Analytical and biomedical applications of microfluidics in traditional Chinese medicine research

Traditional Chinese medicine (TCM) has significant benefits in the prevention and treatment of diseases due to its unique theoretical system and research techniques. However, there are still key issues to be resolved in the full interpretation and use of TCM, such as vague active compounds and mechanism of action. Therefore, it is promising to promote the research on TCM through innovative strategies and advanced cutting-edge technologies. Microfluidic chips have provided controllable unique platforms for biomedical applications in TCM research with flexible composition and large-scale integration. In this review, the analysis and biomedical applications of microfluidics in the field of TCM are highlighted, including quality control of Chinese herbal medicines (CHMs), delivery of CHMs, evaluation of pharmacological activity as well as disease diagnosis. Finally, potential challenges and prospects of existing microfluidic technologies in the inheritance and innovation of TCM are discussed.Copyright © 2022 Elsevier B.V.

Prospects of accelerated fractionation chemoradiotherapy for locally advanced oropharyngeal cancer during the COVID-19 pandemic.

Objective. To comparatively assess the early toxicity of treatment, its tolerability, 1-, 2-, 3-year overall survival, and local regional control rates in a group of patients receiving a radical cycle of accelerated or conventional fractionation chemoradiotherapy. Subjects and methods. The paper presents the interim results of a prospective study that included 115 patients with locally advanced cancer of the oropharynx, tongue root, and larynx who received a radical cycle of conformal chemoradiotherapy using accelerated (the single focal dose (SFD) was 2.4 Gy for 25-26 fractions) or conventional (SFD was 2.0 Gy for 32-33 fractions) fractionation in the period from 2015 to 2020. Results. An analysis comparing the study group with the control one revealed no statistically significant differences in the level of early toxicity of treatment (p=0.41). Complete tumor reversal was achieved in 57 (86.3%) patients in the study group and in 39 (79.5%) in the comparison group (p=0.23). The 1-, 2-, and 3-year local regional control rates in the accelerated fractionation group was 78.3+/-5.3%;65.9+/-6.8%, and 54.5+/-9.2%, respectively. The 3-year overall survival rate was 80.4+/-7.4%. These rates did not differ statistically from those in the conventional radiotherapy group (p=0.12-0.82);53 (80.3%) patients in the study group and 37 (75.5%) in the standard fractionation group received a radiation cycle without a forced interval. The treatment interval in the patients of both groups reduced the 2-year local regional control rates by 30.2% compared to that in the continuous cycle group (p=0.02). Conclusion. Accelerated fractionation chemoradiotherapy (SFD was 2.4 Gy for 25-26 fractions, the daily focal dose was 60.0- 62.4 Gy) is a procedure comparable with conventional radiation in its direct efficiency and safety. During the COVID-19 pandemic, this regimen can be considered to be a mainstay for patients with locally advanced oropharyngeal cancer in order to preserve the previous volumes of specialized healthcare.Copyright © A.V. SEMENOV I.A. GULIDOV O.G. LEPILINA M.U. RADZHAPOVA F.E. SEVRYUKOV K.B. GORDON.

In Situ Electrochemical Trapping and Unraveling the Mechanism of the Toxic Intermediate Metabolite N-Acetyl-p-Benzoquinone Imine of the Acetaminophen Drug and Its Biomimetic Mediated NADH Oxidation Reaction

The integrative study of the pharmacokinetics and dynamics of a drug has been of great research interest due to its authentic description of the biomedical and clinical pros and cons. Acetaminophen (N-acetyl-4-aminophenol, AcAP) is a well-known analgesic having a high therapeutic value, including the Covid-19 treatment. However, an overdose of the drug (>200 mg/kg of men) can lead to liver toxicity. An intermediate, N-acetyl-p-benzoquinone imine (NAPQI), metabolite formation has been found to be responsible for the toxicity. For the detection of NAPQI, several ex situ techniques based on electrochemical methods followed by nuclear magnetic resonance, high-performance liquid chromatography, and LC-MS were stated. For the first time, we report an in situ electrochemical approach for AcAP oxidation and NAPQI intermediate (Mw = 149.1 g mol-1) trapping on a graphitic nanomaterial, carbon black (CB)-modified electrode in pH 7 phosphate buffer solution (CB@NAPQI). The NAPQI-trapped electrode exhibited a surface-confined redox peak at E°′ = 0.350 ± 0.05 V vs Ag/AgCl with a surface excess value of 3.52 n mol cm-2. Physicochemical characterizations by scanning electron microscopy, Raman, FTIR, and in situ electrochemical quartz crystal microbalance (EQCM) techniques supported the entrapment of the molecular species. Furthermore, the scanning electrochemical microscopy (SECM) technique has been adopted for surface-mapping the true active site of the NAPQI-trapped electrode. As a biomimetic study, the mediated oxidation reaction of NADH by CB@NAPQI was demonstrated, and the mechanistic and quantitative aspects were studied using cyclic voltammetry, rotating disc electrode, amperometry, and flow injection analysis techniques. © 2023 American Chemical Society.

