) treatment from January 2013 until July 2018. Five HRD MPC patients treated with MMC were evaluated. All patients received at least one course of treatment. Mean age at MMC treatment initiation was 58 years. There were 3 females and 2 males. All patients had tumors that progressed on platinum-based chemotherapy, four patients had previous exposure to Olaparib. The median PFS was 10.1 months, and the median OS was 12.3 months. Responses were observed only in patients harboring BRCA2 mutations, no response was observed in the PALB2 mutation carrier. MMC in this heavily previously treated PC was safe, with overall manageable grade 2 gastrointestinal toxicities including nausea and vomiting, and G3 hematological toxicities including anemia and thrombocytopenia. Pancreatic cancer patients with HRD may benefit from MMC treatment. Further clinical investigation of MMC in pancreatic cancer is warranted.
Novel Classification of Thrombotic Disorders Based on Molecular Hemostasis and Thrombogenesis Producing Primary and Secondary Phenotypes of Thrombosis
Authors: Chang Jae Chan
Published: October 2022

Thrombosis, the common and deadliest disorder among human diseases, develops as a result of the intravascular hemostasis following an intravascular injury, which can be caused by a variety of trauma, non-traumatic insults or clinical illnesses. Thrombosis can occur at any location of the vascular system supplied by blood from the heart to large and smallest arterial and venous systems and may affect the function and anatomy of the organ and tissue. It more commonly occurs in the smaller circulatory system of the vascular tree such as arterioles and capillaries, and venules of the organs, especially in the brain, lungs, heart, pancreas, muscle and kidneys, and sinusoids of the liver. Thrombosis has been referred as the disease of “blood clots”, which concept is incompletely defined, but represents many different hemostatic diseases from microthrombosis to fibrin clot disease, macrothrombosis, and combined micro-macrothrombosis. Thrombosis is produced following an intravascular injury via one or more combination of four different mechanisms of thrombogenesis: microthrombogenesis, fibrinogenesis, macrothrombogenesis and micro-macrothrombogenesis initiated by normal physiological hemostasis in vivo. The clinical phenotype expression of thrombosis is determined by: (1) depth of the intravascular wall injury, (2) extent of the injury affecting the vascular tree system, (3) physiological character of the involved vascular system, (4) locality of the vascular injury, and (5) underlying non-hemostatic conditions interacting with hemostasis. Recent acquisition of “two-path unifying theory” of hemostasis and “two-activation theory of the endothelium” has opened a new frontier in science of medicine by identifying the pathophysiological mechanism of different thrombotic disorders and also contributing to the better understanding of many poorly defined human diseases, including different phenotypes of stroke and cardiovascular disease, trauma, sepsis and septic shock, multiorgan dysfunction syndrome, and autoimmune disease, and others. Reviewed are the fundamentals in hemostasis, thrombogenesis and thrombosis based on hemostatic theories, and proposed is a novel classification of thrombotic disorders.
The Optimisation of Carrier Selection in Dry Powder Inhaler Formulation and the Role of Surface Energetics
Authors: Abiona Olaitan , Wyatt David , Koner Jasdip , Mohammed Afzal
Published: October 2022

This review examines the effects of particle properties on drug–carrier interactions in the preparation of a dry powder inhaler (DPI) formulation, including appropriate mixing technology. The interactive effects of carrier properties on DPI formulation performance make it difficult to establish a direct cause-and-effect relationship between any one carrier property and its effect on the performance of a DPI formulation. Alpha lactose monohydrate remains the most widely used carrier for DPI formulations. The physicochemical properties of α-lactose monohydrate particles, such as particle size, shape and solid form, are profoundly influenced by the method of production. Therefore, wide variations in these properties are inevitable. In this review, the role of surface energetics in the optimisation of dry powder inhaler formulations is considered in lactose carrier selection. Several useful lactose particle modification methods are discussed as well as the use of fine lactose and force control agents in formulation development. It is concluded that where these have been investigated, the empirical nature of the studies does not permit early formulation prediction of product performance, rather they only allow the evaluation of final formulation quality. The potential to leverage particle interaction dynamics through the use of an experimental design utilising quantifiable lactose particle properties and critical quality attributes, e.g., surface energetics, is explored, particularly with respect to when a Quality-by-Design approach has been used in optimisation.
Pathogenesis of Vascular Retinal Manifestations in COVID-19 Patients: A Review
Authors: D’Alessandro Elisa , Kawasaki Aki , Eandi Chiara M.
Published: October 2022

Pandemic infection secondary to coronavirus disease 2019 (COVID-19) had an important impact on the general population affecting not only respiratory tract but also many other organs. Ocular manifestations are quite common at the level of the anterior segment (conjunctivitis, dry eye), while posterior segment and, in particular, retinal findings are less frequent. In the retina, COVID-19 is associated with vascular events. Since retinal arteries and veins represent an accessible window to the microvasculature of the rest of the body, a better understanding of the profile of retinal vascular occlusive events may help elucidate mechanisms of thrombo-occlusive complications in other organs in patients affected by COVID-19. In this review, we conducted a systematic literature search focused on retinal arterial and/or retinal venous manifestations. Twenty-one studies were included, describing a wide range of manifestations from mild signs like cotton wool spots, focal and flame-shaped hemorrhages, and vein dilation to more severe retinal artery and vein occlusions. Two principal pathogenetic mechanisms are considered responsible for these complications: a hypercoagulative state and a massive inflammatory response leading to a disseminated intravascular coagulation-like syndrome.
Synthesis of Artemether-Loaded Albumin Nanoparticles and Measurement of Their Anti-Cancer Effects
Authors: Pirali-Hamedani Zeynab , Abbasi Ardeshir , Hassan Zuhair Mohammad
Published: October 2022

