Optimal Combination Therapy Research Articles

Implementation of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction (OpTIMa-HF Registry).

The last released European guidelines on the management of heart failure (HF) recommend in patients with chronic HF with reduced ejection fraction (HFrEF) a pharmacological approach based on four fundamental drugs to be rapidly implemented and then uptitrated to modify disease progression. The aim of the Optimization of Therapy in the Italian Management of Heart Failure (OPTIMA-HF) registry is to collect data on chronic HF outpatients in different settings of care. In the present analysis, we report the first analysis of the OPTIMA-HF registry, focusing on the real-life use of guideline-directed medical therapy in patients affected by HFrEF. OPTIMA-HF is an observational, cross-sectional, multicentre, real-life Italian registry conducted in two different clinical settings: HF outpatients' clinics of Italian hospitals and community HF outpatients' services. The study comprises a T0 phase-retrospective data collection, in which data of consecutive HF outpatients seen between January and October 2022 were collected; an educational activity phase; and a T1 phase-prospective data collection, in which data of consecutive HF outpatients seen between September 2023 and November 2023 were collected. In the present analysis, we describe the T0 phase focusing on HFrEF drug prescription rates, types, doses, combination therapy, the presence of contraindications and reasons of non-optimized treatment. Twenty-nine centres enrolled 2110 HF patients, of which 1390 (65.9%) had HFrEF [69.5±11.9years, 76.2% males, 4.1years since HF diagnosis, median ejection fraction (EF) 33%]. Among HFrEF patients, 89.1% were on treatment with renin-angiotensin-aldosterone system inhibitor (RAASi)/angiotensin receptor neprilysin inhibitor (ARNI) (72% ARNI and 17.1% RAASi), 95.1% with beta-blockers, 75.8% with mineralocorticoid receptor antagonists (MRA) and 63.2% with sodium/glucose cotransporter 2 inhibitors (SGLT2i). Despite high prescription rates, a non-negligible number of patients with no contraindications were not treated with each specific drug. Patients taking all four drug classes, as recommended by guidelines, were mere 46.9%. Regarding doses, a still low number of patients on RAASi/ARNI and beta-blockers were treated with a dose ≥50% of the target doses recommended by the European guidelines. The OPTIMA-HF registry reported that HFrEF fundamental drugs are prescribed in most Italian patients; however, <50% of patients receive optimal combination therapy, and still not a satisfying number of patients receive target doses. Strategies to improve implementation of guideline-directed medical therapy are needed to improve HF prognosis.

Advances in immunotherapy for HNSCC

Head and Neck Squamous Cell Carcinoma (HNSCC) is a cancer that originates in the mucosal surfaces of the head and neck, including the mouth, throat, and larynx. Immunotherapy has emerged as a promising treatment for HNSCC, especially for patients whose cancers are resistant to traditional therapies such as surgery, radiation, and chemotherapy. In this minireview article, we summarized the role of immunotherapy in HNSCC. Checkpoint inhibitors are a class of immunotherapy that work by blocking certain proteins that suppress the immune system’s ability to attack cancer cells. In HNSCC, the most studied checkpoint inhibitors are PD-1/PD-L1 Inhibitors. These include drugs like Pembrolizumab (Keytruda) and Nivolumab (Opdivo). PD-1 is a protein on immune cells that, when engaged by its ligands (PD-L1 on cancer cells), dampens the immune response. Blocking PD-1 helps reactivate the immune system to recognize and destroy cancer cells. Drugs like Atezolizumab (Tecentriq) target the PD-L1 protein, which is often upregulated in cancer cells to escape immune surveillance. By blocking PD-L1, these drugs prevent cancer cells from evading the immune system. These checkpoint inhibitors have shown efficacy in advanced or recurrent HNSCC, particularly in patients whose tumors express PD-L1. Combination strategies that combine immunotherapy with other treatments, such as chemotherapy, radiation therapy, or targeted therapy, are also being explored to enhance the effectiveness of immunotherapy in HNSCC. These combinations can help overcome resistance mechanisms and potentially improve outcomes. Chemotherapy may induce immune-stimulatory effects, making the tumor more sensitive to immunotherapy. Radiation can induce "immunogenic cell death," releasing tumor antigens that can enhance the immune system’s response to the cancer when combined with checkpoint inhibitors. While immunotherapy has shown promising results in treating HNSCC, several challenges remain. For example, not all tumors respond equally to immunotherapy, and some cancers develop resistance over time. Tumors can create a microenvironment that suppresses immune activity, making it difficult for immunotherapies to work effectively. Immune-related side effects, such as inflammation or autoimmunity, can occur with checkpoint inhibitors. Research continues into refining biomarkers for patient selection, optimizing combination therapies, and finding ways to overcome resistance. In conclusion, immunotherapy represents a major advancement in the treatment of HNSCC, offering new hope for patients with advanced or recurrent disease. Ongoing research is focusing on improving the efficacy, safety, and applicability of these therapies, with the goal of enhancing patient outcomes and expanding their use across different subtypes of HNSCC.

