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BioRxiv : the Preprint Server For... May 2024Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for...
UNLABELLED
Cyclin-dependent kinase 9 (CDK9) coordinates signaling events that regulate RNA polymerase II (Pol II) pause-release states. It is an important co-factor for transcription factors, such as MYC, that drive aberrant cell proliferation when their expression is deregulated. CDK9 modulation offers an approach for attenuating dysregulation in such transcriptional programs. As a result, numerous drug development campaigns to inhibit CDK9 kinase activity have been pursued. More recently, targeted degradation has emerged as an attractive approach. However, comprehensive evaluation of degradation versus inhibition is still critically needed to assess the biological contexts in which degradation might offer superior therapeutic benefits. We validated that CDK9 inhibition triggers a compensatory mechanism that dampens its effect on MYC expression and found that this feedback mechanism was absent when the kinase is degraded. Importantly, CDK9 degradation is more effective than its inhibition for disrupting MYC transcriptional regulatory circuitry likely through the abrogation of both enzymatic and scaffolding functions of CDK9.
HIGHLIGHTS
- KI-CDK9d-32 is a highly potent and selective CDK9 degrader. - KI-CDK9d-32 leads to rapid downregulation of MYC protein and mRNA transcripts levels. - KI-CDK9d-32 represses canonical MYC pathways and leads to a destabilization of nucleolar homeostasis. - Multidrug resistance ABCB1 gene emerged as the strongest resistance marker for the CDK9 PROTAC degrader.
PubMed: 38952800
DOI: 10.1101/2024.05.14.593352 -
MedRxiv : the Preprint Server For... May 2024HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which...
INTRODUCTION
HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the World Health Organization in 2019 for first-, second-, and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance.
METHODS AND ANALYSIS
DTG RESIST is a multicentre longitudinal study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virologic failure on dolutegravir-based ART. At the time of virologic failure whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (i) individuals who experienced virologic failure on dolutegravir, and (ii) on those who started or switched to such a regimen and were at risk of virologic failure. For population (i), the outcome will be any InSTI drug resistance mutations, and for population (ii) virologic failure defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virologic failure and limited power for analysing factors associated with individual InSTI drug resistance mutations.
ETHICS AND DISSEMINATION
The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa, and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in IeDEA and have obtained ethics approval from their local ethics committee to conduct the additional data collection.
REGISTRATION
NCT06285110.
STRENGTHS AND LIMITATIONS OF THIS STUDY
- DTG RESIST is a large international study to prospectively examine emergent dolutegravir resistance in diverse settings characterised by different HIV-1 subtypes, provision of ART, and guidelines on resistance testing. - Embedded within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST will benefit from harmonized clinical data across participating sites and expertise in clinical, epidemiological, biological, and computational fields. - Procedures for sequencing and assembling genomes from different HIV-1 strains will be developed at the heart of the HIV epidemic, by the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), in Durban, South Africa. Phenotypic testing, Genome Wide Association Study (GWAS) methods and Bayesian evolutionary models will explore and predict treatment failure genotypes. - A significant limitation is the absence of genotypic resistance data from participants before they started dolutegravir treatment, as collecting and bio-banking pre-treatment samples was not feasible at most IeDEA sites. Consistent and harmonized data on adherence to treatment are also lacking. - The distribution of HIV-1 subtypes across different sites is uncertain, which may limit the statistical power of the study in analysing patterns and risk factors for dolutegravir resistance. The results from GWAS and Bayesian modelling analyses will be preliminary and hypothesis-generating.
PubMed: 38952780
DOI: 10.1101/2024.05.23.24307850 -
Avicenna Journal of Phytomedicine 2024Influenza complications are mild to serious, and can cause death in some cases. A great deal of attention has been paid in recent years to the development and use of new...
OBJECTIVE
Influenza complications are mild to serious, and can cause death in some cases. A great deal of attention has been paid in recent years to the development and use of new antiviral compounds to overcome drug resistance in certain strains of the influenza virus and treat the clinical implications. This study aimed to investigate the antiviral effect of punicalagin and its associated mechanism against influenza A (H1N1) virus .
