RESUMO
Background: Meningiomas represent â¼30% of primary central nervous system (CNS) tumors. Although advances in surgery and radiotherapy have significantly improved survival, there remains an important subset of patients whose tumors have more aggressive behavior and are refractory to conventional therapy. Recent advances in molecular genetics and epigenetics suggest that this aggressive behavior may be due to the deletion of the DNA repair and tumor suppressor gene, CHEK2, neurofibromatosis Type 2 (NF2) mutation on chromosome 22q12, and genetic abnormalities in multiple RTKs including FGFRs. Management of higher-grade meningiomas, such as anaplastic meningiomas (AM: WHO grade III), is truly challenging and there isn't an established chemotherapy option. We investigate the effect of active multi tyrosine receptor kinase inhibitor Dovitinib at stopping AM cell growth in in vitro with either frequent codeletion or mutated CHEK2 and NF2 gene.Methods: Treatment effects were assessed using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, western blot analysis, caspases assay, and DNA fragmentation assay.Results: Treatment of CH157MN and IOMM-Lee cells with Dovitinib suppressed multiple angiokinases-mainly FGFRs, leading to suppression of downstream signaling by RAS-RAF-MAPK molecules and PI3K-AKT molecules which are involved in cell proliferation, cell survival, and tumor invasion. Furthermore, Dovitinib induced apoptosis via downregulation of survival proteins (Bcl-XL), and over-expression of apoptotic factors (Bax and caspase-3) regardless of CHEK2 and NF2 mutation status.Conclusions: This study establishes the groundwork for the development of Dovitinib as a therapeutic agent for high-grade AM with either frequent codeletion or mutated CHEK2 and NF2, an avenue with high translational potential.
Assuntos
Benzimidazóis/farmacologia , Quinase do Ponto de Checagem 2/genética , Meningioma/tratamento farmacológico , Neurofibromina 2/genética , Quinolonas/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Meningioma/genética , Meningioma/patologia , Mutação/genética , Estadiamento de Neoplasias , Fosfatidilinositol 3-Quinases/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genética , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/genética , Proteína bcl-X/genéticaRESUMO
Radiation-induced necrosis (RN) is a relatively common side effect of radiation therapy for glioblastoma. However, the molecular mechanisms involved and the ways RN mechanisms differ from regulated cell death (apoptosis) are not well understood. Here, we compare the molecular mechanism of cell death (apoptosis or necrosis) of C6 glioma cells in both in vitro and in vivo (C6 othotopically allograft) models in response to low and high doses of X-ray radiation. Lower radiation doses were used to induce apoptosis, while high-dose levels were chosen to induce radiation necrosis. Our results demonstrate that active caspase-8 in this complex I induces apoptosis in response to low-dose radiation and inhibits necrosis by cleaving RIP1 and RI. When activation of caspase-8 was reduced at high doses of X-ray radiation, the RIP1/RIP3 necrosome complex II is formed. These complexes induce necrosis through the caspase-3-independent pathway mediated by calpain, cathepsin B/D, and apoptosis-inducing factor (AIF). AIF has a dual role in apoptosis and necrosis. At high doses, AIF promotes chromatinolysis and necrosis by interacting with histone H2AX. In addition, NF-κB, STAT-3, and HIF-1 play a crucial role in radiation-induced inflammatory responses embedded in a complex inflammatory network. Analysis of inflammatory markers in matched plasma and cerebrospinal fluid (CSF) isolated from in vivo specimens demonstrated the upregulation of chemokines and cytokines during the necrosis phase. Using RIP1/RIP3 kinase specific inhibitors (Nec-1, GSK'872), we also establish that the RIP1-RIP3 complex regulates programmed necrosis after either high-dose radiation or TNF-α-induced necrosis requires RIP1 and RIP3 kinases. Overall, our data shed new light on the relationship between RIP1/RIP3-mediated programmed necrosis and AIF-mediated caspase-independent programmed necrosis in glioblastoma.
