RESUMEN
Virus entry inhibitors are emerging as an attractive class of therapeutics for the suppression of viral transmission. Naturally occurring pradimicin A (PRM-A) has received particular attention as the first-in-class entry inhibitor that targets N-glycans present on viral surface. Despite the uniqueness of its glycan-targeted antiviral activity, there is still limited knowledge regarding how PRM-A binds to viral N-glycans. Therefore, in this study, we performed binding analysis of PRM-A with synthetic oligosaccharides that reflect the structural motifs characteristic of viral N-glycans. Binding assays and molecular modeling collectively suggest that PRM-A preferentially binds to branched oligomannose motifs of N-glycans via simultaneous recognition of two mannose residues at the non-reducing ends. We also demonstrated, for the first time, that PRM-A can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vitro. Significantly, the anti-SARS-CoV-2 effect of PRM-A is attenuated in the presence of the synthetic branched oligomannose, suggesting that the inhibition of SARS-CoV-2 infection is due to the interaction of PRM-A with the branched oligomannose-containing N-glycans. These data provide essential information needed to understand the antiviral mechanism of PRM-A and suggest that PRM-A could serve as a candidate SARS-CoV-2 entry inhibitor targeting N-glycans.
Asunto(s)
Antivirales , Polisacáridos , Pradimicinas y Benanomicinas , SARS-CoV-2 , Internalización del Virus , SARS-CoV-2/efectos de los fármacos , Polisacáridos/química , Polisacáridos/farmacología , Antivirales/farmacología , Antivirales/química , Antivirales/síntesis química , Humanos , Internalización del Virus/efectos de los fármacos , Tratamiento Farmacológico de COVID-19 , COVID-19/virología , Chlorocebus aethiops , Animales , Células VeroRESUMEN
The relevance of oligodendroglial histological features to patient prognoses is controversial. 93 LrGGs resected for about 2 decades were re-assessed based on WHO2007 with special interest to pure oligodendroglial diagnosis (oligodendroglioma or anaplastic oligodendroglioma) and presence of CFO features. Those histological features, patients OS, and tumor chromosomal/genetic characteristics were correlated each other in each of the 3 IDH-1p/19q-based molecular groups. There was significant association between 1p19q status with the oligodendroglial histological diagnosis as well as presence of CFO in the entire cohort. The oligodendroglial diagnosis was associated with longer OS in IDHmut/codel group; however, this association was not significant in the multivariate analyses. In IDHmut/noncodel and IDH-wildtype groups, the oligodendroglial diagnosis was not associated with patient OS. Presence of CFO was not associated with patient OS in any molecular groups. Gain of 8q was associated with the oligodendroglial diagnosis in IDHmut/noncodel group. Neither the oligodendroglial diagnosis nor CFO was predictive for the methylation status of the MGMT gene in any molecular groups. The oligodendroglial histological features are not independently predictive of either patient prognosis or chemotherapeutic response in LrGGs, leaving the possibility of marginal favorable association only in IDHmut/codel tumors.
Asunto(s)
Neoplasias Encefálicas , Glioma , Oligodendroglioma , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/terapia , Cromosomas Humanos Par 1/genética , Cromosomas Humanos Par 19/genética , Glioma/genética , Glioma/patología , Glioma/terapia , Humanos , Isocitrato Deshidrogenasa/genética , Mutación , Oligodendroglioma/genética , Oligodendroglioma/patología , PronósticoRESUMEN
Pradimicins (PRMs) are an exceptional family of natural products that specifically bind d-mannose (Man). In the past decade, their scientific significance has increased greatly, with the emergence of biological roles of Man-containing glycans. However, research into the use of PRMs has been severely limited by their inherent tendency to form water-insoluble aggregates. Recently, we have established a derivatization strategy to suppress PRM aggregation, providing an opportunity for practical application of PRMs in glycobiological research. This article first outlines the challenges in studying Man-binding mechanisms and structural modifications of PRMs, and then describes our approach to address them. We also present our recent attempts toward the development of PRM-based research tools.
