Effective Therapy Research Articles

Biodegradable Polymers for Application as Robust Immunomodulatory Biomaterial Carrier Systems.

The field of immunotherapeutics is rapidly evolving with the advent of cell therapies, complex biologics, and a host of other compounds. Polymeric carriers are often used to tune the safety and efficacy profiles of these novel drugs. Despite their prevalence in pre-clinical and clinical applications, non-degradable materials present delivery challenges including diffusion-limited release, frustrated phagocytosis, and limited clearance. In contrast, biodegradable polymeric systems provide a safer alternative in addition to displaying advantageous properties for the delivery of immunotherapies. In this review, discussion of polymers including poly(lactic-co-glycolic acid) (PLGA), poly(beta-amino esters) (PBAEs), acetalated dextran (Ace-DEX), chitosan, alginate, and hyaluronic acid (HA) as immunomodulatory biomaterial carriers suggest that a variety of systems can be used to generate tailored formulations for different therapeutic payloads and disease indications. These carrier systems can enhance the delivery of immunotherapies via tunable degradation rates, enhanced antigen-presentation, and inherent immunomodulatory properties of the biomaterials, among other mechanisms. Polymers formulated for immunomodulatory applications can be synthetic, semi-synthetic, or naturally derived. Therefore, it is crucial to consider the environmental impact of polymer sources, particle fabrication methods, and solvent usage to sustainably develop effective immunomodulatory therapies in this evolving field.

Association of clinical variables with methotrexate response in patients with psoriatic arthritis

Objective Methotrexate (MTX) is widely used as first-line treatment in psoriatic arthritis (PsA). Despite the variable efficacy of MTX in PsA compared to newer therapeutic agents, its affordability and availability make it crucial, especially in resource-limited healthcare settings. Identification of factors associated with MTX non-response could facilitate early redirection to more effective therapy. This study aimed to identify baseline clinical, demographic, and psychosocial variables associated with non-response 3 months after MTX initiation in a real-world, treatment-naïve PsA patient cohort. Method Recently diagnosed, disease-modifying anti-rheumatic drug-naïve PsA patients were included. Treatment response was defined by attaining minimal disease activity 3 months after initiation of MTX monotherapy. A multivariate logistic regression analysis was performed, including sensitivity analysis. Missing variables were imputed through multiple imputations. Results In total, 287 patients were included, of whom 199 (69%) were non-responders. The median dose of MTX was 19.5 (interquartile range 15–25) mg/week. Worse baseline functioning (Health Assessment Questionnaire) [odds ratio (OR) 0.28, 95% confidence interval (CI) 0.13–0.60], higher tender joint count in 68 joints (OR 0.91, 95% CI 0.84–0.97), and higher depression scores (Hospital Anxiety and Depression Scale) (OR 0.88, 95% CI 0.78–0.99) were associated with a lower response rate to MTX at 3 months. Conclusion Our findings highlight the need for a comprehensive approach to managing patients with PsA. This involves addressing modifiable risk factors, such as depression, alongside controlling PsA disease activity. Further research is warranted to evaluate whether this integrated strategy could improve treatment efficacy and overall patient outcomes.

Cathepsin B prevents cell death by fragmentation and destruction of pathological amyloid fibrils

Amyloid fibrils cause organ and tissue dysfunction in numerous severe diseases. Despite the prevalence and severity of amyloidoses, there is still no effective and safe anti-amyloid therapy. This study investigates the impact of cysteine protease cathepsin B (CTSB) on amyloids associated with Alzheimer’s and Parkinson’s diseases, hemodialysis, and lysozyme amyloidosis. We analyzed the effect of CTSB on the size, structure, and proteotoxicity of amyloid fibrils formed from alpha-synuclein, abeta peptide (1-42), insulin, and lysozyme using a combination of spectroscopic, microscopic, electrophoretic, and colorimetric methods. Our comprehensive research revealed a dual effect of CTSB on amyloid fibrils. Firstly, CTSB induced amyloid fragmentation while preserving their ordered morphology, and, secondly, it “loosened” the tertiary structure of amyloids and reduced the regularity of the secondary structure. This dual mechanism of action was universal across fibrils associated with different pathologies, although the disruption efficacy and predominant type of degradation products depended on the amyloids’ structure, size, and clustering. Notably, CTSB-induced irreversible degradation significantly reduced the toxicity for immortalized and primary cell lines of low-clustered fibrils, such as alpha-synuclein amyloids associated with Parkinson’s disease. These findings enhance our understanding of how endogenous CTSB may regulate amyloid content at the molecular level in different neuropathologies. In addition, our results suggest the potential of CTSB as a component of anti-amyloid drugs in combination with agents that enhance the accessibility of proteolytic sites within amyloid clots and reduce these clusters stability.

