Combined Approach Research Articles

Inhalable Anti-EGFR Antibody-Conjugated Osimertinib Liposomes for Non-Small Cell Lung Cancer

Background: Non-small cell lung cancer (NSCLC) is a leading cause of cancer deaths globally. The most extensive treatment is Tyrosine Kinase Inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) overexpression. Osimertinib, a third-generation TKI is approved to target EGFR exon 19 deletions or exon 21 L858R mutations. However, resistance is inevitable due to emergence of triple mutations (sensitizing mutations, T790M and C797S). To overcome this challenge, a combinatorial approach was used wherein Osimertinib liposomes were conjugated with cetuximab (CTX), an anti-EGFR monoclonal antibody, to improve drug efficacy and delivery. Additionally, pulmonary administration was employed to minimize systemic toxicity and achieve high lung concentrations. Methods: Osimertinib liposomes (OB-LPs) were prepared using thin film hydration method and immunoliposomes (CTX-OB-LPs) were prepared by conjugating the OB-LPs surface with CTX. Liposomes were characterized for particle size, zeta-potential, drug loading, antibody conjugation efficiency, in vitro drug release, and aerosolization performance. Further, the in vitro efficacy of immunoliposomes was evaluated in H1975 cell line. Results: Immunoliposomes exhibited a particle size of 150 nm, high antibody conjugation efficiency (87%), efficient drug release, and excellent aerosolization properties with an aerodynamic diameter of 3 μm and fine particle fraction of 88%. Furthermore, in vitro studies in H1975 cells showed enhanced cytotoxicity with CTX-OB-LPs displaying 1.7-fold reduction and 1.2-fold reduction in IC50 compared to Osimertinib and OB-LPs, respectively. The CTX-OB-LPs also significantly reduced tumor cell migration and colonization compared to Osimertinib and OB-LPs. Conclusions: These successful results for EGFR-targeting inhalable immunoliposomes exhibited potential for contributing to greater anti-tumor efficacy for the treatment of non-small cell lung cancer.

Prolonged Photobiomodulation with Deep Red Light Mitigates Incipient Retinal Deterioration in a Mouse Model of Type 2 Diabetes

Diabetic retinopathy is a prevalent complication of type 2 diabetes mellitus, characterized by progressive damage to the retinal structure and function. Photobiomodulation therapy, using red or near-infrared light, has been proposed as a non-invasive intervention to mitigate retinal damage, but has been tested generally with short-term stimuli. This study aimed to evaluate the effects of prolonged photobiomodulation with deep red light on retinal structure and function in a type 2 diabetes mouse model. Transgenic LepRdb/J (db/db) mice were exposed to photobiomodulation therapy via LED devices emitting 654 nm light for 12 h daily over ten weeks and compared to untreated mice. Retinal function was evaluated by flash electroretinography, while structural changes were assessed through histology and immunohistochemistry to detect astro- and microgliosis. At 33 weeks of age, db/db mice were obese and severely diabetic, but exhibited only incipient indicators of retinal deterioration. Electroretinogram b-wave peak latencies were prolonged at intermediate flash intensities, while the outer plexiform layer displayed significantly elevated IBA1 expression. Photobiomodulation therapy prevented these two markers of early retinal deterioration but had no effect on other morphological and functional parameters. Photobiomodulation is well-tolerated and maintains potential as a complementary treatment option for diabetic retinopathy but requires further optimization of therapeutic settings and combinatory treatment approaches.

EXTH-16. UNBIASED DISCOVERY OF SYNERGISTIC VULNERABILITIES AGAINST GLIOBLASTOMA: AN INNOVATIVEIN VIVO CRISPR PROFILING PLATFORM TO UNLEASH THE POWER OF TUMOR-TARGETED CYTOKINE THERAPY

