Drug Combinations Research Articles

Preoperative Epidural Infusion for Blood Pressure Control in Phaeochromocytoma

The 2004 World Health Organization (WHO) classification of endocrine tumours defines phaeochromocytoma as a catecholamine-producing intra-adrenal tumour arising from the chromaffin cells. The most important functional characteristics of the adrenal and extra-adrenal sympathetic tissue derived tumours is the production of various types of catecholamines and the related clinical attributes [1]. Preoperative blood pressure control in phaeochromocytoma is an uphill task using multiple medications leading to post operative hypotension. It is well known that complete prevention of perioperative hypertension and tachycardia cannot be achieved by any dose or combination of drugs. Epidural anesthesia is often used for pain control in open resection of these tumours; one of its side effects is hypotension [2]. We describe here a case of phaeochromocytoma in whom perioperative blood pressure control was achieved with the help of epidural drugs instead of systemic antihypertensive medications.

Impact of commonly administered drugs on the progression of spinal cord injury: a systematic review

BackgroundComplications arising from acute traumatic spinal cord injury (SCI) are routinely managed by various pharmacological interventions. Despite decades of clinical application, the potential impact on neurological recovery has been largely overlooked. This study aims to highlight commonly administered drugs with potential disease-modifying effects.MethodsThis systematic literature review included studies referenced in PubMed, Scopus and Web of Science from inception to March 31st, 2021, which assess disease-modifying properties on neurological and/or functional recovery of drugs routinely administered following spinal cord injury. Drug effects were classified as positive, negative, mixed, no effect, or not (statistically) reported. Risk of bias was assessed separately for animal, randomized clinical trials, and observational human studies.ResultsWe analyzed 394 studies conducting 486 experiments that evaluated 144 unique or combinations of drugs. 195 of the 464 experiments conducted on animals (42%) and one study in humans demonstrate positive disease-modifying properties on neurological and/or functional outcomes. Methylprednisolone, melatonin, estradiol, and atorvastatin are the most common drugs associated with positive effects. Two studies on morphine and ethanol report negative effects on recovery.ConclusionDespite a large heterogeneity observed in study protocols, research from bed to bench and back to bedside provides an alternative approach to identify new candidate drugs in the context of SCI. Future research in human populations is warranted to determine if introducing drugs like melatonin, estradiol, or atorvastatin would contribute to enhancing neurological outcomes after acute SCI.

MIRD Pamphlet No. 31: MIRDcell V4-Artificial Intelligence Tools to Formulate Optimized Radiopharmaceutical Cocktails for Therapy.

Radiopharmaceutical cocktails have been developed over the years to treat cancer. Cocktails of agents are attractive because 1 radiopharmaceutical is unlikely to have the desired therapeutic effect because of nonuniform uptake by the targeted cells. Therefore, multiple radiopharmaceuticals targeting different receptors on a cell is warranted. However, past implementations invivo have not met with convincing results because of the absence of optimization strategies. Here we present artificial intelligence (AI) tools housed in a new version of our software platform, MIRDcell V4, that optimize a cocktail of radiopharmaceuticals by minimizing the total disintegrations needed to achieve a given surviving fraction (SF) of tumor cells. Methods: AI tools are developed within MIRDcell V4 using an optimizer based on the sequential least-squares programming algorithm. The algorithm determines the molar activities for each drug in the cocktail that minimize the total disintegrations required to achieve a specified SF. Tools are provided for populations of cells that do not cross-irradiate (e.g., circulating or disseminated tumor cells) and for multicellular clusters (e.g., micrometastases). The tools were tested using model data, flow cytometry data for suspensions of single cells labeled with fluorochrome-labeled antibodies, and 3-dimensional spatiotemporal kinetics in spheroids for fluorochrome-loaded liposomes. Results: Experimental binding distributions of 4 211At-antibodies were considered for treating suspensions of MDA-MB-231 human breast cancer cells. A 2-drug combination reduced the number of 211At decays required by a factor of 1.6 relative to the best single antibody. In another study, 2 radiopharmaceuticals radiolabeled with 195mPt were each distributed lognormally in a hypothetical multicellular cluster. Here, the 2-drug combination required 1.7-fold fewer decays than did either drug alone. Finally, 2 225Ac-labeled drugs that provide different radial distributions within a spheroid require about one half of the disintegrations required by the best single agent. Conclusion: The MIRDcell AI tools determine optimized drug combinations and corresponding molar activities needed to achieve a given SF. This approach could be used to analyze a sample of cells obtained from cell culture, animal, or patient to predict the best combination of drugs for maximum therapeutic effect with the least total disintegrations.