α-asarone activates mitophagy to relieve diabetic encephalopathy via inhibiting apoptosis and oxidative stress.

Diabetic encephalopathy (DE) is a common complication of diabetes that may result in cognitive impairment. Currently, there is limited effective therapy for DE. Herein, we explored the beneficial effect of α-Asarone on DE and its potential mechanisms. DE was induced in Type 2 diabetes mellitus mice and high-glucose (HG)-exposed PC-12 cells. Cognitive function was evaluated by MWM test. Pathological changes in the brain tissues were observed by HE staining. Cell viability was detected by CCK-8. Apoptosis was assessed by Hoechst 33,342 staining, Annexin V/PI staining and TUNEL. Mitochondrial membrane potential was analyzed by JC-1 probe. ROS production was measured by DCFH-DA staining. Target protein levels were analyzed by Western blotting. Network pharmacology was used to elucidate the beneficial mechanisms of α-Asarone in DE. Our study showed that α-Asarone enhanced cell viability and suppressed apoptosis in HG-stimulated PC-12 cells. Furthermore, α-Asarone relieved HG-induced reduction in mitochondrial membrane potential and ROS overproduction. In addition, mitophagy was triggered by α-Asarone, which was responsible for the inhibitory effect of α-Asarone on apoptosis and oxidative stress. Consistently, the in vivo experiments showed that α-Asarone treatment relieved cognitive dysfunction, apoptosis, and oxidative stress of DE mice via mitophagy induction. However, inhibition of mitophagy by Mdivi-1 counteracted the beneficial action of α-Asarone. Mechanistically, network pharmacology analysis identified 10 key targets of α-Asarone. Molecular docking substantiated a strong affinity of α-Asarone with CASP3, EGFR, NFKB1, and ESR1 proteins. Taken together, α-Asarone protected against mitochondrial dysfunction, oxidative stress and apoptosis via activating mitophagy, thereby alleviating DE. Our findings suggest α-Asarone as a potential drug for DE.

Nanoscale strategies: doxorubicin resistance challenges and enhancing cancer therapy with advanced nanotechnological approaches.

Doxorubicin (DOX), an anthracycline, is widely used in cancer treatment by interfering RNA and DNA synthesis. Its broad antitumour spectrum makes it an effective therapy for a wide array of cancers. However, the prevailing drug-resistant cancer has proven to be a significant drawback to the success of the conventional chemotherapy regime and DOX has been identified as a major hurdle. Furthermore, the clinical application of DOX has been limited by rapid breakdown, increased toxicity, and decreased half-time life, highlighting an urgent need for more innovative delivery methods. Although advancements have been made, achieving a complete cure for cancer remains elusive. The development of nanoparticles offers a promising avenue for the precise delivery of DOX into the tumour microenvironment, aiming to increase the drug concentration at the target site while reducing side effects. Despite the good aspects of this technology, the classical nanoparticles struggle with issues such as premature drug leakage, low bioavailability, and insufficient penetration into tumours due to an inadequate enhanced permeability and retention (EPR) effect. Recent advancements have focused on creating stimuli-responsive nanoparticles and employing various chemosensitisers, including natural compounds and nucleic acids, fortifying the efficacy of DOX against resistant cancers. The efforts to refine nanoparticle targeting precision to improve DOX delivery are reviewed. This includes using receptor-mediated endocytosis systems to maximise the internalisation of drugs. The potential benefits and drawbacks of these novel techniques constitute significant areas of ongoing study, pointing to a promising path forward in addressing the challenges posed by drug-resistant cancers.

Leveraging Tumor Microenvironment to Boost Synergistic Photodynamic Therapy, Ferroptosis Anti-Tumor Efficiency Based on a Functional Iridium(III) Complex.

