bluuebunny/crossref_metadata_2025 huggingface dataset:
Low Geriatric Nutritional Risk Index Is Associated with Poorer Prognosis in Elderly Diffuse Large B-Cell Lymphoma Patients Unfit for Intensive Anthracycline-Containing Therapy: A Real-World Study
Authors: Chuang Tzer-Ming , Liu Yi-Chang , Hsiao Hui-Hua , Wang Hui-Ching , Du Jeng-Shiun , Yeh Tsung-Jang , Gau Yuh-Ching , Ke Ya-Lun , Yang Ching-I , Lee Ching-Ping , Hsu Chin-Mu , Cho Shih-Feng
Published: September 2021

Nutritional assessments, including the Geriatric Nutritional Risk Index (GNRI), have emerged as prediction tools for long-term survival in various cancers. This study aimed to investigate the therapeutic strategy and explore the prognostic factors in the elderly patients (≥65 years) with diffuse large B cell lymphoma (DLBCL). The cutoff value of the GNRI score (92.5) was obtained using the receiver operating characteristic curve. Among these patients (n = 205), 129 (62.9%) did not receive standard R–CHOP chemotherapy. Old age (≥80 years), poor performance status, low serum albumin level, and comorbidities were the major factors associated with less intensive anti-lymphoma treatment. Further analysis demonstrated that a lower GNRI score (<92.5) was linked to more unfavorable clinical features. In the patients who received non-anthracycline-containing regimens (non-R–CHOP), multivariate analysis showed that a low GNRI can serve as an independent predictive factor for worse progression-free (HR, 2.85; 95% CI, 1.05–7.72; p = 0.039) and overall survival (HR, 2.98; 95% CI, 1.02–8.90; p = 0.045). In summary, nutritional evaluation plays a role in DLBCL treatment and the GNRI score can serve as a feasible predictive tool for clinical outcomes in frail elderly DLBCL patients treated with non-anthracycline-containing regimens.
Role of Helicobacter pylori and Other Environmental Factors in the Development of Gastric Dysbiosis
Authors: Gomez-Ramirez Uriel , Valencia-Mayoral Pedro , Mendoza-Elizalde Sandra , Murillo-Eliosa Juan Rafael , Solórzano Santos Fortino , Contreras-Rodríguez Araceli , Zúñiga Gerardo , Aguilar-Rodea Pamela , Jiménez-Rojas Verónica Leticia , Vigueras Galindo Juan Carlos , Salazar-García Marcela , Velázquez-Guadarrama Norma
Published: September 2021

Microbiomes are defined as complex microbial communities, which are mainly composed of bacteria, fungi, and viruses residing in diverse regions of the human body. The human stomach consists of a unique and heterogeneous habitat of microbial communities owing to its anatomical and functional characteristics, that allow the optimal growth of characteristic bacteria in this environment. Gastric dysbiosis, which is defined as compositional and functional alterations of the gastric microbiota, can be induced by multiple environmental factors, such as age, diet, multiple antibiotic therapies, proton pump inhibitor abuse, H. pylori status, among others. Although H. pylori colonization has been reported across the world, chronic H. pylori infection may lead to serious consequences; therefore, the infection must be treated. Multiple antibiotic therapy improvements are not always successful because of the lack of adherence to the prescribed antibiotic treatment. However, the abuse of eradication treatments can generate gastric dysbiotic states. Dysbiosis of the gastric microenvironment induces microbial resilience, due to the loss of relevant commensal bacteria and simultaneous colonization by other pathobiont bacteria, which can generate metabolic and physiological changes or even initiate and develop other gastric disorders by non-H. pylori bacteria. This systematic review opens a discussion on the effects of multiple environmental factors on gastric microbial communities.
Competing Bioaerosols May Influence the Seasonality of Influenza-Like Illnesses, including COVID-19. The Chicago Experience
Authors: Shah Richa B. , Shah Rachna D. , Retzinger Damien G. , Retzinger Andrew C. , Retzinger Deborah A. , Retzinger Gregory S.
Published: September 2021

Data from Chicago confirm the end of flu season coincides with the beginning of pollen season. More importantly, the end of flu season also coincides with onset of seasonal aerosolization of mold spores. Overall, the data suggest bioaerosols, especially mold spores, compete with viruses for a shared receptor, with the periodicity of influenza-like illnesses, including COVID-19, a consequence of seasonal factors that influence aerosolization of competing species.
Mediterranean Aquaculture in a Changing Climate: Temperature Effects on Pathogens and Diseases of Three Farmed Fish Species
Authors: Cascarano Maria Chiara , Stavrakidis-Zachou Orestis , Mladineo Ivona , Thompson Kim D. , Papandroulakis Nikos , Katharios Pantelis
Published: September 2021

Climate change is expected to have a drastic effect on aquaculture worldwide. As we move forward with the agenda to increase and diversify aquaculture production, rising temperatures will have a progressively relevant impact on fish farming, linked to a multitude of issues associated with fish welfare. Temperature affects the physiology of both fish and pathogens, and has the potential to lead to significant increases in disease outbreaks within aquaculture systems, resulting in severe financial impacts. Significant shifts in future temperature regimes are projected for the Mediterranean Sea. We therefore aim to review and discuss the existing knowledge relating to disease outbreaks in the context of climate change in Mediterranean finfish aquaculture. The objective is to describe the effects of temperature on the physiology of both fish and pathogens, and moreover to list and discuss the principal diseases of the three main fish species farmed in the Mediterranean, namely gilthead seabream (Sparus aurata), European seabass (Dicentrarchus labrax), and meagre (Argyrosomus regius). We will attempt to link the pathology of each disease to a specific temperature range, while discussing potential future disease threats associated with the available climate change trends for the Mediterranean Sea.
Cellular Organelles Involved in Hepatitis E Virus Infection
Authors: Liu Xing , Wang Menghang , Yin Xin
Published: September 2021