The Role of 5-Phosphodiesterase Inhibitors (PDE-5I) in Current Benign Prostatic Hyperplasia Treatment: A Narrative Review

Introduction: 5-phosphodiesterase inhibitors (PDE-5I) have been investigated as a treatment for urinary dysfunction for almost a decade. The general perception is that they play a significant role in managing lower urinary tract symptoms (LUTS), particularly those associated with benign prostatic hyperplasia (BPH). However, the specific biochemical processes by which PDE-5I repairs urinary function are still poorly understood and there is little instrumental evidence of significant improvement in urinary symptoms. Therefore, we explore the role of 5-phosphodiesterase inhibitors (PDE-5I) as complementary to the conventional treatment of symptomatic BPH; we provide the suggested biological procedures involved in the association between PDE-5 inhibitor use and improvement in LUTS; and we propose new approaches to this topic. Material and Methods: A systematic search for clinical trials, experimental studies, and systematic reviews was performed in electronic libraries (PubMed, EMBASE, Scopus) using the terms “benign prostate hypertrophy”, “benign prostate hyperplasia”, “lower urinary tract symptoms”, “storage symptoms”, “voiding symptoms”, “bladder outlet obstruction” and the keywords “mechanism of action”, “synergy”, “PDE-5 inhibitor”, “alpha1-adrenergic antagonist”, “5-alpha-reductase inhibitors” in various combinations. There was no restriction on publication date. Results: To date, only a few randomized studies have been published in which the effect of the combination of a conventional drug for the treatment of symptomatic BPH and a PDE-5I was investigated. Almost all showed significant improvement in IPSS and QoL. Some studies showed significant improvements in maximum urine flow (Qmax) and postvoiding residual volume (PVR) with combination therapy compared with a single agent alone. Conclusions: PDE-5I seems effective in relieving symptoms of some BPH patients when administered as complementary to agents currently used to treat BPH. However, the mechanism of action of PDE-5 inhibitors in LUTS remains poorly understood and it is difficult to determine the specific subset of BPH patients who will benefit from the combination of PDE-5 inhibitors with the current treatment. Well-designed, sufficiently informative comparative studies focusing on specific target group profiles (age, urogenital parameters) are needed to define new therapeutic options.

Enhancing glioblastoma cytotoxicity through encapsulating O6-benzylguanine and temozolomide in PEGylated liposomal nanocarrier: an in vitro study

Glioblastoma (GBM) (grade IV glioma) is the most fatal brain tumor, with a median survival of just 14 months despite current treatments. Temozolomide (TMZ), an alkylating agent used with radiation, faces challenges such as systemic toxicity, poor absorption, and drug resistance. To enhance TMZ effectiveness, we developed poly(ethylene glycol) (PEG) liposomes co-loaded with TMZ and O6-benzylguanine (O6-BG) for targeted glioma therapy. These liposomes, prepared using the thin-layer hydration method, had an average size of 146.33 ± 6.75 nm and a negative zeta potential (−49.6 ± 3.1 mV). Drug release was slower at physiological pH, with 66.84 ± 4.62% of TMZ and 69.70 ± 2.88% of O6-BG released, indicating stability at physiological conditions. The liposomes showed significantly higher cellular uptake (p < 0.05) than the free dye. The dual drug-loaded liposomes exhibited superior cytotoxicity against U87 glioma cells, with a lower IC50 value (3.99µg/mL) than the free drug combination, demonstrating enhanced anticancer efficacy. The liposome formulation induced higher apoptosis (19.42 ± 3.5%) by causing sub-G0/G1 cell cycle arrest. The novelty of our study lies in co-encapsulating TMZ and O6-BG within PEGylated liposomes, effectively overcoming drug resistance and improving targeted delivery for glioma treatment.

