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CD4+ T Cells from Preeclamptic patients with or without a history of COVID-19 during pregnancy cause hypertension, autoantibodies and cognitive dysfunction in a pregnant rat model Objective: Preeclampsia (PE) new onset hypertension (HTN) during pregnancy, is associated with increased autoantibodies, cerebral blood flow (CBF) impaired cognitive function and memory loss. We have shown adoptive transfer of placentalCD4+T cells from PE women into athymic nude pregnant rats causesHTNand autoantibodies associated with PE.COVID-19 (CV) during pregnancy is associated with increased diagnosis of PE. However, we do not know the role of CD4+ T cells stimulated in response to CV in contributing to the PE phenotype seen patients with a Hx of CV during pregnancy. Therefore, we hypothesize that adoptive transfer of placental CD4+ T cells from patients with a CV History (Hx) during pregnancy with PE causes HTN, increased CBF and cognitive dysfunction in pregnant athymic nude recipient rats. Study Design: Placental CD4+ T cells isolated from normotensive (NP), PE, Hx of CV normotensive (CV Hx NT), and Hx of CV with PE (CV Hx+PE) at delivery. One million CD4+ T cells were injected i.p. into nude athymic rats on gestational day (GD) 12. The Barnes maze and the novel object recognition behavioral assays were used to assess cognitive function on GDs 15-19. Blood pressure (MAP) and CBF were measured by carotid catheter and laser Doppler flowmetry on GD19, respectively. A two-way ANOVA was used for statistical analysis. Result(s):MAPincreased inCVHx+PE (111 +/- 4, n = 4) and PE recipient rats (115 +/- 2 mmHg, n = 5) compared to CV Hx NT (100 +/- 4, n = 5) and NP (99 +/- 3 mmHg, n = 4, P < .05). CV Hx+PE and PE exhibited latency with errors navigating in the Barnes maze compared to CV Hx NT and NP groups. Locomotor activity was decreased in CV Hx+PE (P < .05) compared to PE, CV Hx NT, and NP groups. CV Hx+PE and PE spent more time exploring identical objects compared to CV Hx NT and NP groups. PE and CV Hx+ PE had increased CBF compared to CV Hx NT and NP rats. Conclusion(s): Our findings indicate that pregnant recipients of CD4+ T cells from PE with or without a Hx CV during pregnancy cause HTN, increased CBF and cognitive dysfunction compared to recipients of NP or NT Hx COVID-19 CD4+ T cells.
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Background: This study aimed to evaluate the outcomes of preclinical studies on the safety and immunogenicity of an inactivated COVID-19 vaccine candidate to warrant further clinical evaluation. Method(s): SARS-CoV-2 positive nasopharyngeal swab specimens were confirmed by real-time polymerase chain reaction and next-generation sequencing. The safety and immunogenicity tests of the COVID-19 vaccine were carried out in rats and Rhesus monkeys, and Balb/C mice and Rhesus monkeys, respectively. Result(s): The candidate vaccine was well tolerated and induced promising levels of SARS-CoV-2- specific IgG1, IgG2a, and Granzyme B in Balb/C mice, and anti-SARS-CoV-2 spike IgG and neutralizing antibodies in Rhesus monkeys. Based on cVNT results, the inactivated vaccine in 0.5 and 1 microg/100 microL doses was able to induce a neutralizing effect against the SARS-CoV-2 virus up to a dilution of 1:512 and 1:1000. The protective efficacy of the vaccine candidate was challenged with 2 x108 PFU of live viruses and confirmed by lung CT scan and histopathological evaluations compared to the control group. Repeated intramuscular injection of the candidate vaccine was generally well-tolerated in Rats and Rhesuses. No significant side effects were observed in rats injected with ten full human doses and in the Rhesus monkeys with three full human doses. Conclusion(s): Based on the findings presented in this study, it is recommended that this vaccine be moved into human testing commencing with a phase I clinical trial.Copyright © 2021 Muslim OT et al.
