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Transient soluble oligomers of amyloid-ß (Aß) are toxic and accumulate early prior to insoluble plaque formation and cognitive impairment in Alzheimer's disease (AD). Synthetic cyclic D,L-α-peptides (e.g., 1) self-assemble into cross ß-sheet nanotubes, react with early Aß species (1-3 mers), and inhibit Aß aggregation and toxicity in stoichiometric concentrations, in vitro. Employing a semicarbazide as an aza-glycine residue with an extra hydrogen-bond donor to tune nanotube assembly and amyloid engagement, [azaGly6]-1 inhibited Aß aggregation and toxicity at substoichiometric concentrations. High-resolution NMR studies revealed dynamic interactions between [azaGly6]-1 and Aß42 residues F19 and F20, which are pivotal for early dimerization and aggregation. In an AD mouse model, brain positron emission tomography (PET) imaging using stable 64Cu-labeled (aza)peptide tracers gave unprecedented early amyloid detection in 44-d presymptomatic animals. No tracer accumulation was detected in the cortex and hippocampus of 44-d-old 5xFAD mice; instead, intense PET signal was observed in the thalamus, from where Aß oligomers may spread to other brain parts with disease progression. Compared with standard 11C-labeled Pittsburgh compound-B (11C-PIB), which binds specifically fibrillar Aß plaques, 64Cu-labeled (aza)peptide gave superior contrast and uptake in young mouse brain correlating with Aß oligomer levels. Effectively crossing the blood-brain barrier (BBB), peptide 1 and [azaGly6]-1 reduced Aß oligomer levels, prolonged lifespan of AD transgenic Caenorhabditis elegans, and abated memory and behavioral deficits in nematode and murine AD models. Cyclic (aza)peptides offer novel promise for early AD diagnosis and therapy.
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Enfermedad de Alzheimer , Amiloidosis , Animales , Ratones , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Diagnóstico Precoz , Péptidos beta-Amiloides , Placa Amiloide , Proteínas AmiloidogénicasRESUMEN
BACKGROUND AND AIM: Flexible sigmoidoscopy (FS) without analgesia or sedation can be unpleasant for patients, resulting in unsatisfactory examinations. Prior familiarization videos (FVs) and intra-procedural Entonox inhalation have shown inconsistent effects. This study investigated their effects on undesirable participant factors (anxiety, stress, discomfort, pain, satisfaction, later unpleasant recall of procedure, and vasovagal reactions) and clinical effectiveness (extent of bowel seen, lesions detected, and procedural/recovery times). METHODS: This cluster-randomized single-center study evaluated 138 participants undergoing FS. There were 46 controls, 49 given access to FV, and 43 access to both FV and self-administered Entonox. Participant factors were measured by self-administered questionnaires, independent nurse assessments, and heart rate variability (HRV) metrics. RESULTS: Questionnaires showed that the FV group was slightly more tense and upset before FS, but knowledge of Entonox availability reduced anxiety. Nonlinear HRV metrics confirmed reduced intra-procedural stress response in the FV/Entonox group compared with controls and FV alone (P < 0.05). Entonox availability allowed more bowel to be examined (P < 0.001) but increased procedure time (P < 0.05), while FV alone had no effect. FV/Entonox participants reported 1 month after FS less discomfort during the procedure. Other comparisons showed no significant differences between treatment groups, although one HRV metric showed some potential to predict vasovagal reactions. CONCLUSIONS: Entonox availability significantly improved clinical effectiveness and caused a slight reduction in undesirable participant factors. The FV alone did not reduce undesirable participant factors or improve clinical effectiveness. Nonlinear HRV metrics recorded effects in agreement with stress reduction and may be useful for prediction of vasovagal events in future studies.