Therapeutic drug monitoring (TDM) of β-lactam/β-lactamase inhibitor (BL/BLI) drug combinations: insights from a pharmacometric simulation study.

The emergence of β-lactamase-producing bacteria has led to the use of β-lactam (BL) antibiotic and β-lactamase inhibitor (BLI) drug combinations. Despite therapeutic drug monitoring (TDM) being endorsed for BLs, the impact of TDM on BLIs remains unclear. Evaluate whether BLIs are available in effective exposures at the site of infection and assess if TDM of BLIs could be of interest. Population pharmacokinetic models for 9 BL and BLI compounds were used to simulate drug concentrations at infection sites following EMA-approved dose regimens, considering plasma protein binding and tissue penetration. Predicted target site concentrations were used for probability of target attainment (PTA) analysis. Using EUCAST targets, satisfactory (≥90%) PTA was observed for BLs in patients with typical renal clearance (CrCL of 80 mL/min) across various sites of infection. However, results varied for BLIs. Avibactam achieved satisfactory PTA only in plasma, with reduced PTAs in abdomen (78%), lung (73%) and prostate (23%). Similarly, tazobactam resulted in unsatisfactory PTAs in intra-abdominal infections (79%), urinary tract infections (64%) and prostatitis (34%). Imipenem-relebactam and meropenem-vaborbactam achieved overall satisfactory PTAs, except in prostatitis and high-MIC infections for the latter combination. This study highlights the risk of solely relying on TDM of BLs, as this can indicate acceptable exposures of the BL while the BLI concentration, and consequently the combination, can result in suboptimal performance in terms of bacterial killing. Thus, dose adjustments also based on plasma concentration measurements of BLIs, in particular for avibactam and tazobactam, can be valuable in clinical practice to obtain effective exposures at the target site.

Novel Drug Combinations in Lung Cancer: New Potential Synergies Between 5-FU and Repurposed Drugs

The therapeutic potential of combining 5-FU with repurposed drugs such as Sildenafil, Tezosentan, Levosimendan, and Resveratrol was investigated in lung cancer treatment using the A549 cell line. This study aimed to enhance 5-FU efficacy while mitigating side effects and overcoming drug resistance. The cytotoxic effects of 5-FU were assessed via MTT assay, with an IC50 value of 5.03 µM for A549 cells. Subsequent experiments evaluated the impact of combining 5-FU with the aforementioned drugs on cell viability, clonogenic potential, and morphology. The results demonstrated that while Sildenafil and Tezosentan modestly improved 5-FU efficacy, Levosimendan reduced cell viability by 40% (p &lt; 0.01) and Resveratrol by over 50% (p &lt; 0.001), with clonogenicity reduced by up to 60% (p &lt; 0.001). These findings suggest that combining 5-FU with Levosimendan or Resveratrol offers promising approaches for lung cancer therapy, potentially reducing the need for higher doses of 5-FU and minimizing associated toxicity. Future studies are warranted to elucidate the mechanisms underlying these interactions and assess their clinical relevance.

