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BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects. METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimens to prevent antagonistic effects. CONCLUSIONS: This work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

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INTRODUCTION: The renin-angiotensin system (RAS) has been demonstrated to modulate cell proliferation, desmoplasia, angiogenesis and immunosuppression. We examined the association of RAS inhibitors (RASi)-namely angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB)-with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) preceding radical cystectomy (RC). PATIENTS AND METHODS: We retrospectively investigated concurrent RASi use with NAC prior to RC in 302 patients with MIBC from 3 academic institutions. Outcomes included pathologic complete response (pCR) and overall survival (OS). Pathologic features, performance status (PS), clinical stage, type/number of cycles of NAC, and toxicities were collected. RESULTS: Overall pCR rate was 26.2% and 5-year OS was 62%. Concurrent ACEi intake with NAC approached significance for association with pCR (odds ratio [OR] = 1.71; 95% CI, 0.94-3.11; P = .077). Patients with cT3/4N0-N1 disease receiving ACEi had higher pCR rates (30.8% vs. 17.7%, P = .056) than those not on ACEi. Female sex had a statistically significant favorable interaction for pCR with ACEi intake (P = .044). ACEi intake was not associated with OS, while pCR, PS and lower clinical stage were significantly associated with improved OS. CONCLUSION: ACEi intake is potentially associated with increased pCR in patients with MIBC receiving NAC prior to RC, and this association is more pronounced in patients with higher clinical stage of disease at the initiation of therapy and female sex. Our data suggest the potential relevance of the RAS as a therapeutic target in aggressive MIBC.

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Alkaloid-based urea derivatives were produced with high yield through the reaction of anabasine and cytisine with isoxazolylphenylcarbamates in boiling benzene. Their antitumor activity, in combination with the commonly used five anticancer drugs, namely cyclophosphane, fluorouracil, etoposide, cisplatin, ribomustine with different mechanisms of action, was investigated. Based on the quantum chemical calculations data and molecular docking, hypotheses have been put forward to explain their mutual influence when affecting C6 rat glioma model cells.

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The SS18-SSX fusion protein is an oncogenic driver in synovial sarcoma. At the molecular level, SS18-SSX functions as both an activator and a repressor to coordinate transcription of different genes responsible for tumorigenesis. Here, we identify the proto-oncogene FYN as a new SS18-SSX target gene and examine its relation to synovial sarcoma therapy. FYN is a tyrosine kinase that promotes cancer growth, metastasis and therapeutic resistance, but SS18-SSX appears to negatively regulate FYN expression in synovial sarcoma cells. Using both genetic and histone deacetylase inhibitor (HDACi)-based pharmacologic approaches, we show that suppression of SS18-SSX leads to FYN reactivation. In support of this notion, we find that blockade of FYN activity synergistically enhances HDACi action to reduce synovial sarcoma cell proliferation and migration. Our results support a role for FYN in attenuation of anti-cancer activity upon inhibition of SS18-SSX function and demonstrate the feasibility of targeting FYN to improve the effectiveness of HDACi treatment against synovial sarcoma.

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A unique approach is imperative for the development of drugs aimed at inhibiting various stages of infection, rather than solely focusing on bacterial viability. Among the array of unconventional targets explored for formulating novel antimicrobial medications, blocking the quorum-sensing (QS) system emerges as a highly effective and promising strategy against a variety of pathogenic microbes. In this investigation, we have successfully assessed nine α-aminoamides for their anti-QS activity using Agrobacterium tumefaciensNT1 as a biosensor strain. Among these compounds, three (2, 3and, 4) have been identified as potential anti-QS candidates. Molecular docking studies have further reinforced these findings, indicating that these compounds exhibit favorable pharmacokinetic profiles. Additionally, we have assessed the ligand's stability within the protein's binding pocket using molecular dynamics (MD) simulations and MMGBSA analysis. Further, combination of antiquorum sensing properties with antibiotics viaself-assembly represents a promising approach to enhance antibacterial efficacy, overcome resistance, and mitigate the virulence of bacterial pathogens. The release study also reflects a slow and gradual release of the metronidazole at both pH 6.5 and pH 7.4, avoiding the peaks and troughs associated with more immediate release formulations.