Luteinizing hormone-releasing hormone receptor agonists and antagonists in prostate cancer: effects on long-term survival and combined therapy with next-generation hormonal agents.

Prostate cancer is a leading cause of cancer-related death in men worldwide. Luteinizing hormone-releasing hormone receptor (LHRH-R) agonists and antagonists are known to achieve castration-level testosterone suppression; however, long-term data comparing the survival benefits of these therapies are insufficient to inform treatment decisions. Furthermore, the advent of next-generation hormonal agents (NHAs), such as abiraterone and enzalutamide, have shifted the paradigm of managing prostate cancer. Although LHRH-R agonists and antagonists remain the cornerstone treatment across various stages of prostate cancer, they are increasingly administered with NHAs, because the combination treatment confers a survival advantage. Nevertheless, the differences in efficacy and safety profiles among various combinations of LHRH-R agonists and antagonists and NHAs remain unclear. Hence, this narrative review is aimed at providing a comprehensive overview of the long-term outcomes of various LHRH-R agonists and antagonists. Key data from major clinical studies are summarized, categorized by disease stage. LHRH-R agonists and antagonists, particularly goserelin, have demonstrated long-term survival benefits in patients with localized and locally advanced prostate cancer. The clinical outcomes of different LHRH-R agonists and antagonists in combination with NHAs have also been evaluated. Among the various combinations, goserelin plus abiraterone appears to have a manageable safety profile with relatively low rates of hot flushes and fatigue. Overall, long-term survival data and safety profiles should be considered in selecting optimal combination therapies for prostate cancer treatment.

The Effect of Zeolite Zinc on Memory Performance and Hippocampal Cell Death in a Rat Model of Alzheimer's-like Disease Induced by Aβ1-42.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the slow and progressive loss of brain structure and function, primarily affecting older individuals. Evidence has shown that disruption of zinc homeostasis in the brain contributes to synaptic dysfunction, as well as impairments in learning and memory. In this study, we evaluated the effect of zeolite zinc on memory performance and hippocampal cell death in a rat model of Alzheimer's disease (AD) induced by intracerebroventricular administration of Aβ1-42. We employed the Morris water maze, shuttle box, and open field tests to assess spatial memory, passive avoidance memory, and anxiety-like behavior, respectively. P-Tau and the amyloid precursor protein (APP) expression, along with hippocampal cell death, were also evaluated. Both Aβ1-42 and zeolite zinc were injected intracerebroventricularly. The results showed that zeolite zinc partially reversed Aβ1-42-induced impairments in memory performance and mitigated the effects of Aβ1-42 on locomotor activity, although it did not fully restore baseline levels. In addition, Aβ1-42 increased the expression of APP and P-Tau, as well as the number of dead cells, whereas zeolite zinc reduced these effects. In conclusion, our findings suggest that while zeolite zinc plays a role in modulating the pathophysiology of AD, its therapeutic effects only partially reverse the progression or symptoms of AD, indicating the need for further investigation into optimal dosing or combination therapies.

Denfivontinib activates effector T-cells through NLRP3-inflammasome, yielding potent anticancer effects by combination with pembrolizumab.

