Chemotherapy Research Articles

Treatment of Pediatric, Adolescent, and Young Adult Patients With Fusion-Positive Alveolar Rhabdomyosarcoma Infiltrating Regional Lymph Nodes in the European CWS-2002P and RMS 2005 Studies and the Soft Tissue Sarcoma Registry.

Patients with alveolar rhabdomyosarcoma (ARMS) with regional lymph node involvement (N1) are defined as "very-high-risk rhabdomyosarcoma" in Europe. Different chemotherapy regimens were used in European study protocols. Patients with FOXO1 fusion-positive N1 ARMS registered in the CWS-2002P study, the EpSSG RMS 2005 study, and SoTiSaR were retrospectively investigated. Patients received systemic treatment with chemotherapy (CHT) and local treatment of primary tumor (PT) and involved lymph nodes (LN) with radiotherapy (RT) and/or surgery. Kaplan-Meier estimators and Cox regression were used to examine event-free survival (EFS) and overall survival (OS) according to prognostic factors and treatment. A total of 156 patients registered in RMS 2005 (n = 99), CWS-2002P (n = 20), and SoTiSaR (n = 37) between 2003 and 2020 were eligible for this analysis. Median age at diagnosis was 10.2years [0.1-21.9]. Treatment comprised CHT with IVADo (ifosfamide, vincristine, actinomycin-D, doxorubicin, n = 93; 60%), VAIA (vincristine, actinomycin-D, ifosfamide, adriamycin/doxorubicin, n = 53; 34%) or other regimens (n = 10; 6%); resection of the PT (n = 89; 57%), LN sampling or dissection (n = 92; 59%), and/or RT (n = 139; 89%). Maintenance treatment (MT) was added in n = 99/135 (73%) patients who achieved complete remission. Five-year EFS and OS of the cohort were 45% and 47%, respectively. Age and tumor size were independent prognostic factors for EFS. Local treatment applied to the LN with surgery, RT or both significantly improved EFS (p = 0.02) and OS (p = 0.04), with no difference between the modalities (p = 0.7). Patients with fusion-positive N1 ARMS carry a poor prognosis. Adequate local treatment of LN improved survival.

Genetic Variants Influence the Severity of Oral Mucositis in Pediatric Osteosarcoma Patients.

The variability in patients' risk of oral mucositis (OM) has been, in part, attributed to differences in host genomics. The aim better define the role of genomics as an OM risk by investigating the association between genetic variants and the presence and severity of OM in pediatric patients with osteosarcoma (OS) undergoing chemotherapy (CT). A longitudinal observational retrospective study was conducted. Severity of OM was assessed daily using World Health Organization (WHO) criteria. Blood samples were collected, and DNA was extracted. 54 coding regions were analyzed for 17 candidate genes using next-generation sequencing. A total of 164 CT cycles were evaluated in 14 pediatric patients being treated for OS with HDMTX (66.9%) and doxorubicin + cisplatin (34.1%). OM was diagnosed in 129 cycles (78.7%). Whereas the presence of OM was associated with ABCA3 (rs13332514) in HDMTX cycles, OM severity was associated with ABCC2 (rs2273697) in multivariate analysis. In doxorubicin + cisplatin, genetic variants of ABC family genes (ABCC2 and ABCC6) were associated with OM in multivariate analysis. Oral mucositis risk and severity in a pediatric population being treated for OS with HDMTX, doxorubicin, and cisplatin were associated with genes in the ABC family (ABCA3, ABCC2, and ABCC6 genes).

Hospital pharmacists' perceived competence in providing care to oncology patients - (HoPP-CoP2).

Previous research has shown community pharmacists do not have high perceived competence or confidence providing care to patients on oral anti-cancer medications. There is a paucity of evidence when it comes to hospital pharmacists providing care to oncology patients admitted to the hospital for a reason other than cancer. To assess the perceived competence of hospital pharmacists not working in oncology in managing patients taking anticancer drugs. Additionally, identify factors impacting, potential interventions increasing, and any factors that improve perceived competence. An anonymous cross-sectional survey distributed to hospital pharmacists throughout Canada. Mean perceived competence results ranged from 2.52 to 3.97 out of 7.00 with respondents reporting most perceived competence managing electrolyte disturbances and least competence managing drug-disease interactions and intervening on hepatic dysfunction. Low confidence in knowledge received from previous oncology training was reported with a mean of 2.82 on the 7-point Likert Scale. Continuing education sessions were perceived as the intervention which would most improve perceived competence with a mean value of 5.92 to 5.94 on a 7-point Likert Scale. The number of CE hours completed in the last five years was the only factor shown to have a statistically significant correlation with perceived competence. Hospital pharmacists do not perceive themselves as competent in providing care to oncology patients. The implementation of a continuing education program related to oncology may improve perceived and actual competence.