Abstract BACKGROUND Glioblastoma poses a formidable challenge due to its intricate intra- and intertumoral heterogeneities and its associated immunosuppressive milieu. The standards of care have limited activity, and no major advances have been made in decades. One promising avenue is tumor-targeted cytokine-based therapies, particularly L19-TNF, which is undergoing clinical trials in Europe and the US for patients with newly diagnosed and recurrent glioblastoma. However, there is still an opportunity to find safer and more tolerable combination partners to improve the efficacy of L19-TNF immunotherapy. To address this challenge, we employed a cutting-edge in vivo CRISPR screening approach to identify synergistic vulnerabilities with a focus on druggable targets. METHODS We systematically investigated the dependencies of tumor growth and key signaling pathways under the pressure of L19-TNF immunotherapy in the CT-2A orthotopic murine glioma model. We used an innovative in vivo CRISPR screening approach that enables timed sgRNA activation to mitigate off-target effects and overcome orthotopic tumor cell implantation challenges, such as the bottleneck of cell engraftment. RESULTS We first conducted a genome-wide in vivo screen and identified 400 top-scoring candidate genes, which we subsequently tested again in a targeted in vivo screen to refine our drug selection process. Through this, we uncovered novel and previously unexplored druggable targets for glioblastoma. Out of these, we validated four promising target-specific drugs in preclinical glioblastoma models in downstream in vivo experiments. In addition, we investigated modes of action and resistance. CONCLUSION Our research marks a significant advancement in pursuing novel treatment strategies for glioblastoma. We have unveiled a range of synergistic combinations and paved the way for the rational design of combinatory treatment approaches to maximize the therapeutic efficacy of L19-TNF immunotherapy, laying the groundwork for future clinical translation.

EPCO-06. DIFFUSE MIDLINE GLIOMAS: FROM CELL CYCLE TO THERAPEUTIC OPPORTUNITIES

Abstract The fatal Diffuse Midline Gliomas (DMG) are characterized by an undruggable H3K27M mutation in H3.1 or H3.3. K27M impairs normal development by stalling of differentiation. As replication timing influences gene expression, cell fate, and cellular response to therapeutics, we undertook a multi-omics approach (Repli-seq, cell cycle RNA-seq, single cell RNA-seq) in DMG cells (H3.1K27M and H3.3K27M subgroups) and tumors in comparison to normal brain to gain an appreciation for targetable pathways in DMG. DMG cells presented differential replication timing in each subgroup, which, in turn, correlated with significant differential gene expression including the cholesterol biosynthesis pathway. Consistent with these findings, DMG tumors presented high replication stress and cholesterol biosynthesis pathway signatures. Moreover, DMG cells were specifically vulnerable to an inhibitor of the cholesterol pathway and to a replication stress therapy, singly and in combination. In conclusion, this combinatorial genomics approach revealed insights into therapeutic opportunities for this incurable disease.

TMIC-78. CHEMOTHERAPY INDUCED IMMUNOGENIC RESPONSE IN GLIOMA AND IMPLICATIONS FOR THERAPEUTIC STRATEGIES

Abstract INTRODUCTION Many glioblastoma (GBM) treatments fail because they treat tumor cells in isolation and ignore the surrounding microenvironment. In our phase 1b clinical trial of delivery of Topotecan (TPT) via Convection Enhanced Delivery (CED) in glioma, we demonstrated effective tumor cell elimination accompanied by a robust inflammatory response. We hypothesized that TPT induces an immunogenic response resulting in an unfavorable inflammatory landscape. METHODS To characterize chemotherapy’s effect on myeloid cells, we analyzed pre- and post-treatment biopsies from our trial using bulk RNA sequencing to measure canonical myeloid markers. We validated survival benefit of CED in vivo in our tumor model and characterized post-treatment tissue using single cell RNA sequencing (scRNA seq) after 7 days of treatment. We treated slice cultures generated from surgical samples of GBM with TPT and performed scRNA seq and histologic analysis to assess microenvironment changes after 24 hours of treatment. We used several in vitro assays to characterize the direct and indirect mechanisms of myeloid activation. RESULTS Bulk RNA sequencing of post treatment biopsies demonstrates upregulation of markers associated with activated and exhausted immune cell populations such as IBA1, CD68, MSR1, MARCO and loss of markers associated with homeostatic microglia such as P2RY12 and TMEM119. Similar results are found within 7 days of treatment in vivo, however, are not found in human derived samples treated acutely. Treatment of in vitro mono and co-culture systems demonstrate a tumor cell death dependent activation of myeloid cell populations via immunogenic molecules. CONCLUSIONS Chemotherapies eliminate proliferating glioma cells but also induce inflammation. While many investigators have tried to leverage this activation, our results suggest that chronic inflammation contributes to poor prognosis and recurrence. The identification of molecules responsible for this activation point to new therapeutic targets aimed at controlling treatment-induced inflammation, as part of a combinatorial approach to treat GBM.