Various combination therapies have been investigated to overcome the limitations of using immune checkpoint inhibitors. However, determining the optimal combination therapy remains challenging. To overcome the therapeutical limitation, we conducted a translational research to elucidate the mechanisms by which AXL inhibition enhances the anti-tumor effects when combined with anti-PD-1 antibody therapy. Herein, we demonstrated improved antitumor effects through combination treatment with denfivontinib and pembrolizumab which resulted in enhanced differentiation into effector CD4+ and CD8+ memory T cells, accompanied by an increase in IFN-γ expression in the YHIM-2004 xenograft model derived from patients with NSCLC. Concurrently, a reduction in the number of immunosuppressive M2 macrophages and myeloid-derived suppressor cells was observed. Mechanistically, denfivontinib potentiated the NOD-like receptor pathway, thereby facilitating the NLRP3 inflammasome formation. This leads to macrophage activation via the NF-kB signaling pathway activation. We have confirmed that the positive interaction between macrophages and T cells arises from the enhanced antigen-presenting machinery of activated macrophages. Furthermore, the observed tumor effects in AXL knock-out mice confirmed that AXL inhibition by denfivontinib enhances the anti-tumor effects, thus opening new avenues for therapeutic interventions aimed at overcoming limitations in immunotherapy. To demonstrate the extent to which our findings reflect clinical results, we analyzed bulk-RNA sequencing data from 21 NSCLC patients undergoing anti-PD-1 immunotherapy. The NLRP3 inflammasome score influenced enhanced immune responses in patient data undergoing anti-PD-1 immunotherapy, suggesting a role for NLRP3 inflammasome in activating immune responses during treatment.

A mechanistic approach to optimize combination antibiotic therapy.

Antimicrobial resistance is one of the most significant healthcare challenges of our times. Multidrug or combination therapies are sometimes required to treat severe infections; for example, the current protocols to treat pulmonary tuberculosis combine several antibiotics. However, combination therapy is usually based on lengthy empirical trials, and it is difficult to predict its efficacy. We propose a new tool to identify antibiotic synergy or antagonism and optimize combination therapies. Our model explicitly incorporates the mechanisms of individual drug action and estimates their combined effect using a mechanistic approach. By quantifying the impact on growth and death of a bacterial population, we can identify optimal combinations of multiple drugs. Our approach also allows for the investigation of the drugs' actions and the testing of theoretical hypotheses. We demonstrate the utility of this tool with in vitro Escherichia coli data using a combination of ampicillin and ciprofloxacin. In contrast to previous interpretations, our model finds a slight synergy between the antibiotics. Our mechanistic model allows investigating possible causes of the synergy.

Targeting menin for precision therapy in high-risk acute myeloid leukemia.

This mini-review provides an overview of the current evidence for Revumenib, a first-in-class menin inhibitor, in treating AML with KMT2A rearrangements or NPM1 mutations. This therapy represents a promising advancement by selectively disrupting leukemogenic pathways. The clinical promise of Revumenib in genetically defined AML highlights its potential role in shaping the future treatment landscape. This mini-review underscores the need for ongoing trials to define optimal dosing, safety protocols, and combination therapies, with the ultimate goal of establishing Revumenib as a standard of care for high-risk AML subsets.

