High Safety Margin Research Articles

Antibacterial, Antifungal, and Anticancer Effects of Camel Milk Exosomes: An In Vitro Study

Camel milk (CM) has potent antibacterial and antifungal effects and camel milk exosomes (CM-EXO) have been shown to inhibit the proliferation of a large variety of cancer cells including HepaRG, MCF7, Hl60, and PANC1. However, little is known regarding the effects of CM-EXO on bacteria, fungi, HepG2, CaCo2, and Vero cells. Therefore, this study aimed to evaluate the antibacterial, antifungal, and anticancer effects of CM-EXO. EXOs were isolated from CM by ultracentrifugation and characterized by transmission electron microscope and flow cytometry. Unlike CM, CM-EXO (6 mg/mL) had no bactericidal effects on Gram-positive bacteria (Staphylococcus aureus, Micrococcus luteus, and Enterococcus feacalis) but they had bacteriostatic effects, especially against Gram-negative strains (Escherichia coli, Pseudomonas aeruginosa, and Proteus mirabilis), and fungistatic effects on Candida albicans. HepG2, CaCo2, and Vero cells were respectively treated with CM-EXOs at low (6.17, 3.60, 75.35 μg/mL), moderate (12.34, 7.20, 150.70 μg/mL), and high (24.68, 14.40, 301.40 μg/mL) doses and the results revealed that CM-EXOs triggered apoptosis in HepG2 and CaCo2 cells, but not in normal Vero cells, as revealed by high Bax expression and caspase 3 activities and lower expression of Bcl2. Interestingly, CM-EXOs also induced the elevation of intracellular reactive oxygen species and downregulated the expression of antioxidant-related genes (NrF2 and HO-1) in cancer cells but not in normal cells. CM-EXOs have antibacterial and antifungal effects as well as a selective anticancer effect against HepG2 and CaCo2 cells with a higher safety margin on normal cells.

ОСНОВНЫЕ ПРОБЛЕМЫ МОРСКОГО ЛОГИСТИЧЕСКОГО БИЗНЕСА РФ И ОБЗОР ДОСТУПНЫХ РЕШЕНИЙ

The authors study the problems of the maritime logistics business in Russia in the context of sanctions restrictions on the import of many types of products, on the entry of ships under the Russian flag into international ports, etc. Based on the results of the study, the main barriers hindering the development of Russia’s maritime logistics business were identified, namely: reorientation from Western markets to the markets of the Asia-Pacific region; low availability of ships and sea containers; infrastructural constraints, staffing constraints. In addition, the authors propose directions for the development of the logistics business, which would partially or completely neutralize the impact of sanctions and economic restrictions. The authors analyzed Russia’s plans for the development of shipbuilding and maritime logistics infrastructure. It was noted that these plans are quite ambitious, and in the long term will strengthen Russia’s place in international trade. Summing up, the authors conclude that at the moment the Russian maritime transportation industry is in a rather vulnerable position for a number of reasons, which can be aggregated into one: the Russian maritime logistics business was not fully prepared for the sanctions pressure from Western countries. Nevertheless, there is no critical situation, and there has been no bankruptcy of large operators, which indicates a high margin of safety for Russian companies. However, a more sustainable situation requires significant investment in infrastructure, shipbuilding and container production, as well as diversification of markets and import destinations. Scientific publications of Russian and foreign authors, articles in industry journals, as well as customs data were used as a source of information.

Assessment of hypolipidemic and anti-inflammatory properties of walnut (Juglans regia) seed coat extract and modulates some metabolic enzymes activity in triton WR-1339-induced hyperlipidemia in rat kidney, liver, and heart.