Chemotherapy-Induced Neuropathy Affecting the Gastrointestinal Tract.

Cancer is a major global cause of morbidity and mortality. Survivorship is increasing, bringing new challenges. Cancer treatment, including chemotherapeutic drugs, immunotherapy, and radiotherapy, can have severe and impactful gastrointestinal side effects occurring shortly after treatment (acute toxicity) or persisting for years after treatment ends (late/chronic toxicity). The aim of this article is to review the neurotoxic effects of chemotherapy on the enteric nervous system (ENS) and the gut extrinsic innervation. These effects could contribute to the development of long-term gastrointestinal dysfunctions. Research, primarily conducted in animal models, indicates that antitumoral drugs can lead to chemotherapy-induced enteric neuropathy (CIEN). Studies, mainly performed in the myenteric plexus, show that CIEN is characterized by a reduced density of nerve cells and fibers, as well as an imbalanced representation of neuronal subpopulations or their markers, with enteric glial cells also affected. These alterations underlie changes in neuronal activity and gastrointestinal motor function. Although research on the submucosal plexus remains limited, evidence suggests that CIEN affects the entire ENS. Furthermore, scarce studies show that CIEN also occurs in humans. Moreover, emerging experimental data on chemotherapy-induced alterations in visceral sensitivity suggest that the extrinsic innervation of the gut is also affected, but this has received little attention thus far. Nevertheless, this could contribute to the development of chemotherapy-induced brain-gut axis (BGA) disorders in the long term. Cancer chemotherapy (and probably also immunotherapy and radiotherapy) seems to cause neuropathic effects on the intrinsic and extrinsic innervation of the gastrointestinal tract, with an important impact on gastrointestinal and BGA functions. This is a relatively neglected area deserving further investigation.

Mechanisms of breast cancer metastasis: the role of extracellular matrix.

The components of the extracellular matrix (ECM) are dynamic, and they mediate mechanical signals that modulate cellular behaviors. Disruption of the ECM can induce the migration and invasion of cancer cells via specific signaling pathways and cytokines. Metastasis is a leading cause of high mortality in malignancies, and early intervention can improve survival rates. However, breast cancer is frequently diagnosed subsequent to metastasis, resulting in poor prognosis and distant metastasis poses substantial hurdles in therapy. In breast cancer, there is notable tissue remodeling of ECM proteins, with several identified as essential components for metastasis. Moreover, specific ECM molecules, receptors, enzymes, and various signaling pathways play crucial roles in breast cancer metastasis, drug treatment, and resistance. The in-depth consideration of these elements could provide potential therapeutic targets to enhance the survival rates and quality of life for breast cancer patients. This review explores the mechanisms by which alterations in the ECM contribute to breast cancer metastasis and discusses current clinical applications targeting ECM in breast cancer treatment, offering valuable perspectives for future ECM-based therapies.

Integration of pharmacophore-based virtual screening, molecular docking, ADMET analysis, and MD simulation for targeting EGFR: A comprehensive drug discovery study using commercial databases.

The epidermal growth factor receptor (EGFR), a crucial component of cellular signaling pathways, is frequently dysregulated in a range of cancers. EGFR targeting has become a viable approach in the development of anti-cancer medications. This study employs an integrated approach to drug discovery, combining multiple computational methodologies to identify potential EGFR inhibitors. The co-crystal ligand for the EGFR protein (R85) (PDB ID: 7AEI) was employed as a model for developing pharmacophore hypotheses. Nine databases underwent a ligand-based virtual screening, and 1271 hits meeting the screening criteria were chosen. EGFR protein crystal structure was obtained from the PDB database (PDB ID: 7AEI) and prepared. The hit compounds identified during virtual screening were docked to the prepared EGFR receptor to predict binding affinities by using the glide tool's standard precision mode. The top ten compounds were chosen, and their affinities of binding ranged from -7.691 to -7.338 kcal/mol. The ADMET properties of the selected compounds were predicted, and three compounds MCULE-6473175764, CSC048452634, and CSC070083626 showed better QPPCaco values compared to other identified compounds, so these were selected for further stability analysis. To confirm the stability of the protein-ligand complexes, a 200 ns molecular dynamics (MD) simulation was run using the binding sites of the top three compounds against the EGFR receptor. These results suggest that the selected compounds may be lead compounds in suppressing the biological activity of EGFR, additional experimental investigation is required.