Asunto(s)
Manosa/metabolismo , Antraciclinas , Productos Biológicos , HumanosRESUMEN
Pradimicin A (PRM-A) and related compounds constitute an exceptional family of natural pigments that show Ca2+-dependent recognition of d-mannose (Man). Although these compounds hold great promise as research tools in glycobiology, their practical application has been severely limited by their inherent tendency to form water-insoluble aggregates. Here, we demonstrate that the 2-hydroxyethylamide derivative (PRM-EA) of PRM-A shows little aggregation in neutral aqueous media and retains binding specificity for Man. We also show that PRM-EA stains glycoproteins in dot blot assays, whereas PRM-A fails to do so, owing to severe aggregation. Significantly, PRM-EA is sensitive to glycoproteins carrying high mannose-type and hybrid-type N-linked glycans, but not to those carrying complex-type N-linked glycans. Such staining selectivity has never been observed in conventional dyes, suggesting that PRM-EA could serve as a unique staining agent for the selective detection of glycoproteins with terminal Man residues.
Asunto(s)
Antraciclinas/química , Colorantes/química , Glicoproteínas/análisis , Manosa/química , Estructura Molecular , Coloración y EtiquetadoRESUMEN
OBJECTIVE: As chemotherapy and radiotherapy have developed, the role of a neurosurgeon in the treatment of metastatic brain tumors is gradually changing. Real-time intraoperative visualization of brain tumors by near-infrared spectroscopy (NIRS) is feasible. The authors aimed to perform real-time intraoperative visualization of the metastatic tumor in brain surgery using second-window indocyanine green (SWIG) with microscope and exoscope systems. METHODS: Ten patients with intraparenchymal brain metastatic tumors were administered 5 mg/kg indocyanine green (ICG) 1 day before the surgery. In some patients, a microscope was used to help identify the metastases, whereas in the others, an exoscope was used. RESULTS: NIRS with the exoscope and microscope revealed the tumor location from the brain surface and the tumor itself in all 10 patients. The NIR signal could be detected though the normal brain parenchyma up to 20 mm. While the mean signal-to-background ratio (SBR) from the brain surface was 1.82 ± 1.30, it was 3.35 ± 1.76 from the tumor. The SBR of the tumor (p = 0.030) and the ratio of Gd-enhanced T1 tumor signal to normal brain (T1BR) (p = 0.0040) were significantly correlated with the tumor diameter. The SBR of the tumor was also correlated with the T1BR (p = 0.0020). The tumor was completely removed in 9 of the 10 patients, as confirmed by postoperative Gd-enhanced MRI. This was concomitant with the absence of NIR fluorescence at the end of surgery. CONCLUSIONS: SWIG reveals the metastatic tumor location from the brain surface with both the microscope and exoscope systems. The Gd-enhanced T1 tumor signal may predict the NIR signal of the metastatic tumor, thus facilitating tumor resection.
Asunto(s)
Neoplasias Encefálicas , Imagen Óptica , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Humanos , Verde de Indocianina , Imagen por Resonancia Magnética , Espectroscopía Infrarroja CortaRESUMEN
Pradimicin A (PRM-A) and its derivatives comprise a unique family of antibiotics that show antifungal, antiviral, and antiparasitic activities through binding to d-mannose (Man)-containing glycans of pathogenic species. Despite their great potential as drug leads with an exceptional antipathogenic action, therapeutic application of PRMs has been severely limited by their tendency to form water-insoluble aggregates. Recently, we found that attachment of 2-aminoethanol to the carboxy group of PRM-A via amide linkage significantly suppressed the aggregation. Here, we prepared additional amide derivatives (2-8) of PRM-A to examine the possibility that the amide formation of PRM-A could suppress its aggregation propensity. Sedimentation assay and isothermal titration calorimetry experiment confirmed that all amide derivatives can bind Man without significant aggregation. Among them, hydroxamic acid derivative (4) showed the most potent Man-binding activity, which was suggested to be derived from the anion formation of the hydroxamic acid moiety by molecular modeling. Derivative 4 also exhibited significant antifungal activity comparable to that of PRM-A. These results collectively indicate that amide formation of PRM-A is the promising strategy to develop less aggregative derivatives, and 4 could serve as a lead compound for exploring the therapeutic application of PRM-A.