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Óxido Nitroso , Oxígeno , Sigmoidoscopía , Humanos , Analgesia , Dolor/etiología , Sigmoidoscopía/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: There are no previous studies in which computer-aided diagnosis (CAD) diagnosed colorectal cancer (CRC) subtypes correctly. In this study, we developed an original CAD for the diagnosis of CRC subtypes. METHODS: Pretraining for the CAD based on ResNet was performed using ImageNet and five open histopathological pretraining image datasets (HiPreD) containing 3 million images. In addition, sparse attention was introduced to improve the CAD compared to other attention networks. One thousand and seventy-two histopathological images from 29 early CRC cases at Kyoto Prefectural University of Medicine from 2019 to 2022 were collected (857 images for training and validation, 215 images for test). All images were annotated by a qualified histopathologist for segmentation of normal mucosa, adenoma, pure well-differentiated adenocarcinoma (PWDA), and moderately/poorly differentiated adenocarcinoma (MPDA). Diagnostic ability including dice sufficient coefficient (DSC) and diagnostic accuracy were evaluated. RESULTS: Our original CAD, named Colon-seg, with the pretraining of both HiPreD and ImageNET showed a better DSC (88.4%) compared to CAD without both pretraining (76.8%). Regarding the attentional mechanism, Colon-seg with sparse attention showed a better DSC (88.4%) compared to other attentional mechanisms (dual: 79.7%, ECA: 80.7%, shuffle: 84.7%, SK: 86.9%). In addition, the DSC of Colon-seg (88.4%) was better than other types of CADs (TransUNet: 84.7%, MultiResUnet: 86.1%, Unet++: 86.7%). The diagnostic accuracy of Colon-seg for each histopathological type was 94.3% for adenoma, 91.8% for PWDA, and 92.8% for MPDA. CONCLUSION: A deep learning-based CAD for CRC subtype differentiation was developed with pretraining and fine-tuning of abundant histopathological images.
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BACKGROUND: Reprogrammed metabolic network is a key hallmark of cancer. Profiling cancer metabolic alterations with spatial signatures not only provides clues for understanding cancer biochemical heterogeneity, but also helps to decipher the possible roles of metabolic reprogramming in cancer development. METHODS: Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) technique was used to characterize the expressions of fatty acids in breast cancer tissues. Specific immunofluorescence staining was further carried out to investigate the expressions of fatty acid synthesis-related enzymes. RESULTS: The distributions of 23 fatty acids in breast cancer tissues have been mapped, and the levels of most fatty acids in cancer tissues are significantly higher than those in adjacent normal tissues. Two metabolic enzymes, fatty acid synthase (FASN) and acetyl CoA carboxylase (ACC), which being involved in the de novo synthesis of fatty acid were found to be up-regulated in breast cancer. Targeting the up-regulation of FASN and ACC is an effective approach to limiting the growth, proliferation, and metastasis of breast cancer cells. CONCLUSIONS: These spatially resolved findings enhance our understanding of cancer metabolic reprogramming and give an insight into the exploration of metabolic vulnerabilities for better cancer treatment.
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INTRODUCTION: Fetal surgical anomalies cause significant anxiety. Following the diagnosis, prenatal counseling with shared decision-making occurs. Empowerment is an essential component of shared decision-making. The purpose of this mixed-methods study was to evaluate the association between patient empowerment with depression and anxiety among patients with fetal surgical anomalies. METHODS: An explanatory mixed-methods study was conducted at a large tertiary fetal center among patients with recently diagnosed surgical fetal anomalies from May, 2021 to May, 2022. Validated cross-sectional surveys were used to collect quantitative data regarding patient empowerment, depression, and anxiety. Univariate analysis was used to compare the association of maternal empowerment with depression and anxiety. Qualitative data was obtained from semistructured interviews to explore maternal anxiety and depression relative to the fetal diagnosis. Thematic analysis was performed to identify themes. RESULTS: Seventy-four patients were recruited for the quantitative study. Pregnancy-related empowerment score and patient empowerment score were significantly lower for expectant mothers with high anxiety (P < 0.01). Eighteen patients participated in qualitative interviews. Participants expressed significant anxiety related to their fetal diagnosis. Exacerbating stressors included social determinants, personal history of miscarriage, and changing family dynamics. CONCLUSION: Our results suggest there is an association between increased depression and anxiety with lower empowerment. These findings have important implications for prenatal counseling, as targeted interventions to improve psychosocial support to treat depression and anxiety might also improve empowerment.