Hepatitis E virus (HEV), a major cause of acute hepatitis worldwide, infects approximately 20 million individuals annually. HEV can infect a wide range of mammalian and avian species, and cause frequent zoonotic spillover, increasingly raising public health concerns. To establish a successful infection, HEV needs to usurp host machineries to accomplish its life cycle from initial attachment to egress. However, relatively little is known about the HEV life cycle, especially the functional role(s) of cellular organelles and their associated proteins at different stages of HEV infection. Here, we summarize current knowledge regarding the relation of HEV with the different cell organelles during HEV infection. Furthermore, we discuss the underlying mechanisms by which HEV infection is precisely regulated in infected cells and the modification of host cell organelles and their associated proteins upon HEV infection.
The Antimicrobial and Antibiofilm In Vitro Activity of Liquid and Vapour Phases of Selected Essential Oils against Staphylococcus aureus
Authors: Brożyna Malwina , Paleczny Justyna , Kozłowska Weronika , Chodaczek Grzegorz , Dudek-Wicher Ruth , Felińczak Anna , Gołębiewska Joanna , Górniak Agata , Junka Adam
Published: September 2021

The high resistance of staphylococcal biofilm against antibiotics and developing resistance against antiseptics induces a search for novel antimicrobial compounds. Due to acknowledged and/or alleged antimicrobial activity of EOs, their application seems to be a promising direction to follow. Nevertheless, the high complexity of EOs composition and differences in laboratory protocols of the antimicrobial activity assessment hinders the exact estimation of EOs effectiveness. To overcome these disadvantages, in the present work we analysed the effectiveness of volatile and liquid forms of seven EOs (derived from thyme, tea tree, basil, rosemary, eucalyptus, lavender, and menthol mint) against 16 staphylococcal biofilm-forming strains using cohesive set of in vitro techniques, including gas chromatography–mass spectrometry, inverted Petri dish, modified disk-diffusion assay, microdilution techniques, antibiofilm dressing activity measurement, AntiBioVol protocol, fluorescence/confocal microscopy, and dynamic light scattering. Depending on the requirements of the technique, EOs were applied in emulsified or non-emulsified form. The obtained results revealed that application of different in vitro techniques allows us to get a comprehensive set of data and to gain insight into the analysed phenomena. In the course of our investigation, liquid and volatile fractions of thyme EO displayed the highest antibiofilm activity. Liquid fractions of rosemary oil were the second most active against S. aureus. Vapour phases of tea tree and lavender oils exhibited the weakest anti-staphylococcal activity. The size of emulsified droplets was the lowest for T-EO and the highest for L-EO. Bearing in mind the limitations of the in vitro study, results from presented analysis may be of pivotal meaning for the potential application of thymol as a antimicrobial agent used to fight against staphylococcal biofilm-based infections.
Evaluation of Inhibitory Activity In Silico of In-House Thiomorpholine Compounds between the ACE2 Receptor and S1 Subunit of SARS-CoV-2 Spike
Authors: Vázquez-Valadez Victor H. , Hernández-Serda Alejandro , Jiménez-Cabiedes Ma. Fernanda , Aguirre-Vidal Pablo , González-Tapia Ingrid , Carreño-Vargas Laura , Alarcón-López Yoshio A. , Espejel-Fuentes Andrea , Martínez-Soriano Pablo , Lugo Álvarez Miguel , Velázquez-Sánchez Ana María , Markarian Nathan Marko , Angeles Enrique , Abrahamyan Levon
Published: September 2021

At the end of 2019, the world was struck by the COVID-19 pandemic, which resulted in dire repercussions of unimaginable proportions. From the beginning, the international scientific community employed several strategies to tackle the spread of this disease. Most notably, these consisted of the development of a COVID-19 vaccine and the discovery of antiviral agents through the repositioning of already known drugs with methods such as de novo design. Previously, methylthiomorphic compounds, designed by our group as antihypertensive agents, have been shown to display an affinity with the ACE2 (angiotensin converting enzyme) receptor, a key mechanism required for SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) entry into target cells. Therefore, the objective of this work consists of evaluating, in silico, the inhibitory activity of these compounds between the ACE2 receptor and the S1 subunit of the SARS-CoV-2 spike protein. Supported by the advances of different research groups on the structure of the coronavirus spike and the interaction of the latter with its receptor, ACE2, we carried out a computational study that examined the effect of in-house designed compounds on the inhibition of said interaction. Our results indicate that the polyphenol LQM322 is one of the candidates that should be considered as a possible anti-COVID-19 agent.
Very High Fascioliasis Intensities in Schoolchildren from Nile Delta Governorates, Egypt: The Old World Highest Burdens Found in Lowlands
Authors: Periago M. Victoria , Valero M. Adela , Artigas Patricio , Agramunt Verónica H. , Bargues M. Dolores , Curtale Filippo , Mas-Coma Santiago
Published: September 2021