RESUMEN
Pradimicins (PRMs) constitute an exceptional class of natural products that show Ca2+ -dependent recognition of d-mannose (Man). In addition to therapeutic uses as antifungal drugs, the application of PRMs as lectin mimics for glycobiological research has been attracting considerable interest, since the emerging biological roles of Man-containing glycans have been highlighted. However, only a few attempts have been made to use PRMs for glycobiological purposes. The limited use of PRMs is primarily due to the early assumption that the readily modifiable carboxyl group of PRMs is involved in Ca2+ binding, and thus, not available to prepare research tools. Recently, this assumption has been disproved by structural elucidation of the Ca2+ complex of PRMs, which paves the way for designing carboxyl group modified derivatives of PRMs for research use. This article outlines studies related to Ca2+ -mediated Man binding of PRMs and discusses their application for glycobiology.
Asunto(s)
Antraciclinas/química , Calcio/química , Complejos de Coordinación/química , Lectinas/química , Manosa/química , Antifúngicos/química , Antifúngicos/aislamiento & purificación , Antiparasitarios/química , Antiparasitarios/aislamiento & purificación , Antivirales/química , Antivirales/aislamiento & purificación , Sitios de Unión , Productos Biológicos/química , Conformación de Carbohidratos , Cationes Bivalentes , Glicómica/métodos , Glicómica/tendencias , Humanos , Imitación MolecularRESUMEN
Although promoter methylation status is known to correlate with response to alkylating agents, immunohistochemistry (IHC) is the only available method for MGMT status in many institutions. However, the clinical utility of MGMT IHC is controversial. A hundred and twenty four cases of primary glioblastoma diagnosed by morphology-based criteria over 2 decades were re-appraised based on WHO 2016 classification. Tumor MGMT status was evaluated by IHC and methylation-specific PCR (MSP) to see if any correlation between the results of the 2 methods. The association with patients' prognoses was also investigated. Among 124 cases, 116 were confirmed to be glioblastoma by definition of WHO2016, and median overall survival (OS) of glioblastoma, IDH-wildtype and epithelioid glioblastoma were 18 and 27â¯months, respectively. MGMT promoter methylation status significantly correlated with progression-free survival (PFS) (pâ¯=â¯0.014) but not with OS (pâ¯=â¯0.364) in patients with glioblastoma by the integrated diagnosis. With the cut-off value of 24.5% of positive cell ratio as determined by receiver operating characteristic (ROC) analysis, there was a good correlation between the results of IHC and MSP (pâ¯=â¯0.08â¯×â¯10-24). Accordingly, there was a marginal association between the results of IHC and patients' PFS (pâ¯=â¯0.063), but not OS (pâ¯=â¯0.563). When the patients were divided into pre and post temozolomide era, the association of MGMT promoter methylation status with PFS was only noted in the patients of temozolomide era (pre, pâ¯=â¯0.432; post, pâ¯=â¯0.015).