Communities That HEAL Intervention and Mortality Including Polysubstance Overdose Deaths

The HEALing Communities Study (HCS) evaluated the effectiveness of the Communities That HEAL (CTH) intervention in preventing fatal overdoses amidst the US opioid epidemic. To evaluate the impact of the CTH intervention on total drug overdose deaths and overdose deaths involving combinations of opioids with psychostimulants or benzodiazepines. This randomized clinical trial was a parallel-arm, multisite, community-randomized, open, and waitlisted controlled comparison trial of communities in 4 US states between 2020 and 2023. Eligible communities were those reporting high opioid overdose fatality rates in Kentucky, Massachusetts, New York, and Ohio. Covariate constrained randomization stratified by state allocated communities to the intervention or control group. Trial groups were balanced by urban or rural classification, 2016-2017 fatal opioid overdose rate, and community population. Data analysis was completed by December 2023. Increased overdose education and naloxone distribution, treatment with medications for opioid use disorder, safer opioid prescribing practices, and communication campaigns to mitigate stigma and drive demand for evidence-based interventions. The primary outcome was the number of drug overdose deaths among adults (aged 18 years or older), with secondary outcomes of overdose deaths involving specific opioid-involved drug combinations from death certificates. Rates of overdose deaths per 100 000 adult community residents in intervention and control communities from July 2021 to June 2022 were compared with analyses performed in 2023. In 67 participating communities (34 in the intervention group, 33 in the control group) and including 8 211 506 participants (4 251 903 female [51.8%]; 1 273 394 Black [15.5%], 603 983 Hispanic [7.4%], 5 979 602 White [72.8%], 354 527 other [4.3%]), the average rate of overdose deaths involving all substances was 57.6 per 100 000 population in the intervention group and 61.2 per 100 000 population in the control group. This was not a statistically significant difference (adjusted rate ratio [aRR], 0.92; 95% CI, 0.78-1.07; P = .26). There was a statistically significant 37% reduction (aRR, 0.63; 95% CI, 0.44-0.91; P = .02) in death rates involving an opioid and psychostimulants (other than cocaine), and nonsignificant reductions in overdose deaths for an opioid with cocaine (6%) and an opioid with benzodiazepine (1%). In this clinical trial of the CTH intervention, death rates involving an opioid and noncocaine psychostimulant were reduced; total deaths did not differ statistically. Community-focused data-driven interventions that scale up evidence-based practices with communications campaigns may effectively reduce some opioid-involved polysubstance overdose deaths. ClinicalTrials.gov Identifier: NCT04111939.

Geldanamycins: Potent Hsp90 Inhibitors with Significant Potential in Cancer Therapy.

Geldanamycin, an ansa-macrolide composed of a rigid benzoquinone ring and an aliphatic ansa-bridge, was isolated from Streptomyces hygroscopicus. Geldanamycin is a potent heat shock protein inhibitor with remarkable antiproliferative activity. However, it shows pronounced hepatotoxicity in animal models and unfavorable pharmacokinetic properties. Four geldanamycin analogs have progressed through various phases of clinical trials, but none have yet completed clinical evaluation or received FDA approval. To enhance the efficacy of these Hsp90 inhibitors, strategies such as prodrug approaches or nanocarrier delivery systems could be employed to minimize systemic and organ toxicity. Furthermore, exploring new drug combinations may help overcome resistance, potentially improving therapeutic outcomes. This review discusses the mechanism of action of geldanamycin, its pharmacokinetic properties, and the various approaches employed to alleviate its toxicity and maximize its clinical efficacy. The main focus is on those derivatives that have progressed to clinical trials or that have shown important in vivo activity in preclinical models.

Spheroid culture to select theoretical therapeutic drugs in intravascular large B-cell lymphoma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma that is characterized by the proliferation of lymphoma cells in the lumina of small vessels. Recent progress uncovering the genetic characteristics associated with MYD88/CD79B mutations has stimulated interest in the use of drugs targeting B-cell receptor signaling, including Bruton's tyrosine kinase. However, difficulties in culturing exvivo IVLBCL cells has hampered research on the development of novel therapies. In the present study, we demonstrated the establishment of an exvivo culture system of IVLBCL cells obtained from patient-derived xenograft (PDX) models. The spheroid culture enabled us to culture IVLBCL PDX cells for more than 10 days and to explore the efficacy of drug treatments acting on these cells. We found that carfilzomib and ibrutinib were effective for treating IVLBCL in exvivo experiments and conducted invivo analyses to assess the efficacy of these drugs. Although the efficacy of carfilzomib was difficult to confirm due to its toxicity in our models, ibrutinib showed comparable efficacy to a standard combination of chemotherapy drugs. Together, our data provide a new culture method for IVLBCL PDX cells and a rationale for translating ibrutinib to clinical use in IVLBCL patients.