Colorectal cancer is the third most common cancer in the world. Due to the side effects of common treatments such as chemotherapy and radiotherapy, the use of herbal medicines has received much attention. Artemether (ARM) is an herbal medicine derived from artemisinin, which has many anti-tumor properties. However, factors such as low solubility and short half-life have limited the use of artemether in clinical practice. In this study, we aimed to reduce these limitations by encapsulating artemether in human serum albumin (HSA). The hydrodynamic diameter and the zeta potential value of ARM-ALB nanoparticles (NPs) were 171.3 ± 5.88 nm and −19.1 ± 0.82 mV, respectively. Comparison of the effect of free and encapsulated artemether on CT 26 cell line showed that the use of artemether in capsulated form can reduce the effective concentration of the drug. Additionally, in vivo studies have also shown that albumin–artemether nanoparticles can control tumor growth by increasing the production of cytokine IFN-γ and decreasing the production of IL4. Therefore, ARM-ALB nanoparticles have greater anti-tumor effects than free artemether.
Omicron SARS-CoV-2 Spike-1 Protein’s Decreased Binding Affinity to α7nAChr: Implications for Autonomic Dysregulation of the Parasympathetic Nervous System and the Cholinergic Anti-Inflammatory Pathway—An In Silico Analysis
Authors: Doria Domiziano , Santin Alessandro D. , Tuszynski Jack Adam , Scheim David E. , Aminpour Maral
Published: October 2022

Omicron is the dominant strain of COVID-19 in the United States and worldwide. Although this variant is highly transmissible and may evade natural immunity, vaccines, and therapeutic antibodies, preclinical results in animal models and clinical data in humans suggest omicron causes a less severe form of infection. The molecular basis for the attenuation of virulence when compared to previous variants is currently not well understood. Using protein–ligand docking simulations to evaluate and compare the capacity of SARS-CoV-2 spike-1 proteins with the different COVID-19 variants to bind to the human α7nAChr (i.e., the core receptor under the control of the vagus nerve regulating the parasympathetic nervous system and the cholinergic anti-inflammatory pathway), we found that 10 out of the 14 mutated residues on the RBD of the B.1.1.529 (Omicron) spike, compared to between 0 and 2 in all previous variants, were present at the interaction interface of the α7nAChr. We also demonstrated, through protein–protein docking simulations, that these genetic alterations cause a dramatic decrease in the ability of the Omicron SARS-CoV-2 spike-1 protein to bind to the α7nAChr. These results suggest, for the first time, that the attenuated nature of Omicron infection in humans and animals compared to previous variants may be attributable to a particular set of genetic alterations, specifically affecting the binding site of the SARS-CoV-2 spike-1 protein to the α7nAChr.
Advances in Aptamer-Based Biosensors and Cell-Internalizing SELEX Technology for Diagnostic and Therapeutic Application
Authors: Gan Zixuen , Roslan Muhamad Aidilfitri Mohamad , Abd Shukor Mohd Yunus , Halim Murni , Yasid Nur Adeela , Abdullah Jaafar , Md Yasin Ina Salwany , Wasoh Helmi
Published: October 2022

Aptamers are a group of synthetic single-stranded nucleic acids. They are generated from a random library of single-stranded DNA or RNA by a technology named systematic evolution of ligands by exponential enrichment (SELEX). SELEX is a repetitive process to select and identify suitable aptamers that show high affinity and specificity towards target cells. Great strides have been achieved in the design, construction, and use of aptamers up to this point. However, only a small number of aptamer-based applications have achieved widespread commercial and clinical acceptance. Additionally, finding more effective ways to acquire aptamers with high affinity remains a challenge. Therefore, it is crucial to thoroughly examine the existing dearth and advancement in aptamer-related technologies. This review focuses on aptamers that are generated by SELEX to detect pathogenic microorganisms and mammalian cells, as well as in cell-internalizing SELEX for diagnostic and therapeutic purposes. The development of novel aptamer-based biosensors using optical and electrical methods for microbial detection is reported. The applications and limitations of aptamers are also discussed.
Ultrasensitive and Cost-Effective Detection of Neuropeptide-Y by a Disposable Immunosensor: A New Functionalization Route for Indium-Tin Oxide Surface
Authors: Uludağ İnci , Sezgintürk Mustafa Kemal
Published: October 2022

