Synergistic Effect Of Combination Research Articles

Assessment of tuberculosis drug efficacy using preclinical animal models and in vitro predictive techniques

Tuberculosis (TB) killed approximately 1.3 million people in 2022 and remains a leading cause of death from the bacteria Mycobacterium tuberculosis (M.tb); this number of deaths was surpassed only by COVID-19, caused by the SARS-CoV-2 virus. The alarming emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) M.tb strains presents an urgent need for effective new treatments. Our study aimed to determine the synergistic effects of antibiotic combinations against M.tb. Using a high-throughput in vitro checkerboard assay, we evaluated the interactions of Bedaquiline (BDQ) and other antibiotics including Capreomycin (CAP), Linezolid (LIN), and Sutezolid (SUT) against M.tb H37Rv. BDQ and CAP demonstrated in vitro enhanced effect, which prompted further investigation in vivo using the murine low dose aerosol (LDA) model. After aerosol challenge with M.tb, C57BL/6 mice were treated with BDQ, CAP, or their combination, starting 28 days post-infection. The antimicrobial treatment lasted four weeks, and the bacterial burden in lung and spleen tissues was assessed at the end of treatment. At 4 weeks post-treatment, a significant reduction in bacterial load was observed within the lungs and spleens of mice given BDQ alone or given as a BDQ/CAP combination compared to the untreated group. In contrast, CAP monotherapy led to an increase in bacterial load within the lung and no significant difference in bacterial burden in the spleen in comparison to the untreated mice. These results were confirmed in the guinea pig model of TB, where both BDQ and the BDQ/CAP combination treatment led to a decrease in bacterial burden in the lung and spleen, whereas CAP had no significant effect on bacterial burden at the 4-week post treatment timepoint. We next determined whether there may be differences in vitro with the BDQ/CAP combination against M.tb lineages 1, 2 and 4. We determined that in vitro enhanced effect was not observed in some representative strains of M.tb lineage 4, indicating variability in drug effectiveness across M.tb lineages. This research underscores the complexity of TB treatment and the critical need for innovative approaches to combat this global health threat.

Synergistic Effects of Antimicrobial Peptide Dendrocin‑ZM1 Combined with Conventional Antibiotics Against Methicillin-Resistant <i>Staphylococcus aureus</i>

Background: Methicillin-resistant Staphylococcus aureus (MRSA) is the most prevalent type of bacterial resistance. Consequently, it is crucial to develop novel treatments to address bacterial resistance. Objectives: Dendrocin-ZM1 (DZM1) and vancomycin are two compounds whose effects on MRSA are examined in this study. Methods: The synergistic bactericidal effect of the peptide-conventional antibiotic combinations was evaluated using the minimal inhibitory concentration (MIC), minimum bactericidal concentration (MBC) assays, and checkerboard method. Additionally, the time-killing kinetics of DZM1 alone and in combination with vancomycin on MRSA ATCC 43300 strain were assessed. Structural alterations and morphological changes of the MRSA ATCC 43300 strain exposed to DZM1 (1/16 MBC) and vancomycin (1/8 MBC), alone or in combination (1/16 MBC DZM1 + 1/8 MBC vancomycin), were analyzed using transmission electron microscopy (TEM) and scanning electron microscopy (SEM), respectively. Results: Dendrocin-ZM1 exhibited antimicrobial activity against MRSA clinical isolates and MRSA ATCC 43300 (MIC and MBC: 16 µg/mL). A synergistic effect was observed when DZM1 was combined with vancomycin (FIC: 0.187) against MRSA ATCC 43300. The combination of DZM1 with vancomycin at sub-MBC concentrations demonstrated sustained bactericidal activity against MRSA ATCC 43300 strain. According to SEM results, DZM1 increased bacterial cell membrane permeability, enhancing the antibacterial activity of vancomycin. Transmission electron microscopy analysis revealed severe membrane damage and subsequent cell lysis in the MRSA ATCC 43300 strain when treated with the combination of DZM1 and vancomycin. Conclusions: This study supports the potential use of these compounds to reduce reliance on conventional antibiotics and highlights their promise as alternatives for combating bacterial resistance.