Dual-view jointly learning improves personalized drug synergy prediction.

Accurate and robust estimation of the synergistic drug combination is important for medicine precision. Although some computational methods have been developed, some predictions are still unreliable especially for the cross-dataset predictions, due to the complex mechanism of drug combinations and heterogeneity of cancer samples. We have proposed JointSyn that utilizes dual-view jointly learning to predict sample-specific effects of drug combination from drug and cell features. JointSyn outperforms existing state-of-the-art methods in predictive accuracy and robustness across various benchmarks. Each view of JointSyn captures drug synergy-related characteristics and make complementary contributes to the final prediction of drug combination. Moreover, JointSyn with fine-tuning improves its generalization ability to predict a novel drug combination or cancer sample using a small number of experimental measurements. We also used JointSyn to generate an estimated atlas of drug synergy for pan-cancer and explored the differential pattern among cancers. These results demonstrate the potential of JointSyn to predict drug synergy, supporting the development of personalized combinatorial therapies. Source code and data are available at https://github.com/LiHongCSBLab/JointSyn. Supplementary data are available at Bioinformatics online.

Low Anti-Tumor Necrosis Factor Levels During Maintenance Phase Are Associated With Treatment Failure in Children With Crohn's Disease.

Higher drug levels and combination therapy with low-dose oral methotrexate (LD-MTX) may reduce anti-tumor necrosis factor (TNF) treatment failure in pediatric Crohn's disease. We sought to (1) evaluate whether combination therapy with LD-MTX was associated with higher anti-TNF levels, (2) evaluate associations between anti-TNF levels and subsequent treatment failure, and (3) explore the effect of combination therapy on maintenance of remission among patients with therapeutic drug levels (>5 µg/mL for infliximab and >7.5 µg/mL for adalimumab). We conducted a post hoc analysis of the COMBINE trial, which compared anti-TNF monotherapy to combination therapy with LD-MTX. We included participants who entered maintenance therapy and provided a serum sample approximately 4 months from randomization. Among 112 infliximab and 41 adalimumab initiators, median drug levels were similar between combination therapy and monotherapy (infliximab: 8.8 vs 7.5 μg/mL [P = .49]; adalimumab: 11.1 vs 10.5 μg/mL [P = .11]). Median drug levels were lower in patients experiencing treatment failure (infliximab: 4.2 vs 9.6 μg/mL [P < .01]; adalimumab: 9.1 vs 12.3 μg/mL [P < .01]). Among patients treated with infliximab with therapeutic drug levels, we observed no difference in treatment failure between participants assigned monotherapy or combination therapy. Among patients treated with adalimumab, a trend towards reduced treatment failure in the combination therapy arm was not statistically significant (P = .14). LD-MTX combination was not associated with higher drug levels, but higher drug levels were associated with reduced risk of treatment failure. Among patients with therapeutic drug levels, we observed no benefit of LD-MTX for patients treated with infliximab. A nonsignificant trend towards reduced treatment failure with the addition of LD-MTX patients treated with adalimumab warrants further investigation.

Comparison of Butorphanol-Azaperone-Medetomidine and Nalbuphine-Medetomidine-Azaperone in Free-Ranging Elk (Cervus canadensis) in Pennsylvania, USA.