EXTH-44. ENHANCING THERAPEUTIC APPROACHES IN HIGH-GRADE GLIOMAS: SYNERGISTIC EFFECTS OF LSD1 AND KINASE INHIBITION

Abstract BACKGROUND Glioblastoma (GBM) and Diffuse Intrinsic Pontine Glioma (DIPG) are devastating high-grade gliomas (HGGs) with poor prognoses. Lysine-specific demethylase 1 (LSD1) is a promising therapeutic target and a key regulator in tumor initiation and recurrence. Crosstalk between LSD1 and other signaling pathways, such as the MAPK pathway, frequently hyperactivated in HGG, offers an opportunity to enhance the efficacy of LSD1 inhibitors. This study investigates the combined inhibition of LSD1 and kinase signaling to improve therapeutic outcomes in HGG. METHODS Transcriptional changes following LSD1 knockdown in human GBM cells were analyzed using RNA-seq and GSEA. RPPA and western blotting assessed the impact of LSD1 inhibition on kinase signaling. Pharmacological LSD1 inhibition was tested using NCD38 or bomedemstat in HGG models and normal human astrocytes (NHA). The effects of combining LSD1 inhibitors with kinase inhibitors (osimertinib, afatinib, and ulixertinib) on cell viability were evaluated. Combination treatment was also assessed in orthotopic xenograft models of GBM. RESULTS GSEA revealed LSD1 expression was enriched for gene sets involved in kinase signaling processes. Increased phosphorylated ERK1/2 levels were observed following NCD38 treatment in MDA-GSC17, as shown by RPPA and western blot analyses. The LSD1 inhibitor, NCD38, increased phospho-ERK1/2 levels (72% increase from baseline), while co-treatment with osimertinib mitigated this effect. Combined LSD1 and kinase inhibition (EGFR and ERK inhibition) showed synergistic effects in vitro in GBM and DIPG models but not in the NHA. DISCUSSION Our results demonstrate that kinase activity can be modulated by inhibiting LSD1, potentially leading to a resistant subpopulation. This study underscores the potential of combining LSD1 and kinase inhibition to enhance therapeutic efficacy in HGG, including GBM and DIPG. Future research will focus on elucidating the mechanisms by which LSD1 regulates kinase signaling, aiming to optimize combination therapies.

Microfocused Ultrasound With Visualization (MFU-V) and Hyperdilute Calcium Hydroxylapatite (CaHA-CMC) of the Lower Face and Submentum to Treat Skin Laxity: A Pilot Study Demonstrating Superiority of MFU-V First Followed by Hyperdilute CaHA-CMC.

Microfocused ultrasound with visualization (MFU-V) and hyperdilute calcium hydroxylapatite-carboxymethylcellulose (CaHA-CMC) dermal injections are effective for improving skin laxity in the lower face and submentum by stimulating neocollagenesis and neoelastogenesis. Combining these treatments in an optimal order may inform best practices in aesthetic dermatology. Despite their frequent concurrent use, no study has evaluated the impact of treatment order. This study aimed to determine the optimal sequence for administering MFU-V and hyperdilute CaHA-CMC. Twelve healthy women aged 35-65 were randomized into two groups. Group A received MFU-V followed by hyperdilute CaHA-CMC six weeks later, while Group B received the treatments in the opposite order. Evaluations included histological assessments, aesthetic outcomes, and safety measures. Group A showed greater improvements in subjective global aesthetic improvement scale (sGAIS), investigator global aesthetic improvement scale (iGAIS), and FACE-Q patient-perceived age visual analog scale (VAS) scores. Both groups exhibited similar improvements in FACE-Q Satisfaction with Lower Face and Jawline scores. Histologically, both groups demonstrated significant elastin production at the 120-day follow-up. Group A showed a 143% relative increase in elastin coverage, compared to a 63% increase in Group B. Consequently, Group A exhibited superior qualitative and histologic improvements. Administering MFU-V first, followed by hyperdilute CaHA-CMC six weeks later, is the optimal sequence for this combination therapy. Although both groups experienced increased elastin synthesis and aesthetic improvements, the order of treatments significantly impacted the outcomes, favoring the sequence used in Group A. This finding provides valuable insight for optimizing combination therapies in aesthetic dermatology.

Therapeutic advances in hepatocellular carcinoma: an update from the 2024 ASCO annual meeting.