Asunto(s)
Biomarcadores de Tumor/genética , Neoplasias Encefálicas/diagnóstico , Metilación de ADN , Metilasas de Modificación del ADN/genética , Glioblastoma/patología , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias Encefálicas/genética , Metilasas de Modificación del ADN/metabolismo , Femenino , Glioblastoma/genética , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Regiones Promotoras Genéticas , Curva ROCRESUMEN
Quinocidin (QCD) is a cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium skeleton. We previously found that QCD captures thiols in neutral aqueous media via a Michael addition-type reaction. However, it remains unclear whether the Michael acceptor reactivity of QCD is responsible for its cytotoxicity. In this study, we synthesized thirteen analogs of QCD to examine the relationship among its structure, cytotoxicity, and reactivity toward thiols. Thiol-trapping experiments and cytotoxicity tests collectively suggested that the Michael acceptor function of QCD is independent of its cytotoxic activity, and that the pyridinium moiety with the hydrophobic side chain is a key structural factor for cytotoxicity. These findings further led us to demonstrate that incorporation of an amide group into the side chain of QCD significantly reduced its toxicity but hardly affected the Michael acceptor function. The present study lays the foundation for QCD-based drug design and highlights the potential of QCD as a unique electrophile for use in the development of covalent inhibitors and protein-labeling probes.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Quinolizinas/farmacología , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Estructura Molecular , Quinolizinas/síntesis química , Quinolizinas/química , Relación Estructura-ActividadRESUMEN
Naturally occurring pradimicins (PRMs) show specific recognition of d-mannose (d-Man) in aqueous media, which has never been achieved by artificial small molecules. Although the Ca2+-mediated dimerization of PRMs is essential for their d-Man binding, the dimeric structure has yet to be elucidated, leaving the question open as to how PRMs recognize d-Man. Thus, we herein report the structural elucidation of the dimer by a combination of X-ray crystallography and solid-state NMR spectroscopy. Coupled with our previous knowledge regarding the d-Man binding geometry of PRMs, elucidation of the dimer allowed reliable estimation of the mode of d-Man binding. Based on the binding model, we further developed an azide-functionalized PRM derivative (PRM-Azide) with d-Man binding specificity. Notably, PRM-Azide stained Candida rugosa cells having mannans on their cell surface through conjugation with the tetramethylrhodamine fluorophore. The present study provides the practical demonstration that PRMs can serve as lectin mimics for use in glycobiological studies.
Asunto(s)
Actinobacteria/ultraestructura , Antraciclinas/metabolismo , Manosa/metabolismo , Actinobacteria/metabolismo , Antraciclinas/química , Sitios de Unión , Membrana Celular , Cristalografía por Rayos X/métodos , Dimerización , Humanos , Espectroscopía de Resonancia MagnéticaRESUMEN
Acute infectious endocarditis (IE) is a complex disease that presents as a serious clinical condition associated with a high mortality rate, especially due to intracranial hemorrhaging (ICH). The most common causative organism is Staphylococcus aureus. We herein report a patient with ICH following subacute IE with a positive blood culture for Cardiobacterium hominis. A review of the existing literature revealed that acute IE associated with Cardiobacterium has been reported to cause ICH in only seven previous cases. Prolonged culture-specific antibiotic therapy along with extended surveillance of blood culture is therefore essential for timely intervention.
Asunto(s)
Cardiobacterium , Endocarditis Bacteriana/complicaciones , Infecciones por Bacterias Gramnegativas/complicaciones , Hemorragias Intracraneales/microbiología , Adulto , Antibacterianos/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Cerebral vasospasm is an uncontrollable and sometimes fatal complication occurring after subarachnoid hemorrhage. However, cerebral hyperperfusion syndrome is a rare complication after subarachnoid hemorrhage. Although plain computed tomography of cerebral hyperperfusion syndrome looks similar to cerebral infarction induced by cerebral vasospasm, they should be distinguished from each other because they require completely different treatments. CASE DESCRIPTION: A 65-year-old man complained of severe headache and vomiting. A computed tomography scan of his head showed subarachnoid hemorrhage with acute hydrocephalus caused by intraventricular hematoma and aneurysm of the left middle cerebral artery. After endoscopic irrigation of the ventricular hematoma to decrease the intracranial pressure, we performed neck clipping for the ruptured aneurysm. We used a temporary clip to the proximal M1 segment twice for a total of 15 minutes. Five days after the clipping, a computed tomography scan of the patient's head showed a large low-density area in the left cerebral hemisphere. Although cerebral infarction caused by cerebral vasospasm was suspected, his perfusion computed tomography demonstrated a state of hyperperfusion corresponding to the low-density area. We started treatment to prevent vasodilation and excessive cerebral blood flow instead of treatment for cerebral vasospasm. After changing the treatment, the patient's symptoms gradually improved, and his perfusion computed tomography (8 days after surgery) showed no excessive increased blood flow. CONCLUSIONS: We present a case of cerebral hyperperfusion syndrome and its successful treatment, distinct from that of cerebral vasospasm, after ruptured aneurysm clipping. In addition, we discuss the mechanism of this rare syndrome based on previous reports.