Synthesis, characterization and pharmacological activities of silver nanoparticles using leaves extract of turmeric plant

In present manuscript describes synthesis of silver nanoparticles using turmeric leaves extract, traditional turmeric is a common spice that comes from the root of Curcuma longa, chemical called curcumin. Turmeric has a warm, bitter taste and is frequently used to flavor or color curry powders, mustards, butters, and cheeses. People commonly use turmeric for osteoarthritis, hay fever, depression, high cholesterol, liver disease, itching. There is also no good evidence to support using turmeric for COVID-19. Synthesis of silver nanoparticles AgNO powder was dissolved in distilled water to prepare 10 mM AgNO stock 3 3 solution from which different composition prepared. The AgNO solutions were mixed with urmeric plants 3 t leaves extract in equal proportion in flask. The flask was wrapped with an aluminum foil and was then heated in a water bath at 50-60 C for 2 hours. The synthesis of nanoparticles, which was confirmed by UVSpectra and TEM. UV-Vis spectra and visual observation showed that the color of the fresh leaf extractsof Vinca rosea turned into brownish yellow, respectively, after treatment with silver. In addition, TEM analysis confirmed that AgNO solutions for all concentrations produced ilver nanoparticles and their average size 3 s was less than 20 nm. Turmeric plants extract of fresh leaves can be used as bioreducing agents, drug resistant strains, toxic nature towards microbial agents, play an important role in nanoscience and nanotechnology, particularly in nanomedicine and potential applications in cancer diagnosis and therapy.

Insights into targeting SARS-CoV-2: design, synthesis, in silico studies and antiviral evaluation of new dimethylxanthine derivatives

Aiming to achieve efficient activity against severe acute respiratory syndrome coronavirus (SARS-CoV-2), the expansion of the structure- and ligand-based drug design approaches was adopted, which has been recently reported by our research group. Purine ring is a corner stone in the development of SARS-CoV-2 main protease (Mpro) inhibitors. The privileged purine scaffold was elaborated to achieve additional affinity based on hybridization and fragment-based approaches. Thus, the characteristic pharmacophoric features that are required for the inhibition of Mpro and RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 were utilized along with the crystal structure information of both targets. The designed pathways involved rationalized hybridization with large sulfonamide moieties and a carboxamide fragment for the synthesis of ten new dimethylxanthine derivatives. The synthesis was performed under diverse conditions to afford N-alkylated xanthine derivatives, and cyclization afforded tricyclic compounds. Molecular modeling simulations were used to confirm and gain insights into the binding interactions at both targets' active sites. The merit of designed compounds and the in silico studies resulted in the selection of three compounds that were evaluated in vitro to estimate their antiviral activity against SARS-CoV-2 (compounds 5, 9a and 19 with IC50 values of 38.39, 8.86 and 16.01 muM, respectively). Furthermore, oral toxicity of the selected antiviral candidates was predicted, in addition to cytotoxicity investigations. Compound 9a showed IC50 values of 8.06 and 3.22 muM against Mpro and RdRp of SARS-CoV-2, respectively, in addition to promising molecular dynamics stability in both target active sites. The current findings encourage further specificity evaluations of the promising compounds for confirming their specific protein targeting.Copyright © 2023 RSC.