The tumor microenvironment (TME) severely limits the efficacy of clinical applications of photodynamic therapy (PDT). The development of a functional agent allowing full use of the TME to boost synergistic PDT and ferroptosis anti-tumor efficiency is an appealing yet significantly challenging task. Herein, to overcome the adverse influence on PDT of hypoxia and high level of glutathione (GSH) in the TME, an imine bond is introduced into an Ir(III)-ferrocene complex to construct a small molecule drug, named Ir-Fc, for tumors' imaging and therapy. The cleavage of the imine bond in the lysosome effectively disrupts the photoinduced electron transfer (PET) process, realizing the decomposition of Ir-Fc into Fc-CHO and Ir-NH2. Fc-CHO produces •OH by Fenton reactions under dark conditions and induces ferroptosis in tumor cells, and Ir-NH2 shows prominent performance for type-I and type-II reactive oxygen species (ROS) production. Meanwhile, the ferroptosis pathway simultaneously consumes large amounts of GSH and produces O2 for effectively relieving hypoxia. These distinctive outputs make Ir-Fc an exceptional molecule for effective tumor synergistic therapy. This study thus brings a new and revolutionary PDT protocol for practical cancer treatment.

Molecular subtypes of intrahepatic cholangiocarcinoma.

Intrahepatic cholangiocarcinoma (iCCA) presents in two clinically distinct subtypes: large duct (LD-iCCA) and small duct (SD-iCCA). These subtypes exhibit significant molecular, genetic, and histopathological differences that impact patient prognosis and treatment responsiveness. This review advocates for a subtype-specific approach to iCCA research and clinical management, including tailored therapeutic strategies that consider distinct genetic profiles and tumor microenvironments. Current therapeutic approaches hold promise, yet efficacy varies by subtype. Additionally, subtype-specific molecular diagnostics, including DNA methylation-based classifiers and transcriptomic sequencing, have shown potential in refining iCCA subclassification, thereby guiding precision medicine efforts. This article outlines existing clinical trials, key research trajectories, and future directions for developing more effective subtype-adapted therapies for iCCA.

Barcoded HIV-1 reveals viral persistence driven by clonal proliferation and distinct epigenetic patterns

The HIV reservoir consists of infected cells in which the HIV-1 genome persists as provirus despite effective antiretroviral therapy (ART). Studies exploring HIV cure therapies often measure intact proviral DNA levels, time to rebound after ART interruption, or ex vivo stimulation assays of latently infected cells. This study utilizes barcoded HIV to analyze the reservoir in humanized mice. Using bulk PCR and deep sequencing methodologies, we retrieve 890 viral RNA barcodes and 504 proviral barcodes linked to 15,305 integration sites at the single RNA or DNA molecule in vivo. We track viral genetic diversity throughout early infection, ART, and rebound. The proviral reservoir retains genetic diversity despite cellular clonal proliferation and viral seeding by rebounding virus. Non-proliferated cell clones are likely the result of elimination of proviruses associated with transcriptional activation and viremia. Elimination of proviruses associated with viremia is less prominent among proliferated cell clones. Proliferated, but not massively expanded, cell clones contribute to proviral expansion and viremia, suggesting they fuel viral persistence. This approach enables comprehensive assessment of viral levels, lineages, integration sites, clonal proliferation and proviral epigenetic patterns in vivo. These findings highlight complex reservoir dynamics and the role of proliferated cell clones in viral persistence.

Three-dimensional cell culture-derived extracellular vesicles loaded alginate/hyaluronic acid composite scaffold as an optimal therapy for cartilage defect regeneration

Osteoarthritis (OA) is a chronic musculoskeletal disease characterized by joint inflammation and progressive degeneration of articular cartilage. Currently a definitive cure for OA remains to be a challenge due to the very low self-repair capacity of cartilage, thus development of more effective therapies is needed for cartilage repair. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have shown great potential as therapeutic agents for stimulating regeneration of articular cartilage. However, a standardized protocol is still lacking for manufacturing of highly active EVs for clinical applications. This study aimed to investigate the efficient production of highly active EVs by 3-dimensional (3D) MSC culture, verify the reparative efficacy of EVs on cartilage defect and elucidate the repair mechanisms. Umbilical cord MSCs were embedded in alginate to form MSC spheroids for 3D culture in human platelet lysate (hPL)-containing medium, which produced 3D culture-derived EVs (3D-EVs) with a significantly improved yield. The 3D-EVs expressed higher level of VEGF, and appeared superior to two-dimensional (2D) monolayer MSC culture-derived EVs (2D-EVs) to improve migration and proliferation in MSCs and inflammatory chondrocytes, and to suppress expression of cartilage-degrading factors. Importantly, the 3D-EVs and sodium alginate (SA)-hyaluronic acid (HA) composite hydrogel (3D-EVs/SA-HA) demonstrated significantly improved therapeutic efficacy than 2D-EVs/SA-HA hydrogel for repair of cartilage defectin vivo. The underlying mechanisms are associated with the concomitant upregulation of type II collagen and cartilage synthesis and downregulation of MMP13 in cartilage tissues. Collectively, these data showed that highly active MSC EVs could be efficiently manufactured by 3D cell culture with hPL-containing medium, and these EVs were superior to 2D-EVs for the repair of articular cartilage defect.