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OBJECTIVE: Increased mupirocin use leads to mupirocin resistance and is associated with persistence of methicillin-resistant Staphylococcus aureus (MRSA) carriers, prolonged hospitalization, and significant economic burdens for health systems. The study aimed to investigate the antimicrobial activity of compounds of Salvia rosmarinus L. ("rosemary", formerly Rosmarinus officinalis), alone or in combination with mupirocin, against multidrug resistant MRSA using isolates obtained from pediatric patients. METHODS: The in vitro antibacterial activity of the monoterpene α-pinene (α-Pi), a rosemary essential oil constituent, alone and in combination with mupirocin, was evaluated by determining the minimum inhibitory concentrations and minimum bactericidal concentrations (MBCs) and the fractional inhibitory concentration indices (FICIs) and fractional bactericidal concentration indices against multidrug-resistant clinical MRSA strains. The in vivo efficacy of α-Pi, alone and in combination with mupirocin, to eradicate MRSA infection was determined using an optimized mouse model of MRSA-infected wounds. Mouse skin samples (obtained via biopsy) were assessed for toxicity, and rabbit skin samples for irritation. RESULTS: Both in vitro and in vivo, α-Pi was active against MRSA strains and acted synergistically with mupirocin against MRSA strains. Mupirocin-monoterpene combinations exhibited FICI values of 0.2 to 0.4, reducing the MBC of topical mupirocin 33-fold. A topical formulation containing α-Pi and mupirocin enhanced the efficacy of mupirocin in an in vivo MRSA-infected mouse skin model without significantly harming the skin of mice and rabbits. CONCLUSIONS: A topical formulation combining mupirocin and α-Pi may aid in the development of innovative agents for treating MRSA infections.

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Background and Aims: Emergence of multidrug resistance in non-fermenting Gram-negative bacilli is a threat to public health. Combination therapy is a strategy for the treatment of antibiotic-resistant infections. Methods: In this cross-sectional study, a total of 63 nonduplicate clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa were collected from various specimens. Identification of bacterial isolates was performed by phenotypic and molecular tests. Antibiotic susceptibility patterns and detection of ß-lactamase genes were determined using the broth microdilution and polymerase chain reaction (PCR) techniques, respectively. Then, the combined effects analysis was determined by the checkerboard method. Based on the status of resistance to carbapenems (imipenem and meropenem), 25 isolates of each genus were selected for further investigation. Results: For A. baumannii, bla OXA-23, bla OXA-58, and bla OXA-48 genes were positive in 21 (84%), 17 (68%), and 11 (44%) of isolates, respectively. In P. aeruginosa isolates, bla VIM was the most common gene (44%) and other genes including bla IMP, bla NDM, and bla OXA-23 were found in nine (36%), six (24%), and three (12%) isolates, respectively. Meropenem (MER)-tigecycline (TIG) had a significant synergistic effect against 20 (80%) A. baumannii (p value < 0.001). This combination was also efficient against 5 (20%) P. aeruginosa isolates. Moreover, the other combination, tigecycline-amikacin (TIG-AMK) was effective against 10 (40%) A. baumannii isolates. The combination of colistin (COL) and MER showed a significant synergistic effect against 21 (84%) A. baumannii (p value < 0.001) and 17 (68%) P. aeruginosa isolates (p value < 0.001). Conclusion: The MER-TIG and COL-MER combinations are promising options against resistant bacteria. Our study could be helpful for the development of a new treatment recommendation.

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Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs. Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg administered once every three weeks has substantial anti-cancer activity. It led to a median progression-free survival (PFS) of 6.7 months, which compared favorably to cisplatin and immune checkpoint inhibitors. Further, we explored the combinations of anti-miR-155 with standard-of-care drugs, and found strongly synergistic two- and three-drug combinations. A three-drug combination of anti-miR-155, cisplatin, and pembrolizumab resulted in a median PFS of 13.1 months, while a two-drug combination of anti-miR-155 and cisplatin resulted in a median PFS of 11.3 months, which emerged as a more practical option due to its simple design and cost-effectiveness. Our analyses also provided valuable insights into unfavorable dose ratios for drug combinations, highlighting the need for optimizing dose regimen to prevent antagonistic effects. Thus, this work bridges the gap between preclinical development and clinical translation of anti-miR-155 and unravels the potential of anti-miR-155 combination therapies in NSCLC.