Synergy or Counteraction: Can Multiple Environmental Policies Promote High-Quality Green Transformation of Enterprises?—A Comprehensive Assessment Based on Double Machine Learning Algorithms

As environmental issues grow increasingly complex and multifaceted, the synergistic effects of environmental policies and their implementation methods have become central to the environmental policy system. This paper analyzes panel data from all A-share-listed companies in China between 2013 and 2022 and aims at comprehensively evaluate the role and impact of command-and-control, market-incentive, and public-participation environmental policies along with their combinations on corporate green transformation by using a double machine learning method. The results indicate that (1) all three types of environmental policies positively influence corporate green transformation, with market-based policies having the most pronounced effect; (2) the synergistic effects of policy combinations further enhance corporate green transformation, especially the combination of market-incentive and public-participation environmental policies; (3) heterogeneity analysis highlights differences in the effects of these environmental policies and their combinations on corporate attributes and regional factors; and (4) mechanism analysis indicates that green innovation and financial constraints indirectly drive the high-quality green transformation of enterprises.

Exploring the Synergistic Effects of Biostimulant and Hydrogel Combinations on Brinjal Growth: An Assessment of Growth Parameters

Background: This study at Lovely Professional University, Phagwara, Punjab, evaluates the combined effects of hydrogel and Arka Vegetable biostimulants on brinjal (Solanum melongena L.) production. Brinjal’s high water and nutrient needs make it sensitive to water scarcity and seasonal variations. Hydrogel enhances soil moisture retention, reducing irrigation needs, while Arka Vegetable biostimulants improve plant growth and stress tolerance. Using both together aims to optimize water management and plant health, addressing key challenges in brinjal cultivation. Methods: In the study, the hydrogel was applied during the sowing stage, while Arka Vegetable Special was sprayed twice, with a 15-day interval after transplanting. The treatment designated as V2H2 (5 g/L + 1.5 kg/acre) was utilized, where ‘V’ represents concentration in grams per liter and ‘H’ denotes application rate in kilograms per acre. This treatment is aimed at optimizing vegetative growth. Various levels of Arka Vegetable Special and hydrogel application were tested to observe their effects on growth characteristics. Result: The study’s findings revealed the effectiveness of the V2H2 treatment in enhancing vegetative growth. Application of Arka Vegetable Special and hydrogel at different levels significantly improved all the studied growth characteristics. This suggests the potential of integrating biostimulants and Hydrogel practices to optimize Brinjal production, offering a sustainable solution to meet year-round vegetable demand and mitigate water scarcity challenges in agricultural systems.

PAIRWISE: Deep Learning-based Prediction of Effective Personalized Drug Combinations in Cancer.

Combination therapies offer promise for improving cancer treatment efficacy and preventing recurrence. However, identifying optimal drug combinations tailored to specific cancer subtypes and individual patients is extremely challenging due to the vast number of possible combinations and tumor heterogeneity. To address this gap, we take a machine learning approach combining deep learning with transfer learning to incorporate prior scientific knowledge and predict drug synergy based on tumor-specific transcriptome profiles. This approach, called PAIRWISE, explicitly modeled synergistic effects of drug combinations in cancer cell lines or individual tumor samples based on drug chemical structures, drug targets, and transcriptomes of inferred samples. PAIRWISE outperformed competing models with an area under the receiver operating characteristic curve (AUROC) of 0.85 on held-out cancer cell lines. When applied to an independent dataset of combinations with Bruton Tyrosine Kinase inhibitors (BTKi) in Diffuse Large B Cell Lymphoma (DLBCL) cell lines, PAIRWISE accurately predicted synergistic drug combinations with an AUROC of 0.72. To further confirm the robustness of PAIRWISE predictions, we performed an in silico, patient profile-directed screen for other compounds that would synergize with BTKi in DLBCL patients, and confirmed the synergy of the predictions using a panel of eight non-Hodgkin lymphoma cell lines. These findings demonstrate the ability of PAIRWISE to nominate effective personalized drug combinations, accelerating the development of precision oncology.

