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Systemic lupus erythematosus (SLE) is prototypical autoimmune disease driven by pathological T cell-B cell interactions1,2. Expansion of T follicular helper (TFH) and T peripheral helper (TPH) cells, two T cell populations that provide help to B cells, is a prominent feature of SLE3,4. Human TFH and TPH cells characteristically produce high levels of the B cell chemoattractant CXCL13 (refs. 5,6), yet regulation of T cell CXCL13 production and the relationship between CXCL13+ T cells and other T cell states remains unclear. Here, we identify an imbalance in CD4+ T cell phenotypes in patients with SLE, with expansion of PD-1+/ICOS+ CXCL13+ T cells and reduction of CD96hi IL-22+ T cells. Using CRISPR screens, we identify the aryl hydrocarbon receptor (AHR) as a potent negative regulator of CXCL13 production by human CD4+ T cells. Transcriptomic, epigenetic and functional studies demonstrate that AHR coordinates with AP-1 family member JUN to prevent CXCL13+ TPH/TFH cell differentiation and promote an IL-22+ phenotype. Type I interferon, a pathogenic driver of SLE7, opposes AHR and JUN to promote T cell production of CXCL13. These results place CXCL13+ TPH/TFH cells on a polarization axis opposite from T helper 22 (TH22) cells and reveal AHR, JUN and interferon as key regulators of these divergent T cell states.
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Fatores de Transcrição Hélice-Alça-Hélice Básicos , Linfócitos T CD4-Positivos , Quimiocina CXCL13 , Interferon Tipo I , Lúpus Eritematoso Sistêmico , Proteínas Proto-Oncogênicas c-jun , Receptores de Hidrocarboneto Arílico , Feminino , Humanos , Masculino , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Quimiocina CXCL13/metabolismo , Epigenômica , Perfilação da Expressão Gênica , Interferon Tipo I/imunologia , Interferon Tipo I/metabolismo , Interleucina 22/imunologia , Interleucina 22/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
AIMS: We aimed to identify mechanisms underlying the tolerance of Proteus mirabilis-a common cause of catheter associated urinary tract infection-to the clinically used biocides chlorhexidine (CHD) and octenidine (OCT). METHODS AND RESULTS: We adapted three clinical isolates to grow at concentrations of 512 µg ml-1 CHD and 128 µg ml-1 OCT. Genetic characterization and complementation studies revealed mutations inactivating the smvR repressor and increasing smvA efflux expression were associated with adaptation to both biocides. Mutations in mipA (encoding the MltA interacting protein) were less prevalent than smvR mutations and only identified in CHD adapted populations. Mutations in the rppA response regulator were exclusive to one adapted isolate and were linked with reduced polymyxin B susceptibility and a predicted gain of function after biocide adaptation. Biocide adaptation had no impact on crystalline biofilm formation. CONCLUSIONS: SmvR inactivation is a key mechanism in both CHD and OCT tolerance. MipA inactivation alone confers moderate protection against CHD, and rppA showed no direct role in either CHD or OCT susceptibility.
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Clorexidina , Iminas , Proteus mirabilis , Piridinas , Proteus mirabilis/efeitos dos fármacos , Proteus mirabilis/genética , Proteus mirabilis/fisiologia , Clorexidina/farmacologia , Iminas/farmacologia , Piridinas/farmacologia , Testes de Sensibilidade Microbiana , Humanos , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Infecções por Proteus/microbiologia , Mutação , Farmacorresistência Bacteriana/genética , Anti-Infecciosos Locais/farmacologia , Desinfetantes/farmacologia , Infecções Relacionadas a Cateter/microbiologia , Infecções Urinárias/microbiologiaRESUMO
INTRODUCTION: Participatory health research (PHR) as a research paradigm, guides the research process and strives to achieve positive change in society in the interest of people's health. In this scoping review, PHR will be used as an umbrella term considering a wide range of collaborative research approaches in the health context. PHR is conducted 'with' or 'by' those it intends to benefit, as opposed to 'on' and 'for' them. Their involvement throughout the research process seeks to shift power and decision-making from where they traditionally lay within academia toward community, patient and public end-users. Research cannot be truly participatory without concurrently addressing power dynamics within the partnership and power imbalances in decision making. Therefore, power sharing can be defined as a major factor in building effective academic-community collaborations. This scoping review aims to identify, clarify, and map existing literature on power and power sharing in PHR from both theoretical and practical perspectives. Specifically, we will explore how power is conceptualised throughout the literature, and how power and power sharing are applied and addressed in real-life PHR partnerships. MATERIALS AND METHODS: This scoping review will be conducted in accordance with the guidelines outlined in the Joanna Briggs Institute (JBI) Reviewer's Manual. This scoping review will consider both empirical and non-empirical research that report on understanding power and power sharing in participatory health research partnerships. All appropriate studies will be retrieved from the following five electronic databases: PubMed, Scopus, Embase, PsycINFO, SocIndex. This review will be limited to articles published in English and from January 1998 to March 2024. As the scoping review aims to capture more than peer-reviewed and published literature, it will also include grey literature such as theses and dissertations, reports, conference proceedings, and editorials. Data from the included literature will be extracted based on the data extraction tool, defined in advance. ETHICS AND DISSEMINATION: As primary data will not be collected, ethical approval is not required to conduct the scoping review. The findings of this study will be disseminated through peer-reviewed publications.
