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BACKGROUND: Although immunotherapy shows tremendous potential in the treatment of bladder cancer (BLCA), the overall prognosis and response rates to immunotherapy in BLCA remain suboptimal. METHODS: We performed an extensive evaluation of glycosyltransferase expression patterns in BLCA patients by analyzing 210 glycosyltransferase-related genes. Subsequently, we established correlations between these glycosyltransferase patterns, prognosis, and tumor microenvironment (TME) phenotypes. To offer personalized patient assessments, we developed a glycosyltransferase risk score that accurately predicts prognosis, TME phenotypes, and molecular subtypes. Importantly, we developed a RNA-seq cohort, named Xiangya cohort, to validate our results. RESULTS: Two distinct patterns of glycosyltransferase expression were identified, corresponding to inflamed and noninflamed TME phenotypes, and demonstrated the potential to predict prognosis. We developed and validated a comprehensive risk score that accurately predicted individual patient prognosis in the TCGA-BLCA cohort. Additionally, we constructed a nomogram that integrated the risk score with several key clinical factors. Importantly, this risk score was successfully validated in external cohorts, including the Xiangya cohort and GSE48075. Furthermore, we discovered a positive correlation between this risk score and tumor-infiltrating lymphocytes in both the TCGA-BLCA and Xiangya cohorts, suggesting that patients with a higher risk score exhibited an inflamed TME phenotype and were more responsive to immunotherapy. Finally, we observed that the high and low risk score groups were consistent with the luminal and basal subtypes of BLCA, respectively, providing further validation of the risk score's role in the TME in terms of molecular subtypes. CONCLUSIONS: Glycosyltransferase patterns exhibit distinct TME phenotypes in BLCA. Our comprehensive risk score provides a promising approach for prognostic prediction and assessment of immunotherapy efficacy, offering valuable guidance for precision medicine.
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Glicosiltransferasas , Inmunoterapia , Nomogramas , Fenotipo , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria , Humanos , Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/terapia , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/mortalidad , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Pronóstico , Inmunoterapia/métodos , Glicosiltransferasas/genética , Glicosiltransferasas/metabolismo , Masculino , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Biomarcadores de Tumor/genética , Persona de Mediana Edad , Medición de Riesgo , Anciano , Regulación Neoplásica de la Expresión Génica , Factores de RiesgoRESUMEN
This editorial discusses the status and issues related to perioperative opioid usage monitoring and waste. Opioid detection of wasted material is briefly discussed also. Flowlytics® from Invistics is a digital system to monitor opioid usage and waste in medical facilities. Opioid waste in medical facilities has a two-person witness procedure. Easy to use detection of wasted materials needs to be developed in the future. It is unclear whether the strategies used in medical facilities should be recommended for opioid disposal in the public to reduce opioid diversion. Relevant studies are needed.
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Background: Only a small percentage of patients with acute stroke are currently eligible for thrombolysis, partly due to severe delays in hospital arrival. We had previously conducted the first regional study to assess the factors delaying acute stroke care in India. The present study aims to understand and describe in depth the variables associated with prehospital delay among patients admitted with an acute ischemic stroke. Methods: Data were prospectively collected by conducting an in-depth interview of 470 acute ischemic stroke patients and their bystanders, aged above 18 years, presenting to the Department of Emergency Medicine, Jubilee Mission Medical College and Research Institute, Thrissur. Patients who arrived within 4.5 h of symptom onset were considered as "early arrival" and those who arrived after 4.5 h were considered as "delayed arrival." Univariate and multivariate analyses were undertaken to determine associations between variables of interest and delays to hospital presentation. Results: Of the 470 patients who met the inclusion criteria, 73 patients reached within 4.5 h (15.5%), whereas 397 patients arrived after 4.5 h. The mean age of acute stroke patients who reached within 4.5 h was 63 ± 13.7 years, whereas the mean age of those who reached after 4.5 h was 63 ± 12.1 years. Binary logistic regression performed to quantify the associations of prehospital factors showed an increased risk of prehospital delay among individuals with lack of awareness (odds ratio [OR] = 5.16 [3.040-8.757], P < 0.001), followed by those for whom a vehicle was not available at the site of event (OR = 3.745 [1.864-7.522], P < 0.001). Within the predefined socioeconomic strata, compared to lower class, upper middle class had less risk (OR = 0.135 [0.018-1.035], P = 0.054), whereas the distance from first medical contact to emergency department contributed moderate risk (OR = 1.071 [1.028-1.116], P < 0.001) for prehospital delay. Conclusions: Health promotion techniques that increase public knowledge about the early signs of stroke, transferring patients directly to hospitals with thrombolysis capabilities, and making ambulance services more widely available are appropriate measures to reduce prehospital delay.