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Recent advances in immunotherapies, targeted therapies, and combination treatments have significantly improved outcomes for many patients with HCC. This review summarizes key findings from the 2024 ASCO Annual Meeting, focusing on emerging therapies, including immune checkpoint inhibitors (ICIs), CAR-T cell therapies, oncolytic viruses, and locoregional treatments like transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC). ICIs, particularly when combined with other agents, have shown promising efficacy, though challenges such as immune-related adverse events and resistance mechanisms remain. CAR-T cell therapies and oncolytic viruses offer novel therapeutic avenues for advanced HCC, but their long-term efficacy in solid tumors is still under investigation. Locoregional therapies, especially in combination with systemic treatments, continue to play a critical role in managing unresectable HCC and improving conversion rates to surgical resection. Additionally, the potential of biomarkers, such as hypoxia scores and CTNNB1 mutations, is being explored to better personalize treatment and predict patient responses. These biomarkers could pave the way for more targeted and effective therapeutic strategies. Overall, the recent studies presented at the ASCO meeting highlight progress in HCC treatment, underscoring the importance of continued innovation. Future research should focus on overcoming resistance mechanisms, optimizing combination therapies, and integrating biomarker-driven approaches to improve patient outcomes and enhance personalized treatment strategies.

Sequencing microsphere selective internal radiotherapy after external beam radiotherapy for hepatocellular carcinoma: proof of concept of a synergistic combination.

This study aims to explore the synergistic effects of combining stereotactic body radiation therapy (SBRT) and selective internal radiation therapy (SIRT) in that specific sequence for treating hepatocellular carcinoma (HCC), particularly in patients at high risk of radiation-induced liver disease (RILD). We analysed a case of a patient with HCC who was treated with SBRT at our institution. A virtual 90Y dose distribution was added using our in-house MIDOS model to keep a minimum dose to the healthy liver tissue. BED and EUD metrics were calculated to harmonize the dose distributions of SBRT and SIRT. Our radiation biology-based models suggest that the combination of SBRT and SIRT could maintain effective tumour control while reducing the dose to normal liver tissue. Specifically, an SBRT plan of 10 Gy×3 fractions combined with SIRT yielded comparable tumour control probability to an SBRT-only plan of 10 Gy×5 fractions. The combination of SBRT and SIRT is a promising treatment strategy for HCC patients at high risk of RILD. While the LQ model and associated formalisms provide a useful starting point, further studies are needed to account for factors beyond these models. Nonetheless, the potential for significant dose reduction to normal tissue suggests that this combination therapy could offer substantial clinical benefits. This article presents a proposal to combine SBRT and SIRT, in this specific order, for HCC, discussing its advantages. A framework for future research into optimizing combination therapy for HCC is provided, utilizing a novel HCC vascular model to simulate 90Y doses.

Therapeutic Potential of Glucagon-like Peptide-1 Receptor Agonists in Obstructive Sleep Apnea Syndrome Management: A Narrative Review.

Background: Obstructive Sleep Apnea (OSA) is a prevalent disorder characterized by repetitive upper airway obstructions during sleep, leading to intermittent hypoxia and sleep fragmentation. Current treatments, particularly Continuous Positive Airway Pressure (CPAP), face adherence challenges, necessitating novel therapeutic approaches. Methods: This review explores the potential of Glucagon-like Peptide-1 receptor agonists (GLP-1RA), commonly used for type 2 diabetes and obesity, in managing OSA. GLP-1RA promotes weight loss, enhances insulin sensitivity, and exhibits anti-inflammatory and neuroprotective properties, potentially addressing key pathophysiological aspects of OSA. Results: Emerging evidence suggests that these agents may reduce OSA severity by decreasing upper airway fat deposition and improving respiratory control. Clinical trials have demonstrated significant reductions in the Apnea-Hypopnea Index (AHI) and improvements in sleep quality with GLP-1 therapy. Conclusions: Future research should focus on elucidating the mechanisms underlying GLP-1 effects on OSAS, optimizing combination therapies, and identifying patient subgroups that may benefit the most. Integrating GLP-1RA into OSAS management could revolutionize treatment by addressing both the metabolic and respiratory components of the disorder, ultimately enhancing patient outcomes.