Asunto(s)
Aneurisma Roto/cirugía , Circulación Cerebrovascular , Trastornos Cerebrovasculares/etiología , Hematoma/cirugía , Aneurisma Intracraneal/cirugía , Procedimientos Neuroquirúrgicos/efectos adversos , Hemorragia Subaracnoidea/cirugía , Anciano , Aneurisma Roto/diagnóstico por imagen , Aneurisma Roto/fisiopatología , Angiografía de Substracción Digital , Antipirina/análogos & derivados , Antipirina/uso terapéutico , Angiografía Cerebral/métodos , Circulación Cerebrovascular/efectos de los fármacos , Trastornos Cerebrovasculares/diagnóstico por imagen , Trastornos Cerebrovasculares/tratamiento farmacológico , Trastornos Cerebrovasculares/fisiopatología , Angiografía por Tomografía Computarizada , Imagen de Difusión por Resonancia Magnética , Edaravona , Endoscopía , Glicerol/uso terapéutico , Hematoma/diagnóstico por imagen , Hematoma/fisiopatología , Humanos , Aneurisma Intracraneal/diagnóstico por imagen , Aneurisma Intracraneal/fisiopatología , Ligadura , Masculino , Procedimientos Neuroquirúrgicos/métodos , Imagen de Perfusión/métodos , Recuperación de la Función , Hemorragia Subaracnoidea/diagnóstico por imagen , Hemorragia Subaracnoidea/fisiopatología , Irrigación Terapéutica/métodos , Resultado del TratamientoRESUMEN
Cytotoxicity-guided fractionation of the culture broth of Actinomadura sp. TP-A0019 led to the isolation of quinocidin (1), a cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium ring. The structural assignment was made on the basis of high-field NMR experiments and chemical synthesis. Comparison of the spectral properties of 1 with those of its synthetic counterparts revealed that 1 is a racemic mixture of two enantiomers, which showed similar cytotoxicity against HeLa-S3 cells. Nucleophile-trapping experiments demonstrated that 1 captured 2-mercaptoethanol and N-acetyl-l-cysteine by means of a Michael addition-type reaction, but was inert toward 2-aminoethanol and glycolic acid. Notably, the addition of 1 to thiols proceeded smoothly in neutral aqueous media at room temperature. In view of the thiol-trapping ability and the unusual structure, 1 provides a unique scaffold for designing drug leads and protein-labeling probes.
Asunto(s)
Antibióticos Antineoplásicos/química , Quinolizinas/química , Compuestos de Sulfhidrilo/química , Actinomycetales/química , Actinomycetales/metabolismo , Antibióticos Antineoplásicos/síntesis química , Antibióticos Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Diseño de Fármacos , Glicolatos/química , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , EstereoisomerismoRESUMEN
OBJECTIVE: The purpose of this study was to clarify the clinical and molecular characteristics associated with long-term survival in patients with glioblastoma. METHODS: We analyzed the characteristics of 96 glioblastoma patients. Long-term survivors (LTSs) were classified into moderate LTSs (mLTSs), who survived >3 years, and LTSs, who survived >5 years, and compared with short-term survivors (STSs). Clinical and molecular factors were investigated. RESULTS: Younger age, better recursive partitioning analysis class, lack of subventricular zone (SVZ) involvement, promoter methylation of the O6-methylguanine-DNA methyltransferase (MGMT) gene, and loss of 19q were associated with mLTSs as compared with STSs. After adjustment for these factors, younger age and MGMT methylation remained independently associated with mLTSs. Younger age, better recursive partitioning analysis class, lack of SVZ involvement, and loss of 19q were associated with LTSs as compared with STSs. After adjustment, younger age and better preoperative Karnofsky performance scale (KPS) score remained independently associated with LTSs. Kaplan-Meier analyses revealed that younger age (<50 years), better preoperative KPS score (≥70), lack of SVZ involvement, and loss of 19q were associated with longer overall survival. In the multivariate analysis, only age was significantly associated with overall survival. CONCLUSIONS: Younger age and better preoperative KPS score were the characteristics associated with LTSs as compared with STSs. MGMT promoter methylation was associated with mLTSs, but not with LTSs. In addition, lack of SVZ involvement and loss of 19q might be prognostic for longer survival.