CTIM-06. OUTCOME OF PATIENTS WITH RECURRENT MEDULLOBLASTOMA AND EPENDYMOMA TREATED WITH PEMBROLIZUMAB, AN IMMUNE CHECKPOINT INHIBITOR: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC045)

Abstract BACKGROUND Children with recurrent medulloblastoma and ependymoma typically have a dismal prognosis. Immune checkpoint blockade has revolutionized treatment of some resistant cancers. PBTC045 is a safety and preliminary efficacy study of pembrolizumab, a PD-1 inhibitor, in children with recurrent/progressive brain tumors. Here we present the strata that included children with recurrent/progressive ependymoma and medulloblastoma. METHODS Eligibility included patients aged 1-21 years old with recurrent/progressive ependymoma or medulloblastoma and with functional scores ≥70, no greater than physiologic steroid usage and standard washout periods, among other eligibility criteria. Pembrolizumab was administered at 2mg/kg IV every three weeks. Tumor tissue (if available) and serum were collected for correlative studies. Primary endpoints included toxicity and response, and two stages were planned requiring objective responses for potential expansion. RESULTS Patients with progressive ependymoma (Stratum D, n=13) or medulloblastoma (Stratum E, n=14, one ineligible) were enrolled. The median age at diagnosis was 3.37 years (range, 1-12.7) and 7 years (range, 2.2-13.1), respectively. The median age at study entry was 8.5 years and 11.4 years, respectively. There were no first-stage objective responses in either stratum, and thus the expansion arms were not initiated. Grade 3 or greater treatment-related adverse events included rash (n=1), anemia (n=1) and neutropenia (n=2), with no dose-limiting toxicities. The median progression-free survival (PFS) for ependymoma and medulloblastoma were 1.38 months (range, 1.08-1.51) and 1.41 months (range, 1.22-3.45), respectively. Immune correlative analyses are ongoing. CONCLUSIONS Immune checkpoint inhibition holds potential for CNS cancer treatment, and as a single agent, is well tolerated. However, in the current study, checkpoint inhibition monotherapy does not appear to significantly prolong survival or induce radiographic responses in children with recurrent/progressive ependymoma or medulloblastoma. Potential incorporation of checkpoint inhibitors into treatment for these patients will likely require combinatorial approaches that may be informed by the correlative science.

FOSL1 is a key regulator of a super-enhancer driving TCOF1 expression in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with an unmet clinical need, but its epigenetic regulation remains largely undefined. By performing multiomic profiling, we recently revealed distinct super-enhancer (SE) patterns in different subtypes of breast cancer and identified a number of TNBC-specific SEs that drive oncogene expression. One of these SEs, TCOF1 SE, was discovered to play an important oncogenic role in TNBC. However, the molecular mechanisms by which TCOF1 SE promotes the expression of the TCOF1 gene remain to be elucidated. Here, by using combinatorial approaches of DNA pull-down assay, bioinformatics analysis and functional studies, we identified FOSL1 as a key transcription factor that binds to TCOF1 SE and drives its overexpression. shRNA-mediated depletion of FOSL1 results in significant downregulation of TCOF1 mRNA and protein levels. Using a dual-luciferase reporter assay and ChIP-qPCR, we showed that binding of FOSL1 to TCOF1 SE promotes the transcription of TCOF1 in TNBC cells. Importantly, our data demonstrated that overexpression of FOSL1 drives the activation of TCOF1 SE. Lastly, depletion of FOSL1 inhibits tumor spheroid growth and stemness properties of TNBC cells. Taken together, these findings uncover the key epigenetic role of FOSL1 and highlight the potential of targeting the FOSL1-TCOF1 axis for TNBC treatment.