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The in-silico strategy of identifying novel uses for already existing drugs, known as drug repositioning, has enhanced drug discovery. Previous studies have shown a positive correlation between expression changes induced by the anticancer agent trabectedin and those caused by irinotecan, a topoisomerase I inhibitor. Leveraging the availability of transcriptional datasets, we developed a general in-silico drug-repositioning approach that we applied to investigate novel trabectedin synergisms. We set a workflow allowing the identification of genes selectively modulated by a drug and possible novel drug interactions. To show its effectiveness, we selected trabectedin as a case-study drug. We retrieved eight transcriptional cancer datasets including controls and samples treated with trabectedin or its analog lurbinectedin. We compared gene signature associated with each dataset to the 476,251 signatures from the Connectivity Map database. The most significant connections referred to mitomycin-c, topoisomerase II inhibitors, a PKC inhibitor, a Chk1 inhibitor, an antifungal agent, and an antagonist of the glutamate receptor. Genes coherently modulated by the drugs were involved in cell cycle, PPARalpha, and Rho GTPases pathways. Our in-silico approach for drug synergism identification showed that trabectedin modulates specific pathways that are shared with other drugs, suggesting possible synergisms.

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The repertoire of currently available antiviral drugs spans therapeutic applications against a number of important human pathogens distributed worldwide. These include cases of the pandemic severe acute respiratory coronavirus type 2 (SARS-CoV-2 or COVID-19), human immunodeficiency virus type 1 (HIV-1 or AIDS), and the pregnancy- and posttransplant-relevant human cytomegalovirus (HCMV). In almost all cases, approved therapies are based on direct-acting antivirals (DAAs), but their benefit, particularly in long-term applications, is often limited by the induction of viral drug resistance or side effects. These issues might be addressed by the additional use of host-directed antivirals (HDAs). As a strong input from long-term experiences with cancer therapies, host protein kinases may serve as HDA targets of mechanistically new antiviral drugs. The study demonstrates such a novel antiviral strategy by targeting the major virus-supportive host kinase CDK7. Importantly, this strategy focuses on highly selective, 3D structure-derived CDK7 inhibitors carrying a warhead moiety that mediates covalent target binding. In summary, the main experimental findings of this study are as follows: (1) the in vitro verification of CDK7 inhibition and selectivity that confirms the warhead covalent-binding principle (by CDK-specific kinase assays), (2) the highly pronounced antiviral efficacies of the hit compounds (in cultured cell-based infection models) with half-maximal effective concentrations that reach down to picomolar levels, (3) a particularly strong potency of compounds against strains and reporter-expressing recombinants of HCMV (using infection assays in primary human fibroblasts), (4) additional activity against further herpesviruses such as animal CMVs and VZV, (5) unique mechanistic properties that include an immediate block of HCMV replication directed early (determined by Western blot detection of viral marker proteins), (6) a substantial drug synergism in combination with MBV (measured by a Loewe additivity fixed-dose assay), and (7) a strong sensitivity of clinically relevant HCMV mutants carrying MBV or ganciclovir resistance markers. Combined, the data highlight the huge developmental potential of this host-directed antiviral targeting concept utilizing covalently binding CDK7 inhibitors.