Neuropeptide Y (NPY) is one of the most abundant neuropeptides in the human brain, and its levels in the blood change in neurodegenerative and neuroimmune disorders. This indicates that NPY may serve as a diagnostic and monitoring marker for associated disorders. In this paper, an electrochemical immunosensor was created to detect NPY biomarkers using a novel immobilization technique. The proposed biosensor system enables accurate, specific, cost-effective, and practical biomarker analysis. Indium tin oxide-coated polyethylene terephthalate (ITO-PET) sheets were treated with hexamethylene diisocyanate (HMDC) to covalently immobilize antibodies. Electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV) techniques were used to analyze each step of the biosensors. The proposed NPY biosensor has a broad linear detection range (0.01–100 pg mL−1), a low limit of detection (LOD) (0.02968 pg mL−1), and a low limit of quantification (LOQ) (0.0989 pg mL−1). Atomic force microscopy (AFM) was used to support in the optimization process, study the surface morphology, and visualize it. Studies of repeatability, reproducibility, storage, and Kramers–Kronig transformation were conducted during electrochemical characterization. After analytical experiments, the biosensor’s responses to human serum samples were evaluated. According to the obtained data, the error margin is small, and the created biosensor offers a great deal of promise for the clinical measurement of NPY.
Electrochemical Biosensors for Pathogen Detection: An Updated Review
Authors: Banakar Morteza , Hamidi Masoud , Khurshid Zohaib , Zafar Muhammad Sohail , Sapkota Janak , Azizian Reza , Rokaya Dinesh
Published: October 2022

Electrochemical biosensors are a family of biosensors that use an electrochemical transducer to perform their functions. In recent decades, many electrochemical biosensors have been created for pathogen detection. These biosensors for detecting infections have been comprehensively studied in terms of transduction elements, biorecognition components, and electrochemical methods. This review discusses the biorecognition components that may be used to identify pathogens. These include antibodies and aptamers. The integration of transducers and electrode changes in biosensor design is a major discussion topic. Pathogen detection methods can be categorized by sample preparation and secondary binding processes. Diagnostics in medicine, environmental monitoring, and biothreat detection can benefit from electrochemical biosensors to ensure food and water safety. Disposable and reusable biosensors for process monitoring, as well as multiplexed and conformal pathogen detection, are all included in this review. It is now possible to identify a wide range of diseases using biosensors that may be applied to food, bodily fluids, and even objects’ surfaces. The sensitivity of optical techniques may be superior to electrochemical approaches, but optical methods are prohibitively expensive and challenging for most end users to utilize. On the other hand, electrochemical approaches are simpler to use, but their efficacy in identifying infections is still far from satisfactory.
An Overview of the Design of Metal-Organic Frameworks-Based Fluorescent Chemosensors and Biosensors
Authors: Xia Ning , Chang Yong , Zhou Qian , Ding Shoujie , Gao Fengli
Published: October 2022

Taking advantage of high porosity, large surface area, tunable nanostructures and ease of functionalization, metal-organic frameworks (MOFs) have been popularly applied in different fields, including adsorption and separation, heterogeneous catalysis, drug delivery, light harvesting, and chemical/biological sensing. The abundant active sites for specific recognition and adjustable optical and electrical characteristics allow for the design of various sensing platforms with MOFs as promising candidates. In this review, we systematically introduce the recent advancements of MOFs-based fluorescent chemosensors and biosensors, mainly focusing on the sensing mechanisms and analytes, including inorganic ions, small organic molecules and biomarkers (e.g., small biomolecules, nucleic acids, proteins, enzymes, and tumor cells). This review may provide valuable references for the development of novel MOFs-based sensing platforms to meet the requirements of environment monitoring and clinical diagnosis.
Genome-Wide Gene Expression Analysis Reveals Unique Genes Signatures of Epithelial Reorganization in Primary Airway Epithelium Induced by Type-I, -II and -III Interferons
Authors: Erb Anna , Zissler Ulrich M. , Oelsner Madlen , Chaker Adam M. , Schmidt-Weber Carsten B. , Jakwerth Constanze A.
Published: October 2022

Biosensors such as toll-like receptors (TLR) induce the expression of interferons (IFNs) after viral infection that are critical to the first step in cell-intrinsic host defense mechanisms. Their differential influence on epithelial integrity genes, however, remains elusive. A genome-wide gene expression biosensor chip for gene expression sensing was used to examine the effects of type-I, -II, and -III IFN stimulation on the epithelial expression profiles of primary organotypic 3D air-liquid interface airway cultures. All types of IFNs induced similar interferon-stimulated genes (ISGs): OAS1, OAS2, and IFIT2. However, they differentially induced transcription factors, epithelial modulators, and pro-inflammatory genes. Type-I IFN-induced genes were associated with cell–cell adhesion and tight junctions, while type-III IFNs promoted genes important for transepithelial transport. In contrast, type-II IFN stimulated proliferation-triggering genes associated and enhanced pro-inflammatory mediator secretion. In conclusion, with our microarray system, we provide evidence that the three IFN types exceed their antiviral ISG-response by inducing distinct remodeling processes, thereby likely strengthening the epithelial airway barrier by enhancing cross-cell-integrity (I), transepithelial transport (III) and finally reconstruction through proliferation (II).
HPA Axis Responsiveness Associates with Central Serotonin Transporter Availability in Human Obesity and Non-Obesity Controls
Authors: Schinke Christian , Rullmann Michael , Luthardt Julia , Drabe Mandy , Preller Elisa , Becker Georg A. , Patt Marianne , Regenthal Ralf , Zientek Franziska , Sabri Osama , Then Bergh Florian , Hesse Swen
Published: October 2022