Resistance to Antimalarial Drugs in Uganda: Current Status and Future Directions

Antimalarial drug resistance posed a significant challenge to malaria control in Uganda, where Plasmodium falciparum remains the predominant strain. This review examined the current status of antimalarial drug resistance in Uganda, focusing on the mechanisms underlying resistance, epidemiological trends, and the impact on malaria control programs. Chloroquine and sulfadoxine-pyrimethamine resistance have been well-documented, and recent concerns about reduced efficacy of artemisinin-based combination therapies (ACTs) highlight ongoing challenges. The review identified key mechanisms of resistance, including genetic mutations, drug efflux, metabolic pathway alterations, and potential biofilm formation. The implications of resistance on treatment efficacy, healthcare costs, and policy adjustments are discussed. Future directions included strengthening surveillance systems, optimizing combination therapies, investing in research and development, implementing integrated vector management strategies, and enhancing public education and community engagement. Related published literatures were reviewed and analysis of recent data on drug resistance patterns in Uganda was carried out and utilised in compiling this paper. By exploring these dimensions, the review aims to provide actionable insights for policymakers, healthcare providers, and researchers to effectively address drug resistance and advance malaria control efforts in Uganda. Keywords: Antimalarial Drug Resistance, Plasmodium falciparum, Chloroquine Resistance, Artemisinin-Based Combination Therapies (ACTs), Surveillance and Monitoring.

Treatment options for tumor progression after initial immunotherapy in advanced non-small cell lung cancer: A real-world study

ObjectiveWhether to continue administering immunotherapy to patients with advanced non-small cell lung cancer (NSCLC) who have experienced tumor progression remains controversial after immunotherapy. The aims were to explore survival outcomes after further immunotherapy post-progression and to determine the optimal combination therapy in such cases. MethodsOverall, 507 patients with NSCLC who underwent immunotherapy and experienced tumor progression were retrospectively divided into Immuno-combination and No-immuno groups according to whether additional combination therapy involving immunotherapy was administered post-progression. Progression-free survival (PFS) and overall survival (OS) were evaluated. Subgroup analyses were performed according to the different treatment regimens for patients in the Immuno-combination group. ResultsAfter propensity score matching, there were 150 patients in the No-immuno group and 300 patients in the Immuno combination group. Superior PFS was observed in the Immuno-combination group compared with those in the No-immuno group (6-month PFS: 25.3 % vs. 60.6 %; 12-month PFS: 6.7 % vs. 24.4 %; P < 0.001). Similar intergroup differences were observed for OS (12-month OS: 22.3 % vs. 69.4 %; 18-month OS: 6.4 % vs. 40.4 %; P < 0.001). Superior PFS outcomes were observed in the Immuno+Antiangiogenic group compared with the Immuno+Chemo group (6-month PFS: 51.3 % vs. 71.5 %; 12-month PFS: 23.1 % vs. 25.7 %; P = 0.017). Similar differences in OS were observed between those same subgroups (12-month OS: 62.1 % vs. 77.9 %; 18-month OS: 33.3 % vs. 48.7 %; P = 0.006). ConclusionPatients with NSCLC experiencing tumor progression post-immunotherapy can still benefit from further treatment, with immunotherapy combined with antiangiogenic therapy the most efficacious option.

Optimizing kidney and cardiovascular protection in an era of multiple effective treatments.

After decades of relying on the control of hypertension and treatment with renin angiotensin system inhibitors as the only evidence-based interventions to slow the progression of chronic kidney disease (CKD), we have entered an era when multiple effective treatment options are available. This review considers the mechanisms and benefits of these novel treatments as well as the challenges associated with achieving optimal combination therapy. Over the past 5 years, large clinical trials have provided robust evidence that, when added to renin angiotensin system inhibitors, treatment with sodium glucose cotransporter 2 inhibitors reduces the rate of CKD progression and the risk of cardiovascular events in people with CKD with or without diabetes and with or without albuminuria; nonsteroidal mineralocorticoid antagonists and glucagon-like peptide-1 receptor agonists afford similar benefits in people with type 2 diabetes and CKD. The mechanisms of actions of these novel therapies suggest that combination therapy will produce additive benefits, though specific evidence is sparse. Further trials are warranted to investigate the benefits of combination therapy with novel treatments in people with CKD. Clinical implementation of optimal combination therapy will require reorganization of services to ensure that patients receive adequate education, support and monitoring.