Cell Biology of Cancer Peritoneal Metastasis: Multiclonal Seeding and Peritoneal Tumor Microenvironment.

Peritoneal metastasis, also known as peritoneal dissemination or carcinomatosis, refers to the spread of cancer to the peritoneum that lines the abdominal and pelvic cavities and covers the abdominal organs. Peritoneal metastasis typically occurs in advanced cancers of abdominal origin, most commonly gastrointestinal and gynecological cancers. Conventional chemotherapy has limited efficacy, and no effective molecular-targeted therapy is currently available for peritoneal metastasis. As a result, peritoneal metastasis is associated with poor outcomes and significantly reduced quality of life in patients with advanced cancers. This is largely due to a limited understanding of the molecular and cellular mechanisms underlying peritoneal metastasis. However, recent studies employing innovative approaches have provided novel insights into the mechanisms of peritoneal metastasis, contributing to the development of novel therapeutic strategies. In this review, we summarize recent findings on the cell biological aspects of peritoneal metastasis and potential therapeutic target molecules. In particular, we emphasize the importance of cancer cell clustering within the abdominal cavity, which drives multiclonal peritoneal seeding. We also focus on the interactions of cancer cells with mesothelial cells and cancer-associated fibroblasts within the peritoneal tumor microenvironment.

Horseradish peroxidase/hydrogen peroxide-driven photothermally enhanced hydrogel loaded with black rice extract for treating infected skin wound.

Bacterial infection of the damaged skin area hinders the wound healing process. Photothermal antibacterial therapy has attracted increasing attention. As green, safe, and possessing various bioactive properties, natural plant extracts are a good choice. However, few natural plant extracts exhibit excellent photothermal responsiveness in the near-infrared range, requiring increased concentration and radiation power to achieve satisfactory photothermal therapeutic effects. In this study, the horseradish peroxidase/hydrogen peroxide (HRP/H2O2) catalytic system was used to simultaneously oxidize anthocyanin-rich black rice extract (BRE) and hyaluronic acid-tyramine conjugate (HT), obtaining a hydrogel based on modified hyaluronic acid with enhanced photothermal ability, abbreviated as HTB. Compared to the sole HT hydrogel, the introduction and oxidation of BRE bring in the near infrared ray-responsive photothermal ability of HTB hydrogel. As a result, a lower amount of black rice extract (3 mg/mL) and reduced NIR power density (0.8 mW/cm2) are required to achieve effective photothermal therapy, further improving the hydrogel's antibacterial activity. Besides, the adhesive, coagulant, antioxidant, and anti-inflammatory properties of HTB hydrogel were also promoted. In an infected wound model in mice, the HTB hydrogel combined with photothermal treatment significantly increased CD206 expression while suppressing CD86 expression at the wound site, indicating its bactericidal and anti-inflammatory effects. Additionally, elevated levels of CD31 and α-SMA expression in the wound tissue suggest that the photothermal hydrogel dressing promotes angiogenesis. Therefore, this enzyme-crosslinked HTB hydrogel demonstrates strong photothermal antibacterial activity as well as good anti-inflammatory and pro-angiogenic effects and holds promising potential for application in treating infected wounds.

The roles of intrinsically disordered proteins in neurodegeneration.