Background: Alterations of hypothalamic–pituitary–adrenal (HPA) axis activity and serotonergic signaling are implicated in the pathogenesis of human obesity and may contribute to its metabolic and mental complications. The association of these systems has not been investigated in human obesity. Objective: To investigate the relation of HPA responsiveness and serotonin transporter (5-HTT) availability in otherwise healthy individuals with obesity class II or III (OB) compared to non-obesity controls (NO). Study participants: Twenty-eight OB (21 females; age 36.6 ± 10.6 years; body mass index (BMI) 41.2 ± 5.1 kg/m2) were compared to 12 healthy NO (8 females; age 35.8 ± 7.4 years; BMI 22.4 ± 2.3 kg/m2), matched for age and sex. Methods: HPA axis responsiveness was investigated using the combined dexamethasone/corticotropin-releasing hormone (dex/CRH) test, and curve indicators were derived for cortisol and adrenocorticotropic hormone (ACTH). The 5-HTT selective tracer [11C]DASB was applied, and parametric images of the binding potentials (BPND) were calculated using the multilinear reference tissue model and evaluated by atlas-based volume of interest (VOI) analysis. The self-questionnaires of behavioral inhibition system/behavioral activation system (BIS/BAS) with subscales drive, fun-seeking and reward were assessed. Results: OB showed significant positive correlations of ACTH curve parameters with overall 5-HTT BPND (ACTHAUC: r = 0.39, p = 0.04) and 5-HTT BPND of the caudate nucleus (ACTHAUC: r = 0.54, p = 0.003). In NO, cortisol indicators correlated significantly with BPND in the hippocampus (cortisolAUC: r = 0.59, p = 0.04). In OB, BAS reward was inversely associated with the ACTHAUC (r = −0.49, p = 0.009). Conclusion: The present study supports a serotonergic-neuroendocrine association, which regionally differs between OB and NO. In OB, areas processing emotion and reward seem to be in-volved. The finding of a serotonergic HPA correlation may have implications for other diseases with dysregulated stress axis responsiveness, and for potential pharmacologic interven-tions.
Maintaining the Quality of Mechanical Thrombectomy after Acute Ischemic Stroke in COVID(-)19 Patients
Authors: Chang Yu-Hao , Liao Nien-Chen , Tsuei Yuang-Seng , Chen Wen-Hsieh , Shen Chiung-Chyi , Yang Yi-Chin , Lee Chung-Hsin
Published: October 2022

The COVID-19 pandemic has become increasingly worse worldwide since it was discovered in China in late December 2019. Easy contact transmission between people and a low to moderate mortality rate may cause failure in medical health services if there is no proper personal protective equipment for personnel. During the pandemic, patients with acute ischemic stroke with large-vessel occlusion who required immediate treatment through mechanical thrombectomy (MT) were still being sent to the emergency room. Knowing how to maintain effective treatment standards has become our concern. We used a retrospective, single-center study to select COVID-19 (-) patients with acute ischemic stroke undergoing mechanical thrombectomy during the years 2020–2021. Patients with acute ischemic stroke with large-vessel occlusion received mechanical thrombectomy were compared with patients admitted from December 2020 to May 2021 (the pre-COVID-19 group) and those from June 2021 to November 2021 (the during COVID-19 group). Furthermore, the time disparity of mechanical thrombectomy was compared between these two groups. Of patients confirmed with acute ischemic stroke (AIS) with large-vessel occlusion (LVO) during the study period, 62 were included. Compared with the pre-COVID-19 group (34 patients; median age, 70.5 years), the during COVID-19 group (28 patients; median age, 71.5 years) showed no major median time difference in door-to-computed-tomography-angiography (CTA) time (19.0 min vs. 20.0 min, p = 0.398) and no major median time difference in door-to-groin-puncture time (118.0 min vs. 109.0 min, p = 0.281). In our study, with a prepared protocol for the pandemic having been established in the healthcare system, we could see no difference between the pre-pandemic and during-pandemic time periods when using mechanical thrombectomy to treat COVID-19 (-) patients of AIS with LVO. By means of a quick-PCR test during triage, there was no time delay to perform MT or any lowering of safety protocol for workers in the healthcare system.
Diagnostic Value of the Vestibular Autorotation Test in Menière’s Disease, Vestibular Migraine and Menière’s Disease with Migraine
Authors: Liu Dan , Wang Jun , Tian E , Guo Zhao-qi , Chen Jing-yu , Kong Wei-jia , Zhang Su-lin
Published: October 2022

(1) Background: Vestibular migraine (VM) and Menière’s disease (MD) share multiple features in terms of clinical presentations and auditory-vestibular functions, and, therefore, more accurate diagnostic tools to distinguish between the two disorders are needed. (2) Methods: The study was of retrospective design and examined the data of 69 MD patients, 79 VM patients and 72 MD with migraine patients. Five vestibular autorotation test (VAT) parameters, i.e., horizontal gain/phase, vertical gain/phase and asymmetry were subjected to logistic regression. The receiver operating characteristic (ROC) curves were generated to determine the accuracy of the different parameters in the differential diagnosis of MD and VM. (3) Results: Our results showed that the horizontal gain of VAT significantly outperformed other parameters in distinguishing MD and VM. In addition, the sensitivity, specificity and accuracy of the horizontal gain were 95.7%, 50.6% and 71.6%, respectively, for the differentiation between VM and MD. In most MD patients, the horizontal gain decreased in the range of 3–4 Hz, while in most VM patients, horizontal gain increased in the range between 2–3 Hz. More MD with migraine patients had an increased horizontal gain when the frequency was less than 5.0 Hz and had a decreased horizontal gain when the frequency was greater than 5.0 Hz. (4) Conclusion: Our study suggested the VAT, especially the horizontal gain, as an indicator, may serve as a sensitive and objective indicator that helps distinguish between MD and VM. Moreover, VAT, due to its non-invasive and all-frequency nature, might be an important part of a test battery.
The Challenges of Establishing Healthcare Services in Low- and Middle-Income Countries: The Case of Autism Spectrum Disorders (ASD) in the Kurdistan Region of Iraq—Report from the Field
Authors: Samadi Sayyed Ali
Published: October 2022