Atherosclerosis and cognitive impairment are both influenced by hyperlipidemia. Due to their high margin of safety and low cost, natural chemicals have recently attracted particular attention in the context of the treatment of disease. Hence, the purpose of this study was to investigate the possible amendatory impact of ethanol extract walnut (Juglans regia) seed coat (E-WSC) on some metabolic enzymes (glutathione reductase (GR), paraoxonase-1 (PON1), aldose reductase (AR), sorbitol dehydrogenase (SDH), acetylcholinesterase (AChE), glutathione S-transferase (GST), and butyrylcholinesterase (BChE)) activity in the liver, kidney, and heart of rats with Triton WR-1339-induced hyperlipidemia. Rats were divided into five groups: control group, HL-Control group (Triton WR-1339 400 mg/kg, i.p administered group), E- WSC + 150 (150 mg/kg,o.d given group), E- WSC + 300 (E- WSC 300 mg/kg, o.d given group) and HL+ E-WSC + 300 (Group receiving E- WSC 300 mg/kg, o.d 30 min prior to administration of Triton WR-1339 400 mg/kg, i.p). In HL-Control, AR, SDH, and BChE enzyme activity was significantly increased in all tissues compared to the control, while the activity of other studied enzymes was significantly decreased. The effects of hyperlipidemia on balance were improved and alterations in the activity of the investigated metabolic enzymes were prevented by E-WSC. As a result, promising natural compounds that can be used as adjuvant therapy in the treatment of cognitive disorders and hyperlipidemia may be found in E-WSC powder.

Molecular Tweezers: Supramolecular Hosts with Broad-Spectrum Biological Applications.

Lysine-selective molecular tweezers (MTs) are supramolecular host molecules displaying a remarkably broad spectrum of biologic activities. MTs act as inhibitors of the self-assembly and toxicity of amyloidogenic proteins using a unique mechanism. They destroy viral membranes and inhibit infection by enveloped viruses, such as HIV-1 and SARS-CoV-2, by mechanisms unrelated to their action on protein self-assembly. They also disrupt biofilm of Gram-positive bacteria. The efficacy and safety of MTs have been demonstrated in vitro, in cell culture, and in vivo, suggesting that these versatile compounds are attractive therapeutic candidates for various diseases, infections, and injuries. A lead compound called CLR01 has been shown to inhibit the aggregation of various amyloidogenic proteins, facilitate their clearance in vivo, prevent infection by multiple viruses, display potent anti-biofilm activity, and have a high safety margin in animal models. The inhibitory effect of CLR01 against amyloidogenic proteins is highly specific to abnormal self-assembly of amyloidogenic proteins with no disruption of normal mammalian biologic processes at the doses needed for inhibition. Therapeutic effects of CLR01 have been demonstrated in animal models of proteinopathies, lysosomal-storage diseases, and spinal-cord injury. Here we review the activity and mechanisms of action of these intriguing compounds and discuss future research directions. SIGNIFICANCE STATEMENT: Molecular tweezers are supramolecular host molecules with broad biological applications, including inhibition of abnormal protein aggregation, facilitation of lysosomal clearance of toxic aggregates, disruption of viral membranes, and interference of biofilm formation by Gram-positive bacteria. This review discusses the molecular and cellular mechanisms of action of the molecular tweezers, including the discovery of distinct mechanisms acting in vitro and in vivo, and the application of these compounds in multiple preclinical disease models.

The Fundamental Concepts of High SMAS Facelift: Literature Review

A number of facelift procedures have been introduced by many surgeons but there is no consensus has yet been established to carry. Since the first description of superficial musculoaponeurotic system (SMAS), it is used as the basis for many facelift methods that produce superior result in rejuvenation compared to traditional skin only facelift. Extended SMAS facelift becoming SMAS modification techniques that is still being developed. It produces two different vector of subcutaneous and SMAS flap, that is essential to restore drooping deep facial tissue with natural appearance. Despite the beneficial use of extended SMAS flap, most of plastic surgeons still traditionally incise the SMAS under the zygomatic arch. However, the low SMAS incision results only on rejuvenation of the lower face and is not sufficient to correct mid-facial aging. Fundamental concepts of high SMAS facelift by reviewing some literatures explain that high SMAS flap transection allowing the surgeon to achieve greater vertical elevation of the deep structures of the face by undermining the middle face, combined with fixation to a fixed structure produces lasting results and oblique vector of skin envelope creating no tension look. Incision above zygomatic arch turns out to be safely performed without facial nerve injury thorough knowledge of the anatomy. The final result is a balanced and harmonious elevation of sagging tissues of the midface, cheek, and jawline, to such an extent that high SMAS facelift becomes optimal, durable, technically simple, reproducible and with a comparatively high safety margin in facelift procedures.