PROTECTION AGAINST HETEROLOGOUS CHALLENGE 1 YEAR AFTER INFANT SARS-CoV-2 IMMUNIZATION

Background: Although mRNA SARS-CoV-2 vaccines have received emergencyuse- authorization for infants age 6 months and older, vaccine uptake is slow, stressing that questions of safety and durability of vaccine efficacy remain prominent. Method(s): Infant rhesus macaques (RMs) (n=8/group) at 2 months of age, comparable to human toddler age, were immunized intramuscularly at weeks 0 and 4 with 30mug stabilized prefusion SARS-CoV-2 S-2P spike (S) protein (Washington strain) encoded by mRNA encapsulated in lipid nanoparticles (mRNA-LNP) or 15mug S protein mixed with 3M-052 in stable emulsion (Protein). At 1 year, vaccinated and age-matched unvaccinated RM (n=8) were challenged intranasally (106pfu) and intratracheally (2x106pfu) with B.1.617.2. Lung radiographs and pathology were blindly assessed, viral N gene RNA (vRNA) copies were measured by qPCR in pharyngeal swabs and lung, and neutralizing antibody and peripheral blood T cell responses were measured. Result(s): At 1 year, D614G-specific neutralizing antibody (nAb) titers were still detectable in the Protein (ID50=755;range: 359-1,949) and mRNA-LNP groups (ID50=73;range: 41-240). Both vaccines also induced cross-neutralizing antibodies to B.1.617.2. Peripheral blood CD4+ T cell responses to the ancestral spike protein at week 52 did not differ between the groups. However, median CD8+ T cell responses were higher (p=0.002, Mann Whitney) in the mRNA-LNP group (2.8%;range: 0.9%-7.1%) compared to the Protein group (0.8%;range: 0.1%-1.6%). Control RMs had significantly higher median vRNA copies/ml (1.4+/-2.7x108) in day 4 pharyngeal swabs compared to Protein (3.8+/-6.8x103) or mRNA-LNP (4.4+/-9.7x105) vaccinated RMs. Severe lung pathology was observed in 7 of 8 controls compared to 1 of 8 or 0 of 8 RMs in the mRNA-LNP or Protein group respectively. Protection against lung inflammation was associated with nAb titers (r=-0.592, p=0.003) (Figure 1). Conclusion(s): These results demonstrate that despite lower vaccine doses compared to adults, both protein and mRNA vaccines were safe, induced durable immune responses and provided comparable protective efficacy against infection with a heterologous SARS-CoV-2 variant in infants, implying that early life vaccination of human infants may lead to durable immunity. Neutralizing ID50 antibody titers are a correlate of protection in infant RMs challenged with SARS-CoV-2.

A Randomized Trial on Early Therapy in Covid-19 High-Risk Outpatients in Omicron Era

Background: Antivirals and monoclonal antibodies (mAbs) were approved for early treatment of COVID-19 based on data from trials conducted in unvaccinated people before the Omicron era. The comparative effectiveness of different treatments is unknown. We present the results of the interim analysis of MONET trial (EudraCT: 2021-004188-28). Method(s): In this ongoing multicenter, open-label, phase 4 trial, we randomly assigned, in a 1:1:1 ratio, non-hospitalized patients with early symptomatic Covid-19 (<=5 days after symptoms onset) and >=1 risk factor for disease progression, to receive 500 mg of intravenous sotrovimab (SOT) or 600 mg of intramuscular tixagevimab/cilgavimab (TIX/CIL) or oral 5-days course of NMV/r 300/100 mg BID. Primary outcome was hospitalization or death for any cause within 29 days after randomization, reported as cumulative incidence per 100 (95% CI), and P-value calculated by Fisher's exact test. Inflammatory marker (CRP, d-dimer, and neutrophils-to-lymphocytes ratio) and antibody level (serum anti-S IgG and anti-N IgG) analysed by mixed linear regression with random intercept and P-values for time trend calculated by ANOVA-style test with Bonferroni correction. Result(s): Prespecified interim analysis, including 400 patients (SOT =133, TIX/ CIL=130, NMV/r=137) enrolled from Mar 4 to Nov 16, 2022 (Fig.1A). Overall, 5 pts (3/5 immunosuppressed) had disease progression leading to hospitalization [1.25% (95% CI 0.4%-2.89%)], 1 in SOT (0.75%, 95% CI 0.01%-4.1%), 4 in TIX/CIL (3.08%, 95% CI 0.84%-7.69%) and none in NMV/r arm (P=0.030). No deaths or ICU admissions were observed. Among the hospitalized pts, 3 were infected with BA.2 (1 SOT, 2 TIX/CIL), one with BA.4/5, and one BQ.1.1 (both TIX/ CIL). No serious adverse events and no kidney or liver toxicity were reported. Temporal trend of inflammation markers was similar in the three arms, and their estimates are shown in Fig.1B. Kinetics of antibody was reported in Fig.1C. The plot shows a rapid increase of anti-S in both mAb arm and a linear increase of IgG in the NMV/r arm. Anti-N IgG kinetics was similar in the three arms. Conclusion(s): By these data the overall cumulative risk of clinical failure in mild Covid-19 occurring in the Omicron era is low. The hypothesis that differences in clinical progression among the three arms could be related to different activity against the Omicron subvariant observed in vitro should be further investigated. Type of treatment does not seem to influence the development of the natural antibody response.