Neurodegenerative diseases such as Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, and Huntington's disease share a common pathological hallmark: the accumulation of misfolded proteins, particularly involving intrinsically disordered proteins (IDPs) like TDP-43, FUS, Tau, α-synuclein, and Huntingtin. These proteins undergo pathological aggregation, forming toxic inclusions that disrupt cellular function. The dysregulation of proteostasis mechanisms, including the ubiquitin-proteasome system (UPS), ubiquitin-independent proteasome system (UIPS), autophagy, and molecular chaperones, exacerbates these proteinopathies by failing to clear misfolded proteins effectively. Emerging therapeutic strategies aim to restore proteostasis through proteasome activators, autophagy enhancers, and chaperone-based interventions to prevent the toxic accumulation of IDPs. Additionally, understanding liquid-liquid phase separation (LLPS) and its role in stress granule dynamics offers novel insights into how aberrant phase transitions contribute to neurodegeneration. By targeting the molecular pathways involved in IDP aggregation and proteostasis regulation, and better understanding the specificity of each component, research in this area will pave the way for innovative therapeutic approaches to combat these neurodegenerative diseases. This review discusses the molecular mechanisms underpinning IDP pathology, highlights recent advancements in drug discovery, and explores the potential of targeting proteostasis machinery to develop effective therapies.

Adverse events and impact on quality of life of antibody-drug conjugates in the treatment of metastatic breast cancer: A systematic review and meta-analysis.

Antibody-drug conjugates are novel effective therapies for metastatic breast cancer. Nevertheless, their toxicity profile can significantly affect patients' quality of life over time. This is a systematic review and meta-analysis of randomized controlled trials of antibody-drug conjugates currently approved for the treatment of metastatic breast cancer [trastuzumab-emtansine (T-DM1), trastuzumab deruxtecan (T-DXd) and sacituzumab-govitecan (SG)] versus standard therapy to evaluate the risk of adverse events, discontinuation rate due to toxicity, impact on quality of life according to EORTC QLQ-C30 scale and subdomains. Relative risks (RR) and hazard ratios (HR) with 95% CIs were calculated using random effects models. Nine trials with a total of 5753 patients were included. The most common adverse events of any grade for T-DM1 included thrombocytopenia (RR 7.14, 95% CI 4.13-12.36) and increased alanine-transaminase (ALT)(RR 2.04, 95% CI 1.43-2.91), for T-DXd were nausea (RR 2.39, 95% CI 1.90-3.00) and anemia (RR 1.55, 95% CI 1.27-1.90), while for SG were neutropenia (RR 1.30, 95% CI 1.14-1.49), diarrhea (RR 3.62, 95% CI 2.97-4.42) and nausea (RR1.90, 95% CI 1.65-2.19). Severe adverse events such as interstitial lung disease and left ventricular dysfunction were peculiar of T-DXd. Antibody-drug conjugates significantly delayed clinical deterioration of global health status by EORTC QLQ-C30 (HR .71, 95% CI .59-.86), physical, emotional and social functioning, pain and fatigue symptoms. This meta-analysis offers consolidated data on adverse events associated with antibody-drug conjugates and their effects on patients' quality of life, emphasizing differences based on the specific agent. These findings underscore the critical need for effective strategies to prevent, diagnose and manage these toxicities.

CTGF (CCN2): a multifaceted mediator in breast cancer progression and therapeutic targeting.

Breast cancer, with its diverse subtypes like ER-positive, HER-2-positive, and triple-negative, presents complex challenges demanding personalized treatment approaches. The intricate interplay of genetic, environmental, and lifestyle factors underscores its status as a primary contributor to cancer-related fatalities in women globally. Understanding the molecular drivers specific to each subtype is crucial for developing effective therapies. In this landscape, connective tissue growth factor (CTGF), also referred to as cellular communication network factor 2 (CCN2), emerges as a significant player. CTGF regulates critical biological activities like cell growth, invasion, and migration, impacting breast cancer development and progression. It modulates breast tumor microenvironment by promoting angiogenesis, activating cancer-associated fibroblasts (CAFs), and inducing inflammation. The activity of CTGF depends on several factors including oxygen levels, hormone signals, and growth factors and differs according to the type of breast cancer. CTGF can regulate breast cancer cells by activating various signaling pathways and modulating the transcription of other genes that are involved in tumor development and metastasis including S100A4, glucose transporter 3 (GLUT3), and vascular endothelial growth factor (VEGF). The matricellular protein can be considered a potential therapeutic target, as it can promote tumor growth and confer drug resistance in breast cancer. Numerous tactics, including neutralizing antibodies, antisense oligonucleotides, natural compounds, recombinant proteins, and short hairpin RNAs have been suggested to block its function. This review highlights the structure of CTGF, regulation of its expression, and current knowledge of its oncogenic role in breast cancer, as well as focusing on potential therapeutic strategies for targeting CTGF in breast cancer.