Quantitative coprological analyses of children were performed in Alexandria and Behera governorates, Egypt, to ascertain whether individual intensities in the Nile Delta lowlands reach high levels as those known in hyperendemic highland areas of Latin America. Analyses focused on subjects presenting intensities higher than 400 eggs per gram of faeces (epg), the high burden cut-off according to WHO classification. A total of 96 children were found to shed between 408 and 2304 epg, with arithmetic and geometric means of 699.5 and 629.07 epg, respectively. Intensities found are the highest hitherto recorded in Egypt, and also in the whole Old World. A total of 38 (39.6%) were males and 58 (60.4%) were females, with high intensities according to gender following a negative binomial distribution. The high burden distribution shows a peak in the 7–10 year-old children group, more precocious in females than males. Results showed high burdens in winter to be remarkably higher than those known in summer. The fascioliasis scenario in Egyptian lowlands shows similarities to highlands of Bolivia and Peru. Diagnostic methods, pathogenicity and morbidity in high burdens should be considered. The need for an appropriate quantitative assessment of heavy infected children to avoid post-treatment colic episodes is highlighted.
Development and Validation of Novel PCR Assays for the Diagnosis of Bovine Stephanofilariasis and Detection of Stephanofilaria sp. Nematodes in Vector Flies
Authors: Naseem Muhammad Noman , Raza Ali , Allavena Rachel , McGowan Michael , Morgan Jess A. T. , Constantinoiu Constantin , Tabor Ala E. , James Peter
Published: September 2021

Background: Stephanofilaria spp. nematodes are associated with cutaneous lesions in cattle and other livestock and mammalian wildlife species. In Australia, Haematobia irritans exigua, commonly known as buffalo fly (BF) transmits a well-described but presently unnamed species of Stephanofilaria, which has been speculatively implicated in the aetiology of BF lesions. The sensitivity of current techniques for detecting Stephanofilaria spp. in skin lesions and vector species is low, and there is no genomic sequence for any member of the genus Stephanofilaria currently available in sequence databases. Methods: To develop molecular assays for the detection of the Australian Stephanofilaria sp., skin biopsies were collected from freshly slaughtered cattle with typical lesions near the medial canthus. Adult nematodes and microfilariae were isolated from the biopsies using a saline recovery technique. The nematodes were morphologically identified as Stephanofilaria sp. by scanning electron microscopy. DNA was extracted and the internal transcribed spacer 2 (ITS2) region of rDNA, and the cytochrome c oxidase subunit 1 (cox1) region of mtDNA was amplified and sequenced. Stephanofilaria sp. specific polymerase chain reaction (PCR) and qPCR assays (SYBR Green® and TaqMan™) were developed and optimised from the novel ITS2 sequence obtained. The specificity of each assay was confirmed by testing against nematode species Onchocerca gibsoni and Dirofilaria immitis, as well as host (bovine) and BF DNA. Results: Scanning electron microscopy of the anterior and posterior ends of isolated nematodes confirmed Stephanofilaria sp. A phylogenetic analysis of the cox1 sequence demonstrated that this species is most closely related to Thelazia callipaeda, a parasitic nematode that is a common cause of thelaziasis (or eyeworm infestation) in humans, dogs, and cats. Both conventional and qPCR assays specifically amplified DNA from Stephanofilaria sp. Conventional PCR, TaqMan™, and SYBR Green® assays were shown to detect 1 ng, 1 pg, and 100 fg of Stephanofilaria DNA, respectively. Both qPCR assays detected DNA from single Stephanofilaria microfilaria. Conclusion: Molecular diagnostic assays developed in this study showed high specificity and sensitivity for Stephanofilaria sp. DNA. The availability of an accurate and sensitive PCR assay for Stephanofilaria will assist in determining its role in the pathogenesis of cattle skin lesions, as well as in understanding its epidemiological dynamics. This assay may also have application for use in epidemiological studies with other species of Stephanofilaria, most particularly closely related S. stilesi, but this will require confirmation.
Antidepressants in Alzheimer’s Disease: A Focus on the Role of Mirtazapine
Authors: Correia Ana Salomé , Vale Nuno
Published: September 2021

Mirtazapine belongs to the category of antidepressants clinically used mainly in major depressive disorder but also used in obsessive-compulsive disorders, generalized anxiety, and sleep disturbances. This drug acts mainly by antagonizing the adrenergic α2, and the serotonergic 5-HT2 and 5-HT3 receptors. Neuropsychiatric symptoms, such as depression and agitation, are strongly associated with Alzheimer’s disease, reducing the life quality of these patients. Thus, it is crucial to control depression in Alzheimer’s patients. For this purpose, drugs such as mirtazapine are important in the control of anxiety, agitation, and other depressive symptoms in these patients. Indeed, despite some contradictory studies, evidence supports the role of mirtazapine in this regard. In this review, we will focus on depression in Alzheimer’s disease, highlighting the role of mirtazapine in this context.
Pilot Sub-Study of the Effect of Hepatitis C Cure by Glecaprevir/Pibrentasvir on the Gut Microbiome of Patients with Chronic Hepatitis C Genotypes 1 to 6 in the Mythen Study
Authors: Yilmaz Bahtiyar , Ruckstuhl Lisa , Müllhaupt Beat , Magenta Lorenzo , Kuster Melanie Harrer , Clerc Olivier , Torgler Ralph , Semmo Nasser
Published: September 2021