The present report from the field tries to present challenges associated with establishing healthcare services for individuals with autism spectrum disorders (ASD) in a low- and middle-income area. The given case that has been highlighted is establishing daycare services focusing on rehabilitation and training services for individuals with ASD, and their caregivers and family members, in the Kurdistan Region of Iraq (KRI). Based on my experience, the associated challenges are divided into three primary levels: personal, professional, and organizational. The report highlights the importance of understanding the challenges associated with establishing healthcare services with the desire to put them under control. Plus, understanding the cultural aspects of the healthcare services for individuals with ASD experiences to address the issues at each level shared. It is concluded in the final part of the report that the key to establishing healthcare quality is to understand attitudes toward healthcare at the personal, professional, and organizational levels. This attitude determines the expectation from the services and defines assistance-seeking behaviors. Results offer insight for stakeholders in the healthcare field, allowing for a better understanding and improvement of availability and access to quality-driven healthcare services. A pre- and in-service training approach is practiced to address the associated challenges of establishing healthcare services at the personal level in KRI. A similar policy might be applicable in other LMICs, where there is a lack of professional and skillful healthcare service providers.
The Role of Astrocytes in the Mechanism of Perioperative Neurocognitive Disorders
Authors: Cao Ying , Lin Xiaowan , Liu Xiao , Yu Kang , Miao Huihui , Li Tianzuo
Published: October 2022

Recently, astrocytes are fast climbing the ladder of importance in cognitive-related diseases. Perioperative neurocognitive disorder (PND) is a common consequence of anesthesia and surgery, which is widely investigated in elderly and susceptible individuals. There is no doubt that astrocytes also play an irreplaceable role in the pathogenesis of PND. Reactive astrocytes can be found in the PND model, with an altered phenotype and morphology, suggesting a role in the development of the diseases. As a prominent participant cell in the central inflammatory response, the inflammatory response is unavoidably a crucial pathway in the development of the disease. Astrocytes also play a significant role in the homeostasis of the internal environment, neuronal metabolism, and synaptic homeostasis, all of which have an impact on cognitive function. In this article, we discuss the function of astrocytes in PND in order to establish a framework for investigating treatments for PND that target astrocytes.
Downregulation of GABAARα1 Aggravates Comorbidity of Epilepsy and Migraine via the TLR4 Signaling Pathway
Authors: Lin Yao , Ding Man , Gong Qiaoyu , Xiao Zheman
Published: October 2022

Epilepsy and migraine are among the most prevalent neurological disorders. By being comorbid, the presence of one disorder increases the likelihood of the other. Although several similar clinical features of epilepsy and migraine have been observed as early as the 19th century, only in recent years have researchers engaged in finding a common pathogenic mechanism between them. In this study, the epilepsy–migraine comorbidity rat model was generated, and the pathophysiological basis of epilepsy–migraine comorbidity was examined. Male rats were divided into four groups: control, migraine, epilepsy, epilepsy–migraine comorbidity. After establishing the models, the amount of scratching and the pain threshold of the rats were observed. Western blot and immunofluorescence staining were used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Subsequently, co-immunoprecipitation of GABAARα1 and TLR4 was performed. Then, the rats were divided into three groups: comorbidity, comorbidity + TAK-242, and comorbidity + muscimol. After drug intervention, the seizure latency, seizure level, amount of scratching, and pain threshold were observed. Western blot was used to detect the protein expression levels of TLR4 and GABAARα1 in the temporal cortex, hippocampus, trigeminal ganglion, and medullary dorsal horn. Our results demonstrate that the seizure attacks in comorbidity and epilepsy groups performed severely, and the comorbidity and migraine groups displayed a remarkable increase in the amount of head-scratching and a noticeable decrease in the facial mechanical withdrawal threshold. Further analysis revealed considerably increased Toll-like receptor 4 (TLR4), associated with reduced γ-aminobutyric acid type A receptor α1 (GABAARα1) and microglia enhanced in the epilepsy–migraine comorbidity rat. Additionally, co-immunoprecipitation proved GABAARα1 binding TLR4. Following muscimol to activate GABAARα1, seizure attacks and migraine-like behavior were rescued. GABAARα1 level increment was accompanied by the decline of TLR4, while TAK-242, the inhibitor of TLR4, only decreased TLR4 without affecting GABAARα1 expression. It also ameliorated the migraine-like behavior with no impact on seizure activity. We propose that GABAARα1 binding and negatively regulating TLR4 contribute to epilepsy–migraine comorbidity; TLR4 is a critical intermediate link in epilepsy–migraine comorbidity; immune-induced neuroinflammation in microglia may be involved in migraine and epilepsy–migraine comorbidity.
Relationship between Cardiorespiratory Fitness and Executive Function in Young Adults: Mediating Effects of Gray Matter Volume
Authors: Liu Yuexin , Zhu Lina , Cai Kelong , Dong Xiaoxiao , Xiong Xuan , Liu Zhimei , Chen Aiguo
Published: October 2022