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Background/Objectives: We previously demonstrated that carrying a single pathogenic CFTR allele increases the risk for COVID-19 severity and mortality rate. We now aim to clarify the role of several uncharacterized rare alleles, including complex (cis) alleles, and in trans combinations. Method(s): LASSO logistic regression was used for the association of sets of variants, stratified by MAF, with severity. Immortalized cystic fibrosis bronchial epithelial cell lines and Fischer Rat Thyroid cells were transfected by plasmid carrying specific CFTR mutations. YFP-based assays were used to measure CFTR activity. Result(s): Here we functionally demonstrate that the rare (MAF=0.007) complex G576V/R668C allelemitigates the disease by a gain of function mechanism. Several novel CFTR ultra-rare (MAF <0.001) alleles were proved to have a reduced function;they are associated with disease severity either alone (single or complex alleles) or with another hypomorphic allele in the second chromosome, with a global reduction of CFTR activity between 40 to 72%. Conclusion(s): CFTR is a bidirectional modulator of COVID-19 outcome. At-risk subjects do not have open cystic fibrosis before viral infection and therefore are not easily recognisable in the general population unless a genetic analysis is performed. As the CFTR activity is partially retained, CFTR potentiator drugs could be an option as add-on therapy for at-risk patients.
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Background & Aim: The new UCOE models we have recently developed, tested on many cell groups (including mouse ES and human iPS cells) and human mAb recombinant production studies as well, shows a powerful resistance to DNA methylation- mediated silencing and provides a higher and stable transfection profile. By the urgent need of vaccine development for COVID-19 during the pandemic, in this study we aimed to produce a potential recombinant vaccine by using the new generation UCOEs models of our own design. Methods, Results & Conclusion(s): Existing new-generation UCOE models and standard plasmid vectors to be used as control group were provided. Then, the sequences related to the PCR method were amplified for sufficient stock generation and cloning experiments. Verification in the plasmid vector was carried out in gel electrophoresis. Transfection of 293T cells was performed with clone plasmids carrying antigen genes and plasmids carrying genetic information of lentivirus units for the production of lentiviral vectors. Afterwards, 293T cells produced lentiviral vectors carrying antigen genes. Harvesting of these vectors was carried out during 48th and 72nd hours. Afterwards, CHO cells were transduced with appropriate quantity of lentiviral vectors. Isolation and purification of targeted proteins from the relevant medium were performed by HPLC and Q-TOF methods. A part of the spike and nucleocapsid gene sequences of COVID-19 were firstly cloned into our UCOE models. These UCOEs plasmids were then transferred into 293T cells along with plasmids carrying the genes that will form the lentivirus vectors (LVs). After harvesting and calculation of LV vector titers, the cloned vectors were then transfected into the CHO cells which the targeted recombinant production of the antigen proteins will be carried out. Antigenic structures were then isolated from the culture medium of CHO cells in following days for confirmation. Using HPLC and qTOF mass spectrometer methods, these structures in the medium were confirmed to be the units of spike and nucleocapsid proteins of the COVID-19 virus. In order to produce large amount of the recombinant antigens, the culture was then carried out with bioreactors in liters. At the final stage, these recombinantly produced antigen proteins were tested on rats to measure their immunogenic responses, and the study recently been completed successfully as a potential recombinant vaccine against COVID-19.Copyright © 2023 International Society for Cell & Gene Therapy
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Various guidelines recommend steroid in only severe COVID-19 patients. But in hospitals steroids are being rampantly used even at the beginning of symptom onset. Some studies indicate starting steroid only in severe and/or patients on mechanical ventilation while some suggest starting in first 5-7 days to stave off cytokine storm. Hence this study was undertaken with the aim to study the relationship between initiation of steroid therapy and clinical outcome in hospitalized COVID-19 patients. The data for this study was collected from the medical records of patients diagnosed with COVID-19 in a tertiary care hospital. Evaluation of relationship between day of initiating steroid therapy and dose with the clinical outcome was done in terms of all-cause mortality, duration of hospital stay, requirement of assisted ventilation, requirement of ICU and requirement of oxygen therapy. Patients were categorized according to the day of initiating steroid after symptom onset or RTPCR or RAT positivity date, whichever was earlier in 4-7 days group, 8-10 days group and 11-14 days group. And according to dose given of methylprednisolone per day in 40 mg and 80 mg groups. All-cause mortality was significantly less in 8-10 days group (25.78%) compared to 4-7 days (38%) and 11-14 days group (39.68%) and significantly less in 40 mg group (26.67%) compared to 80 mg group (38.46%). Starting steroid between 8-10 days and in low dose (40 mg) is more beneficial in terms of all-cause mortality.Copyright © 2023, Global Research Online. All rights reserved.