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During the past decade, the outcomes of pediatric patients with acute myeloid leukemia (AML) have plateaued with 5-year event-free survival (EFS) and overall survival (OS) of approximately 46 and 64%, respectively. Outcomes are particularly poor for those children with high-risk disease, who have 5-year OS of 46%. Substantial survival improvements have been observed for a subset of patients treated with targeted therapies. Specifically, children with KMT2A-rearranged AML and/or FLT3 internal tandem duplication (FLT3-ITD) mutations benefitted from the addition of gemtuzumab ozogamicin, an anti-CD33 antibody-drug conjugate, in the AAML0531 clinical trial (NCT00372593). Sorafenib also improved response and survival in children with FLT3-ITD AML in the AAML1031 clinical trial (NCT01371981). Advances in characterization of prognostic cytomolecular events have helped to identify patients at highest risk of relapse and facilitated allocation to consolidative hematopoietic stem cell transplant (HSCT) in first remission. Some patients clearly have improved survival with HSCT, although the benefit is largely unknown for most patients. Finally, data-driven refinements in supportive care recommendations continue to evolve with meaningful and measurable reductions in toxicity and improvements in EFS and OS. As advances in application of targeted therapies, risk stratification, and improved supportive care measures are incorporated into current trials and become standard-of-care, there is every expectation that we will see improved survival with a reduction in toxic morbidity and mortality. The research agenda of the Children's Oncology Group's Myeloid Diseases Committee continues to build upon experience and outcomes with an overarching goal of curing more children with AML.
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Antineoplásicos , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Humanos , Niño , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Pronóstico , Sorafenib/uso terapéutico , Antineoplásicos/uso terapéutico , Gemtuzumab/uso terapéutico , Mutación , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
Nanozymes, which combine enzyme-like catalytic activity and the biological properties of nanomaterials, have been widely used in biomedical fields. Single-atom nanozymes (SANs) with atomically dispersed metal centers exhibit excellent biological catalytic activity due to the maximization of atomic utilization efficiency, unique metal coordination structures, and metal-support interaction, and their structure-activity relationship can also be clearly investigated. Therefore, they have become an emerging alternative to natural enzymes. This review summarizes the examples of nanocatalytic therapy based on SANs in tumor diagnosis and treatment in recent years, providing an overview of material classification, activity modulation, and therapeutic means. Next, we will delve into the therapeutic mechanism of SNAs in the tumor microenvironment and the advantages of synergistic multiple therapeutic modalities (e.g., chemodynamic therapy, sonodynamic therapy, photothermal therapy, chemotherapy, photodynamic therapy, sonothermal therapy, and gas therapy). Finally, this review proposes the main challenges and prospects for the future development of SANs in cancer diagnosis and therapy.
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Nanoestructuras , Neoplasias , Fotoquimioterapia , Humanos , Nanoestructuras/uso terapéutico , Nanoestructuras/química , Metales , Relación Estructura-Actividad , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Catálisis , Microambiente TumoralRESUMEN
OBJECTIVE: To evaluate the utility of prenatal exome sequencing (ES) for isolated increased nuchal translucency (NT) and to investigate factors that increase diagnostic yield. DESIGN: Retrospective analysis of data from two prospective cohort studies. SETTING: Fetal medicine centres in the UK and USA. POPULATION: Fetuses with increased NT ≥3.5 mm at 11-14 weeks of gestation recruited to the Prenatal Assessment of Genomes and Exomes (PAGE) and Columbia fetal whole exome sequencing studies (n = 213). METHODS: We grouped cases based on (1) the presence of additional structural abnormalities at presentation in the first trimester or later in pregnancy, and (2) NT measurement at presentation. We compared diagnostic rates between groups using Fisher exact test. MAIN OUTCOME MEASURES: Detection of diagnostic genetic variants considered to have caused the observed fetal structural anomaly. RESULTS: Diagnostic variants were detected in 12 (22.2%) of 54 fetuses presenting with non-isolated increased NT, 12 (32.4%) of 37 fetuses with isolated increased NT in the first trimester and additional abnormalities later in pregnancy, and 2 (1.8%) of 111 fetuses with isolated increased NT in the first trimester and no other abnormalities on subsequent scans. Diagnostic rate also increased with increasing size of NT. CONCLUSIONS: The diagnostic yield of prenatal ES is low for fetuses with isolated increased NT but significantly higher where there are additional structural anomalies. Prenatal ES may not be appropriate for truly isolated increased NT but timely, careful ultrasound scanning to identify other anomalies emerging later can direct testing to focus where there is a higher likelihood of diagnosis.