Optimized nanoparticle-mediated base editing of cystic fibrosis-causing variants

Background: Next-generation SARS-CoV-2 vaccines demonstrated that nanoparticle messenger ribonucleic acid (mRNA) delivery is effective and safe for in vivo delivery in humans. Current treatments for cystic fibrosis (CF) primarily focus on modulator drug therapies designed to correct malfunctioning CF transmembrane conductance regulator (CFTR) protein, but these modulators are ineffective for the 10% of people with CF with variants that do not allow protein production. Among these is the splice variant 3120 + 1G >A, the most common CF-causing mutation in native Africans. Gene editing would allow production of CFTR protein and enhancement of function using available CFTR modulators. We have demonstrated that electroporation of a modified CRISPR-Cas9 base editor to primary human bronchial epithelial cells carrying 3120 + 1G >A and F508del mutant alleles achieved 75% genome editing of the splice variant, resulting in approximately 40% wild-type (WT) CFTR function [1]. Here,we evaluate the effectiveness of several new nanoparticle formulations at delivering green fluorescent protein (GFP) mRNA to CF bronchial epithelial (CFBE41o-) cells. Using the optimal formulation,we then tested the efficacy correction of the 3120 + 1G >Avariant in a CFTR expression minigene (EMG) integrated into the genome of isogenic CFBE cells using mRNA and plasmid deoxyribonucleic acid (DNA) encoding adenine base editor (ABE) and guide (g)RNA. Method(s): GFP served as a reporter to evaluate transfection efficiency, cell viability, and mean fluorescence intensity (MFI) for three dosages (150, 75, 32.5 ng of mRNA), four polymer-to-mRNA to weight (w/w) ratios (60, 40, 30, 20), and four polymers (R, Y, G, B). 7-AAD served as a live/dead stain to quantify viability, with flow cytometry results analyzed using FlowJo software. CFBE cells stably expressing the 3120 + 1G >A EMG were transfected with the optimized nanoparticle formulation to deliver ABE and gRNA at two dosages (150, 75 ng) of mRNA and DNA. CFTR function in CFBE cellswas measured by short circuit current, forskolin stimulation, and inh-172 inhibition as a measure of editing efficiency. Result(s): Flow cytometry showed that polymer R achieved more than 85% GFP transfection, compared with a maximum of approximately 35% for the other three polymers at the maximum 150-ng dose, with approximately 80% viability normalized to untreated cells. In addition, polymer R achieved GFP MFI more than one order of magnitude as high as other formulations (~30 000 vs 2700 MFI) for the other three polymers at 150-ng dose and 40 w/w ratio. CFBE cells transfected with polymer R nanoparticles containing ABE and guide RNA at 75 ng and 150 ng showed mean CFTR function increase to 10 muA 6 (standard error of the mean [SEM] 1.1 muA) (~10% of WT) and 6.3 muA (SEM 0.9 muA) (~6% of WT), respectively. Greater toxicity at the higher dose could explain the larger increase in CFTR current at the lower dose. DNA-encoded ABE plasmid and gRNA showed a less robust increase in CFTR function (2.9 muA [SEM 0.4 muA] for 75-ng dose;3.0 muA [SEM 0.4 muA] for 150-ng dose), which was probably a result of the nanoparticle formulation being optimized for RNA instead of DNA cargo or the additional intracellular barriers that must be overcome for successful DNA delivery. Conclusion(s): We demonstrated that an optimized nanoparticle formulation containing ABE and gRNA can correct splicing of isogenic cells bearing the 3120 + 1G >A CFTR variant, resulting in recovery of CFTR function. In ongoing work, we are adapting these nanoparticles for RNA- and DNAencoded ABE and gRNA delivery to primary human bronchial epithelial cells.Copyright © 2022, European Cystic Fibrosis Society. All rights reserved

Neuromyelitis optica spectrum disorder after BIBP COVID-19 vaccine: A case report

Background: With the COVID-19 vaccine now available, there have been occasional reports of post-vaccination neurological complications. Case presentation: In this report, we present a case of neuromyelitis optica spectrum disorder (NMOSD) that developed one month after the patient received the second dose of BIBP COVID-19 vaccine (SARS-CoV-2-Vaccine [Vero Cell] Inactivated). The patient presented with itching, numbness in the hand and right side of the face, as well as nausea, vomiting, and hiccups. Brain MRI revelead lesions in the area postrema, medulla, and bilateral hypothalamus, which are typical of NMOSD. Serum antibodies to anti-AQP4 and anti-MOG were negative. Conclusion(s): The pathogenesis of NMOSD development after vaccination is still unknown. NMOSD is generally aggressive and disabling, it is important for the neurologist to be attentive to the highly variable clinical presentation after COVID-19 vaccination for early diagnosis and effective treatment.Copyright © 2023

Pulmonary parenchymal involvement secondary to subcutaneous injection of silicone gels: a case report.