Mainshock-aftershock building fragility methodology for community resilience modeling

This study introduces a methodology for developing fragility functions that enable the assessment of seismic vulnerability and resilience at the community level for buildings subjected to mainshock-aftershock sequences. To date, this has been assessed at a single structural level or through statistical combinatorial approaches. This paper provides a solution for a suite of archetypes including ductile and non-ductile reinforced concrete frames as well as woodframe buildings. The findings highlight the central role of aftershocks in exacerbating damage states and increasing economic losses, emphasizing the importance of including these events in accurate assessments of community resilience and seismic risk. The suite of archetypes is applied at the community level using the IN-CORE platform to quantify the effect of incorporating aftershocks into community-level seismic vulnerability analyses. The ability to accurately include the effect of aftershocks within community-level risk and resilience analyses will be key to planning for earthquakes.

Formulation-dependent differences in paclitaxel distribution to anatomical sites relevant to chemotherapy-induced peripheral neuropathy

IntroductionChemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting adverse event observed in patients receiving paclitaxel, associated with initial pathological changes in the peripheral nervous system, i.e., distal nerves and dorsal root ganglia (DRG). The prevalence of CIPN in patients receiving paclitaxel formulated i) in polyethylated castor oil with ethanol (CreEL-PTX), ii) as albumin-bound (nab-PTX), and iii) in XR17 micelles (micellar-PTX), is unexpectedly varying. We hypothesize that the discrepancy in CIPN prevalence could be governed by differences in the extent of paclitaxel distribution across blood-to-tissue barriers at the CIPN-sites, caused by the specific formulation.MethodsThe recently developed Combinatory Mapping Approach for CIPN was used to determine the unbound tissue-to-plasma concentration ratio Kp,uu,tissue, after a 4-h infusion of 4 mg/kg CreEL-PTX, 4 mg/kg nab-PTX or 1 mg/kg micellar-PTX in male and female Sprague Dawley rats. Kp,uu,tissue was determined in conventional (DRG, sciatic nerve) and non-conventional (brain, spinal cord, skeletal muscle) CIPN-sites.ResultsBased on our data, the Cremophor-free paclitaxel formulations were associated with a higher distribution of paclitaxel to CIPN-sites than CreEL-PTX, e.g., Kp,uu,DRG of 0.70 and 0.60 for nab-PTX and micellar-PTX, respectively, in comparison to 0.27 for CreEL-PTX (p < 0.01). In addition, the fraction of unbound paclitaxel in plasma was on average 1.6-fold higher in nab- and micellar PTX arms and equal to 0.061 and 0.065, respectively, compared to 0.039 for the CreEL-PTX treatment arm (p < 0.0001).DiscussionIn the case of similar unbound paclitaxel concentration in the plasma of patients and assumed species-independent extent of paclitaxel transport across the barriers, nab- and micellar-PTX formulations can lead to higher paclitaxel exposure at CIPN-sites in comparison to CreEL-PTX.

Targeting the EGFR and Spindle Assembly Checkpoint Pathways in Oral Cancer: A Plausible Alliance to Enhance Cell Death

Background/Objectives: Head and neck cancer (HNC) is among the most common cancer types globally, with its incidence expected to increase significantly in the coming years. Oral squamous cell carcinoma (OSCC), the predominant subtype, exhibits significant heterogeneity and resistance to treatment. Current therapies, including surgery, radiation, and chemotherapy, often result in poor outcomes for advanced stages. Cetuximab, an EGFR inhibitor, is widely used but faces limitations. This study explores the combined inhibition of EGFR and mitotic proteins to enhance treatment efficacy. Methods: We analyzed the effects of co-treating OSCC cells with small molecules targeting MPS-1 (BAY1217389), Aurora-B (Barasertib), or KSP (Ispinesib), alongside Cetuximab. The rationale is based on targeting EGFR-mediated survival pathways and the mitotic checkpoint, addressing multiple cell cycle phases and reducing resistance. Results: Our findings indicate that inhibiting MPS-1, Aurora-B, or KSP enhances Cetuximab’s therapeutic potential, promoting increased cancer cell death. Additionally, we examined EGFR, MPS-1, Aurora-B, and KSP expression in OSCC patient samples, revealing their clinicopathologic significance. Conclusions: This combinatorial approach suggests a promising strategy to improve treatment outcomes in OSCC.