A fractional-order model for optimizing combination therapy in heterogeneous lung cancer: integrating immunotherapy and targeted therapy to minimize side effects

This research presents a novel approach to address the complexities of heterogeneous lung cancer dynamics through the development of a Fractional-Order Model. Focusing on the optimization of combination therapy, the model integrates immunotherapy and targeted therapy with the specific aim of minimizing side effects. Notably, our approach incorporates a clever fusion of Proportional-Integral-Derivative (PID) feedback controls alongside the optimization process. Unlike previous studies, our model incorporates essential equations accounting for the interaction between regular and mutated cancer cells, delineates the dynamics between immune cells and mutated cancer cells, enhances immune cell cytotoxic activity, and elucidates the influence of genetic mutations on the spread of cancer cells. This refined model offers a comprehensive understanding of lung cancer progression, providing a valuable tool for the development of personalized and effective treatment strategies. the findings underscore the potential of the optimized treatment strategy in achieving key therapeutic goals, including primary tumor control, metastasis limitation, immune response enhancement, and controlled genetic mutations. The dynamic and adaptive nature of the treatment approach, coupled with economic considerations and memory effects, positions the research at the forefront of advancing precision and personalized cancer therapeutics.

Exploring synergistic and antagonistic interactions in phage-antibiotic combinations against ESKAPE pathogens.

In the era of antimicrobial resistance, phage-antibiotic combinations offer a promising therapeutic option, yet research on their synergy and antagonism is limited. This study aims to assess these interactions, focusing on protein synthesis inhibitors and cell envelope-active agents against multidrug-resistant bacterial strains. We evaluated synergistic and antagonistic interactions in multidrug-resistant Staphylococcus aureus, Enterococcus faecium, and Pseudomonas aeruginosa strains. Phages were combined with protein synthesis inhibitors [linezolid (LZD), minocycline (MIN), gentamicin (GEN), and azithromycin (AZM)] or cell envelope-active agents [daptomycin (DAP), ceftaroline (CPT), and cefepime (FEP)]. Modified checkerboard minimum inhibitory concentration assays and 24-h time-kill analyses were conducted, alongside one-step growth curves to analyze phage growth kinetics. Statistical comparisons used one-way analysis of variance (ANOVA) and the Tukey test (P < 0.05). In the checkerboard and 24-h time-kill analyses (TKA) of S. aureus and E. faecium, phage-LZD and phage-MIN combinations were antagonistic (FIC > 4) while phage-DAP and phage-CPT were synergistic (FIC 0.5) (ANOVA range of mean differences 0.52-2.59 log10 CFU/mL; P < 0.001). For P. aeruginosa, phage-AZM was antagonistic (FIC > 4), phage-GEN was additive (FIC = 1), and phage-FEP was synergistic (ANOVA range of mean differences 1.04-1.95 log10 CFU/mL; P < 0.001). Phage growth kinetics were altered in the presence of LZD and MIN against S. aureus and in the presence of LZD against a single E. faecium strain (HOU503). Our findings indicate that select protein synthesis inhibitors may induce phage-antibiotic antagonism. However, this antagonism may not solely stem from changes in phage growth kinetics, warranting further investigation into the complex interplay among strains, phage attributes, and antibiotic mechanisms affecting bacterial inhibition.IMPORTANCEIn the face of escalating antimicrobial resistance, combining phages with antibiotics offers a promising avenue for treating infections unresponsive to traditional antibiotics. However, while studies have explored synergistic interactions, less attention has been given to potential antagonism and its impact on phage growth kinetics. This research evaluates the interplay between phages and antibiotics, revealing both synergistic and antagonistic patterns across various bacterial strains and shedding light on the complex dynamics that influence treatment efficacy. Understanding these interactions is crucial for optimizing combination therapies and advancing phage therapy as a viable solution for combating antimicrobial resistance.