Asunto(s)
Neoplasias Encefálicas/mortalidad , Glioblastoma/mortalidad , Adulto , Factores de Edad , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Terapia Combinada , Metilación de ADN/genética , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Femenino , Glioblastoma/genética , Glioblastoma/terapia , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pronóstico , Regiones Promotoras Genéticas/genética , Proteínas Supresoras de Tumor/genéticaRESUMEN
BACKGROUND: The purpose of this study was to consider the mechanism of isolated oculomotor nerve palsy after minor head trauma. CASE DESCRIPTION: We report a rare case of delayed and isolated oculomotor nerve palsy following minor head trauma. A 19-year-old boy complained of double vision 1 day after a minor head trauma. Neuro-ophthalmic examination showed isolated left oculomotor nerve palsy. Computed tomography and magnetic resonance imaging examination revealed no abnormal findings and steroid therapy was administered for a week. Three months after the injury, the ptosis and extraocular movements had fully resolved, although the pupillary light reflex was still abnormal. CONCLUSIONS: Delayed and isolated oculomotor nerve palsy may be caused by an injury at the point where the oculomotor nerve runs over the posterior petroclinoid ligament. Because edema of the damaged oculomotor nerve might result in constriction at the point where the nerve pierces the dura of the cavernous sinus, symptoms of oculomotor nerve palsy appeared late after trauma. Steroid treatment reducing edema could be effective for delayed and isolated oculomotor nerve palsy following minor head trauma.
RESUMEN
Pradimicin A (PRM-A) is a unique natural product that recognizes d-mannopyranoside (Man) in the presence of Ca2+ ion. Although the Man binding geometry of PRM-A is largely understood, the molecular basis of Man recognition has yet to be established because of the lack of information regarding Ca2+ binding geometry. In this work, to examine the Ca2+ binding site of PRM-A, we performed a solid-state nuclear magnetic resonance experiment using 111Cd2+ as a surrogate probe for Ca2+. Evaluation of 13C-111Cd distances in the [PRM-A/111Cd2+] complexes by rotational-echo double resonance (REDOR) and 111Cd frequency selective REDOR (FSR) revealed that PRM-A binds 111Cd2+ at the anthraquinone moiety, which contradicts the previous hypothesis of the alanine moiety being the Ca2+ and Cd2+ binding sites of PRM-A. The distances between Cd2+ and the carbon atoms at the binding site of PRM-A were found to be 3.5 ± 0.2 Å. Importantly, Man binding was shown not to alter the distances, indicating that [PRM-A/Ca2+] and [PRM-A/Ca2+/Man] complexes have similar Ca2+ binding geometries. This study provides an important clue to understanding the molecular basis of Man recognition of PRM-A.
Asunto(s)
Antraciclinas/química , Cadmio/química , Calcio/química , Manosa/química , Sitios de Unión , Isótopos , Espectroscopía de Resonancia Magnética/métodos , Imitación Molecular , Estructura MolecularRESUMEN
BACKGROUND: Simultaneous tumor resection and cranioplasty with hydroxyapatite osteosynthesis are sometimes necessary in patients of skull neoplasms or skull-invasive tumors. However, the disadvantage of simultaneous surgery is that mismatches often occur between the skull defect and the hydroxyapatite implant. To solve this problem, the authors developed a customized template for designing the craniotomy line. METHODS: Before each operation, the craniotomy design was discussed with a neurosurgeon. Based on the discussion, 2 hydroxyapatite implants were customized for each patient on the basis of models prepared using computed tomography data. The first implant was an onlay template for the preoperative cranium, which was customized for designing the osteotomy line. The other implant was used for the skull defect. Using the template, the osteotomy line was drawn along the template edge, osteotomy was performed along this line, and the implant was placed in the skull defect. RESULTS: This technique was performed in 3 patients. No implant or defect trimming was required in any patient, good cosmetic outcomes were noted in all patients, and no complications occurred. CONCLUSION: Use of predesigned hydroxyapatite templates for craniotomy during simultaneous skull tumor resection and cranioplasty has some clinical advantages: the precise craniotomy line can be designed, the implant and skull defect fit better and show effective osteoconduction, trimming of the implant or defect is minimized, and the operation time is shortened.