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Secuenciación del Exoma , Medida de Translucencia Nucal , Diagnóstico Prenatal , Trisomía/diagnóstico , Adulto , Estudios de Cohortes , Femenino , Humanos , Valor Predictivo de las Pruebas , Embarazo , Primer Trimestre del Embarazo , Estudios Prospectivos , Estudios Retrospectivos , Trisomía/genética , Ultrasonografía Prenatal , Reino Unido , Estados UnidosRESUMEN
The microbiome has revolutionized the field of cancer immunology and checkpoint therapeutics for gastrointestinal malignancies. Combating hepatocellular carcinoma (HCC) by immune checkpoint blockade (ICB) is a unique challenge due in part to chronic complications that arise from local and systemic metabolic dysfunctions. Gut microbial metabolites modulate key immunological processes that influence liver cancer susceptibility and resistance to ICB. This review discusses recent progresses in linking microbiota functions to HCC tumor immunity and highlights their therapeutic potential.
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Carcinoma Hepatocelular , Inmunoterapia , Neoplasias Hepáticas , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/terapia , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/terapia , Microbiota/fisiologíaRESUMEN
Tumor-targeted near-infrared (NIR) fluorescence imaging by using NIR fluorescent probes has attracted extensive attentions in the field of tumor imaging and is becoming an attractive strategy for early cancer diagnosis and surgical guidance for the past few decades. Especially, due to the high affinity and low toxicity, the peptide-based NIR fluorescent probes play an important role in the field of tumor-targeted imaging and therapy. Extensive attempts have been made to develop a set of nontoxic and efficacious "always-on" peptide-based NIR fluorescent probes. In this review, we give a comprehensive analysis of the "always-on" peptide-based NIR fluorescent probes for tumor-targeting for the past 5 years, highlighting the design strategy, chemical synthesis, therapeutical applications, spectroscopic and pharmacological characterization, as well as the multifaceted roles of peptides. A comprehensive understanding of the tumor-targeted, "always-on" peptide-based NIR fluorescent probes will increase our knowledge of cancer diagnosis and benefit clinical cancer therapeutics.
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Colorantes Fluorescentes , Neoplasias , Humanos , Colorantes Fluorescentes/química , Espectroscopía Infrarroja Corta/métodos , Imagen Óptica/métodos , Neoplasias/diagnóstico por imagen , Péptidos/químicaRESUMEN
Metabolic diseases are broadly defined as diseases caused by problems in metabolic function, including central obesity, insulin resistance, lipid glucose abnormalities, and elevated blood pressure. As an important metabolic organ, the liver plays a key role in regulating many physiological processes such as systemic glucose and lipid metabolism. Numerous studies in recent years have shown that the liver can synthesize and secrete a variety of hepatokines, including FGF21, Fetuin-A and ANGPTL8, which regulate the metabolism in an autocrine/paracrine manner. Intervention of hepatokines expression may contribute to the prevention, diagnosis and treatment of metabolic diseases. However, further studies are needed to be investigated as the mechanism of hepatokines and metabolic homeostasis is still elusive. In this review, we summarize the relationships between hepatokines and metabolic diseases in order to provide new strategies for the treatment of metabolic diseases.