AdaGIN: Adaptive Graph Interaction Network for Click-Through Rate Prediction

The goal of click-through rate (CTR) prediction in recommender systems is to effectively work with input features. However, existing CTR prediction models face three main issues. First, many models use a basic approach for feature combinations, leading to noise and reduced accuracy. Second, there is no consideration for the varying importance of features in different interaction orders, affecting model performance. Third, current model architectures struggle to capture different interaction signals from various semantic spaces, leading to sub-optimal performance. To address these issues, we propose the Adaptive Graph Interaction Network (AdaGIN) with the Graph Neural Networks-based Feature Interaction Module (GFIM), the Multi-semantic Feature Interaction Module (MFIM), and the Negative Feedback-based Search (NFS) algorithm. GFIM explicitly aggregates information between features and assesses their importance, while MFIM captures information from different semantic spaces. NFS uses negative feedback to optimize model complexity. Experimental results show AdaGIN outperforms existing models on large-scale public benchmark datasets.

Myc functions downstream of InR and their concurrent upregulation additively restricts pathogenesis of human poly(Q) disorders in Drosophila disease models

Human polyglutamine [poly(Q)] disorders are caused by abnormal expansion of CAG repeats in one gene (disease specific), yet a plethora of cellular pathways are found to be involved in their pathogenesis and progression. Despite the tremendous effort, all pursuits for the development of intervention therapy against these disorders seem futile. Recent reports suggest combination therapy as a potential strategy to combat the complex pathogenesis of such neurodegenerative disorders. The present study attempted to identify a combinatorial intervention strategy against human poly(Q) disorders in Drosophila disease models. Due to its immense potential to be stimulated by drugs, the evolutionarily conserved insulin signalling cascade which is well-established modifier of human poly(Q) pathogenesis was selected for the selected for the study. Genetic screening studies identified Drosophila Myc as a potential partner of insulin receptor (InR) that conferred additive rescue against poly(Q) induced neurodegeneration. Comprehensive analyses demonstrated InR and Myc to confer additive rescue against several events of pathogenesis, including aggregation of expanded poly(Q) containing proteins, transcriptional dysregulation, upsurge of cell death cascades, etc. Also, the synergistic rescue efficiency of InR and Myc was equally efficient in mitigating poly(Q) induced structural and functional deficits. The study also demonstrates that Myc functions downstream of InR signalling cascade to deliver rescue against human poly(Q) mediated toxicity in Drosophila disease models. In conclusion, the present study suggests that InR and Myc have the potential to be developed as a combinatorial therapeutic approach against human poly(Q) diseases.

Bibliometric Analysis to Improve Combined Treatment Strategies for Glioblastoma in America

Introduction: Bibliometric analysis quantitatively examines scientific literature to extract insights. This article has conducted such analysis on glioblastoma multiforme (GBM) treatment articles. GBM, a prevalent brain tumor, is typically treated with surgery, radiation, and chemotherapy. Objectives: The article aimed to bibliometrically analyze articles discussing combined GBM treatment to identify impactful research areas and encourage collaboration. Materials and Methods: The study encompassed a comprehensive search in the Scopus database, spanning articles published from 1974 to 2022. Inclusion criteria encompassed research conducted in the Americas, both clinical and experimental. A total of 772 articles were collected and categorized based on their primary focus on combined treatment approaches. Results: Clinical studies constituted 52% of articles, suggesting a slight dominance. The analysis unveiled key research moments, including a 1998 focus shift and a pivotal 2005 study on temozolomide- radiation combination. Top journals, trends, and authors were identified, with the USA leading in contributions. Discussions: Despite high brain tumor incidence, research distribution discrepancy is concerning. Regional epidemiological studies have been endorsed. The dominance of US and German authors in GBM collaboration has raised equity issues due to budget and GDP disparities limiting Latin American representation. Conclusion: GBM research in the region is dominated by the USA, while contributions from Latin American countries remain limited. The absence of comprehensive epidemiological studies on GBM in Latin America is concerning, considering the evident impact of the disease in the region. This underscores the urgent need for increased research participation and collaboration to advance the understanding and treatment of GBM across Latin American nations.