MATERIALS AND METHODS
the ant-influenza activity of punicalagin was studied in Madin-Darby Canine Kidney (MDCK) cells using influenza virus A/Puerto Rico/8/34 (H1N1) (PR8) using Hemagglutinin assay (HA) and 50% tissue culture infective dose (TCID). Then, the inhibition of haemagglutination, virucidal activity, inhibitory effect at different times, replication of viral RNA and expression of viral genes were investigated.
RESULTS
Punicalagin could inhibit influenza virus infection with 50% inhibitory concentration (IC) of 3.98 μg/ml and selectivity index (SI) value of 6.1. Punicalagin decreased virus titers with an inhibitory effect on virus hemagglutination (p<0.05). Punicalagin also inhibited viral adsorption. The results of virus RNA replication and viral mRNA (NS1 and HA) expression after treatment with punicalagin showed significant suppression of viral mRNA expression but no effect on replication of viral RNA.
CONCLUSION
The results of the present study indicated that punicalagin was effective against influenza infection most probably via inhibition of haemagglutination activity and virus binding.
PubMed: 38952775
DOI: 10.22038/AJP.2023.23389 -
IScience Jun 2024The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment...
The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment of a novel genetic technique to repress gene expression in , the primary causal fungus of dermatophytosis, we demonstrated that fungal Cdc42 and Rac GTPases are promising antifungal drug targets. Chemical inhibitors of these GTPases impair hyphal formation, which is crucial for growth and virulence in . Conditional repression of Cdc24, a guanine nucleotide exchange factor for Cdc42 and Rac, led to hyphal growth defects, abnormal cell morphology, and cell death. EHop-016 inhibited the promotion of the guanine nucleotide exchange reaction in Cdc42 and Rac by Cdc24 as well as germination and growth on the nail fragments of and improved animal survival in an invertebrate infection model of . Our results provide a novel antifungal therapeutic target and a potential lead compound.
PubMed: 38952678
DOI: 10.1016/j.isci.2024.110139 -
Iranian Journal of Medical Sciences Jun 2024Spontaneous bacterial peritonitis (SBP) is a fatal complication of ascites fluid infection. The causes of SBP in children differ from those in adults, and these bacteria...
Clinical Findings, Bacterial Agents, and Antibiotic Resistance in Children with Spontaneous Peritonitis in Southern Iran: An Academic Tertiary Referral Center's Experience.
BACKGROUND
Spontaneous bacterial peritonitis (SBP) is a fatal complication of ascites fluid infection. The causes of SBP in children differ from those in adults, and these bacteria are frequently resistant to antibiotics. Therefore, this study investigated the clinical findings, bacterial etiology, and antimicrobial resistance in children with SBP.
METHODS
This study was conducted on all new pediatric ascites patients, who were admitted to the Department of Pediatric Gastroenterology, Namazi Hospital, affiliated with Shiraz University of Medical Sciences (Shiraz, Iran) from 2021 to 2022. Required data such as demographic information, and clinical information such as complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Gram staining, blood culture by Automated Blood Culture System (BACTEC), and antibiogram of ascites fluids by disc diffusion method were all collected. Finally, the data were statistically analyzed using SPSS Software (version 26). Besides, the test, Fisher's exact, Mann-Whitney, and Chi square tests were used for data analysis. In all tests, P≤0.05 was considered statistically significant.
RESULTS
The present study examined 62 children with ascites of which 18 (29%) had SBP. The median (IQR) age was 2.5 (8.1) years. Thirty-four (54.8%) of the participants were girls. Abdominal pain was the most common clinical manifestation in patients (54%), and there was a significant association between abdominal pain and SBP (P=0.02). In 12 positive ascites fluid cultures, coagulase-negative staphylococci had the highest frequency (25%), followed by (16.7%). Third-generation cephalosporins had a 25% sensitivity in the total positive cultures. This sensitivity was 33.3% for Gram-negative cultures and 16.6% for Gram-positive cultures.
CONCLUSION
Although third-generation cephalosporins are recommended as the primary antibiotic for the empirical treatment of SBP, the present study found high bacterial resistance. Finally, empirical therapy should be tailored to each region's bacterial resistance features.