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Pesquisa Participativa Baseada na Comunidade , Humanos , Comportamento Cooperativo , Poder Psicológico , Literatura de Revisão como Assunto , Projetos de PesquisaRESUMO
BACKGROUND: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations. METHODS: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined. RESULTS: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients. CONCLUSIONS: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested.
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Líquido da Lavagem Broncoalveolar , Hospedeiro Imunocomprometido , Pneumonia por Pneumocystis , Sensibilidade e Especificidade , Pneumonia por Pneumocystis/diagnóstico , Pneumonia por Pneumocystis/microbiologia , Humanos , Líquido da Lavagem Broncoalveolar/microbiologia , Reação em Cadeia da Polimerase/métodos , Escarro/microbiologia , Sistema Respiratório/microbiologia , Pneumocystis carinii/genética , Pneumocystis carinii/isolamento & purificação , Infecções por HIV/diagnóstico , Reação em Cadeia da Polimerase em Tempo Real/métodosRESUMO
An efficient SNAr approach for generating a wide array of 2-aryl and 2-alkyl pyrimidines in good to high yields was developed. This methodology does not require precious metal catalysts and is compatible with aryl, heteroaryl, and alkyl magnesium halides as nucleophiles. This process is scalable and performed at room temperature well below the temperature of the competing decomposition of the activated 2-tert-butyl sulfonyl pyrimidine electrophile.
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Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR-Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology. Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology. See related commentary by Wainberg, p. 1369.
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Helicase da Síndrome de Werner , Humanos , Helicase da Síndrome de Werner/genética , Camundongos , Animais , Instabilidade de Microssatélites , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Linhagem Celular Tumoral , Ensaios Antitumorais Modelo de Xenoenxerto , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêuticoRESUMO
Leveraging the extensive surface area of the lungs for gene therapy, the inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient delivery of mRNA to the respiratory system. Our results demonstrated the superiority of the MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of the nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful lung-specific mRNA transfection without observable signs of toxicity. This MAP may represent an advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.
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Aerossóis , Lipossomos , Nanopartículas , RNA Mensageiro , Nanopartículas/química , Animais , RNA Mensageiro/genética , RNA Mensageiro/administração & dosagem , Aerossóis/química , Camundongos , Administração por Inalação , Humanos , Lipídeos/química , Microfluídica/métodos , Tamanho da Partícula , Dispositivos Lab-On-A-ChipRESUMO
As airborne methane surveys of oil and gas systems continue to discover large emissions that are missing from official estimates1-4, the true scope of methane emissions from energy production has yet to be quantified. We integrate approximately one million aerial site measurements into regional emissions inventories for six regions in the USA, comprising 52% of onshore oil and 29% of gas production over 15 aerial campaigns. We construct complete emissions distributions for each, employing empirically grounded simulations to estimate small emissions. Total estimated emissions range from 0.75% (95% confidence interval (CI) 0.65%, 0.84%) of covered natural gas production in a high-productivity, gas-rich region to 9.63% (95% CI 9.04%, 10.39%) in a rapidly expanding, oil-focused region. The six-region weighted average is 2.95% (95% CI 2.79%, 3.14%), or roughly three times the national government inventory estimate5. Only 0.05-1.66% of well sites contribute the majority (50-79%) of well site emissions in 11 out of 15 surveys. Ancillary midstream facilities, including pipelines, contribute 18-57% of estimated regional emissions, similarly concentrated in a small number of point sources. Together, the emissions quantified here represent an annual loss of roughly US$1 billion in commercial gas value and a US$9.3 billion annual social cost6. Repeated, comprehensive, regional remote-sensing surveys offer a path to detect these low-frequency, high-consequence emissions for rapid mitigation, incorporation into official emissions inventories and a clear-eyed assessment of the most effective emission-finding technologies for a given region.