Cellular and molecular aspects of drug resistance in cancers.

Cancer drug resistance is a multifaceted phenomenon. The present review article aims to comprehensively analyze the cellular and molecular aspects of drug resistance in cancer and the strategies employed to overcome it. A systematic search of relevant literature was conducted using electronic databases such as PubMed, Scopus, and Web of Science using appropriate key words. Original research articles and secondary literature were taken into consideration in reviewing the development in the field. Cancer drug resistance is a pervasive challenge that causes many treatments to fail therapeutically. Despite notable advances in cancer treatment, resistance to traditional chemotherapeutic agents and novel targeted medications remains a formidable hurdle in cancer therapy leading to cancer relapse and mortality. Indeed, a majority of patients with metastatic cancer experience are compromised on treatment efficacy because of drug resistance. The multifaceted nature of drug resistance encompasses various factors, such as tumor heterogeneity, growth kinetics, immune system, microenvironment, physical barriers, and the emergence of undruggable cancer drivers. Additionally, alterations in drug influx/efflux transporters, DNA repair mechanisms, and apoptotic pathways further contribute to resistance, which may manifest as either innate or acquired traits, occurring prior to or following therapeutic intervention. Several strategies such as combination therapy, targeted therapy, development of P-gp inhibitors, PROTACs and epigenetic modulators are developed to overcome cancer drug resistance. The management of drug resistance is compounded by the patient and tumor heterogeneity coupled with cancer's ability to evade treatment. Gaining further insight into the mechanisms underlying medication resistance is imperative for the development of effective therapeutic interventions and improved patient outcomes.

PFOS and Its Commercial Alternative, 6:2 Cl-PFESA, Induce Multidrug Resistance in Pancreatic Cancer.

Per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonate (PFOS) and its alternative, 2-[(6-chloro-1,1,2,2,3,3,4,4,5,5,6,6-dodecafluorohexyl)oxy]-1,1,2,2-tetrafluoroethanesulfonic acid (6:2 Cl-PFESA), are associated with environmental health concerns and potential cancer progression. However, their impact on multidrug resistance (MDR) in pancreatic cancer (PC) chemotherapy remains unclear. Here, we employed drug-sensitivity assays, including IC50 calculations, in vitro and in vivo models with various chemotherapeutics, and paclitaxel (PTX) as a representative agent, combined with transcriptomic/proteomic sequencing and clinical prognostic analysis, to identify MDR-related genes and validate their relevance, with the objective of establishing the correlation between PFOS/6:2 Cl-PFESA exposure and MDR in PC at molecular, cellular, and animal model levels. Our findings demonstrate that PFOS/6:2 Cl-PFESA exposure increases the drug IC50 in three different PC cell lines for various chemotherapeutic agents. Compared with PFOS, 6:2 Cl-PFESA demonstrated a more pro-MDR effect on PC cells in vitro. In vivo experiments further revealed that PFOS/6:2 Cl-PFESA exposures significantly reduced the efficacy of PTX in PC, with inhibition rates dropping from 78.3% to 23.8%/6.1%, respectively (p < 0.05). This effect was driven by the aberrant activation of the PI3K-ABCB1 pathway, with 6:2 Cl-PFESA demonstrating a stronger capacity to promote this signal pathway's expression and function compared with PFOS. These data suggest that exposure to PFAS may elevate the risk of MDR and subsequent disease progression. Although marketed as a safer alternative to PFOS, the notable impact of 6:2 Cl-PFESA on MDR highlights the necessity for a comprehensive assessment of its potential carcinogenic risks.