Emerging therapies targeting cardiovascular risk factors to prevent or delay the onset of heart failure

Cardiovascular disease (CVD) poses a significant global health concern, contributing to nearly 30% of global deaths. Its prevalence is on the rise, necessitating a deeper understanding of associated risk factors including hypertension, cardiac hypertrophy, and diabetes. Addressing these risk factors is crucial in preventing or slowing the onset of heart failure (HF), a complex chronic condition with high morbidity and mortality rates. This review aims to explore innovative strategies for preventing or delaying HF, focusing on cardiovascular risk (CV) factors. Specifically, it delves into the link between hypertension, cardiac hypertrophy, diabetes, and HF emphasizing the importance of identifying new therapeutic approaches. A comprehensive examination of existing literature, clinical trials, and experimental models forms the basis of this review providing insights into the interconnected nature of cardiovascular risk factors and the efficacy of combination therapies. Evidence from diverse sources supports the adoption of a multifaceted approach to HF prevention. The review underscores the complex associations between hypertension, cardiac hypertrophy, diabetes, and HF highlighting the need for innovative therapeutic interventions. Clinical trials demonstrate promising outcomes with synergistic therapies such as angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors showcasing improved efficacy over single-agent interventions. In conclusion, adopting a multifaceted approach to HF prevention considering the interplay of various risk factors. Such an approach holds the potential for substantial benefits including simultaneous targeting of multiple pathways, individualized care, enhanced patient motivation, and reduced healthcare costs. Further research should focus on optimizing combination therapies and identifying patient population that stands to gain the most from these interventions providing a pathway towards improved cardiovascular health globally.

Liposome co-delivery of quercetin and doxorubicin in inhibiting retinoblastoma by regulating epithelial-mesenchymal transition process

Regulating the process of epithelial-mesenchymal transition(EMT) is an essential strategy to inhibit tumor growth and metastasis. This study is based on the EMT process of retinoblastoma and constructs quercetin(QUE) and doxorubicin(DOX) co-loaded liposome(QD Lipo) to investigate the therapeutic effect and mechanisms of combined QUE and DOX treatment on retinoblastoma. Single-factor experiments were conducted to optimize the prescription process of QD Lipo. Eventually, spherical particles with a diameter of(108.87±1.93) nm, a PDI of 0.13±0.02, and a Zeta potential of(-34.83±1.92) mV were obtained. The encapsulation rates of QUE and DOX were 96.20%±4.40% and 91.17%±4.41%, respectively. Y79 human retinoblastoma cells were used as an in vitro cellular model, and confocal microscopy demonstrated that QD Lipo could enhance Y79 uptake efficiency. The CCK-8 assay confirmed that the optimal combination therapy effect of QUE and DOX occurred at a mass ratio of 1∶1 to 1∶2. Flow cytometry showed that QD Lipo enhanced the induction of apoptosis in Y79 cells. Western blot analysis revealed that QD Lipo significantly reduced the expression of EMT pathway-related proteins vimentin and α-SMA. Fluorescence assays detected a significant decrease in ROS levels in Y79 cells after treatment with QD. These results indicated that liposomal co-delivery of QUE and DOX can enhance drug delivery efficiency to retinoblastoma cells, inhibit the EMT process in retinoblastoma by downregulating ROS levels, and enhance the cytotoxicity of DOX against retinoblastoma.

Strategies for overcoming resistance to Bruton's tyrosine kinase inhibitor zanubrutinib

AbstractBruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment of B‐cell malignancies. They target BTK, a key effector in the B‐cell receptor (BCR) signaling pathway, crucial for B‐cell survival and proliferation. The first‐in‐class irreversible BTK inhibitor, ibrutinib, was approved for various B‐cell malignancies but has limitations due to off‐target effects. Second‐generation inhibitors, such as acalabrutinib and zanubrutinib, offer improved selectivity and reduced side effects. However, resistance to BTK inhibitors, driven by BTK mutations, remains a challenge. Combinatorial therapies with PI3K inhibitors, immune checkpoint inhibitors, BH3 mimetics, and anti‐CD20 antibodies show promise in overcoming resistance. Noncovalent BTK inhibitors and proteolysis‐targeting chimeras (PROTACs) are emerging strategies with potential to combat resistance. Overall, advancements in BTK‐targeted therapies provide hope for improved outcomes in patients with B‐cell malignancies and a promising avenue to address drug resistance. Further research is needed to optimize combination therapies and identify optimal treatment regimens.