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Chronic stress during adolescence increases the susceptibility to many neuropsychiatric diseases in adulthood, including anxiety-like and alcohol drinking behaviors. Social isolation is a particularly profound stressor with increasing human relevance, especially during the COVID-19 pandemic, when millions of adolescents faced prolonged periods of isolation. However, preclinical rodent models of adolescent social stress have produced mixed results that are often sex, species and strain-dependent. Here we examined the effect of intermittent social isolation on alcohol intake and preference during adolescence (PND28-56) and its long-term effects and alcohol drinking on anxiety, irritability, and synaptic transmission in both male and female Wistar rats. To this goal, we developed and utilized a new model of social isolation and alcohol exposure whereby adolescent (PND28) male and female rats were intermittently socially isolated for 24h prior to 2-bottle choice (2BC) access to ethanol (20% v/v, 2h/session, Tues/Thur/Sat) vs. water, for 4 weeks. Two weeks later (young adults), all rats were tested for anxiety in the novelty induced hypophagia test and irritability-like behavior in the bottle brush test, and a subset was used to record spontaneous inhibitory GABAergic postsynaptic currents (sIPSCs) in the central nucleus of the amygdala (CeA). Additionally, we studied genetically selected Marchigian Sardinian alcohol-preferring (msP) rats to compare the effects of social isolation in a rat strain of increased alcohol preference vulnerability and high sensitivity to anxiety. Social isolation increased alcohol preference in both male and female Wistars when compared to the group-housed controls, starting from week 1 and throughout adolescence. All msP rats displayed escalation of drinking during week 1 and 2 and the effect of the isolation was observed starting from week 3 in males only. No isolation effects were observed in female msPs throughout the 4 weeks. Social isolation and alcohol drinking during adolescence increased aggressive-like behavior in male adult Wistar rats, but not females, and did not alter anxiety measures. Baseline frequency of sIPSCs was decreased in socially isolated male Wistar and msP adult rats vs. group-housed, while rise times, amplitudes, and decay times remained unchanged, indicating reduced basal presynaptic GABA release in the CeA. Together, these findings suggest that an intermittent social isolation produces increased alcohol preference in Wistar rats of both sexes and in male msPs, as well as synaptic changes in the CeA.Copyright © 2023
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Purpose of Study Non-diabetic COVID-19 patients with elevated admission fasting blood glucose levels ('hyperglycemia') inexplicably have an increased 28 day mortality and higher inhospital complications including the Acute Respiratory Distress Syndrome (ARDS) but potentially contributing blood glucose changes during ARDS development were not reported (Wang S et al: Diabetologia 2020). Our goal was to determine blood glucose alterations before and during acute lung injury development in a rat model used to study ARDS. Methods Used We sequentially evaluated blood glucose levels for 24 hours and lung lavage protein levels (lung permeability) and lung lavage neutrophil numbers (lung inflammation) at 24 hours to assess acute lung injury ('ARDS') in young (~3 month) and old (~12 month) control and a novel strain of hyperoxia surviving 'resistant' rats before and after administering high and low insulin doses and before and after interleukin- 1/lipopolysaccharide (IL-1/LPS) insufflation. Summary of Results Glucose levels increase rapidly and sequentially in young control, but not young resistant, rats peaking ~2 hours after insufflation. Glucose levels also increase in old control and old resistant rats after insufflation compared to young control and young resistant rats after insufflation. The pattern of glucose levels at 2 hours after insufflation resembles lung lavage proteins and neutrophils at 24 h after insufflation (table 1). Administering high insulin (High In) doses decreases glucose levels ('hypoglycemia') and worsens ARDS while administering low insulin (Low In) doses correct glucose levels and improve ARDS. Conclusions Hyperglycemia develops in both young and old rats developing ARDS and high or low glucose levels parallel worse acute lung inflammation and acute lung injury ('ARDS'). Controlling glucose judiciously with insulin may be beneficial in combatting ARDS caused by SARS-CoV-2 infection and other insults.