Human papillomavirus E6 alters Toll-like receptor 9 transcripts and chemotherapy responses in breast cancer cells in vitro

BackgroundToll-like receptor 9 (TLR9) is a DNA recognizing receptor expressed also in several cancers. Decreased TLR9 expression is associated with poor prognosis in triple negative breast cancer (TNBC), but the role of TLR9 in breast cancer pathophysiology is currently unclear. Regulation of TLR9 expression in breast cancer is poorly understood. Human papillomavirus (HPV) infections suppress TLR9 expression in cervical cancers but the association between HPV and breast cancer has remained controversial. The aim of this study was to test if HPV16 can suppress TLR9 expression in breast cancer cells and affect cell behavior.Methods and resultsHuman T-47D and MDA-MB-231 breast cancer cells were transduced with lentivirus encoding HPV16 E6 oncoprotein. The effects of E6 on TLR9 mRNA and protein expression, and cell proliferation, migration, invasion and sensitivity to chemotherapy were studied in vitro. Breast cancer tissue samples (n = 37) were analyzed for the presence of HPV DNA. E6 expression decreased TLR9 mRNA expression in MDA-MB-231 and T-47D cells in hypoxia. E6 expression altered breast cancer cell proliferation and made cells significantly less sensitive to the growth inhibitory effects of chemotherapeutic agents. HPV L1 gene was not detected in a small pilot cohort of clinical breast cancer specimens.ConclusionHPV16 may influence breast cancer cell TLR9 transcription and chemotherapy responses and could thereby affect breast cancer prognosis. These results suggest that HPV may have a previously unrecognized role in breast cancer pathophysiology and warrant further studies on the topic.

Golden era of radiosensitizers

The past 30 years have brought undeniable progress in medicine, biology, physics, and research. Knowledge of the nature of the human body, diseases, and disorders has been constantly improving, and the same is true regarding their treatment and diagnosis. One of the greatest advances in recent years has been the introduction of nanoparticles (NPs) into medicine. NPs refer to a material at a nanometer scale (0.1–100 nm) with features (specific physical, chemical, and biological properties) that are broadly and increasingly used in the medical field. Their applications in cancer treatment and radiotherapy seem particularly attractive. In this field, inorganic/metal NPs with high atomic number Z have been employed mainly due to their ability to enhance ionizing radiation’s photoelectric and Compton effects and thereby increase conventional radiation therapy’s efficacy. The improvement NPs enable relates to their enhanced permeation ability and longer retention effect in tumor cells, capacity to reduce toxicity of commercially available cancer drugs through advanced NPs drug delivery systems, radiation sensitizers of tumors, or enhancers of radiation doses to tumors. Advanced options according to size, core, and surface modification allow even such multimodal approaches in therapy as nanotheranostics or combined treatments. The current state of knowledge emphasizes the role of gold nanoparticles (AuNPs) in sensitizing tumors to radiation. We have reviewed AuNPs and their radiosensitizing power during radiation treatment. Our results are divided into groups based on AuNPs’ surface modification and/or core structure design. This study provides a complete summary of the in vivo sensitizing effect of AuNPs, surface-modified AuNPs, and AuNPs combined with different elements, providing evidence for further successful veterinarian and clinical implementation.

Microbiota and Cytokine Modulation: Innovations in Enhancing Anticancer Immunity and Personalized Cancer Therapies

The gut microbiota plays a crucial role in modulating anticancer immunity, significantly impacting the effectiveness of various cancer therapies, including immunotherapy, chemotherapy, and radiotherapy. Its impact on the development of cancer is complex; certain bacteria, like Fusobacterium nucleatum and Bacteroides fragilis, can stimulate the growth of tumors by causing immunological evasion and inflammation, while advantageous strains, like Faecalibaculum rodentium, have the ability to suppress tumors by modifying immune responses. Cytokine activity and immune system regulation are intimately related. Cytokines including TGF-β, IL-6, and IL-10 promote tumor development by inhibiting efficient immune surveillance. The gut microbiome exhibits a delicate balance between pro- and anti-tumorigenic factors, as evidenced by the enhancement of anti-tumor immunity by cytokines such as IL-12 and IFN-γ. Improved immunotherapy responses are linked to a diverse microbiota, which is correlated with higher tumor infiltration and cytotoxic T-cell activation. Because microbial metabolites, especially short-chain fatty acids, affect cytokine expression and immune cell activation inside the tumor microenvironment, this link highlights the need to maintain microbial balance for optimal treatment effects. Additionally, through stimulating T-cell activation, bacteria like Lactobacillus rhamnosus and Bifidobacterium bifidum increase cytokine production and improve the efficacy of immune checkpoint inhibitors (ICIs). An option for overcoming ICI resistance is fecal microbiota transplantation (FMT), since research suggests that it improves melanoma outcomes by increasing CD8+ T-cell activation. This complex interaction provides an opportunity for novel cancer therapies by highlighting the possibility of microbiome modification as a therapeutic approach in personalized oncology approaches.