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Although microtubule inhibitors (MTI) remain a therapeutically valuable payload option for antibody-drug conjugates (ADC), some cancers do not respond to MTI-based ADCs. Efforts to fill this therapeutic gap have led to a recent expansion of the ADC payload "toolbox" to include payloads with novel mechanisms of action such as topoisomerase inhibition and DNA cross-linking. We present here the development of a novel DNA mono-alkylator ADC platform that exhibits sustained tumor growth suppression at single doses in MTI-resistant tumors and is well tolerated in the rat upon repeat dosing. A phosphoramidate prodrug of the payload enables low ADC aggregation even at drug-to-antibody ratios of 5:1 while still delivering a bystander-capable payload that is effective in multidrug resistant (MDR)-overexpressing cell lines. The platform was comparable in xenograft studies to the clinical benchmark DNA mono-alkylator ADC platform DGN459 but with a significantly better tolerability profile in rats. Thus, the activity and tolerability profile of this new platform make it a viable option for the development of ADCs.
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Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Ratos , Animais , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Alquilantes , Neoplasias/tratamento farmacológico , DNA/metabolismo , Linhagem Celular Tumoral , Antineoplásicos/farmacologiaRESUMO
Leveraging the extensive surface area of the lungs for gene therapy, inhalation route offers distinct advantages for delivery. Clinical nebulizers that employ vibrating mesh technology are the standard choice for converting liquid medicines into aerosols. However, they have limitations when it comes to delivering mRNA through inhalation, including severe damage to nanoparticles due to shearing forces. Here, we introduce a novel microfluidic aerosolization platform (MAP) that preserves the structural and physicochemical integrity of lipid nanoparticles, enabling safe and efficient mRNA delivery to the respiratory system. Our results demonstrated the superiority of the novel MAP over the conventional vibrating mesh nebulizer, as it avoided problems such as particle aggregation, loss of mRNA encapsulation, and deformation of nanoparticle morphology. Notably, aerosolized nanoparticles generated by the microfluidic device led to enhanced transfection efficiency across various cell lines. In vivo experiments with mice that inhaled these aerosolized nanoparticles revealed successful, lung-specific mRNA transfection without observable signs of toxicity. This pioneering MAP represents a significant advancement for the pulmonary gene therapy, enabling precise and effective delivery of aerosolized nanoparticles.
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The global unmet need for kidney replacement therapy means that millions of people die every year as they cannot afford treatment. Peritoneal dialysis (PD) offers comparable survival to haemodialysis and is often more affordable, but one barrier to increasing access is that conventional manufacturing and distribution of PD fluid is costly. Here we report the results from a pilot proof-of-principal study demonstrating for the first time that the Ellen Medical Devices Point-of-Care system can be used by patients to produce sterile PD fluid at the point-of-care. With further development, this low-cost system could offer a solution to the many millions of people around the world who currently cannot afford treatment for kidney failure.