Chemical immobilization is commonly used to capture and handle free-ranging elk (Cervus canadensis). Butorphanol-azaperone-medetomidine (BAM) and nalbuphine-medetomidine-azaperone (NalMed-A) are compounded drug combinations that are lower-scheduled in the US than drugs historically used for elk immobilizations. We compared BAM and NalMed-A for immobilization of free-ranging elk using free-darting and Clover trapping. From January 2020 to April 2022, 196 female elk were immobilized in Pennsylvania, USA. We report vital rates, induction and recovery times, and the need for supplemental drugs. We built mixed-effects logistic regression models to describe differences between drug choice based on induction and recovery times, capture method, and individual variation. Several models were competing, including our null model, which suggests that BAM and NalMed-A are comparable based on the parameters we evaluated. Supplemental drug administration was more frequently needed in NalMed-A immobilizations (21.2%) than in BAM immobilizations (9.0%). Overall, we found minor differences between BAM and NalMed-A, both of which appear to be effective for immobilizing elk in both free-darting and Clover trapping scenarios when performing moderately invasive, minimally painful procedures on free-ranging elk.

Slowing the progression of diabetic and non-diabetic kidney disease: A summary of the current evidence base for sodium-glucose co-transporter-2 inhibitors.

The global prevalence of chronic kidney disease (CKD) is approximately 9%. CKD is predicted to become the fifth largest global cause of death by 2040. Moreover, CKD causes disability, diminished quality of life and poses a high cost to healthcare systems. Delaying the development and progression of CKD is therefore of the utmost importance. Several kidney-specific outcome trials on sodium-glucose co-transporter-2 inhibitors (SGLT-2s) have recently provided a paradigm shift in the treatment of people with CKD, with or without diabetes, as these agents have been shown to reduce the progression of CKD on top of maximally tolerated renin-angiotensin-aldosterone system (RAAS) blockade. The relative benefit and safety of SGLT-2is seems to be consistent across ethnicities, ages and frailty categories; however, this needs to be tested in dedicated clinical trials. Guidelines make clear recommendations for the prescription of SGLT-2is and RAAS inhibitors as standard of care for people with CKD. Their combination with other newer antidiabetic agents may provide further benefits by targeting different components of CKD mechanisms. Dedicated randomized controlled trials are needed to test whether combination with other agents could extend the use of SGLT2is and identify people in whom a combination of drugs may be most effective. Increased efforts to implement the guidelines on treatment with SGLT-2is for people with CKD are needed, particularly in those at the highest risk of adverse outcomes and without type 2 diabetes. Moreover, strategies to target the equitable use of SGLT-2is are needed.

Drug-drug-interactions in patients with atrial fibrillation admitted to the emergency department.

Polypharmacy is a growing concern in healthcare systems. While available data on potential drug-drug interactions (pDDI) from emergency department (ED) patients is derived from heterogenous populations, this study specifically focused on patients with atrial fibrillation (AF). We hypothesized that patients with AF have similar comorbidities, receive similar drugs, and have similar pDDIs. The overarching aim was to highlight frequent pDDIs, providing practical guidance for treating healthcare professionals and consequently reduce the risk of adverse drug reactions. Two hundred patients ≥18years with AF, who received rate- or rhythm-controlling medication at the ED of the University Hospital Vienna, and who were on long-term medication before admission, were eligible. Long-term medication alone, as well as in combination with medication administered at the ED were analyzed for pDDIs using the Lexicomp® Drug interactions database. Within the long-term medication of patients', we identified 664 pDDIs. Drugs administered at the ED increased pDDIs more than 3-fold to 2085. Approximately, every fifth patient received a contraindicated drug combination (on average 0.24 per patient), while 70% received drug combinations for which therapy modifications are recommended (on average 1.59 per patient). The most frequently involved drugs included amiodarone, propofol, bisoprolol, enoxaparin, and acetylsalicylic acid. Increased risk of bleeding, QTc prolongation, and myopathy were among the most relevant potential consequences of these interactions. In conclusion, an optimization of medication would be advisable in almost every AF patient. Treating healthcare professionals should be cautious of drugs that increase bleeding risk, prolong QTc, or bear a risk for myopathy.