Pulmonary parenchymal involvement secondary to the subcutaneous injection of silicone gels is an unusual condition which occurs more frequently in women aged between 22 and 55 years. Although different theories have been put forward about its etiology, it is unknown and the condition may cause local and systemic complications and even have a fatal outcome. Few cases have been reported in South America and there is no report of this unique entity in Peru. We present the case of a previously healthy 28-year-old male transgender patient who, after an illegal subcutaneous injection of silicone gels in the gluteal region given by a non-healthcare professional, showed progressive respiratory distress and stabbing chest pain of approximately 7 out of 10 on the pain scale within the first 24 hours. Upon admission to the emergency room, respiratory failure was objectively evidenced since the patient had an oxygen saturation of 72 % at a FiO2 of 21 %, as well as pulmonary parenchymal involvement both in the CT scan and chest X-ray with signs highly suggestive of this pathology. Using a SARS-CoV-2 RNA real-time RT-PCR test performed on a respiratory specimen, COVID pneumonia, immunodeficiency disorders and pulmonary embolism were ruled out. Since there is no standard treatment, the patient was given relevant support measures such as the administration of supplemental oxygen at a low flow rate by binasal cannula, intravenous systemic corticosteroids and antibiotic therapy, thus achieving good progress with resolution of the initial clinical presentation. Then, after 10 days of intrahospital treatment, the patient was discharged.Copyright © La revista. Publicado por la Universidad de San Martin de Porres, Peru.

Interpretation of Hepatotoxic Side Effects by Rcv (Reference Change Value) in Covid-19 Patients Treated with Favipiravir

Objectives: Favipiravir was first used against SARS-CoV-2 in Wuhan at the very epicenter of the pandemic. Its side effects include hyperuricemia, decreased neutrophil counts, diarrhea, and increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkalen phospatase ALP, bilirubin. Reference change value (RCV) represents the clinical significance of the variation between the RESULTS of two consecutive tests and laboratory test results exceeding this value are associated with the individual's disease status. In this study, we evaluated the side effects of favipiravir treatment on AST and ALT using RCV. Materials-Methods: We examined retrospectively 40 patients were administered 1600 mg of favipiravir twice daily on day 1, followed by 600 mg twice daily from day 2 to day 5 (or more if needed). The analytic coefficient of variation (CVA:0,47 for AST 0,42 for ALT) was calculated from internal quality control RESULTS. Intra-individual coefficient of variation (CVI) and inter-individual coefficient of variation (CVG) were obtained from Westgard's website, which was updated in 2014.The RCV% is calculated with the following formula Zx21/2x[CVA2+CVI2]1/2 (Using an unidirectional probability of 95%, Z=1.65). Result(s): The RCV% results were calculated as %28 for AST and % 45 for ALT.The individuality index (II) was calculated as 0.532 for AST and 0.466 for ALT. ALT and AST values were evaluated as higher than the calculated RCV value in 70%,62,5% of the patients. Conclusion(s): The use of RCV is recommended as a valuable tool in the follow-up of patient results and side effects of treatment.

A comparison of peripheral blood stem cell collection outcomes for multiple myeloma, mobilization matters in the era of IMiD induction