Synergistic Effect of Tamoxifen and Ruxolitinib Combination in Reducing Disease Burden in Myeloproliferative Neoplasms

Synergistic Effect of Tamoxifen and Ruxolitinib Combination in Reducing Disease Burden in Myeloproliferative Neoplasms

Synergistic Effect of Trifluridine and PARPi Combination in Targeting TP53-Mutated AML

Synergistic Effect of Trifluridine and PARPi Combination in Targeting <i>TP53</i>-Mutated AML

Nano-herbal combination targets apoptosis in oral squamous cell carcinoma

BackgroundThis study evaluates the synergistic effects of the nano-herbal combination of Bischofia javanica leaves and Phaleria macrocarpa fruits on oral squamous cell carcinoma (OSCC), a metastatic keratinocyte malignancy. Materials and MethodsThirty-six male Wistar rats were divided into six groups: a negative control group (K0), an OSCC-induced control group (K1), and four treatment groups (P1-P4), which received oral treatments for four weeks. Blood samples were analyzed for superoxide dismutase (SOD), malondialdehyde (MDA), and vascular endothelial growth factor (VEGF) levels, while immunohistochemistry was used to assess the expression of heat shock protein 70 (HSP-70), caspase-3, caspase-8, caspase-10, and MDA. ResultsNano-herbal treatment significantly reduced MDA levels, particularly in groups P3 and P4, with reductions comparable to those seen in the Vitamin C treatment group (p < 0.05). SOD levels were highest in group P3 (p < 0.05), similar to the negative control group (K0), while VEGF levels were significantly elevated in the positive control group (K1) (p < 0.05). Group P3 exhibited the highest expression of HSP-70 (p < 0.05). Caspase-3 expression was significantly higher in P3 compared to K1 (p = 0.0007), while caspase-8 and caspase-10 expressions were also significantly elevated in groups P2, P3, and P4 (p < 0.05). Group P3 showed the most pronounced effects in promoting apoptosis, with caspase-3 and caspase-8 levels markedly higher compared to K1. ConclusionThe combined nano-herbal formulations of Bischofia javanica leaves and Phaleria macrocarpa fruits effectively mitigates oxidative stress, induces apoptosis, and holds potential as a therapeutic approach for managing oral squamous cell carcinoma (OSCC).

Fenbendazole and Diisopropylamine Dichloroacetate Exert Synergistic Anti-cancer Effects by Inducing Apoptosis and Arresting the Cell Cycle in A549 Lung Cancer Cells.

Lung cancer is the leading cause of cancer-related mortality worldwide, accounting for approximately 2 million new cases and 1.8 million deaths annually. Standard treatment options include surgery, radiation therapy, chemotherapy, and targeted therapies. Despite advancements over the past 25 years, the prognosis of patients with lung cancer remains poor. This study evaluated the synergistic anticancer effects of fenbendazole (FZ) and diisopropylamine dichloroacetate (DADA) on A549 lung cancer cells. Fenbendazole (methyl N-(6-phenylsulfanyl-1H-benzimidazol-2-yl) carbamate) is a broad-spectrum benzimidazole anthelmintic commonly used in veterinary medicine. Diisopropylamine Dichloroacetate (DADA), an over-the-counter treatment for chronic liver disease, has demonstrated anti-tumor properties as an inhibitor of pyruvate dehydrogenase kinase. The combination of FZ and DADA exhibited a synergistic effect on inhibiting the proliferation of A549 lung cancer cells. After 48 h of treatment, the FZ-DADA combination produced reactive oxygen species (ROS) and promoted apoptosis by down-regulating Bcl2 and up-regulating BAX protein expression. The combination activated caspase-3, caspase-7, and PARP, further driving apoptosis in A549 cells. The FZ-DADA treatment also induced cell cycle arrest, as evidenced by the inhibition of Cyclin A and Cyclin E proteins. The synergistic anticancer effects of the FZ-DADA combination were confirmed at both cellular and protein levels in A549 lung cancer cells. The combination modulates key apoptotic proteins, induces cell cycle arrest, and increases mitochondrial ROS production, suggesting a promising approach for lung cancer treatment that warrants further investigation and development.

Synergistic effects of bacteriophage cocktail and antibiotics combinations against extensively drug-resistant Acinetobacter baumannii