Binding of small molecules at the P-stalk site of ricin A subunit trigger conformational changes that extend into the active site.

Ricin is a Category B agent for bioterrorism and Shiga toxins are the primary virulence factors of Shiga toxin (Stx) producing E. coli (STEC). Ricin and Stxs bind the ribosomal P-stalk proteins to depurinate the sarcin/ricin loop (SRL) on the eukaryotic ribosome and inhibit translation. Both toxins are prime targets for therapeutic intervention because no effective therapy exists for ricin intoxication or STEC infection. Binding of ricin toxin A subunit (RTA) to the ribosomal P-stalk stimulates depurination of the SRL by an unknown mechanism. We previously identified compounds that bind the P-stalk pocket of RTA and inhibit catalytic activity. Here we characterize a second-generation lead compound, which binds the P-stalk pocket of RTA with over 30-fold improved affinity relative to the original compound and inhibits the cytotoxicity of ricin holotoxin in Vero cells with no apparent cellular toxicity by itself. This compound also shows protection against Stx2A1. X-ray crystal structure of RTA-inhibitor complexes suggests that the orientation of the carboxylic acid influences the inhibitor contacts at the P-stalk site of RTA and contributes to inhibitor potency. The structural changes triggered at the P-stalk site of RTA were validated by solution NMR based chemical shift perturbation analysis. A key finding by NMR is that binding induced conformational changes extend beyond the P-stalk site to residues in the active site cleft of RTA. Collectively, these results provide valuable new insight into the conformational flexibility in the C-terminal domain of RTA and its potential role in mediating the remarkable catalytic activity of ricin.

Novel biomarkers of fetal and neonatal environmental exposure, effect and susceptibility.

Rapid advancements in science and technology have allowed medical providers to treat wider ranges of diseases with safer and more effective therapies than ever before. One of the areas of health that has been consistently understudied, however, is one that affects us all: environmental health or the effects that the chemicals we are exposed to every day have on our acute and chronic health. This effect can be exacerbated during and shortly after pregnancy, as an individual exposure is often shared by both the mother and the fetus/neonate. The diagnosis and monitoring of chemical exposure can be quite challenging, and improving our understanding of the effects of exposure will therefore require effective use of an expanding set of biomarker tests and biological matrices. This review covers the background and history of neonatal biomarkers of exposure, effect, and susceptibility, focusing on the potential uses for the non-invasive matrix of exhaled breath for the detection and monitoring of chemical exposures. IMPACT: Provides a brief overview of Food and Drug Administration and National Institutes of Health Joint Leadership Council BEST (Biomarkers, EndpointS, and other Tools) Resource. Summarizes new and potential biomarkers for fetal exposure. Collates studies using breath as a matrix for environmental exposures.

Exploring neuroblastoma's cellular microenvironment: A novel approach using cellular automata to model Celyvir treatment.

Neuroblastoma is a significant health concern in children, as it is one of the most common types of cancer among this age group and is associated with poor survival rates. Currently, there are no effective therapies that significantly improve outcomes for these patients. This study explores the efficacy of Celyvir - an advanced therapy comprising mesenchymal stem cells (MSCs) carrying the oncolytic virus ICOVIR 5 - against neuroblastoma, by means of an individual-based model. A probabilistic cellular automaton was developed to implement the dynamic interactions between neuroblastoma cells, T lymphocytes, and the therapeutic agent Celyvir. The model examines various sizes, shapes, and positions of the tumour within a lattice, along with different infection probabilities associated with the action of Celyvir and various treatment schedules. This analysis identifies the most influential infection probabilities according to the cellular automaton model, and demonstrates that different treatment regimens can effectively eradicate the tumour, in contrast to standard clinical approaches. Additionally, Kaplan-Meier curves have been generated to assess different treatment schedules under specific tumour scenarios, highlighting the importance of precise treatment scheduling to optimise therapeutic outcomes. This study provides insights into the potential of Celyvir in neuroblastoma treatment, emphasising the need to understand tumour dynamics and strategically implement treatment schemes to improve clinical outcomes.

A microRNA-regulated transcriptional state defines intratumoral CD8+ Tcells that respond to immunotherapy.