In this small pilot sub-study, longitudinal gut microbiota composition changes, after successful treatment of hepatitis C virus (HCV) with the co-formulated glecaprevir/pibrentasvir (GLE/PIB), were analyzed before treatment (baseline) and 12 weeks post-treatment. Participating patients provided a fresh stool sample the week before their study visit, from which microbial DNA was extracted and sequenced for the 16S rRNA region in an Illumina MiSeq2 platform. Microbial and statistical analyses were conducted to determine the alpha-diversity (number of different taxa within a sample) and beta-diversity (number of overlapping taxa between samples). Stool samples from 58 patients were eligible for analysis. There were 27 patients with HCV genotype 1, 10 with genotype 2, 16 with genotype 3, and 5 with genotype 4. No statistically significant differences in gut microbiota diversity, species richness, or microbial community pattern were found at baseline and at post-treatment Week 12. Lack of statistically significant differences remained consistent in further analysis by demographic and baseline disease characteristics. Surprisingly, no statistically significant changes in alpha- and beta-diversity were seen in the microbiota after GLE/PIB treatment, though there was a trend toward less richness over time. Further investigation is needed into this unexpected outcome to better understand the role of HCV treatment and the gut microbiota.
Neuropsychiatric Disorders and COVID-19: What We Know So Far
Authors: Majolo Fernanda , Silva Guilherme Liberato da , Vieira Lucas , Anli Cetin , Timmers Luís Fernando Saraiva Macedo , Laufer Stefan , Goettert Márcia Inês
Published: September 2021

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more common in patients with severe infection according to their respiratory status and divided into three categories: (1) CNS manifestations; (2) cranial and peripheral nervous system manifestations; and (3) skeletal muscle injury manifestations. Patients with pre-existing cerebrovascular disease are at a higher risk of admission to the intensive care unit (ICU) and mortality. The neurological manifestations associated with COVID-19 are of great importance, but when life-threatening abnormal vital signs occur in severely ill COVID-19 patients, neurological problems are usually not considered. It is crucial to search for new treatments for brain damage, as well as for alternative therapies that recover the damaged brain and reduce the inflammatory response and its consequences for other organs. In addition, there is a need to diagnose these manifestations as early as possible to limit long-term consequences. Therefore, much research is needed to explain the involvement of SARS-CoV-2 causing these neurological symptoms because scientists know zero about it.
Manufacturing Bacteriophages (Part 1 of 2): Cell Line Development, Upstream, and Downstream Considerations
Authors: Tanir Tayfun , Orellana Marvin , Escalante Aster , Moraes de Souza Carolina , Koeris Michael S.
Published: September 2021

Within this first part of the two-part series on phage manufacturing, we will give an overview of the process leading to bacteriophages as a drug substance, before covering the formulation into a drug product in the second part. The principal goal is to provide the reader with a comprehensive framework of the challenges and opportunities that present themselves when developing manufacturing processes for bacteriophage-based products. We will examine cell line development for manufacture, upstream and downstream processes, while also covering the additional opportunities that engineered bacteriophages present.
The Metabolomic Approach Reveals the Alteration in Human Serum and Cerebrospinal Fluid Composition in Parkinson’s Disease Patients
Authors: Plewa Szymon , Poplawska-Domaszewicz Karolina , Florczak-Wyspianska Jolanta , Klupczynska-Gabryszak Agnieszka , Sokol Bartosz , Miltyk Wojciech , Jankowski Roman , Kozubski Wojciech , Kokot Zenon , Matysiak Jan
Published: September 2021

Parkinson’s disease (PD) is a major public health problem. Since currently there are no reliable diagnostic tools to reveal the early steps of PD, new methods should be developed, including those searching the variations in human metabolome. Alterations in human metabolites could help to establish an earlier and more accurate diagnosis. The presented research shows a targeted metabolomics study of both of the serum and CSF from PD patients, atypical parkinsonian disorders (APDs) patients, and the control. The use of the LC-MS/MS system enabled to quantitate 144 analytes in the serum and 51 in the CSF. This information about the concentration enabled for selection of the metabolites useful for differentiation between the studied group of patients, which should be further evaluated as candidates for markers of screening and differential diagnosis of PD and APDs. Among them, the four compounds observed to be altered in both the serum and CSF seem to be the most important: tyrosine, putrescine, trans-4-hydroxyproline, and total dimethylarginine. Furthermore, we indicated the metabolic pathways potentially related to neurodegeneration processes. Our studies present evidence that the proline metabolism might be related to neurodegeneration processes underlying PD and APDs. Further studies on the proposed metabolites and founded metabolic pathways may significantly contribute to understanding the molecular background of PD and improving the diagnostics and treatment in the future.
Mesenchymal Stromal Cells: Potential Option for COVID-19 Treatment
Authors: Primorac Dragan , Čemerin Martin , Matišić Vid , Molnar Vilim , Strbad Marko , Girandon Lenart , Zenić Lucija , Knežević Miomir , Minger Stephen , Polančec Denis
Published: September 2021