BackgroundThe extensively drug-resistant (XDR) strains of Acinetobacter baumannii have become a major cause of nosocomial infections, increasing morbidity and mortality worldwide. Many different treatments, including phage therapy, are attractive ways to overcome the challenges of antibiotic resistance.MethodsThis study investigates the biofilm formation ability of 30 XDR A. baumannii isolates and the efficacy of a cocktail of four tempetate bacteriophages (SA1, Eve, Ftm, and Gln) and different antibiotics (ampicillin/sulbactam, meropenem, and colistin) in inhibiting and degrading the biofilms of these strains.ResultsThe majority (83.3%) of the strains exhibited strong biofilm formation. The bacteriophage cocktail showed varying degrees of effectiveness against A. baumannii biofilms, with higher concentrations generally leading to more significant inhibition and degradation rates. The antibiotics-bacteriophage cocktail combinations also enhanced the inhibition and degradation of biofilms.ConclusionThe findings suggested that the bacteriophage cocktail is an effective tool in combating A. baumannii biofilms, with its efficacy depending on the concentration. Combining antibiotics with the bacteriophage cocktail improved the inhibition and removal of biofilms, indicating a promising strategy for managing A. baumannii infections. These results contribute to our understanding of biofilm dynamics and the potential of bacteriophage cocktails as a novel therapeutic approach to combat antibiotic-resistant bacteria.

Synergistic effects of antimicrobial components of the human-derived composite amnion-chorion membrane on bacterial growth.

The human-derived amnion-chorion membrane (ACM) has endogenous antimicrobial properties, which are important for preventing the colonization and survival of oral bacteria on exposed membranes. This project aimed to decipher the underlying mechanism by identifying the components of ACM that confer antibacterial properties. In addition, the antimicrobial efficacy of these identified components on oral bacteria was assessed. Four antimicrobial proteins, histone H2A/H2B, cathelicidin LL-37, lactoferrin, and lysozyme, were identified via mass spectrometry in ACM. These proteins were then assessed for their efficacy in killing Streptococcus gordonii Challis. Log-phased bacterial cells were cultured with the commercially available proteins that were identified in ACM, either individually or in combination, at different concentrations. After incubation for 8 or 24 hours, the bacteria were stained with a live/dead viability kit and analyzed via confocal microscopy. The combination of these proteins effectively killed S. gordonii in a dose-dependent fashion after 8 or 24 hours of incubation. When each protein was tested individually, it killed S. gordonii at a much lower efficacy relative to the combinations. The synergistic effects of the antimicrobial protein combinations were also observed in both the viable cell count recovery and minimum inhibitory concentration assays. By shedding light on the mechanisms in the ACM's antimicrobial property, this study may raise more awareness of the potential benefit of utilization of a membrane with endogenous antimicrobial properties in regeneration surgeries.

Lactobacillus gasseri BNR17 and Limosilactobacillus fermentum ABF21069 Ameliorate High Sucrose-Induced Obesity and Fatty Liver via Exopolysaccharide Production and β-oxidation.

Obesity and metabolic dysfunction-associated fatty liver disease (MAFLD) are prevalent metabolic disorders with substantial global health implications that are often inadequately addressed by current treatments and may have side effects. Probiotics have emerged as promising therapeutic agents owing to their beneficial effects on gut health and metabolism. This study investigated the synergistic effects of a probiotic combination of BNR17 and ABF21069 on obesity and MAFLD in C57BL/6 mice fed a high-sucrose diet. The probiotic combination significantly reduced body weight and fat accumulation compared with the high-sucrose diet. It also alleviated elevated serum leptin levels induced by a high-sucrose diet. Histological analysis revealed a significant reduction in white adipose tissue and fatty liver in the mice treated with the probiotic combination. Furthermore, increased expression of genes related to β-oxidation, thermogenesis, and lipolysis suggested enhanced metabolic activity. The probiotic groups, particularly the BNR17 group, showed an increase in fecal exopolysaccharides, along with a tendency toward a lower expression of intestinal sugar transport genes, indicating reduced sugar absorption. Additionally, inflammatory markers in the liver tissue exhibited lower expression in the ABF21069 group than in the HSD group. Despite each strain in the combination group having distinct characteristics and functions, their combined effect demonstrated synergy in mitigating obesity and MAFLD, likely through the modulation of fecal exopolysaccharides content and improvement in lipid metabolism. These findings underscore the potential of probiotic supplementation as a promising assistant therapy for managing obesity and MAFLD and provide valuable insights into its therapeutic mechanisms in metabolic disorders.