A trafficking regulatory subnetwork governs αVβ6 integrin-HER2 cross-talk to control breast cancer invasion and drug resistance.

HER2 and αVβ6 integrin are independent predictors of breast cancer survival and metastasis. We identify an αVβ6/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αVβ6 recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2). The RAB5/RAB7A/GDI2 functional module mediates direct cross-talk between αVβ6 and HER2, affecting receptor trafficking and signaling. Acute exposure to trastuzumab increases recruitment of the subnetwork to αVβ6, but trastuzumab resistance decouples GDI2 recruitment. GDI2, RAB5, and RAB7A cooperate to regulate migration and transforming growth factor-β activation to promote invasion. However, these mechanisms are dysregulated in trastuzumab-resistant cells. In patients, RAB5A, RAB7A, and GDI2 expression correlates with patient survival and αVβ6 expression predicts relapse following trastuzumab treatment. Thus, the RAB5/RAB7A/GDI2 subnetwork regulates αVβ6-HER2 cross-talk to drive breast cancer invasion but is subverted in trastuzumab-resistant cells to drive αVβ6-independent and HER2-independent tumor progression.

Mechanisms of ferroptotic and non-ferroptotic organ toxicity of chemotherapy: protective and therapeutic effects of ginger, 6-gingerol and zingerone in preclinical studies.

Chemotherapy (CT) is one of the flagship options for the treatment of cancers worldwide. It involves the use of cytotoxic anticancer agents to kill or inhibit the proliferation of cancer cells. However, despite its clinical efficacy, CT triggers side effect toxicities in several organs, which may impact cancer patient's quality of life and treatment outcomes. While the side effect toxicity is consistent with non-ferroptotic mechanisms involving oxidative stress, inflammation, mitochondrial impairment and other aberrant signalling leading to apoptosis and necroptosis, recent studies show that ferroptosis, a non-apoptotic, iron-dependent cell death pathway, is also involved in the pathophysiology of CT organ toxicity. CT provokes organ ferroptosis via system Xc-/GPX-4/GSH/SLC7A11 axis depletion, ferritinophagy, iron overload, lipid peroxidation and upregulation of ferritin-related proteins. Cisplatin (CP) and doxorubicin (DOX) are common CT drugs indicated to induce ferroptosis in vitro and in vivo. Studies have explored natural preventive and therapeutic strategies using ginger rhizome and its major bioactive compounds, 6-gingerol (6G) and zingerone (ZG), to combat mechanisms of CT side effect toxicity. Ginger extract, 6G and ZG mitigate non-ferroptotic oxidative inflammation, apoptosis and mitochondrial dysfunction mechanisms of CT side effect toxicity, but their effects on CT-induced ferroptosis remain unclear. Systematic investigations are, therefore, needed to unfold the roles of ginger, 6G and ZG on ferroptosis involved in CT side effect toxicity, as they are potential natural agents for the prevention of CT toxicity. This review reveals the ferroptotic and non-ferroptotic toxicity mechanisms of CT and the protective mechanisms of ginger, 6G and ZG against CT-induced, ferroptotic and non-ferroptotic organ toxicities.

Synthesis of Novel Derivatives of 4,6-Diarylpyrimidines and Dihydro-Pyrimidin-4-one and In silico Screening of Their Anticancer Activity

: Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted pyrimidines were synthesized by cyclocondensation of α-aminoamidines with various sat-urated carbonyl derivatives and their analogs. The therapeutic potential of the newly syn-thesized derivatives for cancer treatment was evaluated using molecular docking calcula-tions. The molecular docking results indicate that some of the synthesized diaryl deriva-tives of pyrimidine exhibit high binding affinity towards PIK3γ. Aim and Objective: 4,6-Diaryl-substituted pyrimidines have shown high inhibitory poten-cy against phosphoinositide 3-kinases (PI3Ks), which are important targets in oncology. Inhibition of PI3Ks could potentially be a viable therapy for human cancers. Materials and Methods: The synthesis of pyrimidinone and dihydropyrimidinone deriva-tives as well as a series of 2,4-diaryl-substituted pyrimidines were described. These com-pounds were synthesized by cyclocondensation of α-aminoamidines with various saturated carbonyl derivatives and their analogs. Results: Derivatives of pyrimidinone, dihydropyrimidinone, and 2,4-diaryl-substituted py-rimidines were synthesized by combining α-aminoamidines with various saturated car-bonyl derivatives and their analogs. By adjusting the large substituents in the 2-position, we gained the ability to modify the therapeutic properties of the resulting compounds. The potential of the newly synthesized derivatives for cancer treatment was assessed using mo-lecular docking calculations. The results of the docking calculations suggest that some of the synthesized diaryl derivatives of pyrimidine have a strong binding affinity towards PIK3γ, making them promising candidates for the development of new anticancer medica-tions. Conclusion: We synthesized some pyrimidinones, dihydropyrimidinones, and 2,4-diaryl-substituted pyrimidines by combining α-aminoamidines with various saturated carbonyl derivatives and similar compounds. Molecular docking results suggest that certain diaryl derivatives of pyrimidine have a strong binding affinity for PIK3γ. Moreover, diphenyl de-rivatives of pyrimidine exhibited dual inhibitory activity against PI3K and tubulin, show-ing promise for the development of next-generation microtubule-targeting agents for use in combination therapies.