The COVID-19 pandemic has significantly impacted the way of life worldwide and continues to bring high mortality rates to at-risk groups. Patients who develop severe COVID-19 pneumonia, often complicated with ARDS, are left with limited treatment options with no targeted therapy currently available. One of the features of COVID-19 is an overaggressive immune reaction that leads to multiorgan failure. Mesenchymal stromal cell (MSC) treatment has been in development for various clinical indications for over a decade, with a safe side effect profile and promising results in preclinical and clinical trials. Therefore, the use of MSCs in COVID-19-induced respiratory failure and ARDS was a logical step in order to find a potential treatment option for the most severe patients. In this review, the main characteristics of MSCs, their proposed mechanism of action in COVID-19 treatment and the effect of this therapy in published case reports and clinical trials are discussed.
The GluN2B-Selective Antagonist Ro 25-6981 Is Effective against PTZ-Induced Seizures and Safe for Further Development in Infantile Rats
Authors: Mareš Pavel , Kozlová Lucie , Mikulecká Anna , Kubová Hana
Published: September 2021

The GluN2B subunit of NMDA receptors represents a perspective therapeutic target in various CNS pathologies, including epilepsy. Because of its predominant expression in the immature brain, selective GluN2B antagonists are expected to be more effective early in postnatal development. The aim of this study was to identify age-dependent differences in the anticonvulsant activity of the GluN2B-selective antagonist Ro 25-6981 and assess the safety of this drug for the developing brain. Anticonvulsant activity of Ro 25-6981 (1, 3, and 10 mg/kg) was tested in a pentylenetetrazol (PTZ) model in infantile (12-day-old, P12) and juvenile (25-day-old, P25) rats. Ro 25-6981 (1 or 3 mg/kg/day) was administered from P7 till P11 to assess safety for the developing brain. Animals were then tested repeatedly in a battery of behavioral tests focusing on sensorimotor development, cognition, and emotionality till adulthood. Effects of early exposure to Ro 25-6981 on later seizure susceptibility were tested in the PTZ model. Ro 25-6981 was effective against PTZ-induced seizures in infantile rats, specifically suppressing the tonic phase of the generalized tonic–clonic seizures, but it failed in juveniles. Neither sensorimotor development nor cognitive abilities and emotionality were affected by early-life exposure to Ro 25-6981. Treatment cessation did not affect later seizure susceptibility. Our data are in line with the maturational gradient of the GluN2B-subunit of NMDA receptors and demonstrate developmental differences in the anti-seizure activity of the GluN2B-selective antagonist and its safety for the developing brain.
Goals and Challenges of Stem Cell-Based Therapy for Corneal Blindness Due to Limbal Deficiency
Authors: Calonge Margarita , Nieto-Miguel Teresa , de la Mata Ana , Galindo Sara , Herreras José M. , López-Paniagua Marina
Published: September 2021

Corneal failure is a highly prevalent cause of blindness. One special cause of corneal failure occurs due to malfunction or destruction of the limbal stem cell niche, upon which the superficial cornea depends for homeostatic maintenance and wound healing. Failure of the limbal niche is referred to as limbal stem cell deficiency. As the corneal epithelial stem cell niche is easily accessible, limbal stem cell-based therapy and regenerative medicine applied to the ocular surface are among the most highly advanced forms of this novel approach to disease therapy. However, the challenges are still great, including the development of cell-based products and understanding how they work in the patient’s eye. Advances are being made at the molecular, cellular, and tissue levels to alter disease processes and to reduce or eliminate blindness. Efforts must be coordinated from the most basic research to the most clinically oriented projects so that cell-based therapies can become an integrated part of the therapeutic armamentarium to fight corneal blindness. We undoubtedly are progressing along the right path because cell-based therapy for eye diseases is one of the most successful examples of global regenerative medicine.
A New Validation Methodology for In Silico Tools Based on X-ray Computed Tomography Images of Tablets and a Performance Analysis of One Tool
Authors: Bollmann Sebastian , Kleinebudde Peter
Published: September 2021

In silico tools which predict the dissolution of pharmaceutical dosage forms using virtual matrices can be validated with virtual matrices based on X-ray micro-computed tomography images of real pharmaceutical formulations. Final processed images of 3 different tablet batches were used to check the performance of the in silico tool F-CAD. The goal of this work was to prove the performance of the software by comparing the predicted dissolution profiles to the experimental ones and to check the feasibility and application of the validation concept for in silico tools. Both virtual matrices based on X-ray micro-computed tomography images and designed by the software itself were used. The resulting dissolution curves were compared regarding their similarity to the experimental curve. The kinetics were analysed with the Higuchi and Korsmeyers–Peppas plot. The whole validation concept as such was feasible and worked well. It was possible to identify prediction errors of the software F-CAD and issues with the virtual tablets designed within the software.
Topical Triamcinolone Acetonide-Loaded Liposome Formulation Used as an Adjuvant to Intravitreal Ranibizumab Therapy for Neovascular Age-Related Macular Degeneration
Authors: Navarro-Partida Jose , Altamirano-Vallejo Juan Carlos , Aceves Franco Luis Abraham , Gonzalez-Cortes Jesús , Hernandez-Da Mota Sergio , García-Aguirre Jose Gerardo , Azuara-Galindo Carlos David , Castro-Castaneda Carlos Rodrigo , Armendariz-Borunda Juan , Santos Arturo
Published: September 2021