Asunto(s)
Diseño Asistido por Computadora , Craneotomía/métodos , Durapatita , Osteotomía/métodos , Procedimientos de Cirugía Plástica/métodos , Prótesis e Implantes , Neoplasias Craneales/cirugía , Cráneo/cirugía , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
Chikungunya virus (CHIKV) has been spreading rapidly, with over one million confirmed or suspected cases in the Americas since late 2013. Infection with CHIKV causes devastating arthritic and arthralgic symptoms. Currently, there is no therapy to treat this disease, and the only medications focus on relief of symptoms. Recently, protein kinase C (PKC) modulators have been reported to inhibit CHIKV-induced cell death in cell assays. The salicylate-derived bryostatin analogues described here are structurally simplified PKC modulators that are more synthetically accessible than the natural product bryostatin 1, a PKC modulator and clinical lead for the treatment of cancer, Alzheimer's disease, and HIV eradication. Evaluation of the anti-CHIKV activity of these salicylate-derived bryostatin analogues in cell culture indicates that they are among the most potent cell-protective agents reported to date. Given that they are more accessible and significantly more active than the parent natural product, they represent new therapeutic leads for controlling CHIKV infection. Significantly, these analogues also provide evidence for the involvement of a PKC-independent pathway. This adds a fundamentally distinct aspect to the importance or involvement of PKC modulation in inhibition of chikungunya virus replication, a topic of recent and growing interest.
Asunto(s)
Productos Biológicos/química , Productos Biológicos/farmacología , Brioestatinas/química , Brioestatinas/farmacología , Virus Chikungunya/fisiología , Proteína Quinasa C/metabolismo , Salicilatos/química , Salicilatos/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Muerte Celular/efectos de los fármacos , Humanos , Estructura Molecular , Proteína Quinasa C/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Pradimicin A (PRM-A) is a unique antibiotic with a lectin-like ability to bind D-mannose (D-Man) in the presence of Ca(2+) ion. Although accumulated evidences suggest that PRM-A recognizes the 2-, 3-, and 4-hydroxyl groups of D-Man, BMY-28864, an artificial PRM-A derivative, was shown not to bind L-fucose (L-Fuc) and L-galactose (lLGal), both of which share the characteristic array of the three hydroxyl groups with D-Man. To obtain a plausible explanation for this inconsistency, we performed co-precipitation experiments of PRM-A with L-Fuc, L-Gal, and their methyl pyranosides (L-Fuc-OMe, L-Gal-OMe) by taking advantage of aggregate-forming propensity of the binary [PRM-A/Ca(2+)] complex. While L-Fuc and L-Gal were hardly incorporated into the aggregate, L-Fuc-OMe and L-Gal-OMe were found to exhibit significant binding to PRM-A. However, increased Ca(2+) concentration abolished this binding, raising the possibility that poor binding of L-Fuc and L-Gal to PRM-A is attributed to their chelation with Ca(2+) ion. This possibility was partly supported by (1)H NMR analysis that detected interaction of L-Fuc and L-Gal with Ca(2+) ion in aqueous solution. These results collectively indicate that PRM-A binds pyranosides of L-Fuc and L-Gal when Ca(2+) concentration is not excessive to trap these sugars by chelation but sufficient to form the [PRM-A/Ca(2+)] complex.
Asunto(s)
Antraciclinas/farmacología , Antibacterianos/farmacología , Fucosa/metabolismo , Galactosa/metabolismo , Glicósidos/metabolismo , Manosa/metabolismo , Sitios de Unión , Calcio/metabolismo , Fucosa/química , Galactosa/química , Glicósidos/química , Manosa/químicaRESUMEN
Bryostatin 1 is in clinical trials for the treatment of cancer and Alzheimer's disease and is a candidate for a first-in-class approach to HIV/AIDS eradication. It is neither readily available nor optimally suited for clinical use. Using a function oriented synthesis strategy, a new class of bryostatin-inspired analogs was designed with a simplified salicylate-derived subunit, enabling step-economical synthesis (23 total steps) of agents exhibiting bryostatin-like affinity to protein kinase C (PKC).