Collection of peripheral blood stem cells (PBSCs) for autologous stem cell transplant (ASCT) requires mobilization from the bone marrow. There is variation in mobilization choice;during the COVID-19 pandemic BSBMT&CT guidelines recommended using granulocyte-colony stimulating factor (G-CSF) alone to minimize the use of chemotherapy. We report on the impact of mobilization regimen on stem cell collection, and whether IMiD-containing induction therapy impacts on mobilization and consequently transplant engraftment times for 83 patients undergoing ASCT at Leeds Teaching Hospitals. Cyclophosphamide plus G-CSF (cyclo-G) mobilization yielded more CD34+ cells (8.94 vs. 4.88 x106/kg, p = < 0.0001) over fewer days (1.6 vs. 2.4 days, p = 0.007), and required fewer doses of salvage Plerixafor than G-CSF only (13.6% vs. 35%, p = 0.0407). IMiD-containing induction impaired all of these factors. CD34+ doses > 8x106/kg were more frequent with Cyclo-G (62% vs. 11%, p = 0.0001), including for those receiving IMiD 1st line induction (50% vs. 13.3%, p = 0.0381). Note that 92.6% of those receiving IMiD-free inductions were mobilized with Cyclo-G. The novel agents used in modern induction regimens (e.g Daratumumab) have been shown to impair yields, increasing the importance of optimizing mobilization regimens in the first instance. Furthermore, as cellular therapies become established in the management of multiple myeloma emerging data highlights the potential benefits of stem cell top up in the management of the haematological toxicities of these therapies. Our findings support re-adoption of Cyclo-G as the gold standard for mobilization to optimize PBSC harvesting and ensure sufficient cells for subsequent ASCTs.Copyright © 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

Post-Transplantation Cyclophosphamide for the Prevention of Graft-Versus-Host Disease Should Not Limit Transplantation for Acute Lymphoblastic Leukemia in People with Trisomy 21

Introduction: Use of hematopoietic cell transplantation (HCT) in patients with trisomy 21 (+21) is infrequent given concerns about increased toxicity with cytotoxic chemotherapy.1 Due to increasing evidence of benefit from post-HCT cyclophosphamide (PTCy) for graft-vs.-host disease (GVHD) prophylaxis and lack of prior descriptions in patients with +21,2-4 we report on 2 patients with +21 and acute lymphoblastic leukemia (ALL) who underwent HCT with PTCy. Method(s): Retrospective data were collected from 2 patients with ALL and +21 who underwent allogeneic HCT with PTCybased GVHD prophylaxis from 2019 to 2021. Data collected included age, disease risk, HCT-CI, GVHD incidence, and survival. Result(s): Patient 1 is a 22-year-old male and patient 2 a 25-year-old female. Both had Ph-negative, B-cell ALL. Patient 1 had ETV6/RUNX1 rearrangement, del 12p, gain of X, and he had recurrence of measurable residual disease (MRD) after initial MRD-negative CR with two lines of therapy pre-HCT. Patient 2 had normal cytogenetics and relapsed disease with 4 prior lines of therapy. Both achieved MRD-negativity pre-HCT. Both received fludarabine and melphalan conditioning, and patient 1 also received thiotepa 2.5 mg/kg. PTCy was given on days +3 and 4 at 50 mg/kg with sirolimus and tacrolimus for GVHD prophylaxis. Patient 1 had a haploidentical donor and received one dose of rabbit ATG (1 mg/kg) on day +5. Patient 2 had a matched unrelated donor. There was no significant delay in engraftment of ANC (day 16-19) or platelets (day 15-16). Patient 2 developed acute GVHD at day 30 (stage I skin, stage II GI) that resolved with steroids which were tapered off by day 96 without recurrence. Sirolimus stopped at day 79 (pt 1) and 103 (pt 2) and tacrolimus was stopped at day 274 (pt 1) and 469 (pt 2). Patient 1 developed a sirolimus-induced pericardial effusion at day 84 which did not recur after sirolimus discontinuation. Patient 2 developed moyamoya 8 months post-HCT during tacrolimus taper without other GVHD symptoms. Response to steroids was noted, so tacrolimus was restarted for residual neurological deficit. Neither patient developed chronic GVHD or left ventricular ejection fraction decline, and neither patient had disease relapse at follow-up of 30 and 16 months respectively. Patient 2 developed COVID pneumonia 16 months post-HCT and died while in CR. Patient 1 remains alive, in CR, and off immunosuppression nearly 3 years post HCT. Conclusion(s): Allogeneic HCT with PTCy at standard doses did not appear prohibitively toxic in patients with +21 when administered after reduced-intensity conditioning. In this case series, GVHD rates seemed consistent with larger series in patients without +21. Moyamoya development is associated with autoimmunity in patients with +21 and hence may have been GVHD-related5. Trisomy 21 should not be a barrier to patients otherwise eligible for HCT, even with PTCy prophylaxis.Copyright © 2023 American Society for Transplantation and Cellular Therapy

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CBD Treatment Improves Fatal Inflammatory Response Exhibited in SEB-Induced ARDS