We evaluated the association between cardiorespiratory fitness (CRF) and executive function (EF) in young adults and the mediating effects of GMV on this relationship. This study involved 217 college students. An incremental load exercise program was used to evaluate VO2max. EF was estimated by the Flanker task, the 2-back task, and the more-odd shifting task, while structural magnetic resonance and region-based morphometry (RBM) were used to analyze GMV. The high CRF group had a shorter updating reaction time (RT) (p ≤ 0.05). CRF was positively correlated with the right orbital part of the middle frontal gyrus (ORBmid.R) GMV (p ≤ 0.05). ORBmid.R GMV was negatively correlated with updating RT (p ≤ 0.05). Model 4 in SPSS was used to assess the mediating effects of ORBmid.R GMV between CRF and updating RT. ORBmid.R GMV was established to have a partially mediating role between CRF and updating RT, which accounted for 19.6% of the total effect value. These findings indicate that the negative correlation between CRF and EF was significant, and ORBmid.R GMV played a mediating role in the relationship between CRF and EF, providing new evidence toward comprehensively revealing that CRF promotes EF performance.
History of Brain Injury Alters Cerebral Haemodynamic Oscillations with Cardiac Influence
Authors: Neary J. Patrick , Singh Jyotpal , Sirant Luke W. , Gaul Catherine A. , Martin Steve , Stuart-Hill Lynneth , Candow Darren G. , Mang Cameron S. , Kratzig Gregory P.
Published: October 2022

(1) Background: Cerebral autoregulation is altered during acute mild traumatic brain injury, or concussion. However, it is unknown how a history of concussion can impact cerebral haemodynamic activity during a task that elicits an autoregulatory response. (2) Methods: We assessed cerebral haemodynamic activity in those with a history of three or more concussions. The study included 44 retired athletes with concussion history and 25 control participants. We recorded participants’ relative changes in right and left pre-frontal cortex oxygenation collected by near-infrared spectroscopy and continuous beat-to-beat blood pressure measured by finger photoplethysmography. Participants completed a 5-min seated rest followed by a 5-min repeated squat (10-s) stand (10-s) maneuver (0.05 Hz) to elicit a cerebral autoregulatory response. Wavelet transformation was applied to the collected signals, allowing separation into cardiac interval I (0.6 to 2 Hz), respiratory interval II (0.145 to 0.6 Hz), and smooth muscle cell interval III (0.052 to 0.145 Hz). (3) Results: Significant increases at cardiac interval I were found for the wavelet amplitude of oxy-haemoglobin and haemoglobin difference at the right pre-frontal cortex. No significant difference was found at the left pre-frontal cortex or the blood pressure wavelet amplitudes. (4) Conclusions: Contributions from cardiac activity to the pre-frontal cortex oxygenation are elevated when eliciting dynamic cerebral autoregulation in those with a history of three or more concussions.
Aging and Complexity Effects on Hemisphere-Dependent Movement-Related Beta Desynchronization during Bimanual Motor Planning and Execution
Authors: Van Hoornweder Sybren , Blanco-Mora Diego Andres , Depestele Siel , van Dun Kim , Cuypers Koen , Verstraelen Stefanie , Meesen Raf
Published: October 2022

With aging comes degradation of bimanual movement performance. A hallmark feature of bimanual movements is movement-related beta desynchronization (MRBD), an attenuation in the amplitude of beta oscillations associated with sensorimotor activation. Here, we investigated MRBD in 39 healthy adults (20 younger and 19 older adults) in frontal, central, and parietal regions across both hemispheres, during the planning and execution of a bimanual tracking task. Task accuracy decreased with age and during more difficult conditions when both hands had to move at different relative speeds. MRBD was mostly situated in the central region, and increased in older versus younger adults during movement execution but not planning. Irrespective of age, motor planning and execution were associated with increased MRBD in the left and right hemispheres, respectively. Notably, right central MRBD during motor planning was associated with bimanual task performance, particularly in older adults. Specifically, persons who demonstrated high MRBD during motor planning performed better on the bimanual tracking task. Our results highlight the importance of lateralized MRBD during motor planning, thereby shining new light on previous research and providing a promising avenue for future interventions.
The Role of Isolated Nasal Surgery in Obstructive Sleep Apnea Therapy—A Systematic Review
Authors: Schoustra Emily , van Maanen Peter , den Haan Chantal , Ravesloot Madeline J. L. , de Vries Nico
Published: October 2022