Topics: Humans; Peritonitis; Child; Female; Male; Iran; Child, Preschool; Anti-Bacterial Agents; Tertiary Care Centers; Infant; Adolescent; Drug Resistance, Bacterial; Ascites; Bacterial Infections; Microbial Sensitivity Tests
PubMed: 38952643
DOI: 10.30476/ijms.2023.98747.3082 -
Frontiers in Oncology 2024B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with... (Review)
Review
B7-H3 (CD276), an immune checkpoint molecule, is overexpressed in various types of cancer and their tumor vasculature, demonstrating significant associations with adverse clinical outcomes. In addition to its well-known immune functions, B7-H3 exhibits dual co-stimulatory/co-inhibitory roles in normal physiology and the tumor microenvironment. The non-immune functions of B7-H3 in tumor cells and the tumor vasculature, including promoting tumor cell anti-apoptosis, proliferation, invasion, migration, drug resistance, radioresistance, as well as affecting cellular metabolism and angiogenesis, have increasingly gained attention from researchers. Particularly, the co-expression of B7-H3 in both tumor cells and tumor endothelial cells highlights the higher potential and clinical utility of therapeutic strategies targeting B7-H3. This review aims to summarize the recent advances in understanding the non-immune functions of B7-H3 in tumors and provide insights into therapeutic approaches targeting B7-H3, focusing on its co-expression in tumor cells and endothelial cells. The aim is to establish a theoretical foundation and practical reference for the development and optimization of B7-H3-targeted therapies.
PubMed: 38952550
DOI: 10.3389/fonc.2024.1408051 -
Materials Today. Bio Jun 2024Smart dressings integrated with bioelectronics have attracted considerable attention and become promising solutions for skin wound management. However, due to the...
Smart dressings integrated with bioelectronics have attracted considerable attention and become promising solutions for skin wound management. However, due to the mechanical distinction between human body and the interface of electronics, previous smart dressings often suffered obvious degradation in electrical performance when attached to the soft and curvilinear wound sites. Here, we report a stretchable dressing integrated with temperature and pH sensor for wound status monitoring, as well as an electrically controlled drug delivery system for infection treatment. The wound dressing was featured with the deployment of liquid metal for seamless connection between rigid electrical components and gold particle-based electrodes, achieving a stretchable soft-hard interface. Stretching tests showed that both the sensing system and drug delivery system exhibited good stretchability and long-term stable conductivity with the resistance change rate less than 6 % under 50 % strain. Animal experiments demonstrated that the smart dressing was capable of detecting bacterial infection via the biomarkers of temperature and pH value and the infection factors of wound were significantly improved with therapy through electrically controlled antibiotics releasing. This proof-of-concept prototype has potential to significantly improve management of the wound, especially those with dynamic strain.
PubMed: 38952538
DOI: 10.1016/j.mtbio.2024.101107 -
Pakistan Journal of Medical Sciences Jul 2024This study was aimed to investigate the multidrug resistance patterns in clinical isolates of and their correlation with integrons and phylogenetic groupings.
OBJECTIVE
This study was aimed to investigate the multidrug resistance patterns in clinical isolates of and their correlation with integrons and phylogenetic groupings.
METHODS
A total of 37 clinical isolates were evaluated for drug resistance patterns by disk diffusion method. Phylogenetic groupings and the presence of integrons among were determined by multiplex PCR assays.
RESULTS
Multidrug resistance was identified in 84% of the clinical isolates of with higher resistance found against cephalosporins (94.6%) and fluoroquinolones (83.8%), while lower resistance was observed against polymyxins (24.3%) and carbapenems (29.7%). Metallo-β-lactamases were found in all carbapenem resistant isolates. The phylogenetic group B2 was the most dominant (40.5%), followed by groups A (35.1%), D (13.5%) and B1 (10.8%). Integrons were detected in 25 (67.6%) isolates and , , and genes were found in 62.2%, 18.9% and 10.8% of isolates respectively.
CONCLUSION
Our results show that phylogenetic classification of is not relevant with antimicrobial resistance. However, there was strong association between the integron classes and resistance against β-lactam and fluoroquinolones antimicrobials. Additionally, this study highlighted that the presence of integrons plays a crucial role in the development of multidrug resistance in clinical isolates of . Most significantly, this is the first report of detection of three classes of integron among clinical isolates of in Pakistan.