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Background: Post-COVID conditions are a wide range of new, returning, or ongoing health problems employees can experience more than four weeks after first being infected with the COVID-19 virus. Long term complications of COVID drastically affects the productivity of working population. Objective(s): A cluster of employees with COVID-19 infection were successively intervened at TATA Motors, Jamshedpur. We aimed to reduce the post COVID complications amongst infected employees thereby reducing the morbidity and improving the productivity at workplace. Method(s): Employees with COVID-19 (confirmed by RAT/ CBNAAT or RT-PCR) were retrospectively enrolled. Based on various international guidelines, Post COVID functional status Scale and Post-COVID Mental Stress Assessment Scale were developed and introduced amongst target population. Employees with poor functional status Scale score (with score 3 and 4) were undergone mandatory preventive health checks (including physical, systemic, radiology/pathology examination). Employees with high mental stress score (with score 15 and above) were undergone psychiatric evaluation. Follow up assessment was done after six months. Result(s): 590 employees who got diagnosed COVID Positive between March 11, 2021, and June 9, 2021, were retrospectively enrolled. Universal sampling method was used for subject selection. The cohort included 519 (88%) men and 71 (12%) women, and the mean age was 45 5 years. The mean number of employees with poor functional status score (score 3 and 4) was 48 (8.1%). The mean number of employees with moderate mental stress score (score 10 to 14) was 27 (4.5%) and severe mental stress score (score 15 to 19) was 11 (1.8%). Employees with history of hospitalization (for more than 3 days) predominantly got diagnosed with poor functional and mental stress score (46 out of total 158 hospitalizations). At the end of six months interventions, around 42 (87%) employees got migrated from poor score category to mild category. The prevalence of major chronic systemic illnesses (3 cases of chronic Cardiac disease, 2 cases of Chronic Respiratory issues and 2 cases of psychiatry illnesses) remained below national prevalence. Conclusion(s): Preventive health interventions are really effective in achieving the prevalence of Post COVID morbidities amongst employees below the average national prevalence. Repeated medical follow up after first and six months of infection ensured better physical and mental wellbeing of employees improving their productivity at workplace. .
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Background and Aims: The covid-19 pandemic has reversed years of progress in the fight to end tuberculosis. So, the discovery of new drugs as antituberculosis is very much needed. Our previous studies have shown that the extract of Centella asiatica is able to inhibit the growth of Mycobacterium tuberculosis in vitro and requires further research. The aims of this study is to prove the effect of Centella asiatica inhibit Mycobacterium tuberculosis in rat model tuberculosis. Method(s): The protocol in this study was approved by the veterinary ethics committee of Airlangga University. The rat tuberculosis model was induced by intrathecal injection of a suspension of Mycobacterium tuberculosis strain H37 Rv. Twenty-eight tuberculosis rat were randomly divided into four groups. Groups 1,2, and 3 were treated with ethanol extract of Centella asiatica at 375 mg/kgBW, 750 mg/kgBW and 1500 mg/kgBW, and the fourth group was the control group. Centella asiatica extract is administered orally via an intragastric feeding tube for two weeks, once daily At the end of the experimental period, rats were sacrificed by cervical decapitation. The left lung tissue was taken aseptically and cultured on Middlebrook 7H10. Result(s): The results showed that there was no bacterial growth on the culture media in the group that received Centella asiatica extract at a dose of 750 and 1500 mg/kg BW. Conclusion(s): The conclusion in this study, that Centella asiatica extract inhibit the growth of Mycobacterium tuberculosis at doses of 750 and 1500 mg/kg BW. We thank the Directorate of Research and Community Services, the Directorate General of Higher Education, and Ministry of Education and Culture in Indonesia for the financial supportCopyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
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Background Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that emerged in late 2019 continues to spread globally. Reverse transcriptase polymerase chain reaction (RT-PCR), which is considered the gold standard for diagnosis, does not always indicate contagiousness. This study was planned to evaluate the performance of the rapid antigen test (RAT) with the duration of symptoms and the usefulness of these tests in determining the infectivity of patients by performing sub-genomic RT-PCR. Methodology This prospective, observational study was designed to compare the diagnostic value of the COVID-19 RAT (SD Biosensor, Korea) with COVID-19 RT-PCR (Thermo Fisher, USA) by serial testing of patients. To evaluate the infectivity of the virus, sub-genomic RT-PCR was performed on previous RAT and RT-PCR-positive samples. Results Of 200 patients, 102 were positive on both RT-PCR and RAT, with 87 patients serially followed and tested. The sensitivity and specificity of RAT were 92.73% and 93.33%, respectively, in symptomatic patients. The mean duration of RAT positivity was 9.1 days, and the mean duration of RT-PCR positivity was 12.6 days. Sub-genomic RT-PCR test was performed on samples that were reported to be positive by RAT, and 73/87 (83.9%) patients were found to be positive. RAT was positive in symptomatic patients whose duration of illness was less than 10 days or those with a cycle threshold value below 32. Conclusions Thus, RAT can be used as the marker of infectivity of SARS-CoV-2 in symptomatic patients, especially in healthcare workers.