The novel SARS-CoV-2 virus known to cause the COVID-19 outbreak has resulted in a global healthcare crisis that has persisted the past 3 years. Thus, understanding the mechanisms underlying this disease are vital at this time. While there are issues of research infrastructure to handle the virus and because of the refractoriness of rodents to this disease, the availability of these tools is still limited. The cytokine storm and fatality presented in patients with severe COVID-19 can be mimicked with Staphylococcal enterotoxin B (SEB)-induced Acute Respiratory Distress Syndrome (ARDS). Within ~7 days, the survival rate drops to 0% for C3H/HeJ mice exposed to a dual dose of SEB. In this study, we administered cannabidiol (CBD) intraperitoneally for 3 days pre- and post-SEB dosing and found that the clinical outcomes improved significantly. Initial evaluation of scRNASeq data from lungs comparing naive to SEB-induced ARDS mice illustrated an increase in infiltrating immune cells, and a loss in pulmonary epithelial cells in the latter group. When evaluating the effect of CBD treatment on SEB-induced ARDS, we were able to demonstrate that CBD reduced the macrophage population. To characterize the mechanism by which CBD treatment ameliorated the inflammatory response, we found that CBD treated mice had significant reduction in infiltrating immune cells and alveolar thickening. This same histology and infiltration is presented in ARDS. MicroRNA expression analysis showed a significant increase in the expression mmu-miR-298-5p and mmu-miR- 566 with CBD treatment. Ingenuity Pathway Analysis (IPA) indicated that the dysregulated miRNAs were also implicated in pathways associated with macrophage activation, respiratory disease and inflammation, interferon stimulated genes, as well as genes which have been upregulated in the disease state of this model. These targets include but are not limited to Cebpb, Efhd2, Stat3, Socs3, Cxcl5, Gbp2, and Birc3. This finding offers insights for the development of preventive and therapeutic strategies in the treatment of ARDS, including that induced in COVID-19. Supported by NIH grants P01AT003961, P20GM103641, R01ES003961, R01AI129788, R01AI123947, R01AI160896 to MN and PSN and K99GM147910 to KW.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.

Toxicity Evaluation and Effect-Based Identification of Chlorine Disinfection Products of the Anti-COVID-19 Drug Chloroquine Phosphate.

Antiviral transformation products (TPs) generated during wastewater treatment are an environmental concern, as their discharge, in considerable amounts, into natural waters during a pandemic can pose possible risks to the aquatic environment. Identification of the hazardous TPs generated from antivirals during wastewater treatment is important. Herein, chloroquine phosphate (CQP), which was widely used during the coronavirus disease-19 (COVID-19) pandemic, was selected for research. We investigated the TPs generated from CQP during water chlorination. Zebrafish (Danio rerio) embryos were used to assess the developmental toxicity of CQP after water chlorination, and hazardous TPs were estimated using effect-directed analysis (EDA). Principal component analysis revealed that the developmental toxicity induced by chlorinated samples could be relevant to the formation of some halogenated TPs. Fractionation of the hazardous chlorinated sample, along with the bioassay and chemical analysis, identified halogenated TP387 as the main hazardous TP contributing to the developmental toxicity induced by chlorinated samples. TP387 could also be formed in real wastewater during chlorination in environmentally relevant conditions. This study provides a scientific basis for the further assessment of environmental risks of CQP after water chlorination and describes a method for identifying unknown hazardous TPs generated from pharmaceuticals during wastewater treatment.

A review on Artificial Intelligence Approaches and Rational approaches in Drug Discovery.

Artificial intelligence (AI) speeds up the drug development process and reduces its time, as well as the cost which is of enormous importance in outbreaks such as COVID-19. It uses a set of machine learning algorithms that collects the available data from resources, categorises, processes and develops novel learning methodologies. Virtual screening is a successful application of AI, which is used in screening huge drug-like databases and filtering to a small number of compounds. The brain's thinking of AI is its neural networking which uses techniques such as Convoluted Neural Network (CNN), Recursive Neural Network (RNN) or Generative Adversial Neural Network (GANN). The application ranges from small molecule drug discovery to the development of vaccines. In the present review article, we discussed various techniques of drug design, structure and ligand-based, pharmacokinetics and toxicity prediction using AI. The rapid phase of discovery is the need of the hour and AI is a targeted approach to achieve this.