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This commentary discusses the issues related to the current pharmacotherapy using super long-acting opioids (for the potential convenience for both patients and medical providers) for opioid addiction and argues for the potential to use a non-scheduled short-acting opioid to taper off opioids to reduce total number of patients on opioids and ultimately reduce opioid-related death. This article also proposes to develop short-acting opioids for addiction management instead of the current long-acting regimen. The authors further suggest that dezocine, a previously FDA approved medication for perioperative pain management and a non-scheduled opioid, be brought back to clinical practice in the US as a potential alternative addiction management medication, especially for those who are highly motivated to quit opioids completely using a taper off strategy.
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Analgésicos Opioides , Trastornos Relacionados con Opioides , Humanos , Analgésicos Opioides/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológicoRESUMEN
Postoperative gastrointestinal disorder (POGD) was a common complication after surgery under anesthesia. Strategies in combination with Traditional Chinese Medicine and Western medicine showed some distinct effects but standardized clinical practice guidelines were not available. Thus, a multidisciplinary expert team from various professional bodies including the Perioperative and Anesthesia Professional Committees of the Chinese Association of Integrative Medicine (CAIM), jointly with Gansu Province Clinical Research Center of Integrative Anesthesiology/Anesthesia and Pain Medical Center of Gansu Provincial Hospital of Traditional Chinese Medicine and WHO Collaborating Center for Guideline Implementation and Knowledge Translation/Chinese Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) Center/Gansu Provincial Center for Medical Guideline Industry Technology/Evidence-based Medicine Center of Lanzhou University, was established to develop evidence-based guidelines. Clinical questions (7 background and 12 clinical questions) were identified through literature reviews and expert consensus meetings. Based on systematic reviews/meta-analyses, evidence quality was analyzed and the advantages and disadvantages of interventional measures were weighed with input from patients' preferences. Finally, 20 recommendations were developed through the Delphi-based consensus meetings. These recommendations included disease definitions, etiologies, pathogenesis, syndrome differentiation, diagnosis, and perioperative prevention and treatment.
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Enfermedades Gastrointestinales , Medicina Integrativa , Humanos , Medicina Tradicional China , Enfermedades Gastrointestinales/prevención & control , Medicina Basada en la EvidenciaAsunto(s)
Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular , Humanos , Datos de Salud Recolectados Rutinariamente , Accidente Cerebrovascular/epidemiología , Accidente Cerebrovascular/terapia , Isquemia Encefálica/terapia , China/epidemiología , Resultado del Tratamiento , TrombectomíaRESUMEN
Artificial cells are constructed from synthetic materials to imitate the biological functions of natural cells. By virtue of nanoengineering techniques, artificial cells with designed biomimetic functions provide alternatives to natural cells, showing vast potential for biomedical applications. Especially in cancer treatment, the deficiency of immunoactive macrophages results in tumor progression and immune resistance. To overcome the limitation, a BaSO4@ZIF-8/transferrin (TRF) nanomacrophage (NMΦ) is herein constructed as an alternative to immunoactive macrophages. Alike to natural immunoactive macrophages, NMΦ is stably retained in tumors through the specific affinity of TRF to tumor cells. Zn2+ as an "artificial cytokine" is then released from the ZIF-8 layer of NMΦ under tumor microenvironment. Similar as proinflammatory cytokines, Zn2+ can trigger cell anoikis to expose tumor antigens, which are selectively captured by the BaSO4 cavities. Therefore, the hierarchical nanostructure of NMΦs allows them to mediate immunogenic death of tumor cells and subsequent antigen capture for T cell activation to fabricate long-term antitumor immunity. As a proof-of-concept, the NMΦ mimics the biological functions of macrophage, including tumor residence, cytokine release, antigen capture and immune activation, which is hopeful to provide a paradigm for the design and biomedical applications of artificial cells.