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Com o aumento de microrganismos resistentes nos canais radiculares, os estudos de extratos de plantas com ação antibacteriana têm aumentado visando terapias alternativas. O objetivo deste estudo foi avaliar os efeitos sinérgicos sobre Enterococcus faecalis, Enterococcus faecium, Candida albicans, Fusobacterium nucleatum e Porphyromonas gingivalis e a ação antibiofilme dos extratos hidroetanólicos de Rosmarinus officinalis L. (alecrim) e Plinia cauliflora (jabuticaba). Foram determinadas a Concentração Inibitória Mínima (CIM) e Concentração Microbicida Mínima (CMM) por microdiluição em caldo e Índice de Concentração Inibitória Fracionada e Índice de Concentração Microbicida Fracionada por microdiluição checkerboard. Posteriormente, a ação da concentração efetiva dos extratos foi avaliada sobre biofilmes formados em poços de placa de microtitulação. Os biofilmes foram expostos a dois diferentes períodos de tratamento com os extratos, por 5 min e 24 h, sendo n=10 para cada grupo experimental. Como controles foram utilizados solução salina 0,9% (C+) e hipoclorito de sódio 2,5% (C-), totalizando 5 grupos para cada microrganismo e cada tempo experimental. Em seguida, os biofilmes foram submetidos ao teste de MTT. Foram realizadas análises da atividade citotóxica dos extratos sobre as linhagens de queratinócitos humanos (HaCat) pelo teste de MTT. A análise estatística foi feita aplicando método ANOVA e teste de Dunn (significância de 5%). Ambos os extratos demonstraram fitocompostos fenólicos e flavonóides e possuem ação antioxidante. Os extratos apresentam ação antimicrobiana para as cepas estudadas e quando foram associados, apresentaram concentrações aditivas para cepa de E. faecalis. Em relação a propriedade antibiofilme, o extrato de alecrim apresentou boa redução da viabilidade microbiana de E. faecalis, com redução de 52% para o tempo de 5 min e de 40% para 24 h. Para as cepas de microrganismos anaeróbios, para a cepa de F. nucleatum, o extrato de jabuticaba reduziu em até 73% o biofilme. Para a cepa de P. gingivalis houve redução de até 41% para o extrato de jabuticaba e de até 57% para o extrato de alecrim. Quanto a citotoxicidade em HaCat, demonstrou que após tratamento com diferentes concentrações dos extratos, ambos apresentaram citotoxicidade estatisticamente semelhante ao hipoclorito de sódio 2,5%. Diante disso, pode-se concluir que ambos os extratos apresentam ação antioxidante e antimicrobiana em culturas planctônicas, exceto o extrato de jabuticaba para C. albicans. Quanto a associação dos extratos, não houve ação sinérgica, mas obteve-se resultado aditivo para cepa clínica de E. faecalis 2. A ação antibiofilme foi efetiva para as cepas de E. faecalis, F nucleatum e P. gingivalis. A citotoxicidade dos extratos apresentou semelhança estatística com o hipoclorito de sódio 2,5% para ambos. (AU)

With the increase in resistant microorganisms in root canals, studies of plant extracts with antibacterial action have increased aiming at alternative therapies. The objective of this study was to evaluate the synergistic effects on Enterococcus faecalis, Enterococcus faecium, Candida albicans, Fusobacterium nucleatum and Porphyromonas gingivalis and the antibiofilm action of hydroethanolic extracts of Rosmarinus officinalis L. (rosemary) and Plinia cauliflora (jabuticaba). The Minimum Inhibitory Concentration (MIC) and Minimum Microbicide Concentration (MCC) were determined by broth microdilution and the Fractional Inhibitory Concentration Index and Fractional Microbicide Concentration Index by checkerboard microdilution. Subsequently, the effect of the effective concentration of the extracts was evaluated on biofilms formed in microtiter plate wells. The biofilms were exposed to two different periods of treatment with the extracts, for 5 min and 24 h, with n=10 for each experimental group. As controls, 0.9% saline solution (C+) and 2.5% sodium hypochlorite (C-) were used, totaling 5 groups for each microorganism and each experimental time. Then, the biofilms were subjected to the MTT test. Analysis of the cytotoxic activity of the extracts on human keratinocyte lines (HaCat) was carried out using the MTT test. Statistical analysis was performed using the ANOVA method and Dunn's test (5% significance level). The results that both extracts demonstrated phenolic and flavonoid phytocompounds and have antioxidant action. The extracts have antimicrobial action for the strains studied and when they were combined, they presented additive concentrations only for the E. faecalis strain. Regarding the antibiofilm property, the rosemary extract showed a good reduction in the microbial viability of E. faecalis, with a reduction of 52% for 5 min and 40% for 24 h. For strains of anaerobic microorganisms, in contact with the F. nucleatum strain, the jabuticaba extract reduced biofilm by up to 73%. For the P. gingivalis strain, there was a reduction of up to 41% for the jabuticaba extract and up to 57% for the rosemary extract. As for cytotoxicity in HaCat, it was demonstrated that after treatment with different concentrations of extracts, both showed cytotoxicity statistically similar to 2.5% sodium hypochlorite. Given this, it can be concluded that both extracts have antioxidant and antimicrobial action in planktonic cultures, except the jabuticaba extract for C. albicans. Regarding the association of extracts, there was no synergistic action, but an additive result was obtained for the clinical strain of E. faecalis 2. The antibiofilm action was effective for the strains of E. faecalis, F nucleatum and P. gingivalis. The cytotoxicity of the extracts showed statistical similarity with 2.5% sodium hypochlorite for both.(AU)