Antibacterial synergistic effect of sea cucumber extract and kelulut honey combination

Natural products remain one of the major sources of new drug molecules today. The combination of sea cucumber extract with stingless bee honey holds great potential for health supplement. However, the specific results of the combination have yet to be determined. In this study, the antibacterial activity of kelulut honey and Phyllophorus spiculata sea cucumber extract samples individually and in combination were assessed with disk-diffusion assays and broth dilution method. Most of the samples exhibit small or absence of inhibitory activity using disk-diffusion assay method. Only kelulut honey sample with 100% concentration has a positive antagonism effect against Escherichia coli and Staphylococcus epidermidis. For the broth dilution method, Gram-positive bacteria were found to be more susceptible as compared to Gram-negative bacteria species, with lower minimum inhibitory concentration (MIC) value of kelulut honey, sea cucumber or combination sample. The growth of gram-positive S. epidermidis is inhibited by sea cucumber extract at MIC value of 0.031 mg/mL, kelulut honey at MIC value of 0.063 mg/ mL and combination sample at MIC value of 0.063 mg/mL, all of which are of lower MIC value as compared to E. coli inhibition. The absorbance at optical density (OD) 600nm wavelength was also measured to monitor the growth of bacteria in solution. From the results, broth dilution proves to be a more effective method to assess the antibacterial activity in the combination samples. Two combinations showed the best antibacterial synergy (OD600 value of 0.000) against both Gram-positive and Gram-negative bacteria, which were (1) ½ sea cucumber: ½ kelulut honey combination and (2) ¾ sea cucumber: ¼ kelulut honey combination. This preliminary evidence on their antibacterial synergistic activities is promising and shows possible commercialization potential.

Synergistic anticancer effects and reduced genotoxicity of silver nanoparticles and tamoxifen in breast cancer cells

AbstractNanotechnology is emerging as a promising tool to enhance traditional cancer treatments due to rising chemotherapy resistance and the severe side effects of toxic drugs. Silver nanoparticles (AgNPs) are widely acknowledged for their antimicrobial and antiproliferative properties. Given these AgNP characteristics, this research conducts a comprehensive nanotoxicological assessment of strategic combinations involving AgNPs (68 nm) commercial formulation and tamoxifen on MCF‐7 and MDA‐MB‐231 breast tumor cells. Utilizing CompuSyn software, the combination index was determined, revealing a synergistic cytotoxic and antiproliferative effect in AgNPs and tamoxifen combinations (CI &lt; 0.97). Furthermore, this combination impaired cell migration (the scratch zone expanded by over 270%) and significantly increased reactive oxygen species production (up to 96% for MDA‐MB‐231 and 52% for MCF‐7 cells). Surprisingly, the genotoxic effect of these mixtures was minimal (below the allowable genotoxicity index of 1.5). Additionally, both breast tumor cell lines exhibited increased proapoptotic and oxidative stress gene expression following the combined treatment. The internalization of AgNPs into breast cancer cells was observed, enhancing their synergistic antiproliferative effect when combined with tamoxifen. These findings suggest the potential of combining AgNPs with chemotherapeutic agents for innovative studies in oncology therapy.

Abstract C046: Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related mortality in the United States. While Poly (ADP-ribose) polymerase (PARP) inhibitors show promise for PDAC with Homologous Recombination Deficiency (HRD), this mutation is present in less than 10% of cases. Our research focuses on exploiting a vulnerability in the remaining 90% of HR proficient (HRP) tumors. We identified that wild-type isocitrate dehydrogenase 1 (IDH1) plays a critical role in HR repair. By inhibiting IDH1, we discovered suppression of the homologous recombination (HR) pathway, leading to compromised genomic integrity. This renders cancer cells more susceptible to PARP inhibitor therapy, offering a novel therapeutic approach for HRP PDAC. Methods:We assessed the impact of IDH1 inhibition on HR pathway activity using Western blotting to measure HR repair protein levels and HR reporter assays. The effect of IDH1 inhibition (Ivosidenib) combined with PARP inhibition (Olaparib) on in vitro growth inhibition was assessed through drug combination assays. Additionally, we investigated the molecular mechanisms underlying the synergistic effects of the drug combination. To further evaluate the therapeutic potential of IDH1 inhibition in combination with PARP inhibitors, we examined tumor growth in xenograft models of PDAC in athymic nude mice and survival studies were performed in C57BL/6J mice transplanted with orthotopic murine pancreatic cancer. Results:Wild-type IDH1 blockade induces a BRCA-like phenotype by decreasing α-ketoglutarate (αKG) levels and causing histone hypermethylation. This leads to decreased HR repair efficiency in HRP pancreatic cancer cells (MiaPaCa-2 and Panc-1), resulting in a strong synergistic effect when combined with the DNA-damaging agent Olaparib. The combination treatment significantly reduced cell survival in both short and long-term assays. Furthermore, we discovered that these compounds complemented each other in the DNA damage response, leading to increased γ-H2AX (DNA damage marker) and apoptosis. In vivo studies using murine PDAC models demonstrated that the combination of ivosidenib and olaparib synergistically enhanced anti-tumor activity compared to either single agent alone. Conclusion:These data provide novel insight into the mechanisms underlying in the context of HRP cancer susceptibility to a dual treatment approach involving an IDH1 inhibitor and a PARP inhibitor. This approach holds promise for precision medicine in pancreatic cancer treatment, although further pre- clinical studies are needed for validation and refinement. Citation Format: Mehrdad Zarei, Omid Hajihassani, Hallie J. Graor, Soubhi Tahhan, Alexander W. Loftus, Faith Nakazzi, Semmer A. Ali, Parnian Naji, Luke D. Rothermel, Jonothan R. Brody, Jordan M. Winter. Targeting wild-type IDH1 sensitizes homologous recombination proficient pancreatic cancer to PARP inhibition [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C046.