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OBJECTIVES: Saliva is one of the most promising body fluids in the research of new biomarker for various diseases diagnosis. However, serial sampling in this condition is very dangerous and pose iatrogenic anemia with blood loss. This study was done to evaluate the cost-effectiveness of point-of-care salivary tests and identify the validity of salivary markers. METHODS: Rats were randomly assigned to four experimental groups: (1) control (2) IR-3 h (3) IR-6 h (4) IR-24 h. Both renal pedicles were occluded for 55 min and then were declamped to allow reperfusion for 3, 6 and 24 h in IR groups. After reperfusion, all rats received pilocarpine 1 mg/kg to collect saliva. Plasma samples were also collected. Renal parameters including Cr, uric acid, and urea, malondialdehyde (MDA) levels, Bax/Bcl2 ratio, nitrite/nitrate ratio, corticosterone levels and oxidant/antioxidant ratio were measured in both plasma and salivary samples. RESULTS: There were significant increased level of renal function parameters, MDA levels, Bax/Bcl2 ratio, nitrite/nitrate ratio and corticosterone in both saliva and plasma. The comparison of above parameters in both saliva and plasma showed significant correlation. CONCLUSIONS: This study demonstrated that concentrations of indices specifically renal functional parameters increase in saliva in the IR-induced kidney injury in male rats and result indicate the potential of saliva as a tool to monitoring AKI. Measurement of salivary parameters may can become reliable diagnostic tests for patients with AKI.
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Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase involved in the metabolism of biologically active peptides. Its most important physiological function is the conversion of angiotensin II to angiotensin-(1–7), which initiates the protective arm of the renin–angiotensin system (RAS). To evaluate the physiological relevance of this revision of the RAS, numerous different animal models have been engineered with genetic alterations in ACE2 expression. The characterization of ACE-deficient mice led to the discovery of a second function of the protein being responsible for the trafficking of the neutral amino acid transporter B(0)AT1 to the plasma membrane of gut epithelial cells, thereby promoting the intestinal uptake of certain amino acids. These two different functions are mediated by two domains of ACE2 with homologies to ACE and to collectrin, respectively, which have been fused during evolution. Moreover, some coronaviruses, such as SARS-CoV and SARS-CoV-2, hijack ACE2 for their entry into host cells, and again genetically altered mouse models expressing human ACE2 became instrumental to study virus infection and to develop therapeutic strategies. This chapter will summarize the different transgenic and knockout mouse and rat models with altered expression of ACE2 and the insights they have provided for the functions of this versatile protein. © 2023 Elsevier Inc. All rights reserved.
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Background and purpose: The sequence of Omp25 is conserved in all Brucella species. The high antigenicity of the product of this gene stimulates the host's immune system. Using engineered probiotic bacteria is an appropriate method for vaccine transport. The aim of this study was to express the Omp25 of the Brucella abortus pathogenic bacterium in Lactococcus lactis probiotic bacterium. Materials and methods: In this experimental study, the required vector was designed and synthesized to include the gene of interest and a signal peptide (pNZ8148-Usp45-Omp25). E. coli strain TOP10F was transformed using the pNZ8148-Usp45-Omp25 expression vector based on induction by nisin. The recombinant plasmid was extracted from the transformed bacteria using a plasmid extraction kit. The L. lactis was transformed by pNZ8148-Usp45-Omp25 vector using electroporation. Evaluation of the expression of Omp25 gene at the RNA level was assessed by reverse transcription method and confirming the presence of recombinant Omp25 protein in the engineered bacteria using SDS-PAGE method. Results: Successful expression of B. abortus Omp25 in L. lactis was verified by RT-PCR. Subsequently, the proteins were separated based on molecular weight using sodium dodecyl sulfate- polyacrylamide gel electrophoresis (SDS-PAGE). The protein expression analysis showed the expression of Omp25 as a 25 kDa extra band in transformed L. lactis compared to the L. lactis receiving the vector lacking the target gene. Conclusion: This study shows that Omp25 is expressed in L. lactis transformed via pNZ8148-Usp45-Omp25 by electroporation. Transformed L. lactis can be successfully used as a subunit oral vaccine in prevention of Brucellosis.