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OBJECTIVES: Patients undergoing long-term anticancer therapy typically require one of 3 venous access devices: Hickman-type device (HICK), peripherally inserted central catheter (PICC), or implantable chest wall port (PORT). Recent evidence has shown PORT is safer and improves patient satisfaction. However, PORT did not show improvement in quality-adjusted life-years and was more expensive. Decisions regarding cost-effectiveness in the United Kingdom are typically informed by a cost-per-quality-adjusted life-year metric. However, this approach is limited in its ability to capture the full range of relevant outcomes, especially in the context of medical devices. This study assessed the potential cost-effectiveness of HICK, PICC, and PORT in routine clinical practice. METHODS: This is a cost-consequence analysis to determine the trade-offs between the following outcomes: complication, infection, noninfection, chemotherapy interruption, unplanned device removals, health utilities, device insertion cost, follow-up cost, and total cost, using data from the Cancer and Venous Access clinical trial. We conducted value of implementation analysis of a PORT service. RESULTS: PORT was superior in terms of overall complication rate compared with both HICK (incidence rate ratio 0.422; 95% CI 0.286-0.622) and PICC (incidence rate ratio 0.295; 95% CI 0.189-0.458) and less likely to lead to an unplanned device removal. There was no difference in chemotherapy interruption or health utilities. Total cost with device in situ was lower on PORT than HICK (-£98.86; 95% CI -189.20 to -8.53) and comparable with PICC -£48.57 (95% CI -164.99 to 67.86). Value of implementation analysis found that PORT was likely to be considered cost-effective within the National Health Service. CONCLUSION: Decision makers should consider including PORT within the suite of venous access devices available within in the National Health Service.
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Cateterismo Venoso Central , Cateterismo Periférico , Neoplasias , Humanos , Cateterismo Venoso Central/efeitos adversos , Análise Custo-Benefício , Medicina Estatal , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Cateterismo Periférico/efeitos adversosRESUMO
Background: The skin, our body's largest organ, hosts a complex microbiome that plays a pivotal role in maintaining health and protecting against pathogens. Even slight disruptions to this delicate balance can influence skin health and disease. Among the diverse microbial community, Cutibacterium acnes (C. acnes) subspecies defendens is known for its positive contribution to skin health. However, the interaction between living microbe probiotics and wound healing after aesthetic procedures, such as microneedling, remains unexplored. Methods: Our study included 40 participants with acne scars who underwent four microneedling sessions spaced three weeks apart. They were randomly assigned to Group 1, receiving a regimen with live C. acnes defendens strain XYCM42, or Group 2, following a conventional skincare routine with a cleanser, moisturizer, and sunscreen. Our study assessed various endpoints, including the Clinician's Global Aesthetic Improvement Scale (CGAIS), clinical safety, improvement in acne scars using Goodman and Baron's Qualitative and Quantitative Acne Scars Grading Scale and Subject's Global Aesthetic Improvement Scale (SGAIS). Results: Our analysis of live and photo grading data for CGAIS unveiled a statistically significant difference between the two groups, with Group 1 (XYCM42-based regimen) showing remarkable improvement. A similar positive trend was observed in the photo grading for CGAIS. Additionally, participant diaries indicated that Group 1 experienced a faster decline in posttreatment parameters, including erythema, swelling, burning/tingling, and itching. Conclusion: Integrating a microbiome-optimized, probiotic XYCM42-based regimen with microneedling demonstrated a high safety profile and enhanced treatment outcomes. These findings mark a milestone in aesthetic dermatology, supporting innovative microbiome-based approaches to improve skin health and aesthetics.
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Background: Acne is an inflammatory disease of the pilosebaceous unit that occurs primarily in adolescents. There is no current ideal treatment for acne vulgaris, as many mainstay prescription treatment modalities can compromise the skin microbiome or have deleterious health effects. Further research is needed to investigate novel treatment modalities that account for the importance of the skin microbiome. Other developing treatment modalities for acne are still taking a similar mode of action as current treatments by trying to eliminate Cutibacterium acnes despite growing evidence that some C. acnes strains may be symbiotic in nature. The perception that microneedling will exacerbate the disease state and trigger more acneic lesions via the spread of acne-associated microbes has hindered research investigating whether microneedling is a safe and effective treatment. This pilot clinical study challenges such perceptions by clinical assessment to determine if microneedling may produce beneficial treatment outcomes without disrupting critical skin structure or skin microbiome. Objectives: Test the safety and efficacy of microneedling as an effective treatment modality for acne vulgaris. Methods: Subjects were split into two groups, one group received three treatments 4 weeks apart, and the second group received four treatments 2 weeks apart. Subjects received an acne assessment by an expert clinical grader at all clinical visits. Results: There was a statistically significant reduction in both non-inflammatory and inflammatory lesions at the 2-month follow-up compared to the baseline for Group 1. Group 1 and Group 2 saw a decline of 48.20% and 54.00% in non-inflammatory lesions and 57.97% and 36.67% in inflammatory lesions, respectively, at their last visit compared to baseline. Conclusion: This study expands the utility of microneedling into a potential therapeutic modality for acne vulgaris. The data generated during the duration of this clinical study demonstrates that there is no scientific reason for microneedling to be contraindicated for acne. In this pilot, microneedling did not cause post-treatment complications and was seen to reduce acne lesions effectively. Thus, microneedling may have the potential to be a well-tolerated option for those suffering from acne, being a treatment that neither damages the sebaceous glands nor disrupts the skin microbiome.