Techno-economic evaluation of obtaining valuable rare sugars from thermo-mechanical pulping side streams utilizing the latest technology

The current work describes a process for converting hemicellulose-rich industrial side streams to specialty sugars utilizing green technology and commercially available acidic heterogeneous catalysts. Focus is placed on the detailed overall process design and techno-economic assessment of integrating the concept into an existing thermo-mechanical pulping plant, namely the Hallsta Paper Mill, located near Hallstavik in Sweden. The techno-economic analysis is based on laboratory relevant results for the process under study including catalyst performance and kinetics as well as extensive operational and economic data on cost formation. A detailed sensitivity analysis was also performed to evaluate the performance of concept in a changing economic environment. The results show that the process would be highly profitable in the studied case with a rather high safety margin. The process is widely applicable to other biorefinery concepts with hemicellulose containing side streams and the presented techno-economic analysis is very relevant for the evaluation of site-specific viability.

Ecological compensation of stochastic wetland biodiversity: National or regional policy schemes?

The aim of this study is to compare policy schemes for ecological compensation applied at national and regional levels, using exploited inland wetlands as an example. We study whether uncertainty, due to natural variability and measurement difficulties, motivates compensation that is carried out in the same region as that of the exploited site, or whether it rather motivates nationwide compensation schemes. For this purpose, we develop an empirical, chance-constrained programming model of cost-effective wetland management. The model is spatially differentiated and accounts for heterogeneity in wetland quality across wetland types and regions. Wetland quality is defined by three alternative biodiversity indices: species richness, population-weighted species richness, and red-listed species richness, estimated from voluntarily reported data on breeding bird species observations. Results show that regional schemes are more expensive, in particular if the policy maker dislikes uncertainty and wants to prioritize uncommon species. Contrary to expectations from the theoretical analysis, regional schemes would lead to a higher risk-adjusted level of biodiversity at the national level. However, regionalization also implies that targets cannot be achieved if a high safety margin is imposed. Trading ratios are robust to the choice of wetland quality index.

Understanding the Antilymphoma Activity of Annona macroprophyllata Donn and Its Acyclic Terpenoids: In Vivo, In Vitro, and In Silico Studies.

Annona macroprophyllata Donn (A. macroprophyllata) is used in traditional Mexican medicine for the treatment of cancer, diabetes, inflammation, and pain. In this work, we evaluated the antitumor activity of three acyclic terpenoids obtained from A. macroprophyllata to assess their potential as antilymphoma agents. We identified the terpenoids farnesyl acetate (FA), phytol (PT) and geranylgeraniol (Gg) using gas chromatography–mass spectroscopy (GC-MS) and spectroscopic (1H, and 13C NMR) methods applied to petroleum ether extract of leaves from A. macroprophyllata (PEAm). We investigated antitumor potential in Balb/c mice inoculated with U-937 cells by assessing brine shrimp lethality (BSL), and cytotoxic activity in these cells. In addition, to assess the potential toxicity of PEAm, FA, PT and Gg in humans, we tested their acute oral toxicity in mice. Our results showed that the three terpenoids exhibited considerable antilymphoma and cytotoxic activity. In terms of lethality, we determined a median lethal dose (LD50) for thirteen isolated products of PEAm. Gg, PT and AF all exhibited a higher lethality with values of 1.41 ± 0.42, 3.03 ± 0.33 and 5.82 ± 0.58 µg mL−1, respectively. To assess cytotoxic activity against U-937 cells, we calculated the mean cytotoxic concentration (CC50) and found that FA and PT were closer in respect to the control drug methotrexate (MTX, 0.243 ± 0.007 µM). In terms of antilymphoma activity, we found that FA, PT and Gg considerably inhibited lymph node growth, with median effective doses (ED50) of 5.89 ± 0.39, 6.71 ± 0.31 and 7.22 ± 0.51 mg kg−1 in females and 5.09 ± 0.66, 5.83 ± 0.50 and 6.98 ± 0.57mg kg −1 in males, respectively. Regarding acute oral toxicity, we classified all three terpenoids as category IV, indicating a high safety margin for human administration. Finally, in a molecular docking study of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, we found binding of terpenoids to some amino acids of the catalytic site, suggesting an effect upon activity with a resulting decrease in the synthesis of intermediates involved in the prenylation of proteins involved in cancer progression. Our findings suggest that the acyclic terpenoids FA, PT, and Gg may serve as scaffolds for the development of new treatments for non-Hodgkin’s lymphoma.