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Despite the availability of currently approved antiviral drugs, infections with human cytomegalovirus (HCMV) still cause clinically challenging, sometimes life-threatening situations. There is an urgent need for enhanced anti-HCMV drugs that offer improved efficacy, reduced dosages and options for long-term treatment without risk of the development of viral drug resistance. Recently, we reported the pronounced anti-HCMV efficacy of pharmacological inhibitors of cyclin-dependent kinases (CDKs), in particular, the potential of utilizing drug synergies upon combination treatment with inhibitors of host CDKs and the viral CDK-like kinase pUL97 (vCDK/pUL97). Here, we expand this finding by further assessing the in vitro synergistic antiviral interaction between vCDK and CDK inhibitors towards HCMV as well as non-human cytomegaloviruses. An extension of this synergy approach was achieved in vivo by using the recombinant MCMV-UL97/mouse model, confirming the high potential of combination treatment with the clinically approved vCDK inhibitor maribavir (MBV) and the developmental CDK7 inhibitor LDC4297. Moreover, mechanistic aspects of this synergistic drug combination were illustrated on the levels of intracellular viral protein transport and viral genome replication. The analysis of viral drug resistance did not reveal resistance formation in the case of MBV + LDC4297 combination treatment. Spanning various investigational levels, these new results strongly support our concept, employing the great potential of anti-HCMV synergistic drug treatment.

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BACKGROUND: There is widespread consensus that adjuvant local use of antimicrobial agents in combination with their systemic administration can better prevent and treat implant-associated musculoskeletal infections. The advantage of local antibiotics lies in their particular pharmacokinetics with initially high antibiotic concentrations at the implant site with only low systemic uptake. AIM OF TREATMENT: The aim of local application is to protect the foreign bodies directly at the implantation site from bacterial colonization and biofilm formation (prophylaxis) and to support the eradication of an already established infection after surgical debridement (treatment). Since the observations of Prof. Buchholz, bone cement has been the most frequently used local carrier system. APPLICATION: In cases of infection, surgeons should ideally work together with microbiologists, infectiologists or clinical pharmacists to determine which anti-infective agents are indicated systemically for the patient and which ones are indicated locally with PMMA cement, based on the pathogen(s) and antibiograms. However, for the anti-infective agents administered with bone cement, there is still uncertainty about which agents can be added to this carrier material and at what concentrations. Accordingly, the authors of this review article not only summarize the rationale and evidence for local antibiotic use but also elaborate on the points that must be considered for admixing these agents to the cement.

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The lack of anticancer agents that overcome innate/acquired drug resistance is the single biggest barrier to achieving a durable complete response to cancer therapy. To address this issue, a new drug family was developed for intracellular delivery of the bioactive aminothiol WR1065 by conjugating it to discrete thiol-PEG polymers: 4-star-PEG-S-S-WR1065 (4SP65) delivers four WR1065s/molecule and m-PEG6-S-S-WR1065 (1LP65) delivers one. Infrequently, WR1065 has exhibited anticancer effects when delivered via the FDA-approved cytoprotectant amifostine, which provides one WR1065/molecule extracellularly. The relative anticancer effectiveness of 4SP65, 1LP65, and amifostine was evaluated in a panel of 15 human cancer cell lines derived from seven tissues. Additional experiments assessed the capacity of 4SP65 co-treatments to potentiate the anticancer effectiveness and overcome drug resistance to cisplatin, a chemotherapeutic, or gefitinib, a tyrosine kinase inhibitor (TKI) targeting oncogenic EGFR mutations. The CyQUANT®-NF proliferation assay was used to assess cell viability after 48-h drug treatments, with the National Cancer Institute COMPARE methodology employed to characterize dose-response metrics. In normal human epithelial cells, 4SP65 or 1LP65 enhanced or inhibited cell growth but was not cytotoxic. In cancer cell lines, 4SP65 and 1LP65 induced dose-dependent cytostasis and cytolysis achieving 99% cell death at drug concentrations of 11.2 ± 1.2 µM and 126 ± 15.8 µM, respectively. Amifostine had limited cytostatic effects in 11/14 cancer cell lines and no cytolytic effects. Binary pairs of 4SP65 plus cisplatin or gefitinib increased the efficacy of each partner drug and surmounted resistance to cytolysis by cisplatin and gefitinib in relevant cancer cell lines. 4SP65 and 1LP65 were significantly more effective against TP53-mutant than TP53-wild-type cell lines, consistent with WR1065-mediated reactivation of mutant p53. Thus, 4SP65 and 1LP65 represent a unique prodrug family for innovative applications as broad-spectrum anticancer agents that target p53 and synergize with a chemotherapeutic and an EGFR-TKI to prevent or overcome drug resistance.