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Resistencia a la Insulina , Enfermedades Metabólicas , Hormonas Peptídicas , Humanos , Enfermedades Metabólicas/metabolismo , Resistencia a la Insulina/fisiología , Hígado/metabolismo , Obesidad , Glucosa/metabolismo , Proteínas Similares a la Angiopoyetina/metabolismo , Hormonas Peptídicas/metabolismoRESUMEN
Lung cancer is the leading cause of cancer death in both males and females in the U.S. and worldwide. Owing to advances in prevention, screening/early detection, and therapy, lung cancer mortality rates are decreasing and survival rates are increasing. These innovations are based on scientific discoveries in imaging, diagnostics, genomics, molecular therapy, and immunotherapy. Outcomes have improved in all histologies and stages. This review provides information on the clinical implications of these innovations that are practical for the practicing physicians, especially oncologists of all specialities who diagnose and treat patients with lung cancer. IMPLICATIONS FOR PRACTICE: Lung cancer survival rates have improved because of new prevention, screening, and therapy methods. This work provides a review of current standards for each of these areas, including targeted and immunotherapies. Treatment recommendations are provided for all stages of lung cancer.
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Neoplasias Pulmonares , Femenino , Genómica , Humanos , Inmunoterapia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/terapia , Masculino , Tamizaje Masivo , Tasa de SupervivenciaRESUMEN
Conjugated polymers (CPs) are capable of coordinating the electron coupling phenomenon to bestow powerful optoelectronic features. The light-harvesting and light-amplifying properties of CPs are extensively used in figuring out the biomedical issues with special emphasis on accurate diagnosis, effective treatment, and precise theranostics. This review summarizes the recent progress of CP materials in bioimaging, cancer therapeutics, and introduces the design strategies by rationally tuning the optical properties. The recent advances of CPs in bioimaging applications are first summarized and the challenges to clear the future directions of CPs in the respective area are discussed. In the following sections, the focus is on the burgeoning applications of CPs in phototherapy of the tumor, and illustrates the underlying photo-transforming mechanism for further molecular designing. Besides, the recent progress in the CPs-assistant drug therapy, mainly including drug delivery, gene therapeutic, the optical-activated reversion of tumor resistance, and synergistic therapy has also been discussed elaborately. In the end, the potential challenges and future developments of CPs on cancer diagnosis and therapy are also illuminated for the improvement of optical functionalization and the promotion of clinical translation.
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Nanopartículas , Neoplasias , Humanos , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , Fototerapia , Polímeros , Nanomedicina TeranósticaRESUMEN
Serious bacterial infections (SBI) can lead to devastating complications with CD19 CAR T cells and cytokine release syndrome (CRS). Little is known about consequences of and risk factors for SBI with novel CAR T-cell constructs or with CRS complicated by HLH-like toxicities. We report on three patients with B-cell acute lymphoblastic leukemia treated with CD22 CAR T cells who developed SBI and CRS-associated HLH. Serum cytokine profiling revealed sustained elevations well beyond CRS resolution, suggesting ongoing systemic inflammation. Heightened inflammatory states converging with SBI contribute to poor outcomes, and recognition and prevention of extended inflammation may be needed to improve outcomes.