Novel strategies have been developed to reduce or avoid intravitreal injections (IVTs) of the antiangiogenic (ranibizumab (RBZ)) and anti-inflammatory (triamcinolone acetonide (TA)) agents used to treat vitreoretinal diseases. One of the strategies includes liposomes. This study evaluated the safety and efficacy of a topical triamcinolone-loaded liposome formulation (TALF) as an adjuvant to intravitreal RBZ therapy in treatment- naïve patients with neovascular age-related macular degeneration (nAMD). Subjects were randomly assigned to the RBZ-TALF or the RBZ-pro re nata (RBZ-PRN) groups. Patients from the RBZ-TALF group were instructed to apply TALF for 12 months after a single dose of RBZ. Patients from the RBZ-PRN group received three monthly RBZ-IVTs. Retreatment with RBZ was considered in the case of nAMD reactivation. Regarding safety, non-ocular abnormalities were observed during TALF therapy. Concerning efficacy, non-significant differences were identified in terms of visual acuity or central foveal thickness when the RBZ-PRN and RBZ-TALF groups were compared. It is worth noting that the average number of RBZ injections was significantly lower in the RBZ-TALF group (2.5 ± 1.4 vs. 6.1 ± 1.3 IVTs; p = 0.0004). Therefore, TALF used as an adjuvant to RBZ reduces the need for RBZ-IVT retreatment with optimal visual and anatomic results.
M1 Macrophage-Derived Exosomes Loaded with Gemcitabine and Deferasirox against Chemoresistant Pancreatic Cancer
Authors: Zhao Yongmei , Zheng Yuanlin , Zhu Yan , Zhang Yi , Zhu Hongyan , Liu Tianqing
Published: September 2021

Pancreatic cancer is a malignant disease with high mortality and poor prognosis due to lack of early diagnosis and low treatment efficiency after diagnosis. Although Gemcitabine (GEM) is used as the first-line chemotherapeutic drug, chemoresistance is still the major problem that limits its therapeutic efficacy. Here in this study, we developed a specific M1 macrophage-derived exosome (M1Exo)-based drug delivery system against GEM resistance in pancreatic cancer. In addition to GEM, Deferasirox (DFX) was also loaded into drug carrier, M1Exo, in order to inhibit ribonucleotide reductase regulatory subunit M2 (RRM2) expression via depleting iron, and thus increase chemosensitivity of GEM. The M1Exo nanoformulations combining both GEM and DFX significantly enhanced the therapeutic efficacy on the GEM-resistant PANC-1/GEM cells and 3D tumor spheroids by inhibiting cancer cell proliferation, cell attachment and migration, and chemoresistance to GEM. These data demonstrated that M1Exo loaded with GEM and DFX offered an efficient therapeutic strategy for drug-resistant pancreatic cancer.
Synthetic Antiferromagnetic Gold Nanoparticles as Bimodal Contrast Agents in MRI and CT—An Experimental In Vitro and In Vivo Study
Authors: D’Hollander Antoine , Van Roosbroeck Ruben , Trekker Jesse , Stakenborg Tim , Dresselaers Tom , Vande Velde Greetje , Struys Tom , Lambrichts Ivo , Lammertyn Jeroen , Lagae Liesbet , Himmelreich Uwe
Published: September 2021

The use of multimodal contrast agents can potentially overcome the intrinsic limitations of individual imaging methods. We have validated synthetic antiferromagnetic nanoparticles (SAF-NPs) as bimodal contrast agents for in vitro cell labeling and in vivo cell tracking using magnetic resonance imaging (MRI) and computed tomography (CT). SAF-NP-labeled cells showed high contrast in MRI phantom studies (r2* = 712 s−1 mM−1), while pelleted cells showed clear contrast enhancement in CT. After intravenous SAF-NP injection, nanoparticles accumulated in the liver and spleen, as visualized in vivo by significant MRI contrast enhancement. Intravenous injection of SAF-NP-labeled cells resulted in cell accumulation in the lungs, which was clearly detectable by using CT but not by using MRI. SAF-NPs proved to be very efficient cell labeling agents for complementary MRI- and CT-based cell tracking. Bimodal monitoring of SAF-NP labeled cells is in particular of interest for applications where the applied imaging methods are not able to visualize the particles and/or cells in all organs.
Microfluidic Technology for the Production of Hybrid Nanomedicines
Authors: Ottonelli Ilaria , Duskey Jason Thomas , Rinaldi Arianna , Grazioli Maria Vittoria , Parmeggiani Irene , Vandelli Maria Angela , Wang Leon Z. , Prud’homme Robert K. , Tosi Giovanni , Ruozi Barbara
Published: September 2021

Microfluidic technologies have recently been applied as innovative methods for the production of a variety of nanomedicines (NMeds), demonstrating their potential on a global scale. The capacity to precisely control variables, such as the flow rate ratio, temperature, total flow rate, etc., allows for greater tunability of the NMed systems that are more standardized and automated than the ones obtained by well-known benchtop protocols. However, it is a crucial aspect to be able to obtain NMeds with the same characteristics of the previously optimized ones. In this study, we focused on the transfer of a production protocol for hybrid NMeds (H-NMeds) consisting of PLGA, Cholesterol, and Pluronic® F68 from a benchtop nanoprecipitation method to a microfluidic device. For this aim, we modified parameters such as the flow rate ratio, the concentration of core materials in the organic phase, and the ratio between PLGA and Cholesterol in the feeding organic phase. Outputs analysed were the chemico–physical properties, such as size, PDI, and surface charge, the composition in terms of %Cholesterol and residual %Pluronic® F68, their stability to lyophilization, and the morphology via atomic force and electron microscopy. On the basis of the results, even if microfluidic technology is one of the unique procedures to obtain industrial production of NMeds, we demonstrated that the translation from a benchtop method to a microfluidic one is not a simple transfer of already established parameters, with several variables to be taken into account and to be optimized.
Effect of Lactic Acid Bacteria on the Pharmacokinetics and Metabolism of Ginsenosides in Mice
Authors: Jeon Ji-Hyeon , Lee Jaehyeok , Park Jin-Hyang , Lee Chul-Haeng , Choi Min-Koo , Song Im-Sook
Published: September 2021