Exploring potential of tobramycin complexes for combating biofilms: In silico and In vitro studies

Nosocomial infections linked to medical implants, wound infections, and cystic fibrosis infections are mostly caused by biofilms linked to Pseudomonas aeruginosa. The development of biofilms on medical equipment continues to a growing health and financial burden with increased the risk of infections and patient morbidity associated with indwelling medical devices. Pseudomonas aeruginosa exhibited high antibiotic resistance, posing challenges for effective treatment of infections associated with medical implants. Therefore, our objective was to adopt a combinatorial approach for formulating antibiotic complexes for maximum eradication of biofilms associated with medical implants.In this study, we optimized the ratio of Tobramycin (TOB) complexes with complexing agents such as sodium bicarbonate (BC), β-cyclodextrin (β-CD), and ethylenediaminetetraacetic acid (EDTA). Further stability and flexibility of the complexes were examined through molecular docking and dynamics. Subculturing and gram staining were performed for the isolation and identification of Pseudomonas aeruginosa. The antibacterial activity was tested using the broth dilution method and well diffusion method to calculate the MIC (minimum inhibitory concentration) against Pseudomonas aeruginosa planktonic cells and biofilms, respectively. The MIC tests indicated that optimised complexes required a concentration of 8 μg/ml to eradicate both planktonic cells as well as biofilms. However, the TOB-BC-(β-CD)-EDTA complex showed lower optical density (OD) compared to other complexes exhibiting better biofilm inhibition. Subsequently a gel formulation using this optimised (TOB-BC-(β-CD)-EDTA) complex that could be applied to medical equipment or potentially converted into a film using different polymer concentrations was developed. The TOB-BC-(β-CD)-EDTA gel formulation was characterized for pH, viscosity, spread-ability, % yield, moisture content, drug content, in-vitro drug diffusion, and antibacterial efficacy assay. Among all batches, F2 demonstrated the highest % drug diffusion after 24 hours and fit well to the Korsmeyer-Peppas kinetic model. The viscosity of the F2 batch remained within acceptable limits and was stable at 40 ± 0.5 ºC and 75.0 ± 5% RH. The gel efficiently delivered antimicrobial drugs to bacteria within biofilms. In conclusion, tobramycin complex gel showed promising potential for addressing infections related to biofilms on medical implants.

Experimental Realization of Fluoroborophene.

Borophene, an anisotropic metallic Dirac material exhibits superlative physical and chemical properties. While the lack of bandgap restricts its electronic chip applications, insufficient charge carrier density and electrochemical/catalytically active sites, restricts its energy storage and catalysis applications. Fluorination of borophene can induce bandgap and yield local electron injection within its crystallographic lattice. Herein, a facile synthesis of fluoroborophene with tunable fluorine content through potassium fluoride-assisted solvothermal-sonochemical combinatorial approach is reported. Fluoroborophene monolayers with lateral dimension 50 nm-5 µm are synthesized having controlled fluorine content (12-35%). Fluoroborophene exhibits inter-twinned crystallographic structure, with fluorination-tunable visible-range bandgap ≈1.5-2.5 eV, and density functional theory calculations also corroborate it. Fluoroborophene is explored for electrocatalytic oxygen evolution reaction in an alkaline medium and bestow a good stability. Tunable bandgap, electrophilicity and molecular anchoring capability of fluoroborophene will open opportunities for novel electronic/optoelectronic/spintronic chips, energy storage devices, and in numerous catalytic applications.

Enhancing Bucket Sort Efficiency: A Combinatorial Approach to Algorithm Optimization

Abstract: The efficiency of sorting algorithms is critical to numerous computational processes, including data management, search operations, and real-time applications. Among these algorithms, Bucket Sort is notable for its linear-time performance when data is uniformly distributed over a defined range. However, its efficiency suffers significantly with non-uniform data distributions, resulting in unbalanced buckets and increased sorting time. In our research, we explore how combinatorial algorithms can enhance Bucket Sort’s efficiency by optimizing bucket partitioning, dynamic allocation, and internal sorting strategies. Through rigorous mathematical proofs and analysis, we demonstrate that the application of combinatorial techniques yields substantial improvements in average-case performance, particularly in handling skewed data distributions. Practical case studies in large-scale data processing illustrate the adaptability and effectiveness of these optimizations, supporting their potential in real-world applications.

Demystifying the management of cancer through smart nano-biomedicine via regulation of reactive oxygen species.