Pathway-based prediction of the therapeutic effects and mode of action of custom-made multiherbal medicines.

Multiherbal medicines are traditionally used as personalized medicines with custom combinations of crude drugs; however, the mechanisms of multiherbal medicines are unclear. In this study, we developed a novel pathway-based method to predict therapeutic effects and the mode of action of custom-made multiherbal medicines using machine learning. This method considers disease-related pathways as therapeutic targets and evaluates the comprehensive influence of constituent compounds on their potential target proteins in the disease-related pathways. Our proposed method enabled us to comprehensively predict new indications of 194 Kampo medicines for 87 diseases. Using Kampo-induced transcriptomic data, we demonstrated that Kampo constituent compounds stimulated the disease-related proteins and a customized Kampo formula enhanced the efficacy compared with an existing Kampo formula. The proposed method will be useful for discovering effective Kampo medicines and optimizing custom-made multiherbal medicines in practice.

MULTI-OMIC INTEGRATION REVEAL INTRA-TUMOUR HETEROGENEITY AND IDENTIFY DISULfiRAM AND COPPER AS A SYNERGISTIC THERAPY IN PAEDIATRIC EPENDYMOMA

Abstract AIMS Ependymoma (EPN) is the second most malignant paediatric brain tumour. The PF-A subgroup, associated with a hypoxic microenvironment, has a dismal survival rate of 50% with clinical trials failing to demonstrate a significant survival advantage from chemotherapy to date. As the lack of genomic alterations makes it difficult to uncover novel therapeutic targets, we present a multi-omic integration investigating whether spatially-distinct tumour microenvironments represent targetable metabolic niches in PF-A EPN. METHOD Surgical sampling of spatially-distinct regions was performed on eight PF-A patients. Metabolites and RNA were simultaneously extracted from the same cellular population and analysed using liquid chromatography-mass spectrometry (LC-MS) and RNAseq. Multi-omic integration was performed using Metscape3 and functional assays evaluating proliferation, invasion and siRNA-mediated knockdown were performed in 2D and 3D models of intra-tumour region patient-derived cell lines. Selected single and drug combination therapy was performed in normoxia and hypoxia, and synergy assessed using the Chou-Talalay method. RESULTS Multi-omic integration revealed 124 dysregulated metabolic pathways, encompassing 156 genes and 49 metabolites with the largest number of interactions occurring in the gluconeogenesis pathway. Each anatomical region also presented at least one unique gene-metabolite interaction demonstrating heterogeneity within and across PF-A EPN tumours. Four selected drug targets (Disulfiram, Vandetanib, Mildronate and FBP1 inhibitor) based on metabolically relevant genes (ALDH3A1, FMO3, BBOX1, FBP1) showed impairment of metabolic viability in vitro, with limited chemosensitivity observed in control human cerebellar astrocytes. The addition of Cu2+ significantly sensitized cells to Disulfiram, particularly under hypoxic conditions. This synergistic combination significantly impaired invasion in both normoxia and hypoxia. CONCLUSION This is the first instance where multi-omic data integration and intra-tumour heterogeneity has been investigated for paediatric EPN revealing novel therapeutic targets in the context of gene-metabolite correlations. Drug tolerability will be further assessed in vivo using the previously characterised PF-A EPN orthotopic mouse xenograft MAF-928.

Retrospective analysis of survival and safety of bevacizumab biosimilar and original drug combination chemotherapy in non-small cell lung cancer.