The rising incidence of advanced-stage colorectal cancer (CRC) and poor survival outcomes necessitate new and effective therapies. Immune checkpoint inhibitors (ICIs), specifically anti-PD-1 therapy, show promise, yet clinical determinants of a positive response are suboptimal. Here, we identify microRNA-155 (miR-155) as necessary for CD8+ Tcell-infiltrated tumors through an unbiased invivo CRISPR-Cas9 screen identifying functional tumor antigen-specific CD8+ Tcell-expressed microRNAs. Tcell miR-155 is required for anti-PD-1 responses and for a vital intratumor CD8+ Tcell differentiation cascade by repressing Ship-1, inhibiting Tcf-1 and stemness, and subsequently enhancing Cxcr6 expression, anti-tumor immunity, and effector functions. Based on an underlying miR-155-dependent CD8+ Tcell transcriptional profile, we identify a gene signature that predicts ICI responses across 12 diverse cancers. Together, our findings support a model whereby miR-155 serves as a central regulator of CD8+ Tcell-dependent cancer immunity and ICI responses that may be leveraged for future therapeutics.

Enhancing Antibiotic-Resistant Bacterial Infection Therapy: Self-Assembling Gemini Quaternary Ammonium-Functionalized Peptide Nanoassemblies with Multiple Antibacterial Mechanisms.

The rising threat of antimicrobial-resistant (AMR) infections highlights the urgent need for effective antimicrobial agents and therapies. Peptide-based antimicrobial nanomaterials are well-placed to meet this need. Here, we explore the conjugation of antimicrobial gemini quaternary ammonium compounds (GQAs) with designed short hexapeptides to create cationic antimicrobial nanomaterials with low cytotoxicity and minimal resistance tendency. (WA)3GQA8C self-assembles into nanoparticles and exhibits potent antimicrobial activity against drug-resistant pathogens and enhanced stability. (WA)3GQA8C protects against subcutaneous abscess infection and rescues mice from acute peritonitis infection by reducing the systemic bacterial burden and alleviating organ damage, with superior effects to vancomycin. Notably, (WA)3GQA8C thoroughly disrupts bacterial membrane integrity akin to peeling fruit to induce bacterial membrane disintegration, a feat inaccessible to conventional antibiotics. Mechanistic studies suggest that (WA)3GQA8C targets the bacterial membrane phospholipids phosphatidylglycerol (PG), inducing PG deformation to form fibrous or lamellar structures, which leads to the disruption of the bacterial membrane. Furthermore, the interference in lipoprotein trafficking exacerbates damage to bacterial membrane integrity. (WA)3GQA8C also synergizes antimicrobial activity by impairing the protein synthesis function of the ribosome. These quaternized peptide nanoassemblies provide a rational strategy for designing peptide-based antimicrobial nanomaterials to combat the growing threats of resistant bacteria.

Cabozantinib for brain metastases in renal cell carcinoma: a single-institution retrospective analysis.

Brain metastases from renal cell carcinoma (RCC) present considerable treatment challenges and poor prognoses. In this study, we evaluated the efficacy of cabozantinib, a multi- tyrosine kinase inhibitors (TKIs), in improving the progression-free survival (PFS) and overall survival (OS) of patients with RCC with brain metastases. This retrospective study included 30 patients with RCC and brain metastases treated at a single institution between 2010 and 2024. Patient demographics, treatment modalities, and survival outcomes were analyzed. Systemic therapies included cabozantinib, TKIs, and immune checkpoint inhibitors (ICIs). Local therapies included Gamma Knife surgery (GKS) and whole-brain radiation therapy (WBRT). Survival outcomes were evaluated using Kaplan-Meier analysis and Cox proportional hazards models. Cabozantinib-treated patients (n=12) exhibited significantly longer median PFS (21.6 vs. 4.1months; P<.001) and OS (25.7 vs. 8.3months; P=.019) compared to non-cabozantinib patients (n=18). In patients treated with GKS, cabozantinib further improved PFS (29.6 vs. 3.9months; P<.001) and OS (25.7 vs. 12.8months; P<.001). Cox regression analysis identified cabozantinib as the sole independent predictor of improved PFS (hazard ratio [HR], 0.09; P=.004) and OS (HR, 0.17; P=.009). Cabozantinib significantly improved survival outcomes in RCC patients with brain metastases, underscoring its role as an effective systemic therapy. However, potential risks such as brain hemorrhage highlight the importance of careful patient selection and close monitoring. Further prospective studies are warranted to explore optimal combination strategies.