Advancements in therapeutic strategies and combinatorial approaches for cancer management have led to the majority of cancers in the initial stages to be regarded as treatable and curable. However, certain high-grade cancers in the initial stages are still regarded as chronic and difficult to manage, requiring novel therapeutic strategies. In this era of targeted and precision therapy, novel strategies for targeted delivery of drug and synergistic therapies, integrating nanotherapeutics, polymeric materials, and modulation of the tumor microenvironment are being developed. One such strategy is the study and utilization of smart-nano biomedicine, which refers to stimuli-responsive polymeric materials integrated with the anti-cancer drug that can modulate the reactive oxygen species (ROS) in the tumor microenvironment or can be ROS responsive for the mitigation as well as management of various cancers. The article explores in detail the ROS, its types, and sources; the antioxidant system, including scavengers and their role in cancer; the ROS-responsive targeted polymeric materials, including synergistic therapies for the treatment of cancer via modulating the ROS in the tumor microenvironment, involving therapeutic strategies promoting cancer cell death; and the current landscape and future prospects.

Combinatorial approach to predict synergistic ablation behavior of carbon fiber phenolic composites under aerodynamic loading

The study conducts a comprehensive analysis across 1-D, 2-D, and 2-D axisymmetric geometries, investigating temperature profiles, surface recession patterns, pyrolysis gas flow dynamics, and density fluctuations within the composite material. The findings highlight the effectiveness of the FEA technique in modeling complex multi-physical interactions associated with ablation phenomena. The carbon-phenolic composites, characterized by low thermal conductivity, high specific heat capacity, and substantial char yield, are shown to be particularly well-suited as ablative materials. The char layer formed during ablation acts as an additional insulating barrier, enhancing thermal protection. In a specific case study, a 2 cm thick composite laminate was subjected to an intense heat flux of 200 W/cm2 for 180 s. The results demonstrate that the Thermal Protection System (TPS) effectively maintains the back face temperature below 350 K for the initial 60 s under uniform heat flux conditions. However, beyond this period, the back face temperature gradually increases, reaching 1698 K at the end of the 180-s simulation. These insights into the material’s thermal performance under severe heat exposure conditions provide valuable guidance for applications requiring effective heat management and thermal protection.

Cuminaldehyde in combination with tetracycline shows promising antibiofilm activity against drug-resistant Pseudomonas aeruginosa

Pseudomonas aeruginosa, an opportunistic pathogen often causes biofilm-linked infections. A combinatorial approach involving tetracycline (antibiotic) and cuminaldehyde (phytochemical) was explored to combat this infectious pathogen. The results showed that both tetracycline and cuminaldehyde individually demonstrated antibacterial effects. However, when the compounds were applied together, there was a significant increase in their antimicrobial potential. The determined fractional inhibitory concentration index of 0.43 indicated a synergistic interaction between the two compounds. Furthermore, a series of experiments demonstrated that the combined application of cuminaldehyde and tetracycline could lead to a significant enhancement of their antibiofilm potential. This enhanced antibiofilm potential was attributed to the accumulation of reactive oxygen species and increased cell membrane permeability. Besides, this combinatorial application reduced the secretion of various virulence factors from P. aeruginosa. Therefore, this combined approach holds promise for effectively treating P. aeruginosa biofilms.

Neuroimaging to Genotype: Delineating the Spectrum of Disorders With Deficient Myelination in the Indian Population.

Several genetic disorders are associated with either a permanent deficit or a delay in central nervous system myelination. We investigated 24 unrelated families (25 individuals) with deficient myelination after clinical and radiological evaluation. A combinatorial approach of targeting and/or genomic testing was employed. Molecular diagnosis was achieved in 22 out of 24 families (92%). Four families (4/9, 44%) were diagnosed with targeted testing and 18 families (18/23, 78%) were diagnosed using broad genomic testing. Overall, 14 monogenic disorders were identified. Twenty disease-causing variants were identified in 14 genes including PLP1, GJC2, POLR1C, TUBB4A, UFM1, NKX6-2, DEGS1, RNASEH2C, HEXA, ATP7A, SETBP1, GRIN2B, OCLN, and ZBTB18. Among these, nine (45%) variants are novel. Fourteen families (82%, 14/17) were diagnosed using proband-only exome sequencing (ES) complemented with deep phenotyping, thus highlighting the utility of singleton ES as a valuable diagnostic tool for identifying these disorders in resource-limited settings.