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Dezocine is a partial mu opioid receptor agonist previously used as an analgesic for perioperative acute pain in the US and is now the most used perioperative analgesic in China. In general, dezocine is well-tolerated, with relatively minimal risk of fatal respiratory depression. To our knowledge, there are no reports of dezocine addiction, which suggests that the abuse liability of dezocine is low. The overarching goal of this study was to determine the efficacy of a novel formulation of dezocine (Cyc-dezocine), developed for intraperitoneal or intranasal administration, to reduce voluntary opioid taking in rats. One cohort of male rats self-administered intravenous oxycodone on a fixed-ratio 5 schedule of reinforcement. Once oxycodone taking stabilized, rats were pretreated with systemic injections of vehicle or Cyc-dezocine. Cyc-dezocine dose-dependently reduced intravenous oxycodone self-administration. A second cohort of male and female rats self-administered oral oxycodone from drinking water. Once oxycodone taking stabilized, rats were pretreated with intra-nasal Cyc-dezocine. Consistent with the effects of i.p. Cyc-dezocine in our intravenous oxycodone studies, intra-nasal Cyc-dezocine attenuated oral oxycodone self-administration. Together, these findings support the need for further studies investigating the therapeutic potential of Cyc-dezocine for treating opioid use disorder.
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Analgésicos Opioides , Oxicodona , Humanos , Ratas , Masculino , Femenino , Animales , Oxicodona/farmacología , Oxicodona/uso terapéutico , Tetrahidronaftalenos/farmacología , Analgésicos/farmacología , Relación Dosis-Respuesta a Droga , Receptores Opioides mu/agonistasRESUMEN
Reactive oxygen species (ROS)-involved tumor therapeutic strategy, chemodynamic therapy (CDT), has attracted extensive research interest in the scientific community. However, the therapeutic effect of CDT is insufficient and unsustainable owing to the limited endogenous H2 O2 level in the tumor microenvironment. Here, peroxidase (POD)-like RuTe2 nanozyme with the immobilization of glucose oxidase (GOx) and allochroic 3,3',5,5'-tetramethylbenzidine (TMB) molecule have been synthesized to construct RuTe2 -GOx-TMB nanoreactors (RGT NRs) as cascade reaction systems for tumor-specific and self-replenishing cancer therapy. GOx in sequential nanocatalysts can effectively deplete glucose in tumor cells. Meanwhile, a sustainable supply of H2 O2 for subsequent Fenton-like reactions catalyzed by RuTe2 nanozyme is achieved in response to the mild acidic tumor microenvironment. Through this cascade reaction, highly toxic hydroxyl radicals (·OH) are produced, which can further oxidize TMB to trigger tumor-specific "turn-on" photothermal therapy (PTT). In addition, PTT and massive ROS can stimulate the tumor immune microenvironment and activate the systematic anti-tumor immune responses, exerting a notable effect on hindering tumor recurrence and metastasis. This study paves a promising paradigm for synergistic starvation therapy, PTT, and CDT cancer therapy with high efficiency.
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Neoplasias , Humanos , Especies Reactivas de Oxígeno , Neoplasias/tratamiento farmacológico , Glucosa , Glucosa Oxidasa/uso terapéutico , Peroxidasa , Microambiente Tumoral , Peróxido de Hidrógeno , Línea Celular TumoralRESUMEN
Background: Stroke has been the leading cause of death in China for decades. The extremely low intravenous thrombolysis rate is largely due to the prehospital delays that make patients ineligible for the time-sensitive therapy. Limited studies evaluated prehospital delays across China. We investigated prehospital delays in the stroke population across China and the associated age, rurality, and geographic disparities. Methods: A cross-sectional study design was employed using the Bigdata Observatory platform for Stroke of China in 2020, the nationwide, prospective, multicentre registry of patients with acute ischaemic stroke (AIS). Mixed-effect regression models were used to account for the clustered data. Findings: The sample contained 78,389 AIS patients. The median onset-to-door (OTD) time was 24 h, with only 11.79% (95% confidence interval [CI]: 11.56-12.02%) patients arriving at hospitals within 3 h. About 12.43% (95% CI: 12.11-12.74%) of patients 65 years or older arrived at hospitals within 3 h, which was significantly higher than the young and middle-aged patients (11.03%; 95% CI: 10.71-11.36%). After controlling for potential confounders, young and middle-aged patients were less likely to present to hospitals within 3 h (adjusted odds ratio: 0.95; 95% CI: 0.90-0.99) compared to patients 65 years or older. The 3-h hospital arrival rate was the highest in Beijing (18.40%, 95% CI: 16.01-20.79%), which was almost 5 times higher than that in Gansu (3.45%, 95% CI: 2.69-4.20%). The arrival rate in urban areas was almost 2 times higher than that in rural areas (13.35% versus. 7.66%). Interpretation: We found that the low rates of timely arrival at hospitals after a stroke is more salient in the younger population, rural settings, or those residing in less developed geographic regions. This study calls for more tailored interventions focusing on younger people, rural areas, and less developed geographic regions. Funding: The National Natural Science Foundation of China; CIHR, Grant/Award Number: 81973157, PI: JZ. Natural Science Foundation of Shanghai; CIHR, Grant/Award Number: 17dz2308400, PI: JZ. Funding from the University of Pennsylvania; Grant/Award Number: CREF-030, PI: RL.