Purpose: Nasal obstruction is believed to play a significant role in the pathophysiology and management of obstructive sleep apnea (OSA). However, controversy remains about the ability of isolated nasal surgery to improve OSA. The objective of this systematic review is to give an updated overview of the literature on whether isolated nasal surgery can improve OSA subjectively (Epworth Sleepiness Scale (ESS)) and/or objectively (polysomnography (PSG)). Methods: A systematic review was performed searching the electronic databases PubMed, Embase.com (accessed on 20 June 2022) Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (CENTRAL) up to 20 June 2022. Eligible studies were reviewed for methodological quality using the NIH Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Results: Twenty-one studies met the inclusion criteria. The majority of the included studies reported no significant reduction in the apnea–hypopnea index (AHI) after isolated nasal surgery in patients with OSA. The meta-analysis suggests that the AHI slightly decreases after nasal surgery. The ESS was significantly lower after nasal surgery in eighteen studies. Conclusion: Based on the present analysis of objective outcomes, isolated nasal surgery did not improve the AHI significantly in the majority of the studies. The meta-analysis suggests a slight decrease in AHI after nasal surgery, but this reduction is not clinically relevant in terms of treatment success. Isolated nasal surgery should therefore not be recommended as a first-line treatment for OSA. Because of high study heterogeneity, these results should be interpreted with caution. Isolated nasal surgery can possibly improve OSA subjectively. Perhaps only OSA patients with complaints of nasal obstruction or OSA patients experiencing difficulty with continuous positive airway pressure (CPAP) compliance would benefit from isolated nasal surgery.
Risk Factors for Hiccups after Deep Brain Stimulation of Subthalamic Nucleus for Parkinson’s Disease
Authors: Wu Bin , Ling Yuting , Zhang Changming , Liu Yi , Xuan Ruoheng , Xu Jiakun , Li Yongfu , Guo Qianqian , Wang Simin , Liu Lige , Jiang Lulu , Huang Zihuan , Chu Jianping , Chen Ling , Jiang Nan , Liu Jinlong
Published: October 2022

Background: After deep brain stimulation (DBS), hiccups as a complication may lead to extreme fatigue, sleep deprivation, or affected prognosis. Currently, the causes and risk factors of postoperative hiccups are unclear. In this study, we investigated the risk factors for hiccups after DBS of the subthalamic nucleus (STN) for Parkinson’s disease (PD) under general anesthesia. Methods: We retrospectively included patients who underwent STN DBS in the study, and collected data of demographic characteristics, clinical evaluations, and medications. According to the occurrence of hiccups within seven days after operation, the patients were divided into a hiccups group and non-hiccups group. The potentially involved risk factors for postoperative hiccups were statistically analyzed by logistic regression analysis. Results: A total of 191 patients were included in the study, of which 34 (17.80%) had postoperative transient persistent hiccups. Binary univariate logistic regression analysis showed that male, higher body mass index (BMI), smoker, Hoehn and Yahr stage (off), preoperative use of amantadine, hypnotic, Hamilton anxiety scale and Hamilton depression scale scores, and postoperative limited noninfectious peri-electrode edema in deep white matter were suspected risk factors for postoperative hiccups (p < 0.1). In binary multivariate logistic regression analysis, male (compared to female, OR 14.00; 95% CI, 1.74–112.43), postoperative limited noninfectious peri-electrode edema in deep white matter (OR, 7.63; 95% CI, 1.37–42.37), preoperative use of amantadine (OR, 3.64; 95% CI, 1.08–12.28), and higher BMI (OR, 3.50; 95% CI, 1.46–8.36) were independent risk factors for postoperative hiccups. Conclusions: This study is the first report about the risk factors of hiccups after STN DBS under general anesthesia for PD patients. The study suggests that male, higher BMI, preoperative use of amantadine, and postoperative limited noninfectious peri-electrode edema in deep white matter are independent risk factors for postoperative hiccups of STN-DBS for PD patients. Most hiccups after STN-DBS for PD patients were transient and self-limiting.
A Modeling Method for Finite Element Analysis of Corroded Steel Structures with Random Pitting Damage
Authors: Zeng Shenghui , Gu Song , Ren Songbo , Gu Ying , Kong Chao , Yang Liqiong
Published: October 2022

Aiming at simulating the surface morphology of corroded steel and providing a modeling method with higher accuracy, the accelerated corrosion test was used to obtain six groups of corroded specimens, and then applied to stochastic finite element analysis (FEA) for studying the mechanical behavior of corroded steel. The pitting parameters (the depth, width, and diameter–depth ratio) of all specimens were investigated and statistically analyzed. Considering the irregularity of corroded surface, the random pitting model (RPM) was established based on the secondary development of ABAQUS. Moreover, the rough surface meshing method (RSMM) was subsequently proposed to optimize the element quality of the FEA model. At last, the modeling method was applied to investigate the bearing capacity of corroded steel beams. The results indicate that, firstly, the pitting parameters of all specimens obeyed log-normal distribution, and their logarithmic mean values grew with increase in corrosion time. The corroded surface the RPM can reproduce the evolution behaviors of a corroded surface with higher accuracy. In addition, the FEA model of corroded steel structures can be meshed easily into hexahedron elements by using the RSMM and effectively optimizing the number and quality of elements. By comparing with other test results, the calculation results of the FEA model of steel beams established by using the modeling method proposed in this study demonstrate a good accuracy in mechanical behavior analysis. The modeling method provides further support for the study of mechanical properties of corroded steel structures.
Vulvar Malignant Melanoma: A Narrative Review
Authors: Falcicchio Giovanni , Vinci Lorenzo , Cicinelli Ettore , Loizzi Vera , Arezzo Francesca , Silvestris Erica , Resta Leonardo , Serio Gabriella , Cazzato Gerardo , Mastronardi Marialuigia , Mongelli Michele , Marinaccio Marco , Cormio Gennaro
Published: October 2022