The SoCAP (Social Communication, Affiliation, and Presence) Taxonomy of Social Features: Scoping Review of Commercially Available eHealth Apps.

eHealth interventions have proven to be valuable resources for users with diverse mental and behavioral health concerns. As these technologies continue to proliferate, both academic researchers and commercial app creators are leveraging the use of features that foster a sense of social connection on these digital platforms. Yet, the literature often insufficiently represents the functionality of these key social features, resulting in a lack of understanding of how they are being implemented. This study aimed to conduct a methodical review of commercially available eHealth apps to establish the SoCAP (social communication, affiliation, and presence) taxonomy of social features in eHealth apps. Our goal was to examine what types of social features are being used in eHealth apps and how they are implemented. A scoping review of commercially available eHealth apps was conducted to develop a taxonomy of social features. First, a shortlist of the 20 highest-rated eHealth apps was derived from One Mind PsyberGuide, a nonprofit organization with trained researchers who rate apps based on their (1) credibility, (2) user experience, and (3) transparency. Next, both mobile- and web-based versions of each app were double-coded by 2 trained raters to derive a list of social features. Subsequently, the social features were organized by category and tested on other apps to ensure their completeness. Four main categories of social features emerged: (1) communication features (videoconferencing, discussion boards, etc), (2) social presence features (chatbots, reminders, etc), (3) affiliation and identity features (avatars, profiles, etc), and (4) other social integrations (social network and other app integrations). Our review shows that eHealth apps frequently use resource-intensive interactions (eg, videoconferencing with a clinician and phone calls from a facilitator), which may be helpful for participants with high support needs. Furthermore, among commercially available eHealth apps, there is a strong reliance on automated features (eg, avatars, personalized multimedia, and tailored content) that enhance a sense of social presence without requiring a high level of input from a clinician or staff member. The SoCAP taxonomy includes a comprehensive list of social features and brief descriptions of how these features work. This classification system will provide academic and commercial eHealth app creators with an understanding of the various social features that are commonly implemented, which will allow them to apply these features to enhance their own apps. Future research may include comparing the synergistic effects of various combinations of these social features.

The passive optimization mechanism of winter thermal performance in commercial complex based on coupled multi-spatial parameters

In cold regions, public buildings often suffer from suboptimal thermal performance due to cold air intrusion. This study explores the synergistic impact of multiple spatial parameters on winter thermal environments to discover the passive optimization potential in commercial complexes. Airflow analysis covers the entire connected space from the entrance to the large atrium, integrating the collective effects of all critical spatial parameters. Based on 4500 Computational Fluid Dynamics (CFD) simulation, the study establishes how these parameters influence wind resistance and thermal comfort. Key findings reveal that the “Atrium-plan Ratio,” “Transitional Space-width,” and “Atrium-height,” are most impactful on wind resistance, contributing over 53 % collectively. For thermal comfort, “Atrium-volume,” “Atrium-section Form,” and “Atrium-height,” are most significant, with a combined weight exceeding 57 %. As wind speed increases, the effect of single parameters gradually diminishes, highlighting the synergistic effect of spatial combinations. A case study demonstrates an 80.5 % improvement in thermal performance score following optimization, underscoring the potential for low-carbon, high-efficiency design in commercial complexes.

Synergistic combination effect of the PCA-1/ALKBH3 inhibitor HUHS015 on prostate cancer drugs in vitro and in vivo.