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BACKGROUND: Prehospital care including recognition of stroke symptoms by the public and professionals combined with an efficient and effective emergency medical service (EMS) is essential to increase access to effective acute stroke care. We undertook a survey to document the status of stroke prehospital care globally. METHODS: A survey was distributed via email to the World Stroke Organization (WSO) members. Information was sought on the current status of stroke prehospital delay globally, including (1) ambulance availability and whether payment for use is required, (2) ambulance response times and the proportion of patients arriving at hospital by ambulance, (3) the proportion of patients arriving within 3 h and more than 24 h after symptom, (4) whether stroke care training of paramedics, call handlers, and primary care staff, (5) availability of specialist centers, and (6) the proportion of patients taken to specialist centers. Respondents were also asked to identify the top three changes in prehospital care that would benefit their population. Data were analyzed descriptively at both country and continent level. RESULTS: Responses were received from 116 individuals in 43 countries, with a response rate of 4.7%. Most respondents (90%) reported access to ambulances, but 40% of respondents reported payment was required by the patient. Where an ambulance service was available (105 respondents) 37% of respondents reported that less than 50% of patients used an ambulance and 12% less than 20% of patients used an ambulance. Large variations in ambulance response times were reported both within and between countries. Most of the participating high-income countries (HIC) offered a service used by patients, but this was rarely the case for the low- and middle-income countries (LMIC). Time to admission was often much longer in LMIC, and there was less access to stroke training for EMS and primary care staff. CONCLUSIONS: Significant deficiencies in stroke prehospital care exist globally especially in LMIC. In all countries, there are opportunities to improve the quality of the service in ways that would likely result in improved outcomes after acute stroke.
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Servicios Médicos de Urgencia , Accidente Cerebrovascular , Humanos , Accidente Cerebrovascular/terapia , Accidente Cerebrovascular/diagnóstico , Ambulancias , Encuestas y Cuestionarios , HospitalesRESUMEN
Boron nitride nanoparticles have been reported for boron drug delivery. However, its toxicity has not been systematically elucidated. It is necessary to clarify their potential toxicity profile after administration for clinical application. Here, we prepared erythrocyte membrane-coated boron nitride nanoparticles (BN@RBCM). We expect to use them for boron neutron capture therapy (BNCT) in tumors. In this study, we evaluated the acute toxicity and subacute toxicity of BN@RBCM of about 100 nm and determined the half-lethal dose (LD50) of the particles for mice. The results showed that the LD50 of BN@RBCM was 258.94 mg/kg. No remarkable pathological changes by microscopic observation were observed in the treated animals throughout the study period. These results indicate that BN@RBCM has low toxicity and good biocompatibility, which have great potential for biomedical applications.
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Designing nanozymes that match natural enzymes have always been an attractive and challenging goal. In general, researchers mainly focus on the construction of metal centers and the control of non-metallic ligands of nanozyme to regulate their activities. However, this is not applicable to lactate oxidase, i.e., flavoenzymes with flavin mononucleotide (FMN)-dependent pathways. Herein, we propose a coordination strategy to mimic lactate oxidase based on engineering the electronic properties at the N center by modulating the Co number near N in the Cox-N nanocomposite. Benefitting from the manipulated coordination fields and electronic structure around the electron-rich N sites, Co4N/C possesses a precise recognition site for lactate and intermediate organization and optimizes the absorption energies for intermediates, leading to superior oxidation of the lactate α-C-sp(3)-H bond toward ketone. The optimized nanozyme delivers much improved anticancer efficacy by reversing the high lactate and the immunosuppressive state of the tumor microenvironment, subsequently achieving excellent tumor growth and distant metastasis inhibition. The developed Co4N/C NEs open a new window for building a bridge between chemical catalysis and biocatalysis.