Malignant melanoma is a fatal disease that affects all skin sites. Among these, vulvar melanoma (VM) is a rare gynecological condition that accounts for 5% of all vulvar neoplasms. VM primarily affects older Caucasian women and its relationship to sun exposure is undefined. Diagnosis is defined by biopsy but many clinical, dermatoscopic, and confocal microscopic features can guide doctors. The molecular profile is characterized by the KIT mutation, revealed by all of the technologies that are used (classical sequencing, next-generation sequencing, and immunohistochemical staining). BRAF and NRAS mutations are also common in VM. All of these mutations are possible therapeutic targets. Today, surgery remains the first treatment choice for primary VM. The role of neoadjuvant and adjuvant therapy is scarce and the treatment of relapses is widely debated.
FTO Inhibits Epithelial Ovarian Cancer Progression by Destabilising SNAI1 mRNA through IGF2BP2
Authors: Sun Meige , Zhang Xiaocui , Bi Fangfang , Wang Dandan , Zhou Xin , Li Xiao , Yang Qing
Published: October 2022

Fat mass and obesity-associated protein (FTO) regulates critical pathways in various diseases, including malignant tumours. However, the functional link between FTO and its target genes in epithelial ovarian cancer (EOC) development remains to be elucidated. In this study, the biological functions of FTO were verified in vitro and in vivo. The m6A modification and the binding sites of SNAI1 mRNA were confirmed by m6A RNA immunoprecipitation (MeRIP) and RIP experiments. The actinomycin D assay was used to test the stability of RNA. We found that FTO was downregulated with increased m6A levels in EOC. Reduced expression of FTO was associated with a higher FIGO stage in patients with EOC. Mechanistically, FTO decreased the m6A level and stability of SNAI1 mRNA, causing downregulation of SNAI1 and inhibiting epithelial–mesenchymal transition (EMT). Furthermore, FTO-mediated downregulation of SNAI1 expression depended on IGF2BP2, which acted as an m6A reader binding to the 3′ UTR region of SNAI1 mRNA to promote its stability. In conclusion, FTO inhibits SNAI1 expression to attenuate the growth and metastasis of EOC cells in an m6A-IGF2BP2-dependent manner. Our findings suggest that the FTO-IGF2BP2-SNAI1 axis is a potential therapeutic target in EOC.
Aptamer-Based Sandwich Assay Formats for Detection and Discrimination of Human High- and Low-Molecular-Weight uPA for Cancer Prognosis and Diagnosis
Authors: Dreymann Nico , Sabrowski Wiebke , Danso Jennifer , Menger Marcus M.
Published: October 2022

Urokinase-type plasminogen activator (urokinase, uPA) is a frequently discussed biomarker for prognosis, diagnosis, and recurrence of cancer. In a previous study, we developed ssDNA aptamers that bind to different forms of human urokinase, which are therefore assumed to have different binding regions. In this study, we demonstrate the development of aptamer-based sandwich assays that use different combinations of these aptamers to detect high molecular weight- (HMW-) uPA in a micro titer plate format. By combining aptamers and antibodies, it was possible to distinguish between HMW-uPA and low molecular weight- (LMW-) uPA. For the best performing aptamer combination, we calculated the limit of detection (LOD) and limit of quantification (LOQ) in spiked buffer and urine samples with an LOD up to 50 ng/mL and 138 ng/mL, respectively. To show the specificity and sequence dependence of the reporter aptamer uPAapt−02−FR, we have identified key nucleotides within the sequence that are important for specific folding and binding to uPA using a fluorescent dye-linked aptamer assay (FLAA). Since uPA is a much-discussed marker for prognosis and diagnosis in various types of cancers, these aptamers and their use in a micro titer plate assay format represent a novel, promising tool for the detection of uPA and for possible diagnostic applications.
Metabolic Reprogramming in Tumor-Associated Macrophages in the Ovarian Tumor Microenvironment
Authors: Kumar Sudhir , Mittal Sonam , Gupta Prachi , Singh Mona , Chaluvally-Raghavan Pradeep , Pradeep Sunila
Published: October 2022

The interaction between tumor cells and macrophages in the tumor microenvironment plays an essential role in metabolic changes in macrophages and reprograms them towards a pro-tumorigenic phenotype. Increasing evidence indicates that macrophage metabolism is a highly complex process and may not be as simple as previously thought. Pro-inflammatory stimuli switch macrophages towards an M1-like phenotype and rely mainly on aerobic glycolysis and fatty acid synthesis, whereas anti-inflammatory stimuli switch macrophages towards an M2-like phenotype. M2-like macrophages depend more on oxidative phosphorylation (OXPHOS) and fatty acid oxidation. However, this metabolically reprogrammed phenotypic switch in macrophages remained a mystery for a while. Therefore, through this review, we tend to describe how macrophage immunometabolism determines macrophage phenotypes and functions in tumor microenvironments (TMEs). Furthermore, we have discussed how metabolic reprogramming in TAM can be used for therapeutic intervention and drug resistance in ovarian cancer.