Prostate cancer antigen-1/ALKBH3, a DNA/RNA demethylase of 3-methylcytosine, 1-methyladenine (1-meA), and 6-meA, was found in prostate cancer as an important prognostic factor. Additionally, 1-meA has been associated with other cancers. The ALKBH3 inhibitor HUHS015 was found to be effective against prostate cancer both in vitro and in vivo. Herein, we investigated the effect of HUHS015 in combination with drugs for prostate cancer approved in Japan (including bicalutamide, cisplatin, mitoxantrone, prednisolone, ifosfamide, tegafur/uracil, docetaxel, dacarbazine, and estramustine) by treating DU145 cells with around IC50 value concentrations of these drugs for 3 days. Additionally, the cells were observed for additional 9 days after drug removal. Combination treatment with dacarbazine, estramustine, tegafur/uracil, and HUHS015 showed a slight additive effect after 3 days. After drug washout of them and mitoxantrone, the combined effects and levels were enhanced and sustained, although the effects of each treatment alone declined. HUHS015 combined with cisplatin or docetaxel elicited synergistic and sustained effects. In vivo, combining HUHS015 and docetaxel, the first chemotherapeutic agent for castration-resistant prostate cancer, showed notable effects in the DU145 xenograft model. In conclusion, HUHS015 exhibited a synergistic effect with docetaxel and drugs acting on DNA in vitro, even after drug removal. Since cancer chemotherapy is typically administered during rest periods due to its high toxicity, combining it with an ALKBH3 inhibitor could be a promising strategy for enhancing cancer treatment, as it can elicit an additive effect during treatment, allowing dosage reduction, and synergistically sustain the effect after drug washout during rest periods.

MMFSyn: A Multimodal Deep Learning Model for Predicting Anticancer Synergistic Drug Combination Effect.

Combination therapy aims to synergistically enhance efficacy or reduce toxic side effects and has widely been used in clinical practice. However, with the rapid increase in the types of drug combinations, identifying the synergistic relationships between drugs remains a highly challenging task. This paper proposes a novel deep learning model MMFSyn based on multimodal drug data combined with cell line features. Firstly, to ensure the full expression of drug molecular features, multiple modalities of drugs, including Morgan fingerprints, atom sequences, molecular diagrams, and atomic point cloud data, are extracted using SMILES. Secondly, for different modal data, a Bi-LSTM, gMLP, multi-head attention mechanism, and multi-scale GCNs are comprehensively applied to extract the drug feature. Then, it selects appropriate omics features from gene expression and mutation omics data of cancer cell lines to construct cancer cell line features. Finally, these features are combined to predict the synergistic anti-cancer drug combination effect. The experimental results verify that MMFSyn has significant advantages in performance compared to other popular methods, with a root mean square error of 13.33 and a Pearson correlation coefficient of 0.81, which indicates that MMFSyn can better capture the complex relationship between multimodal drug combinations and omics data, thereby improving the synergistic drug combination prediction.

Diclofenac Sodium Restores the Sensitivity of Colistin-Resistant Gram-Negative Bacteria to Colistin.

The continuous rise of multidrug-resistant (MDR) Gram-negative bacteria poses a severe threat to public health worldwide. Colistin(COL), employed as the last-line antibiotic against MDR pathogens, is now at risk due to the emergence of colistin-resistant (COL-R) bacteria, potentially leading to adverse patient outcomes. In this study, synergistic activity was observed when colistin and diclofenac sodium (DS) were combined and used against clinical COL-R strains of Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Acinetobacter baumannii (A. baumannii), and Pseudomonas aeruginosa (P. aeruginosa) both in vitro and in vivo. The checkerboard method and time-killing assay showed that DS, when combined with COL, exhibited enhanced antibacterial activity compared to DS and COL monotherapies. Crystal violet staining and scanning electron microscopy showed that COL-DS inhibited biofilm formation compared with monotherapy. The in vivo experiment showed that the combination of DS and COL reduced bacterial loads in infected mouse thighs. Synergistic activity was observed when COL and DS were use in combination against clinical COL-R strains of E. coli, K. pneumoniae, A. baumannii and P. aeruginosa both in vitro and in vivo. The synergistic antibacterial effect of the COL-DS combination has been confirmed by performing various in vitro and in vivo experiments, which provides a new treatment strategy for infections caused by MDR bacteria.