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BACKGROUND: Acute myeloid leukaemia (AML) remains difficult to treat despite the development of novel formulations and targeted therapies. Activating mutations in the FLT3 gene are common among patients and make the tumour susceptible to FLT3 inhibitors, but resistance to such inhibitors develops quickly. METHODS: We examined combination therapies aimed at FLT3+-AML, and studied the development of resistance using a newly developed protocol. Combinations of FLT3, CDK4/6 and PI3K inhibitors were tested for synergism. RESULTS: We show that AML cells express CDK4 and that the CDK4/6 inhibitors palbociclib and abemaciclib inhibit cellular growth. PI3K inhibitors were also effective in inhibiting the growth of AML cell lines that express FLT3-ITD. Whereas resistance to quizartinib develops quickly, the combinations overcome such resistance. CONCLUSIONS: This study suggests that a multi-targeted intervention involving a CDK4/6 inhibitor with a FLT3 inhibitor or a pan-PI3K inhibitor might be a valuable therapeutic strategy for AML to overcome drug resistance. Moreover, many patients cannot tolerate high doses of the drugs that were studied (quizartinib, palbociclib and PI3K inhibitors) for longer periods, and it is therefore of high significance that the drugs act synergistically and lower doses can be used.

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Scrub typhus can be adequately treated with doxycycline or azithromycin unless it is treated too late. Such cases present as severe scrub typhus, and their treatment remains a challenging problem. In this article, we briefly review the literature on the treatment of scrub typhus and the limitations of the combination of doxycycline and azithromycin. Several options are suggested for further study in the treatment of severe scrub typhus (such as encephalitis, myocarditis, and pneumonia), including dose escalation of doxycycline, the adjuvant use of steroids, the selective use of beta-lactam antibiotics, and the use of tigecycline.

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Breast cancer alone accounts for the majority of cancer deaths among women, with the most commonly diagnosed subtype being estrogen receptor positive (ER+). Survival has greatly improved for patients with ER+ breast cancer, due in part to the development of antiestrogen compounds, such as tamoxifen. While treatment of the primary disease is often successful, as many as 30% of patients will experience recurrence and metastasis, mainly due to developed endocrine therapy resistance. In this study, we discovered two tamoxifen combination therapies, with simeprevir and VX-680, that reduce the tumor burden in animal models of ER+ breast cancer more than either compound or tamoxifen alone. Additionally, these tamoxifen combinations reduced the expression of HER2, a hallmark of tamoxifen treatment, which can facilitate acquisition of a treatment-resistant phenotype. These combinations could provide clinical benefit by potentiating tamoxifen treatment in ER+ breast cancer.