The advent of bevacizumab has considerably transformed the therapeutic landscape for non-small cell lung cancer (NSCLC) patients devoid of specific genetic mutations. A pivotal milestone has been reached with the recent approval of a bevacizumab biosimilar, following rigorous phase III clinical investigations, poised to augment NSCLC therapeutic strategies. This retrospective analysis encompasses a large-scale study conducted between January 2021 and December 2023, involving 1058 NSCLC patients (metastatic or locally advanced stages). The research design entailed a comparative assessment of the safety and efficacy profiles of combined therapies using the original bevacizumab and its biosimilar, adhering to RECIST v1.1 criteria. Adverse event grading was standardized using the National Cancer Institute's CTCAE v5.0. Notably, the biosimilar demonstrated an objective response rate (ORR) of 29.79% in 606 patients, closely paralleling the 27.41% ORR observed in 452 patients receiving the original drug, with insignificant risk differences (-0.03) and a risk ratio of 0.987, affirming equivalence. Progression-free survival (PFS) was influenced by radiation status, treatment lines, and regimen combinations, while dosage intensity and genetic factors had negligible impacts. The incidence of treatment-emergent adverse events (TEAEs) was slightly higher in the biosimilar group (75.11%) versus the original drug group (72.78%), with grade 3 or more severe TEAEs occurring in 23.6% and 18.5% of patients, respectively (Detailed criteria for the definition and assessment of TEAEs have been added to the Methods section, including the use of the National Cancer Institute's CTCAE v5.0 for grading). The study affirms that bevacizumab biosimilars offer equivalent therapeutic efficacy and a similar safety profile to the originator product in the management of locally advanced or metastatic NSCLC. The tolerability of the toxicity profile, coupled with the absence of unforeseen adverse reactions, underscores the viability of biosimilar bevacizumab as a valuable addition to NSCLC treatment regimens. These findings also imply potential benefits for a broader patient population beyond clinical trial confines through the adoption of biosimilar beta-adrenergic blocking agents.

Combinatorial Effects of 5-Fluorouracil and Menadione on Wnt/β-Catenin Pathway in Human Colorectal Cancer Cells.

The incidence and mortality rates of colorectal cancer (CRC) are alarmingly high, and the scientific community is consistently engaged in developing newer therapeutic options for cancer cure or prevention. The fluoropyrimidine drug, 5-fluorouracil (5FU), remains the first line of treatment against CRC; nevertheless, relapses frequently occur since the cells gain resistance over time through various mechanisms. Studies have highlighted the significance of combinatorial treatment of a Wnt signaling inhibitor and 5FU as a better treatment strategy to overcome 5FU resistance. Small molecules that specifically target and disrupt β-catenin-TCF interaction, a crucial step of the Wnt signaling, are promising in CRC treatment. In this study, we investigated the synergistic cytotoxic activity of menadione with 5FU as the former has previously been shown to downregulate Wnt signaling in CRC cells. Docking and experimental results suggest that the drug combination interfered with key protein-protein interactions in the β-catenin-TCF complex, exerted synergistic anti-cancerous effects in CRC cells, and downregulated the expression of Wnt signaling proteins. Taken together, our data suggest that the simultaneous binding of 5FU and menadione to β-catenin can block Wnt signaling by disrupting β-catenin-TCF interaction and inhibit the proliferation of CRC cells.

Hormones as a double-edged sword: the role of hormones in cancer progression and the potential of targeted hormone therapies.

Cancer remains a significant cause of mortality in the world, with increasing prevalence worldwide. There are numerous treatments ranging from surgery to chemotherapy and radiotherapy, but since cancer is a heterogeneous disease, only few patients possibly respond to treatments. However, it opens a huge space for the advent of targeted therapies such as hormone therapy, immunotherapy, and target-specific drugs. Hormonal therapy using hormone agonists/antagonists or hormone receptor inhibitors-called the next-generation hormonal agents-hits distinct hormonal pathways that are involved in breast, prostate and ovarian cancer. Preliminary results show that through combination of drugs, it is possible that the synergistic effects may actually lead to better survival than with the use of single drugs. With manageable adverse effects, hormonal therapy offers much hope for treatment of this rather challenging malignancy of the hormone-sensitive cancers, especially in combination with other treatments.