This study aims to investigate the effect of lactic acid bacteria (LAB) on in vitro and in vivo metabolism and the pharmacokinetics of ginsenosides in mice. When the in vitro fermentation test of RGE with LAB was carried out, protopanaxadiol (PPD) and protopanaxadiol (PPD), which are final metabolites of ginsenosides but not contained in RGE, were greatly increased. Compound K (CK), ginsenoside Rh1 (GRh1), and GRg3 also increased by about 30%. Other ginsenosides with a sugar number of more than 2 showed a gradual decrease by fermentation with LAB for 7 days, suggesting the involvement of LAB in the deglycosylation of ginsenosides. Incubation of single ginsenoside with LAB produced GRg3, CK, and PPD with the highest formation rate and GRd, GRh2, and GF with the lower rate among PPD-type ginsenosides. Among PPT-type ginsenosides, GRh1 and PPT had the highest formation rate. The amoxicillin pretreatment (20 mg/kg/day, twice a day for 3 days) resulted in a significant decrease in the fecal recovery of CK, PPD, and PPT through the blockade of deglycosylation of ginsenosides after single oral administrations of RGE (2 g/kg) in mice. The plasma concentrations of CK, PPD, and PPT were not detectable without change in GRb1, GRb2, and GRc in this group. LAB supplementation (1 billion CFU/2 g/kg/day for 1 week) after the amoxicillin treatment in mice restored the ginsenoside metabolism and the plasma concentrations of ginsenosides to the control level. In conclusion, the alterations in the gut microbiota environment could change the ginsenoside metabolism and plasma concentrations of ginsenosides. Therefore, the supplementation of LAB with oral administrations of RGE would help increase plasma concentrations of deglycosylated ginsenosides such as CK, PPD, and PPT.
Development of a Compartmental Pharmacokinetic Model for Molecular Radiotherapy with 131I-CLR1404
Authors: Neira Sara , Gago-Arias Araceli , Gónzalez-Crespo Isabel , Guiu-Souto Jacobo , Pardo-Montero Juan
Published: September 2021

Pharmacokinetic modeling of the radiopharmaceuticals used in molecular radiotherapy is an important step towards accurate radiation dosimetry of such therapies. In this paper, we present a pharmacokinetic model for CLR1404, a phospholipid ether analog that, labeled with 124I/131I, has emerged as a promising theranostic agent. We follow a systematic approach for the model construction based on a decoupling process applied to previously published experimental data, and using the goodness-of-fit, Sobol’s sensitivity analysis, and the Akaike Information Criterion to construct the optimal form of the model, investigate potential simplifications, and study factor prioritization. This methodology was applied to previously published experimental human time-activity curves for 9 organs. The resulting model consists of 17 compartments involved in the CLR1404 metabolism. Activity dynamics in most tissues are well described by a blood contribution plus a two-compartment system, describing fast and slow uptakes. The model can fit both clinical and pre-clinical kinetic data of 124I/131I. In addition, we have investigated how simple fits (exponential and biexponential) differ from the complete model. Such fits, despite providing a less accurate description of time-activity curves, may be a viable alternative when limited data is available in a practical case.
Surface-Modified Multifunctional Thymol-Loaded Biodegradable Nanoparticles for Topical Acne Treatment
Authors: Folle Camila , Díaz-Garrido Natalia , Sánchez-López Elena , Marqués Ana Maria , Badia Josefa , Baldomà Laura , Espina Marta , Calpena Ana Cristina , García María Luisa
Published: September 2021

The present work is focused on the development of novel surface-functionalized poly(lactic-co-glycolic acid) nanoparticles loaded with thymol (TH-NPs) for topical administration enhancing thymol anti-inflammatory, antioxidant and wound healing activities against acne. TH-NPs were prepared by solvent evaporation method using different surface functionalization strategies and obtaining suitable physicochemical parameters and a good short-term stability at 4 °C. Moreover, TH-NPs skin penetration and antioxidant activity were assessed in ex vivo pig skin models. Skin penetration of TH-NPs followed the follicular route, independently of the surface charge and they were able to enhance antioxidant capacity. Furthermore, antimicrobial activity against Cutibacterium acnes was evaluated in vitro by the suspension test showing improved antibacterial performance. Using human keratinocyte cells (HaCat), cytotoxicity, cellular uptake, antioxidant, anti-inflammatory and wound healing activities were studied. TH-NPs were non-toxic and efficiently internalized inside the cells. In addition, TH-NPs displayed significant anti-inflammatory, antioxidant and wound healing activities, which were highly influenced by TH-NPs surface modifications. Moreover, a synergic activity between TH-NPs and their surface functionalization was demonstrated. To conclude, surface-modified TH-NPs had proven to be suitable to be used as anti-inflammatory, antioxidant and wound healing agents, constituting a promising therapy for treating acne infection and associated inflammation.
Detection of Small Moving Objects in Long Range Infrared Videos from a Change Detection Perspective
Authors: Kwan Chiman , Larkin Jude
Published: September 2021