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Morganella morganii, a non-negligent opportunistic pathogen of the family Enterobacteriaceae, enlisted recently in the global priority pathogens by WHO for its swift propensity to acquire drug-resistant genes, engendering enhanced death rates. A combination of diverse antimicrobials could be recycled to overcome the ongoing acquisition of resistance mechanisms by M. morganii. Herein, we investigated the in vitro synergistic effect of colistin with meropenem, rifampicin, minocycline and linezolid against three intrinsic colistin-resistant M. morganii strains collected from critical departments of tertiary care hospitals. The strains were identified and tested for antimicrobial susceptibility by VITEK 2 automated system. The 16S rRNA sequencing was used to reconfirm the species identification. Minimum inhibitory concentrations (MICs) of colistin, meropenem, rifampicin, minocycline and linezolid were determined by the broth microdilution method. Synergistic interactions were studied by checkerboard and time-kill assay. The VITEK 2 identification and 16S rRNA sequencing confirmed that the strains were M. morganii. The automated antimicrobial susceptibility test revealed that all three isolates were multi-drug resistant. The checkerboard analysis demonstrated the synergy of all four combinations with FICI values ranging from 0.06 to 0.31 in all three isolates. These results suggest a potential role of meropenem as an adjuvant for treating M. morganii infections. The current work presented the first evidence of synergy between colistin and other antibiotics against M. morganii infection, which needs validation through in vitro and in vivo studies using a larger number of isolates. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03551-w.

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BACKGROUND: Remimazolam is a new short-duration anesthetic currently used for gastroscopy and can be mixed with propofol and potent opioids. AIM: The study aimed to investigate the synergistic interaction between remimazolam and propofol after sufentanil administration and to determine the appropriate dose ratios between remimazolam and propofol. METHOD: This study used a randomized controlled design. Patients scheduled for gastrointestinal endoscopy were included and randomized into five groups. The randomized block design was applied at a randomization ratio of 1:1. Patients in each group received sufentanil (0.1 µg/kg) and the calculated doses of remimazolam and propofol. Using the up and down method, the median effective dose (ED50) and the 95% confidence interval (CI) were determined based on whether the eyelash reflex disappeared in each treatment group. Isobolographic analysis was used to analyze the presence of drug interactions. The interaction coefficient and the dose ratio between remimazolam and propofol were calculated by algebraic analysis. Statistical analysis was performed using interval estimates and 95% CI for statistical attributes. RESULTS: Cross-sectional analysis of the isobologram showed a clinically significant synergistic effect between remimazolam and propofol. When 0.016, 0.032, and 0.047 mg/kg of remimazolam were combined with 0.477, 0.221, and 0.131 mg/kg of propofol, the interaction coefficients were 1.04, 1.21, and 1.06, respectively. The dose ratio of remimazolam to propofol was approximately 1:7. CONCLUSION: Remimazolam and propofol have synergistic clinical effects. A strong synergistic effect was observed when the remimazolam and propofol dose ratio was 1:7 (mg/kg). CLINICAL TRIAL: The study protocol was registered at the Chinese Clinical Trial Registry (ChiCTR2100052425).

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There has been an explosion in the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) because of the indiscriminate use of antibiotics. In this study, we repurposed hexestrol (HXS) as an antibacterial agent to fight planktonic and biofilm-related MRSA infections. HXS is a nonsteroidal synthetic estrogen that targets estrogen receptors (ERα and ERß) and has been used as a hormonal antineoplastic agent. In our work, the minimum inhibitory concentrations (MICs) were determined using the antimicrobial susceptibility of MSSA and MRSA strains. Anti-biofilm activity was evaluated using biofilm inhibition and eradication assays. Biofilm-related genes were analyzed with or without HXS treatment using RTqPCR analysis of S. aureus. HXS was tested using the checkerboard dilution assay to identify antibiotics that may have synergistic effects. Measurement of ATP and detection of ATPase allowed the determination of bacterial energy metabolism. As shown in the results, HXS showed effective antimicrobial activity against S. aureus, including both type strains and clinical isolations, with MICs of 16 µg/mL. Sub-HXS strongly inhibited the adhesion of S. aureus. The content of extracellular polymeric substances (EPS) and the relative transcription levels of eno, sacC, clfA, pls and fnbpB were reduced after HXS treatment. HXS showed antibacterial effects against S. aureus and synergistic activity with aminoglycosides by directly interfering with cellular energy metabolism. HXS inhibits adhesion and biofilm formation and eradicates biofilms formed by MRSA by reducing the expression of related genes. Furthermore, HXS increases the susceptibility of aminoglycosides against MRSA. In conclusion, HXS is a repurposed drug that may be a promising therapeutic option for MRSA infection.

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