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Bacteriemia , Síndrome de Liberación de Citoquinas , Linfohistiocitosis Hemofagocítica , Antígenos CD19 , Bacteriemia/inmunología , Bacteriemia/microbiología , Síndrome de Liberación de Citoquinas/inmunología , Humanos , Inmunoterapia Adoptiva , Linfohistiocitosis Hemofagocítica/inmunología , Linfohistiocitosis Hemofagocítica/microbiología , Receptores Quiméricos de Antígenos , Linfocitos TRESUMEN
BACKGROUND/OBJECTIVES: While outcomes for pediatric T-cell acute lymphoblastic leukemia (T-ALL) are favorable, there are few widely accepted prognostic factors, limiting the ability to risk stratify therapy. DESIGN/METHODS: Dana-Farber Cancer Institute (DFCI) Protocols 05-001 and 11-001 enrolled pediatric patients with newly diagnosed B- or T-ALL from 2005 to 2011 and from 2012 to 2015, respectively. Protocol therapy was nearly identical for patients with T-ALL (N = 123), who were all initially assigned to the high-risk arm. End-induction minimal residual disease (MRD) was assessed by reverse transcription polymerase chain reaction (RT-PCR) or next-generation sequencing (NGS), but was not used to modify postinduction therapy. Early T-cell precursor (ETP) status was determined by flow cytometry. Cases with sufficient diagnostic DNA were retrospectively evaluated by targeted NGS of known genetic drivers of T-ALL, including Notch, PI3K, and Ras pathway genes. RESULTS: The 5-year event-free survival (EFS) and overall survival (OS) for patients with T-ALL was 81% (95% CI, 73-87%) and 90% (95% CI, 83-94%), respectively. ETP phenotype was associated with failure to achieve complete remission, but not with inferior OS. Low end-induction MRD (<10-4 ) was associated with superior disease-free survival (DFS). Pathogenic mutations of the PI3K pathway were mutually exclusive of ETP phenotype and were associated with inferior 5-year DFS and OS. CONCLUSIONS: Together, our findings demonstrate that ETP phenotype, end-induction MRD, and PI3K pathway mutation status are prognostically relevant in pediatric T-ALL and should be considered for risk classification in future trials. DFCI Protocols 05-001 and 11-001 are registered at www.clinicaltrials.gov as NCT00165087 and NCT01574274, respectively.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasia Residual/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Adolescente , Adulto , Niño , Preescolar , Ensayos Clínicos Fase III como Asunto , Femenino , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Masculino , Neoplasia Residual/tratamiento farmacológico , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third most common cause of cancer-related death. Long-term prognosis remains poor with treatment options frequently limited by advanced tumor stage, tumor location, or underlying liver dysfunction. Stereotactic ablative body radiotherapy (SABR) utilizes technological advances to deliver highly precise, tumoricidal doses of radiation. There is an emerging body of literature on SABR in HCC demonstrating high rates of local control in the order of 80-90% at 3 years. SABR is associated with a low risk of radiation-induced liver disease or decompensation in appropriately selected HCC patients with compensated liver function and is now being incorporated into guidelines as an additional treatment option. This review outlines the emerging role of SABR in the multidisciplinary management of HCC and summarizes the current evidence for its use as an alternative ablative option for early-stage disease, as a bridge to transplant, and as palliation for advanced-stage disease. We outline specific considerations regarding patient selection, toxicities, and response assessment. Finally, we compare current international guidelines and recommendations for the use of SABR and summarize ongoing studies.
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Carcinoma Hepatocelular/radioterapia , Neoplasias Hepáticas/radioterapia , Radiocirugia/métodos , Carcinoma Hepatocelular/patología , Terapia Combinada , Femenino , Humanos , Neoplasias Hepáticas/patología , Masculino , Estadificación de Neoplasias , Selección de Paciente , Guías de Práctica Clínica como Asunto , Traumatismos por Radiación/etiología , Traumatismos por Radiación/prevención & control , Radiocirugia/efectos adversos , Dosificación RadioterapéuticaRESUMEN
Cardiovascular diseases (CVDs) are the leading cause of death worldwide, causing approximately 17.9 million deaths annually, an estimated 31% of all deaths, according to the WHO. CVDs are essentially rooted in atherosclerosis and are clinically classified into coronary heart disease, stroke and peripheral vascular disorders. Current clinical interventions include early diagnosis, the insertion of stents, and long-term preventive therapy. However, clinical diagnostic and therapeutic tools are subject to a number of limitations including, but not limited to, potential toxicity induced by contrast agents and unexpected bleeding caused by anti-platelet drugs. Nanomedicine has achieved great advancements in biomedical area. Among them, cell membrane coated nanoparticles, denoted as CMCNPs, have acquired enormous expectations due to their biomimetic properties. Such membrane coating technology not only helps avoid immune clearance, but also endows nanoparticles with diverse cellular and functional mimicry. In this review, we will describe the superiorities of CMCNPs in treating cardiovascular diseases and their potentials in optimizing current clinical managements.