Accurate Assessment and Tracking the Process of Liver-Specific Injury by the Residual Tissue Activity of Carboxylesterase 1 and Dipeptidyl Peptidase 4

Accurately assessing and tracking the progression of liver-specific injury remains a major challenge in the field of biomarker research. Here, we took a retrospective validation approach built on the mutuality between serum and tissue biomarkers to characterize the liver-specific damage of bile duct cells caused by a-naphthyl isothiocyanate (ANIT). We found that carboxylesterase 1 (CES1), as an intrahepatic marker, and dipeptidyl peptidase 4 (DPP-IV), as an extrahepatic marker, can reflect the different pathophysiolo-gies of liver injury. Levels of CES1 and DPP-IV can be used to identify liver damage itself and the inflam-matory state, respectively. While the levels of the conventional serological biomarkers alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were all con-comitantly elevated in serum and tissues after ANIT-induced injury, the levels of bile acids decreased in bile, increased in serum, and ascended in intrahepatic tissue. Although the level of c-glutamyl transpeptidase (c-GT) changed in an opposite direction, the duration was much shorter than that of CES1 and was quickly restored to normal levels. Therefore, among the abovementioned biomarkers, only CES1 made it possible to specifically determine whether the liver cells were destroyed or damaged with-out interference from inflammation. CES1 also enabled accurate assessment of the anti-cholestasis effects of ursodeoxycholic acid (UDCA;single component) and Qing Fei Pai Du Decoction (QFPDD;multi-component). We found that both QFPDD and UDCA attenuated ANIT-induced liver damage. UDCA was more potent in promoting bile excretion but showed relatively weaker anti-injury and anti-inflammatory effects than QFPDD, whereas QFPDD was more effective in blocking liver inflammation and repairing liver damage. Our data highlights the potential of the combined use of CES1 (as an intra-hepatic marker of liver damage) and DPP-IV (as an extrahepatic marker of inflammation) for the accurate evaluation and tracking of liver-specific injury-an application that allows for the differentiation of liver damage and inflammatory liver injury.(c) 2021 THE AUTHORS. Published by Elsevier LTD on behalf of Chinese Academy of Engineering and Higher Education Press Limited Company. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Prediction of Anti-SARS CoV-2 Activity from Green Tea Catechin (Camellia sinensis L. Kuntze) Compound Against To Receptors Non-structural Protein 3 (6W6Y) And Non-structural Protein 5 (6M2N)

Green tea catechin compounds (Camellia sinensis L. Kuntze) have an antiviral activity such as influenza, hepatitis B, hepatitis C, herpes simplex virus, HIV, and proven in vitro antiviral influenza against NSP5 in SARS CoV. These considerations are used in this study using Non-structural Protein (NSP), namely NSP3 and NSP5 in SARS CoV-2, which have a role in viral replication and transcription. This study aims to predict the physicochemical properties according to the five rules of Lipinski's using swissADME. Prediction of toxicity with LD50 classification using the Protox II online tool. Catechin compound activity based on ligand interaction with NSP3 (PDB ID: 6W6Y) and NSP5 (PDB ID: 6M2N) receptors using Molegro Virtual Docker (MVD) 6.0. The results showed the predictions of physicochemical properties of the (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC) compounds fulfilled the five rules of Lipinski's. Catechin compounds have toxicity at levels 4 and 6. The activity of catechin compounds on NSP3 (PDB ID: 6W6Y) and NSP5 (PDB ID: 6M2N) receptors indicated that all catechin compounds had inhibitory activity. The best potential activity compound is (-)-epigallocatechin-3-gallate (EGCG) with a rerank score of-102.8200 and-134.1800 Kcal/mol so EGCG can be recommended as a candidate for the SARS CoV-2 antiviral compound. © 2022, Universitas Gadjah Mada - Faculty of Pharmacy. All rights reserved.

Applying an Epidemiological Model to Evaluate the Propagation of Toxicity related to COVID-19 on Twitter

The prevalence of social media has increased the propagation of toxic behavior among users. Toxicity can have detrimental effects on users' emotion and insight and disrupt beneficial discourse. Evaluating the propagation of toxic content on social networks such as Twitter can provide the opportunity to understand the characteristics of this harmful phenomena. Identifying a mathematical model that can describe the propagation of toxic content on social networks is a valuable approach to this evaluation. In this paper, we utilized the SEIZ (Susceptible, Exposed, Infected, Skeptic) epidemiological model to find a mathematical model for the propagation of toxic content related to COVID-19 topics on Twitter. We collected Twitter data based on specific hashtags related to different COVID-19 topics such as covid, mask, vaccine, and lockdown. The findings demonstrate that the SEIZ model can properly model the propagation of toxicity on a social network with relatively low error. Determining an efficient mathematical model can increase the understanding of the dynamics of the propagation of toxicity on a social network such as Twitter. This understanding can help researchers and policymakers to develop methods to limit the propagation of toxic content on social networks. © 2022 IEEE Computer Society. All rights reserved.