Chemotherapy and radiotherapy for advanced pancreatic cancer.

Chemotherapy and radiotherapy for advanced pancreatic cancer.

Alteration of the Tumor Microenvironment With Intratumoral Dendritic Cells Before Chemotherapy in ERBB2 Breast Cancer

Current chemotherapy regimens for patients with ERBB2 (formerly HER2)-positive breast cancer are associated with considerable morbidity. These patients may benefit from more effective and less toxic therapies. To evaluate the safety, immunogenicity, and preliminary efficacy of intratumoral (IT) delivery of conventional type 1 dendritic cells (cDC1) in combination with ERBB2-targeted therapies. This phase 1 (lead-in phase of a single-center phase 2 trial) nonrandomized clinical trial was conducted at Moffitt Cancer Center (Tampa, Florida). Patients were enrolled from October 2021 to October 2022. Data were analyzed in 2023 Patients with early-stage ERBB2-positive breast cancer with tumors 1 cm or larger were eligible. Treatment included IT delivery of cDC1, 6 times weekly, followed by paclitaxel, 80 mg/m2, intravenously, 12 times weekly. Trastuzumab (8 mg/kg loading dose, then 6 mg/kg) and pertuzumab (840 mg loading dose, then 420 mg) were administered intravenously every 3 weeks for 6 cycles starting from day 1 of cDC1 injections. Two dose levels (DLs) of IT cDC1 (DL1 = 50 million and DL2 = 100 million cells) were evaluated, including 6 patients in each DL. The primary outcomes were the safety and immune response, and the secondary outcomes were the antitumor efficacy as measured by breast magnetic resonance imaging and residual cancer burden at surgery following neoadjuvant therapy. Twelve ERBB2-positive patients were enrolled and received treatment (DL1 = 6 and DL2 = 6). Nine patients had hormone receptor-positive disease and 3 had hormone receptor-negative disease, with clinical stage I (n = 5), II (n = 4), and III (n = 3). The most frequently observed adverse events with cDC1 were grade 1 to 2 chills (50%), fatigue (41.7%), headache (33%), and injection site reactions (33%). DL2 was associated with a diminished anti-ERBB2 CD4 T-helper 1 blood response with a concomitant increase in innate and adaptive responses within the tumor. Preimmunotherapy and postimmunotherapy breast magnetic resonance imaging results showed 9 objective responses, 6 partial responses, 3 complete responses, and 3 stable diseases. Following surgery, 7 patients had a pathologic complete response. In this nonrandomized clinical trial, the addition of IT cDC1 and trastuzumab/pertuzumab before neoadjuvant chemotherapy was well tolerated with manageable adverse effects. Based on safety and immunogenicity, DL2 was selected for the phase 2 dose. ClinicalTrials.gov Identifier: NCT05325632.