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Materiales Biomiméticos/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Membrana Celular/química , Materiales Biomiméticos/síntesis química , Materiales Biomiméticos/química , Sistemas de Liberación de Medicamentos , Humanos , NanopartículasRESUMEN
(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA5m.SA.KuE was synthesized successfully. AAZTA5.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA5m.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [68Ga]Ga-DATA5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA5.SA.KuE and DATA5m.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [177Lu]Lu-AAZTA5.SA.KuE, [44Sc]Sc-AAZTA5.SA.KuE and [68Ga]Ga-DATA5m.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.
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Antígenos de Superficie/química , Quelantes/química , Glutamato Carboxipeptidasa II/química , Radiofármacos/química , Animales , Quelantes/síntesis química , Técnicas de Química Sintética , Diagnóstico por Imagen/métodos , Modelos Animales de Enfermedad , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Xenoinjertos , Humanos , Marcaje Isotópico , Cinética , Ratones , Estructura Molecular , Neoplasias/diagnóstico por imagen , Neoplasias/etiología , Unión Proteica , Radiofármacos/síntesis química , Investigación Biomédica TraslacionalRESUMEN
CONTEXT: Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% event-free survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment. METHODS: Eight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m² on days 1, 4, 7, associated with cytarabine 2000 mg/m² and fludarabin 30 mg/m² on days 1 to 5. RESULTS: Six patients achieved complete remission (CR) (blast count morphology ≤5 × 10-2 , CR-MRD flow <1 × 10-3 for four patients). Five patients received a second course. We observed 11 episodes of febrile neutropenia, including 6 septicemias without complication. There was no fungal infection or toxic death. Two patients received granulocyte colony stimulating factor. One patient had partial platelet recovery; one, prolonged pancytopenia. All patients received hematopoietic stem cell transplantation (HSCT). We observed five mild-to-severe sinusoidal obstruction syndromes during HSCT procedures, particularly in patients who did not receive defibrotide prophylaxis. At the date of last contact (median follow-up: 58 months; range: 22-78), six patients were in continuous CR with negative MRD. Two patients died of post-HSCT relapse. CONCLUSION: FLA-GO is a good salvage regimen for pediatric refractory AML, with significant but acceptable toxicity. HSCT is mandatory to achieve sustained CR in these patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Trasplante de Células Madre Hematopoyéticas/mortalidad , Leucemia Mieloide Aguda/terapia , Recurrencia Local de Neoplasia/terapia , Terapia Recuperativa , Adolescente , Niño , Terapia Combinada , Citarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Gemtuzumab/administración & dosificación , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Recurrencia Local de Neoplasia/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Vidarabina/administración & dosificación , Vidarabina/análogos & derivadosRESUMEN
BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a rare lymphatic anomaly with significant morbidity and mortality. KLA is characterized by diffuse multifocal lesions comprised of focal areas of "kaposiform" spindled cells accompanying malformed lymphatic channels. The goal of this study was to identify activated signaling pathways in cells isolated from three KLA patients for the purpose of testing new therapies. PROCEDURE: Cells were obtained from the lungs of one patient isolated at autopsy and the spleen of two patients removed in surgery due to disease complications. A protein kinase array was performed on the KLA cell lysates and normal lymphatic endothelial cells. RESULTS: Higher activation of key signaling pathways in the KLA cells, including PRAS40, AKT1/2/3, and ERK-1/2, was identified by protein kinase array and confirmed by Western blot analysis. This indicated a role for highly activated PI3K-AKT and MAPK-ERK-1/2 signaling pathways in KLA cells. Cell proliferation studies assessed PI3K inhibitors (LY294002; BYL719), AKT inhibitor ARQ092, mTOR inhibitor rapamycin, and MAPK inhibitor U0126. These studies demonstrated that PI3K-AKT-mTOR and MAPK signaling are important mediators of KLA cell proliferation. BYL719 and rapamycin were more effective at inhibiting KLA cell proliferation than U0126. CONCLUSIONS: Our studies using cells from KLA patient lesions demonstrate that these cells are highly proliferative and the PI3K-AKT-mTOR and MAPK pathways are promising therapeutic targets. Development and clinical trials of PI3K, AKT, and MAPK inhibitors for cancer treatment and the data in this study lend support for early clinical trials assessing the efficacy of these inhibitors in KLA patients.