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Ácido Láctico , Neoplasias , Humanos , Nitrógeno , Oxigenasas de Función Mixta/química , Neoplasias/tratamiento farmacológico , Catálisis , Microambiente TumoralRESUMEN
AIM: The aim of the study is to check whether dyngo-4a can inhibit neuroblastoma (NB) proliferation and induce NB cell differentiation Background: Dynamin plays a role in regulating neurotransmission, signaling pathways, nutrient uptake, and pathogen infection, enhancing cell proliferation, tumor invasion, and metastasis. Studies have reported that dyngo-4a, a dynamin inhibitor, can be used to identify potential biomarkers and promising novel therapeutic targets for cancer treatment. OBJECTIVE: To our knowledge, no published reports are showing that dynamin inhibitors can reduce NB cell proliferation and induce differentiation. In this study, we report that dyngo-4a can inhibit NB proliferation and induce NB cell differentiation. METHODS: In this study, mouse neuroblastoma (Neuro-2a) cells were cultured in the presence or absence of dyngo-4a or retinoic acid (RA), or in the presence of both dyngo-4a and RA, or in the presence of sequential administration of dyngo-4a and RA to compare the effects on the inhibition of cell proliferation and effects on neuroblastoma cell differentiation induction. The neural cell markers, Nestin and Tuj 1 (Neuron-specific class III beta-tubulin), were used to demonstrate that the differentiated cells have neuronal cell features. The phosphorylation of Protein Kinase B (AKT), extracellular signalregulated kinases1/2 (ERK1/2), and epidermal growth factor receptor (EGFR) were determined to examine the potential mechanisms of induced differentiation. RESULTS: Dyngo-4a or RA or dyngo-4a with subsequent RA administration induced Neuro-2a cell differentiation. However, RA with subsequent dyngo-4a administration results in almost total death of the Neuro-2a cells. The differentiation rate induced by dyngo-4a was significantly higher than the rate by RA treatment (72.5 ± 1.4% vs. 52.9 ± 3.1% with neuron features, P<0.05; 39.0 ± 0.8% vs. 29.9 ± 1.8% for axons under light microscopy, p<0.05). The differentiation rate of cells treated with dyngo-4a first, followed by RA, was greater than when they were added together (74.8 ± 3.8% vs. 10.6 ± 3.6%; 45.5 ± 1.6% vs. 12.4 ± 0.6%, p<0.01). Co-administration of dyngo-4a and RA at the same time diminished differentiation efficacy significantly. Dyngo-4a induced Neuro-2a cell differentiation and increased Tuj-1 positive staining by the 6th day post- treatment. Dyngo-4a also inhibited Neuro-2a cell proliferation in a dose-dependent manner. Regarding the mechanism, dyngo-4a treatment showed a significant increase in p-AKT and p-ERK1/2 but not in p-EGFR. CONCLUSION: At a level comparable to RA, dynamin inhibition with dyngo-4a lowers proliferation and causes differentiation of Neuro-2a mouse NB cells in vitro. The AKT pathway is activated by dynago- 4a, which results in differentiation. The combination of RA with dynago-4a reduces the efficiency of differentiation. The application of dynago-4a followed by RA, on the other hand, enhances the differentiating effect, implying alternative mechanistic roles in the process.
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Neuroblastoma , Proteínas Proto-Oncogénicas c-akt , Animales , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Sistema de Señalización de MAP Quinasas , Línea Celular Tumoral , Diferenciación Celular/fisiología , Neuroblastoma/patología , Tretinoina/metabolismo , Tretinoina/farmacología , Tretinoina/uso terapéutico , Receptores ErbB/metabolismo , Receptores ErbB/farmacología , Receptores ErbB/uso terapéuticoRESUMEN
Catalytic nanomedicine with the innate features of catalysts brings incomparable properties to biomedicine over traditional drugs. The temperature-dependent activity of catalysts provides catalytic nanomedicines with a facile strategy to control their therapeutic performance. Tuning catalytic nanomedicine by cold treatment (4-37 °C) is safe and desired for practical applications, but there is a lack of cold-catalytic platforms. Herein, with black phosphorus (BP) as a model pyroelectric nanocatalyst, we explored the potential of cold-catalysts for antitumor therapy. BP nanosheets with pyro-catalytic activity catalyze the generation of oxidative stress to activate antitumor immunity under cold treatment. Due to the cold-catalytic immunomodulation, immune memory was successfully achieved to prevent tumor metastasis and recurrence. Considering the safety and conductive depth (>10 mm) of cold in the body, pyroelectric nanocatalysts open up exciting opportunities for the development of cold-catalytic nanomedicine.