Detection of small moving objects in long range infrared (IR) videos is challenging due to background clutter, air turbulence, and small target size. In this paper, we present two unsupervised, modular, and flexible frameworks to detect small moving targets. The key idea was inspired by change detection (CD) algorithms where frame differences can help detect motions. Our frameworks consist of change detection, small target detection, and some post-processing algorithms such as image denoising and dilation. Extensive experiments using actual long range mid-wave infrared (MWIR) videos with target distances beyond 3500 m from the camera demonstrated that one approach, using Local Intensity Gradient (LIG) only once in the workflow, performed better than the other, which used LIG in two places, in a 3500 m video, but slightly worse in 4000 m and 5000 m videos. Moreover, we also investigated the use of synthetic bands for target detection and observed promising results for 4000 m and 5000 m videos. Finally, a comparative study with two conventional methods demonstrated that our proposed scheme has comparable performance.
Substrate Cleaning Threshold for Various Coated Al Alloys Using a Continuous-Wave Laser
Authors: Sun Xudong , Yu Qiansong , Bai Xiaoyu , Jin Guangyong , Cai Jixing , Yuan Boshi
Published: September 2021

In this study, different coatings (gray epoxy primer, white epoxy varnish and red alkyd paint) of 7075 aluminum alloy are cleaned with a 500 W continuous-wave (CW) fiber laser. We analyzed the influence of the laser power density on the temperature evolution and target surface morphology. Under the condition of continuous laser irradiation for 1 s, the experimental results indicated that the suitable cleaning thresholds of epoxy primer, epoxy primer and epoxy varnish, as well as epoxy primer, epoxy varnish and alkyd paint were 177.74, 192.89 and 147.44 W/mm2. The results show that the cleaning threshold of thicker three-layer paint target was smaller than the single-layer paint layer, and we analyze the mechanism of this phenomenon.
Passive Athermal Optical Design Method Considering Thermal-Induced Surface Deformation
Authors: Liu Tao , Wang Chong , Yu Yi , Liu Zhenyu , He Fengyun
Published: September 2021

Temperature variation not only results in changes in refractive index, radius, thickness, and air space, but also leads to surface deformation due to the mismatch in thermal expansion coefficients between glass and mechanical materials. However, existing passive athermal optical design methods cannot optimize thermal-induced surface deformation, and optimization methods usually focus on structural optimization or thermal control rather than optical optimization. Here, we investigate the deterioration in image quality caused by thermal-induced surface deformation and propose a passive athermal optical design method to reduce deterioration. To this end, MATLAB was utilized to jointly call finite element analysis (FEA) software (COMSOL) and optical design software (Code V) to realize the data exchange of an optical–mechanical–thermal integrated analysis for iterative optical optimization. This process makes automatic iterative optimization possible by transforming parametric FEA results into Zernike coefficients in each iteration of optimization. The theoretical and design examples indicate that our method can effectively reduce the degradation in image quality with surface deformation. Our method provides an optical optimization approach for optical designers to work on a passive athermal optical design by considering thermal-induced surface deformation.
A Novel Time Delay Estimation and Calibration Method of TI-ADC Based on a Coherent Optical Communication System
Authors: Zhao Yongjie , Li Sida , Li Longqing , Huang Zhiping
Published: September 2021

In optical communication systems, coherent detection is a standard method. The received signal enters the digital domain after passing through a time-interleaved analog-to-digital converter (TI-ADC). However, the time delay of the ADC brings noise into the signal, which decreases the signal quality; therefore, ADC calibration is essential. At present, there are many calibration methods for time delay, but their performances are not satisfactory at a high sampling frequency. This paper presents a method of time delay estimation and calibration in a coherent optical communication system. First, the expected maximum (EM) method is used to roughly estimate the time delay and then transfer the estimated value into the trained back propagation (BP) neural network to generate more accurate results. Second, the sampled signal is reconstructed, and then a finite impulse response (FIR) filter is designed to compensate for the time delay. There are several advantages of the proposed method compared with previous works: the convergence with a BP network is faster, the estimation accuracy is higher, and the calibration does not affect the sample operation of the ADC working in the background mode. In addition, the proposed calibration method does not need additional circuits and its low power consumption provides more sources for dispersion compensation, error correction, and other subsequent operations in the coherent optical communication system. Based on the quadrature phase shift keying (QPSK) system, the proposed method was implemented in a 16-channel/8-bit, 40-GS/s ADC. After estimation and calibration, the relative error of estimation was below 1%, the signal noise distortion rate (SNDR) reached 55.9 dB, the spurious free dynamic range (SFDR) improved to 61.2 dB, and the effective number of bits (ENOB) was 6.7 bits. The results demonstrate that the proposed method has a better calibration performance than other methods.
Hydrogen Sulfide Enhances Plant Tolerance to Waterlogging Stress
Authors: Li Yaoqi , Sun Da , Xu Ke , Jin Libo , Peng Renyi
Published: September 2021

Hydrogen sulfide (H2S) is considered the third gas signal molecule in recent years. A large number of studies have shown that H2S not only played an important role in animals but also participated in the regulation of plant growth and development and responses to various environmental stresses. Waterlogging, as a kind of abiotic stress, poses a serious threat to land-based waterlogging-sensitive plants, and which H2S plays an indispensable role in response to. In this review, we summarized that H2S improves resistance to waterlogging stress by affecting lateral root development, photosynthetic efficiency, and cell fates. Here, we reviewed the roles of H2S in plant resistance to waterlogging stress, focusing on the mechanism of its promotion to gained hypoxia tolerance. Finally, we raised relevant issues that needed to be addressed.