DVGEDR: a drug repositioning method based on dual-view fusion and graph enhancement mechanism in heterogeneous networks

Drug repositioning, the discovery of new therapeutic uses for existing drugs, is increasingly gaining attention as a cost-effective and high-yield drug discovery strategy. Existing methods integrate diverse biological information into heterogeneous networks, providing a comprehensive framework for understanding complex drug–disease associations, which also will introduces noise into the data and affect the performance of the model. In this paper, first, a novel drug repositioning method, namely DVGEDR, is proposed, which generates two subgraphs of the target drug–disease pair to fuse biological information and integrate drug–disease associations from two distinct perspectives: drug–disease heterogeneous network and similarity networks. Next, a Multiple Attention Graph encoder (MAGencoder) module is designed to learn subgraph features and explore relationships between entities, which also improve the interpretability of the model. Finally, a graph enhancement mechanism is devised to improve the perception of critical information of model, enabling the model to flexibly process different graph structures. Performance comparisons with baseline models on three public datasets validate the state-of-the-art performance of DVGEDR in the field of drug repositioning. In case study, DVGEDR identifies 10 new candidate drugs for breast cancer and COVID-19, demonstrating not only superior performance in experimental settings but also potential therapeutic advantages in clinical environments. Furthermore, we select two sets of instances and further analyzed the attention distribution of the different nodes in the subgraph to explain the decision process of the model.

A Review on Evolution and Challenges of Pharmaceutical Patent Protection in India

The Indian pharmaceutical patent system has undergone substantial changes through amendments to the Patents Act of 1970, particularly with the 2005 TRIPS compliance modifications. The system's cornerstone, Section 3(d), prevents patent extensions through minor molecular modifications unless significant therapeutic benefits are demonstrated. This provision gained global attention during the Novartis Glivec patent dispute, establishing India's firm stance on patentability criteria. India maintains specific safeguards within its patent framework, including a dual-opposition system and compulsory licensing provisions, which have proven crucial in maintaining medicine affordability. The Bayer-Natco case involving the cancer drug Nexavar highlighted the practical application of compulsory licensing to address public health needs. Patent office modernization efforts have targeted prolonged examination timelines and application backlogs, though administrative challenges persist. While multinational pharmaceutical companies express concerns about innovation protection, India's approach has enabled a robust generic drug industry that supplies affordable medicines globally. The patent system continues to evolve, balancing domestic healthcare requirements with international patent obligations. Recent technological upgrades in patent offices and refined examination guidelines demonstrate India's commitment to efficient patent administration while maintaining its public health priorities.

Multiorgan-on-a-chip for cancer drug pharmacokinetics-pharmacodynamics (PK-PD) modeling and simulations.

Cancer is one of the most common and fatal diseases worldwide and kills millions of people every year. Cancer drug resistance, lack of efficacy, and safety are significant problems in cancer patients. A multiorgan-on-a-chip (MOC) device consisting of breast and liver compartments was designed with AutoCAD software. The MOC molds were printed by a Formlabs Form 2 3D printer. MDA-MB-231, HepG2, and MCF-10A cells were used for the MOC experiments. The cell lines were cultured at 37°C with 5% CO2, and cell viability was assessed via Alamar blue dye to generate pharmacodynamics (PD) data. Drug concentrations from the cell culture media were analyzed via Agilent 1260 Infinity II HPLC with a Waters Symmetry C18 column and used to generate pharmacokinetics (PK) data. The PK and PD data were modeled and simulated by Monolix and Simulix software, respectively. The safety and efficacy of drug dosing regimens were compared, and the best dosing regimens were selected. This research designed and fabricated a unique MOC consisting of liver and breast compartments that overcomes the need for sealing or assembling. It was used for PK-PD modeling and simulations, and its functionality was proven experimentally. The new MOC will be helpful in preclinical trials to evaluate the efficacy and safety of drugs.

Biomimetic Nanovesicles Synergize with Short-Term Fasting for Enhanced Chemotherapy of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer among women. Chemotherapy acts as the standard regimen for TNBC treatment but suffers from limited drug accumulation in tumor regions and undesired side effects. Herein, we developed a synergistic strategy by combining a red blood cell (RBC) membrane-liposome hybrid nanovesicle with short-term fasting (STF) for improved chemotherapy of TNBC. The biomimetic nanovesicles exhibited reduced phagocytosis by macrophages while displaying a significant increase in tumor cell uptake through caveolae/raft-mediated endocytosis under nutrient-deprivation conditions. Importantly, drug-loaded nanovesicles and STF treatment synergistically increased the cytotoxicity of tumor cells by inhibiting their cell cycles and aerobic glycolysis as well as amplifying the reactive oxygen species (ROS) and autophagosomes generation. In the STF-treated mice, biomimetic nanovesicles greatly improved the antitumor efficacy at a lower drug dosage and inhibited the undesired metastasis of TNBC. Overall, we demonstrated that biomimetic nanovesicles synergizing with STF therapy serve as a promising therapeutic strategy for enhanced chemotherapy of malignant TNBC.