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The overall survival rate of extracorporeal life support (ECLS) remains at 60%. Research and development has been slow, in part due to the lack of sophisticated experimental models. This publication introduces a dedicated rodent oxygenator ("RatOx") and presents preliminary in vitro classification tests. The RatOx has an adaptable fiber module size for various rodent models. Gas transfer performances over the fiber module for different blood flows and fiber module sizes were tested according to DIN EN ISO 7199. At the maximum possible amount of effective fiber surface area and a blood flow of 100 mL/min, the oxygenator performance was tested to a maximum of 6.27 mL O2/min and 8.2 mL CO2/min, respectively. The priming volume for the largest fiber module is 5.4 mL, while the smallest possible configuration with a single fiber mat layer has a priming volume of 1.1 mL. The novel RatOx ECLS system has been evaluated in vitro and has demonstrated a high degree of compliance with all pre-defined functional criteria for rodent-sized animal models. We intend for the RatOx to become a standard testing platform for scientific studies on ECLS therapy and technology.
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DSPAα1 is a potent rude thrombolytic protein with high medicative value. DSPAα1 has two natural N-glycan sites (N153Q-S154-S155, N398Q-K399-T400) that may lead to immune responses when administered in vivo. We aimed to study the effect of its N-glycosylation sites on DSPAα1 in vitro and in vivo by mutating these N-glycosylation sites. In this experiment, four single mutants and one double mutant were predicted and expressed in Pichia pastoris. When the N398Q-K399-T400 site was mutated, the fibrinolytic activity of the mutant was reduced by 75%. When the N153Q-S154-S155 sites were inactivated as described above, the plasminogen activating activity of its mutant was reduced by 40%, and fibrin selectivity was significantly reduced by 21-fold. The introduction of N-glycosylation on N184-G185-A186T and K368N-S369-S370 also considerably reduced the activity and fibrin selectivity of DSPAα1. The pH tolerance and thermotolerance of all mutants did not change significantly. In vivo experiments also confirmed that N-glycosylation mutations can reduce the safety of DSPAα1, lead to prolonged bleeding time, non-physiological reduction of coagulation factor (α2-AP, PAI) concentration, and increase the risk of irregular bleeding. This study ultimately demonstrated the effect of N-glycosylation mutations on the activity and safety of DSPAα1.
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The COVID-19 pandemic is raging across the globe, with the total active cases increas-ing each day. Globally over 63 million COVID-19cases and more than 1.4 million deaths have been reported to WHO. Throughout the world, academicians, clinicians and scientists are working tirelessly on developing a treatment to combat this pandemic. The origin of novel SARS-CoV-2 virus still remains foggy but is believed to have originated from a bat coronavirus RaTG13 with which it shares approximately 96% sequence similarity. In the present review, the authors have pro-vided an overview of the COVID-19 pandemic, epidemiology, transmission, developments related to diagnosis, drugs and vaccines, along with the genetic diversity and lifecycle of the SARS-CoV-2 based on the current studies and information available.Copyright © 2022 Bentham Science Publishers.