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Surface silanols (Si-OH) play a vital role on fused silica surfaces in chromatography. Here, we used an atmospheric-pressure, gas-phase reactor to modify the inner surface of a gas chromatography, fused silica capillary column (0.53 mm ID) with a small, reactive silane (tris(dimethylamino)methylsilane, TDMAMS). The deposition of TDMAMS on planar witness samples around the capillary was confirmed with X-ray photoelectron spectroscopy (XPS), ex situ spectroscopic ellipsometry (SE), and wetting. The number of surface silanols on unmodified and TDMAMS-modified native oxide-terminated silicon were quantified by tagging with dimethylzinc (DMZ) via atomic layer deposition (ALD) and counting the resulting zinc atoms with high sensitivity-low energy ion scattering (HS-LEIS). A bare, clean native oxide - terminated silicon wafer has 3.66 OH/nm2, which agrees with density functional theory (DFT) calculations from the literature. After TDMAMS modification of native oxide-terminated silicon, the number of surface silanols decreases by a factor of ca. 10 (to 0.31 OH/nm2). Intermediate surface testing (IST) was used to characterize the surface activities of functionalized capillaries. It suggested a significant deactivation/passivation of the capillary with some surface silanols remaining; the modified capillary shows significant deactivation compared to the native/unmodified fused silica tubing. We believe that this methodology for determining the number of residual silanols on silanized fused silica will be enabling for chromatography.
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Silanos , Silício , Capilares , Dióxido de Silício , ÓxidosRESUMO
Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.
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While STING agonists have proven to be effective preclinically as anti-tumor agents, these promising results have yet to be translated in the clinic. A STING agonist antibody-drug conjugate (ADC) could overcome current limitations by improving tumor accessibility, allowing for systemic administration as well as tumor-localized activation of STING for greater anti-tumor activity and better tolerability. In line with this effort, a STING agonist ADC platform was identified through systematic optimization of the payload, linker, and scaffold based on multiple factors including potency and specificity in both in vitro and in vivo evaluations. The platform employs a potent non-cyclic dinucleotide STING agonist, a cleavable ester-based linker, and a hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built with the resulting STING agonist platform induced robust and durable anti-tumor activity and demonstrated high stability and favorable pharmacokinetics in nonclinical species.
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Antineoplásicos , Imunoconjugados , Neoplasias , Humanos , Imunoconjugados/farmacocinética , Anticorpos Monoclonais , Antineoplásicos/farmacocinética , Neoplasias/tratamento farmacológicoRESUMO
AIMS: The care of patients undergoing long-term urethral catheterization is frequently complicated by Proteus mirabilis infection. This organism forms dense, crystalline biofilms, which block catheters leading to serious clinical conditions. However, there are currently no truly effective approaches to control this problem. Here, we describe the development of a novel theranostic catheter coating, to simultaneously provide early warning of blockage, and actively delay crystalline biofilm formation. METHODS AND RESULTS: The coating comprises of a pH sensitive upper polymer layer (poly(methyl methacrylate-co-methacrylic acid); Eudragit S 100®) and a hydrogel base layer of poly(vinyl alcohol), which is loaded with therapeutic agents (acetohydroxamic acid or ciprofloxacin hydrochloride) and a fluorescent dye, 5(6)-carboxyfluorescein (CF). The elevation of urinary pH due to P. mirabilis urease activity results in the dissolution of the upper layer and release of cargo agents contained in the base layer. Experiments using in vitro models, which were representative of P. mirabilis catheter-associated urinary tract infections, demonstrated that these coatings significantly delay time taken for catheters to block. Coatings containing both CF dye and ciprofloxacin HCl were able to provide an average of ca. 79 h advanced warning of blockage and extend catheter lifespan ca. 3.40-fold. CONCLUSIONS: This study has demonstrated the potential for theranostic, infection-responsive coatings to form a promising approach to combat catheter encrustation and actively delay blockage.