The in vitro anti-inflammatory activity of N-antipyrine-3,4-dichloromaleimide derivatives is due to an immunomodulatory effect on cytokines environment

Background and aim Inflammation is the immune response to a harmful stimulus, and its purpose is to destroy foreign agents so that the affected site can be repair. When uncontrolled or unresolved, inflammation can lead to significant tissue damage. Many classes of compounds are used today as anti-inflammatory drugs. However, there is an ongoing demand for new, more effective molecules with higher safety margins. In this regard, the anti-inflammatory effect of six synthetic compounds of N-antipyrine-3,4-dichloromaleimide was evaluated. Methods RAW 264.7 cells were used to evaluate the cytotoxicity and the anti-inflammatory activity, by measuring the effect of these molecules on nitric oxide, IL-1β, IL-6, MCP-1 (CCL2), TNF-α, INF-γ, IL-4, and IL-13 levels, as well as under NF-κB activation. Results Some of the tested compounds showed significant cytotoxicity (CC50 < 100 µM). Subsequently, the potential of nitric oxide (NO) inhibition as screening for potential anti-inflammatory action was evaluated. Three of the compounds tested showed a promising profile (1, 3, and 5). When the effect of these compounds was evaluated on the production of IL-1β, IL-6, MCP-1 (CCL2), TNF-α, and INF-γ, only N-antipyrine-3,4-dichloromaleimide (1) and N-antipyrine-3-chloro-4-(3,4-dichloroaniline) maleimide (3) showed significant inhibition profiles. These two compounds were also able to increase the production of cytokines known for having an anti-inflammatory profile (IL-4 and IL-13) and inhibit the phosphorylation of the p-p65 NF-κB subunit significantly. Conclusion In conclusion, these two compounds present a significant and unusual anti-inflammatory mechanism (increasing the production of anti-inflammatory mediators). They are therefore considered promising prototypes for the development of new anti-inflammatory drugs with immunomodulatory characteristics.

Flexible Loading Pattern Approach in Overkill Steam Sterilization Based on the Physical Properties of Steam and Thermodynamics of Sterilization.

Because overkill steam sterilization processes in autoclaves are considered critical, they are highly scrutinized, and the use of autoclaves in fixed loading patterns is a common approach to the interpretation of regulatory requirements. Many such regulations are attributed to tradition and a buildup of restrictions that aim to improve the levels of assurance of the process and minimize risk. However, these measures complicate the operation and qualification of autoclaves, becoming cumbersome, time-consuming, and costly. In actuality, overkill sterilization is one of several processes in the pharmaceutical industry that provides the highest levels of sterility assurance. This method provides a minimum reduction of highly durable spore populations of 12 logs, achieving a probability of a nonsterile unit (PNSU) of 10-6 Because these spores are far sturdier than the common microorganisms that can be found in pharmaceutical facilities, overkill sterilization effects significantly lower PNSU values for the latter. The physical properties of steam and the thermodynamics of steam sterilization constitute a predictable and repeatable process that can be monitored and verified. The high assurance level of overkill sterilization, combined with the properties of steam, actualizes a high safety margin that encompasses nearly every load type and load configuration when the cycle is performed under certain basic rules. The aim of this article is to present data that advocate and favor an approach that allows greater freedom and variability in arranging items in an autoclave when running overkill cycles, without the need to qualify each configuration.

Oral acute toxicity study on stem bark extracts of Bombax costatum Pellegr. and Vuillet on wistar albino rats

BackgroundAcute toxicity (LD50) test provides an indication on the range of doses of a substance that could be toxic to the body systems. This study was aimed at determining the LD50 of different extracts of Bombax costatum stem bark and its effects on the histology of liver and kidneys in rats.ResultsPhytochemical screening of n-hexane, ethanol and chloroform extracts of B. costatum stem bark has revealed the presence of alkaloids, flavonoid, saponins, steroid, terpenes, anthraquinones and cardiac glycosides. No mortality was recorded after testing all the different extracts on rats. However, mild body weaknesses and pilo erection were observed in the first hour of extracts’ administration. No statistically significant differences was observed in most of the serum levels of kidney function biomarkers, although a significant decrease (p < 0.05) in bicarbonate and increase (p < 0.05) in urea, respectively, were observed in chloroform extract treated group when compared to control. Further, no marked differences (p > 0.05) were observed in hematological parameters as well as in the liver functions biomarkers in all the 3 extract exposed groups when compared to the control, except significant decrease (p < 0.05) of total bilirubin level in chloroform extract exposed rats. Finally, histological sections of the liver and kidneys showed no aberrations.ConclusionsSince no mortality and serious clinical manifestation were recorded, it is suggestive that oral acute administration of n-hexane, chloroform and ethanol extracts of B. costatum is greater than 5000 mg/kg. Hence, the plant has high safety margin and can be used within the dose of 5000 mg/kg body weight.

Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation.

A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.

Safety evaluation of aqueous extract from Eugenia uniflora leaves: Acute and subacute toxicity and genotoxicity in vivo assays

Ethnopharmacological relevanceEugenia uniflora Linn (Myrtaceae) is the native species of Brazil. The leaves of this species are used in folk medicine to treat different inflammatory and gastrointestinal disorders. However, research on the safety of using E. uniflora leaves has been poorly explored. Aim of the studyThis approach aims to investigate the phytochemical composition as well as the acute, subacute toxicity, and in vivo genotoxic profile of the aqueous extract of E. uniflora leaves. Materials and methodsThe chemical composition of E. uniflora leaf extract was determined by Fingerprint by High-Performance Thin Layer and High-Performance Liquid Chromatography. The acute toxicity in vivo was evaluated for 14 days after the administration of E. uniflora leaves extract (2000 mg/kg). For the evaluation of subacute toxicity, mice were daily treated for 28 days with E. uniflora extract (250, 500, or 1000 mg/kg). Signs of behavioral toxicity and biochemical and hematological alterations, including the multiple organ toxicities were investigated. In addition, the micronucleus assay was used to evaluate the in vivo genotoxicity of the leaves extract in murine erythrocytes. ResultsThe phytochemical analysis showed the majority presence of phenolic compounds (gallic acid, ellagic acid, and myricitrin). Single or repeated doses of the aqueous extract of E. uniflora leaves did not reveal any signs of in vivo toxicity. Daily doses of the extract for 28 days induced a slight reduction in cholesterol and triglyceride levels. Furthermore, E. uniflora leaves extract (1000–2000 mg/kg) showed no genetic damage in the micronucleus assay, indicating the absence of genotoxicity of the herbal species. ConclusionThe aqueous extract of E. uniflora leaves showed a predominance of phenolic compounds, with non-toxic and non-genotoxic action in vivo. This approach sheds light on the chemical composition of the leaves of E. uniflora and suggests a high margin of safety in the popular use of the leaves of this plant species.

Emblica officinalis medicinal plants

The herbal medicine is in the great demand in the developed as well as developing countries for primary health care because of their large biological activities, higher safety margin and lesser cost. one of the common traditional herbal drugs is Emblica officinalis, commonly known as Amla, is a member of a small genus Emblica (Euphorbiaceae). The earlier study has demonstrated potent anti-microbial, adaptogenic, hepatoprotective, anti-tumour and anti-ulcerogenic activities in the fruits of Emblica officinalis. Leaf extracts have been shown to possess anti-inflammatory activity. vitamin C, tannins and flavonoids present in amla have very powerful antioxidant activity. Due to rich in vitamin C amla is successfully use in the treatment of human scurvy. The extracts from various parts of E. officinalis, especially fruit, contain numerous phytoconstituents viz. higher amount of polyphenols like gallic acid, ellagic acid, different tannins, minerals, vitamins, amino acids, fixed oils, and flavonoids like rutin and quercetin. The extract or plant is identified to be efficacious against diversified ailments like inflammation, cancer, osteoporosis, neurological disorders, hypertension together with lifestyle diseases, parasitic and other infectious disorders.

Predictiveness of the Human-CYP3A4-Transgenic Mouse Model (Cyp3aXAV) for Human Drug Exposure of CYP3A4-Metabolized Drugs.

The extrapolation of drug exposure between species remains a challenging step in drug development, contributing to the low success rate of drug approval. As a consequence, extrapolation of toxicology from animal models to humans to evaluate safe, first-in-human (FIH) doses requires high safety margins. We hypothesized that a human-CYP3A4-expressing transgenic (Cyp3aXAV) mouse is a more predictive model for human drug exposure of CYP3A4-metabolized small-molecule drugs. Population pharmacokinetic models based on wild-type (WT) and Cyp3aXAV mouse pharmacokinetic data of oral lorlatinib, brigatinib, ribociclib and fisogatinib were allometrically scaled and compared to human exposure. Extrapolation of the Cyp3aXAV mouse model closely predicted the observed human exposure for lorlatinib and brigatinib with a 1.1-fold and 1.0-fold difference, respectively, compared to a 2.1-fold and 1.9-fold deviation for WT-based extrapolations of lorlatinib and brigatinib, respectively. For ribociclib, the extrapolated WT mouse model gave better predictions with a 1.0-fold deviation compared to a 0.3-fold deviation for the extrapolated Cyp3aXAV mouse model. Due to the lack of a human population pharmacokinetic model for fisogatinib, only median maximum concentration ratios were calculated, resulting in ratios of 1.0 and 0.6 for WT and Cyp3aXAV mice extrapolations, respectively. The more accurate predictions of human exposure in preclinical research based on the Cyp3aXAV mouse model can ultimately result in FIH doses associated with improved safety and efficacy and in higher success rates in drug development.