PubMed: 38952530
DOI: 10.12669/pjms.40.6.8886 -
Pakistan Journal of Medical Sciences Jul 2024To determine the antimicrobial activity of silver nano-particles(AgNPs) with tetracycline and ampicillin against multi-drug resistance (MDR) and extensively-drug...
OBJECTIVES
To determine the antimicrobial activity of silver nano-particles(AgNPs) with tetracycline and ampicillin against multi-drug resistance (MDR) and extensively-drug resistance (XDR) .
METHODS
Cross sectional non-probability purposive study was conducted from September, 2021 to May, 2022 at Microbiology department PNS Shifa, Hospital Karachi. Blood cultures of patients suspicious of typhoid fever were collected and incubated in automated Bact/Alert system. Positive cultures were identified on blood and MacConkey and processed by API-10S, confirmed by serotyping (O9 antisera) (SSI Diagnostica's . Antibiotic resistance was done by Kirby-Bauer disk diffusion (Sigma and Rich). MDR and XDR isolates were preserved in Brain Heart Infusion in a volume of 2ml in screw capped bottles at -70°C. Antimicrobial powders (ampicillin and tetracycline (Alfa Aesar) weighed by an electrical weighing balance (OHAUS) to take 1mg of antimicrobial drug. Absorbance spectra of serial concentrations of antibiotics (UV-Vis spectrophotometer (Mole-Qule-) AgNPs (10nm) (nanocomposix) + Antibiotic in (1:1 volume ratio). Conjugation of silver nanoparticles with tetracycline and ampicillin was done by FTIR (thermos scientificThermos ScientificNicolet 50).
RESULTS
Out of 77 isolates, 54 were resistant to ceftriaxone (XDR) and 23 sensitive to ceftriaxone (MDR). All isolates were susceptible to azithromycin and meropenem. Comparison of zone of inhibitions of ampicillin and Amp-AgNPsas and tetracycline with Tet-AgNPs was done. Minimal inhibitory concentration was also done to determine antimicrobial activity.
CONCLUSION
Significant synergistic inhibitory effects against isolates were obtained by combination of tetracycline with silver nano-particles even at low concentration.
PubMed: 38952512
DOI: 10.12669/pjms.40.6.7900 -
Pakistan Journal of Medical Sciences Jul 2024Identification of MBL, AmpC and ESBLs in colistin intrinsic and acquired resistant uropathogenic gram negative bacteria.
OBJECTIVE
Identification of MBL, AmpC and ESBLs in colistin intrinsic and acquired resistant uropathogenic gram negative bacteria.
METHOD
Urine samples were collected from Hayatabad Medical Complex, Peshawar during 17 January to 30 June 2019. Collected urine samples were aseptically transported microbiology lab of Health Research Institution (HRI), National Institute of Health (NIH), Khyber Medical College, Peshawar and streaked on different media. Positive growth was identified by API-10s. Antibiotic sensitivity profile was done by Modified Kirby Bauer disc diffusion method. Detection of metallo βlactamases (MBL) production by Imipenem EDTA synergy test, Double Disc Synergy Test (DDST) for detection of ESBLs and D-test for the detection of inducible AmpC beta lactamases test was used. Colistin resistance was identified via broth micro dilution according to CLSI manual. Colistin resistant bacteria was divided in two categories; acquired and intrinsic resistant bacteria according to CLSI manual.
RESULTS
Out of 2000 urine samples, 281(14%) gram-negative bacteria were isolated. Among positive samples, acquired colistin resistant bacteria were 241 and intrinsic resistant bacteria were 40 isolates. MBL was produce by twenty one (11.7%) and seventeen (40.5 and were ESBLs producing bacteria. AmpC production was prevalent in fourteen (7.8%) and twelve (28.6. Fifty-five samples showed resistance to colistin out of 241 samples. In colistin resistant bacteria, two were MBL, ESBLs, while one was ESBLs, AmpC co-producing bacteria. The most prevalent extended drug resistant bacteria were 6.1%), While 155(86.6%) , 25 (59.5%) and 22 (95.7%) was multi drug resistant bacteria.
CONCLUSION
Current study concluded that ESBL, MBL AmpC enzymes and their co-expression was observed with colistin resistance in and .
PubMed: 38952491
DOI: 10.12669/pjms.40.6.8516