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Introduction & Objectives: Patients with high risk non muscle invasive bladder cancer (NMIBC) who experience BCG failure have limited bladder preserving treatment options as radical cystectomy currently represents the standard therapeutical approach. Systematic immunotherapy (IO) has changed the landscape in advanced bladder cancer and is currently being investigated in NMIBC. Based on the hypothesis that intravesical administration will not be related with severe adverse events, we evaluated the role of intravesically administered durvalumab in NMIBC patients after BCG failure. Material(s) and Method(s): An open label, single-arm, multi-center, phase II clinical trial was conducted. A run-in phase had the objective to determine the maximum tolerated dose (MTD) of durvalumab and to exclude a detrimental effect on disease relapse by this strategy. Durvalumab was administered for a total of 6 instillations per patient at consecutive levels of 500, 750 and 1000 mg. Phase II has as primary end point the 1-year high-grade-relapse-free (HGRF)-rate. Secondary endpoints included toxicity, and high-grade progression-free rat at 1, 3 and 6 months after treatment. Result(s): Thirty patients were enrolled (run in phase: 9, phase II: 21). One patient withdrew consent prior to receiving study treatment, so 29 patients were included in efficacy and toxicity analyses. Mean age was 66.5 years. MTD of durvalumab was set at 1000 mg as no dose related toxicities (DLTs) occurred at any level studied. Three of 9 patients included in the run-in phase (33.3%) were tumor free one month after the last durvalumab instillation, therefore, the null hypothesis was rejected by the futility analysis. Western blot showed that durvalumab remained stable in urine during instillation. One patient died from Covid-19, 3 months after the last durvalumab administration. All patients concluded at least 1 year follow up. One-year HGRF rate was 34.6%. HGRF rates at 1, 3 and 6 months was 73%, 65.3% and 50% respectively. Five patients (17%) experienced a T2 or above disease relapse. Five out of the six patients who received 500mg or 750mg of durvalumab relapsed within 1 year. When efficacy analyses were restricted to patients receiving 1000mg of durvalumab, 1-year HGRF rate was 35%. Interestingly, 2 out of 2 patients with only CIS disease at baseline experienced a tumor complete response, which was durable and was maintained at least for a year. No severe adverse events were noted. The most common adverse event was Grade 1 hematuria. Conclusion(s): Intravesical IO using durvalumab was proved to be feasible with an excellent safety profile. Oncological results seem to be promising and comparable with other bladder preserving strategies in BCG failure with the advantage of a better safety profile. Further study of intravesical IO in high-risk patients with NMIBC after BCG failure is warranted.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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Objective: Pegagan embun (Hydrocotyle sibthorpioides Lam.) is one of the herbs used in ethnomedicines as an immunostimulant during the COVID-19 pandemic. This present study aims to discover the potential toxicity effect of pegagan embun extract through sub-acute administration on the SGPT and SGOT levels of Wistar white male rats. Method(s): Thirty-six test animals were divided into four groups: the control group was given Na CMC 0.5%, and the treatment groups were treated with ethanol extract of pegagan embun at doses of 7, 35, and 150 mg/kgBW. All groups were treated orally for 7, 14, and 21 d once daily. On the 8th, 15th, and 22nd day, the SGPT and SGOT of the test animal level were measured. The data were analyzed by two-way ANOVA followed by Duncan's multiple range test (p<0.05). Result(s): The study revealed that administration of pegagan embun extract did not cause any harmful effect on the liver but significantly decreased the level of SGPT and SGOT influenced by the variety of doses and duration of administration (p<0.05). Significant reductions in SGPT and SGOT levels are seen after extract administration at dosages of 7 mg/kgBW for 21 d. Conclusion(s): This study showed that pegagan embun (Hydrocotyle sibthorpioides Lam.) extract sub-acute administration at doses of 7, 35, and 150 mg/kgBW is relatively non-toxic and safe to be used as an immunostimulant. There was no sign of damage showed in the liver of treated rats based on the levels of SGOT and SGPT.Copyright © 2023 The Authors. Published by Innovare Academic Sciences Pvt Ltd.
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The proceedings contain 67 papers. The topics discussed include: role of endomyocardial biopsy in differential diagnosis of non- -ischemic cardiomyopathy;metformin treatment is associated with improved quality of life and outcome in patients with diabetes and advanced heart failure (HFREF);translational research in the field of inherited arrhythmias;same day discharge via a dedicated radial lounge - results of 1-year experience during the COVID-19 pandemic;functional assessment of microcirculation in takotsubo cardiomyopathy - a pilot study;an interplay of genetics and inflammation affecting left ventricular reverse remodeling in dilated cardiomyopathy;sildenafil inhibits pulmonary hypertension induced by left heart pressure overload in rats;predicting long-term survival after an ischemic stroke;and longitudinal trends in blood pressure, prevalence, awareness, treatment, and control of hypertension in the Czech population. are there any sex differences?.