The anti-COVID-19 drug Favipiravir: Degradation, Method development, Validation, NMR/LC–MS characterization, and In-vitro safety evaluation

It is critical to characterize the degradation products of therapeutic drugs to determine their safety as these degradation products may possess fatal effects on the human physiological system. Favipiravir (FVP), a novel anti-Covid-19 drug, that is recently used all over the world with a great impact on humanity was our target to explore more about its toxicity, the margins of its safety, and its degradants in different degradation conditions. The goal of this study is to identify, characterize, and confirm the structures of FVP oxidative and alkaline breakdown products, as well as to assess their safety utilizing in-vitro SRB cytotoxicity assay on normal human skin fibroblasts (NHSF) cell lines. After oxidative and alkaline degradation of FVP, one degradation product was produced in each condition which was isolated from FVP using flash chromatography, characterized by 1HNMR and LC–MS/MS techniques. A reversed-phase Thermo Fischer Hypersil C18 column (4.6 × 150 mm, 5 m) was used to achieve HPLC chromatographic separation. Acetonitrile-5 mM potassium dihydrogen phosphate (pH 2.5) (50:50, v/v) was employed as the mobile phase, with a flow rate of 1 mL/min. At 332 nm, the column effluent was measured. Over the concentration range of 0.5–100 µg/mL, the calibration curve was linear. The intra-day and inter-day relative standard deviations were less than 2%, and good percentage recoveries were obtained that fulfilled the acceptance criteria of the International Conference on Harmonization (ICH) recommendations. The Plackett–Burman design was used to assess the robustness. Each degradant was isolated single using Flash chromatography and methylene chloride: methanol gradient mobile phase. The chemical structures of the degradation products have been confirmed and compared to the intact FVP using 1H-NMR, and Mass spectroscopy. A postulated mechanism of the degradation process has been depicted and the degradants fragmentation pattern has been portrayed. In addition, the in vitro SRB cytotoxicity assay to evaluate the safety profile of FVP and the degradation end products showed their high safety margin in both conditions with IC50 ˃100 µg/ml with no signs of toxicity upon examination of the treated NHSF cells under the optical microscope

Dexmedetomidine:” Role in Pediatric Dentistry

A number of sedative agents have been in use in pediatric dentistry to gain a child’s cooperation with dental treatment. Dexmedetomidine is one such agent that was introduced as a sedative in the dental practice in 2005 due to a more stable respiratory drive and higher success rates in allowing pediatric dentists to carry out non-painful dental examinations and procedures compared to other sedatives such as chloral hydrate and midazolam. The most distinguishing feature of this sedative is its ability to produce a form of sedation that mimics natural sleep. The high safety margin of dexmedetomidine and its satisfactory sedative action makes it important for us to review its potential applications in pediatric dentistry.

Experimental Study on UHPC-Based Grouting Materials and Mechanical Performance of Grouted Splice Sleeve Joints

The prefabricated concrete structure is regarded as the main body of the green construction technology, while the joint connection of the prefabricated components is the weak link of force. In addition, the grouting sleeve connection is a widely used connection method in the prefabricated component joints. The effective anchorage of reinforcement is realized by the implementation of a mechanical bite force, friction force and bonding force between reinforcement, grouting material and sleeve inner wall, respectively. Along these lines, in this work, a UHPC-based grouting material was prepared, and its main technical performance was tested. The influence of the grouting mix proportion and anchorage length on the stress performance was thoroughly investigated by carrying out a unidirectional tension test of eight grout-filled splice sleeves. The acquired results show that UHPC grouting containing micro and particles possess high mechanical strength and durability. The incorporation of UHPC grouting containing steel fibers can further improve the compressive and flexural strength. However, its fluidity will be reduced and grouting difficulties will be induced. For that reason, the utilization of UHPC-based grouting material without steel fibers is recommended. The grout-filled splice sleeve joints with UHPC meet also the strength requirements, and the sleeve can be found in the elastic stage in the test, indicating that sleeve joints possess a higher safety margin.

Abstract 5461: H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC

Abstract BACKGROUND: Resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is a major challenge in non-small cell lung cancer (NSCLC) treatment. EGFR activating mutations, such as exon 19 deletions (Del19) and L858R substitution, have been reported in 10-50% of patients with NSCLC. Although these patients respond well to early generations of TKIs, acquired resistance by mechanisms such as T790M mutation compromises their efficacy. Recently, the C797S mutation in combination with Del19 or L858R, and with T790M, has emerged as one of the most common mechanisms underlying on-target resistance to a third generation EGFR TKI, osimertinib. We are developing a fourth-generation EGFR inhibitor, H002, with a wide spectrum and high selectivity to address the growing unmet needs in NSCLC patients harboring C797S mutation. METHODS: H002’s selectivity was assessed by KINOMEscan against more than 400 human kinases. A panel of 44 kinases was further evaluated to enable early identification of off-target effect. In vitro and in vivo anti-tumor efficacy was determined in drug-resistant mutant cell lines, CDX and PDX models. Single mutants (Del or L858R), double mutants (Del/T790M or L858R/T790M) and triple mutants (Del/T790M/C797S or L858R/T790M/C797S) as well as wild type EGFR were assessed. Drug metabolism and pharmacokinetic (DMPK) properties were further assessed. H002’s safety profile was evaluated in rats and beagle dogs, and by hERG potassium channel assay. Acute toxicity, and repeated dose GLP toxicity studies were also conducted in IND-enabling studies. RESULTS: High kinase selectivity and very low off-target effects were demonstrated by kinome-wide profiling and safety screening. H002 was highly active against all forementioned single, double or triple EGFR mutants (IC50 &amp;lt; 5 nM), and highly selective against wild type EGFR. H002 also exhibited potent anti-tumor effects in a dose-dependent manner in various CDX and PDX models. Excellent PK properties were observed in rats and beagle dogs with bioavailability over 70%. H002 was shown to cross the blood-brain barrier post i.g. administration in rats. No adverse effects of respiratory, cardiovascular and central nervous system were observed in safety studies. Repeated-dose toxicity studies only showed EGFR-related adverse reactions, such as gastrointestinal and liver toxicity, with high safety margin over 10-folds. CONCLUSION: H002 has been demonstrated as a promising next generation EGFR inhibitor, with high selectivity, a wide spectrum and potent anti-tumor activity against various EGFR activating mutations, favorable DMPK and safety profiles. It will be further developed as a fourth-generation EGFR inhibitor to overcome drug resistance in NSCLC. Citation Format: Wei Huang, Lin Zhu, Xiaoe Yan, Xin Huang, Jia Hao, Shan Li, Xiangyu Li, Zhiming Chen, Yunchuan Jia, Haibo Li, Jianming Zhang, Xianming Deng, Caihong Yun. H002: A wide spectrum, highly selective fourth-generation EGFR inhibitor overcoming resistance harboring C797S mutation in NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5461.

The Current Status, Bioactivity, Food, and Pharmaceutical Approaches of Calocybe indica: A Review.

Over the past few years, mushrooms have been extensively explored in the field of pharmaceutical and food science, and researchers are heading toward the search for vital components with a higher safety margin and multitarget applications. Moreover, among all age group populations, mushroom consumption has increased immensely owing to their great nutritional aspects, desirable organoleptic properties, and aroma. In addition, mushrooms continue to generate much attention chiefly in their consumption as food, as a cure for different ailments, as well as a vital commodity globally, owing to their dietary, antioxidant, and therapeutic values. Mushrooms are considered one of the important and suitable diets for patients having multiple types of diseases. Additionally, due to potential immunomodulatory effects, quality protein, and low fat, and cholesterol content, mushrooms are used as an important ingredient for food formulation. Therefore, this review article provides detailed information on Calocybe indica as they are the third most important commercially grown mushroom following button and oyster mushrooms. This review brings tangible evidence that milky white mushrooms are a great source of natural components and antioxidants with potential application in pharmaceuticals and in treating and managing different diseases. Several food applications of milky white mushrooms have also been discussed and reviewed.