Assuntos
Raios gama/efeitos adversos , Glioblastoma/radioterapia , Necrose/metabolismo , Necrose/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Lesões por Radiação/metabolismo , Lesões por Radiação/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/metabolismo , Western Blotting , Caspases , Proliferação de Células , Glioblastoma/metabolismo , Glioblastoma/patologia , Técnicas Imunoenzimáticas , Masculino , Necrose/etiologia , Lesões por Radiação/etiologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Recurrent meningiomas constitute an uncommon but significant problem after standard (surgery and radiation) therapy failure. Current chemotherapies (hydroxyurea, RU-486, and interferon-α) are only of marginal benefit. There is an urgent need for more effective treatments for meningioma patients who have failed surgery and radiation therapy. Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM are some of the plant derivatives that have anti-tumorgenic properties and cause cell death in meningioma cells in vitro. Due to its ease of administration, long-term tolerability, and low incidence of long-term side effects, we explored its potential as a therapeutic agent against meningiomas by examining their efficacy in vitro against meningioma cells. Treatment effects were assessed using MTT assay, Western blot analysis, caspases assay, and DNA fragmentation assay. Results indicated that treatments of IOMM-Lee and CH157MN meningioma cells with Limonin, Tangeritin, Zerumbone, 6-Gingerol, Ganoderic Acid A, and Ganoderic Acid DM induced apoptosis with enhanced phosphorylation of glycogen synthase kinase 3 ß (GSK3ß) via inhibition of the Wnt5/ß-catenin pathway. These drugs did not induce apoptosis in normal human neurons. Other events in apoptosis included downregulation of tetraspanin protein (TSPAN12), survival proteins (Bcl-XL and Mcl-1), and overexpression apoptotic factors (Bax and caspase-3). These results provide preliminary strong evidence that medicinal plants containing Limonin, Tangeritin, 6-Gingerol, Zerumbone, Ganoderic Acid A, and Ganoderic Acid DM can be applied to high-grade meningiomas as a therapeutic agent, and suggests that further in vivo studies are necessary to explore its potential as a therapeutic agent against malignant meningiomas.
Assuntos
Catecóis/administração & dosagem , Álcoois Graxos/administração & dosagem , Flavonas/administração & dosagem , Ácidos Heptanoicos/administração & dosagem , Lanosterol/análogos & derivados , Limoninas/administração & dosagem , Meningioma/tratamento farmacológico , Sesquiterpenos/administração & dosagem , Triterpenos/administração & dosagem , Apoptose/efeitos dos fármacos , Catecóis/química , Linhagem Celular Tumoral , Fragmentação do DNA/efeitos dos fármacos , Álcoois Graxos/química , Flavonas/química , Quinase 3 da Glicogênio Sintase/biossíntese , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Ácidos Heptanoicos/química , Humanos , Lanosterol/administração & dosagem , Lanosterol/química , Limoninas/química , Meningioma/genética , Meningioma/patologia , Sesquiterpenos/química , Triterpenos/química , Via de Sinalização Wnt/efeitos dos fármacosRESUMO
The incidence of acute and chronic spinal cord injury (SCI) in the United States is more than 10,000 per year, resulting in 720 cases per million persons enduring permanent disability each year. The economic impact of SCI is estimated to be more than 4 billion dollars annually. Preclinical studies, case reports, and small clinical trials suggest that early treatment may improve neurological recovery. To date, no proven therapeutic modality exists that has demonstrated a positive effect on neurological outcome. Emerging data from recent preclinical and clinical studies offer hope for this devastating condition. This review gives an overview of current basic research and clinical studies for the treatment of SCI.
Assuntos
Traumatismos da Medula Espinal , Ensaios Clínicos como Assunto , Humanos , Traumatismos da Medula Espinal/epidemiologia , Traumatismos da Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/terapia , Estados Unidos/epidemiologiaRESUMO
Glioblastoma, the most lethal brain tumor, remains incurable despite aggressive chemotherapy and surgical interventions. New chemotherapeutics for glioblastoma have been explored in preclinical models and some agents have reached the clinical setting. However, success rates are not significant. Previous investigations involving diallyl trisulfide (DATS), a garlic compound, indicated significant anti-cancer effects in glioblastoma in vitro. DATS has also been shown to inhibit histone deacetylase activity and impede glioblastoma tumor progression. We hypothesized that DATS would block ectopic U87MG tumor by multiple pro-apoptotic pathways via inhibiting histone deacetylase (HDAC). To prove this, we developed ectopic U87MG tumors in SCID mice and treated them daily with intraperitoneal injections of DATS for 7 days. Results indicated that DATS (10 µg/kg-10 mg/kg) dose-dependently reduced tumor mass and number of mitotic cells within tumors. Histological and biochemical assays demonstrated that DATS reduced mitosis in tumors, decreased HDAC activity, increased acetylation of H3 and H4, inhibited cell cycle progression, decreased pro-tumor markers (e.g., survivin, Bcl-2, c-Myc, mTOR, EGFR, VEGF), promoted apoptotic factors (e.g., bax, mcalpian, active caspase-3), and induced DNA fragmentation. Our data also demonstrated an increase in p21Waf1 expression, which correlated with increased p53 expression and MDM2 degradation following DATS treatment. Finally, histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. Collectively, our results clearly demonstrated that DATS could be an effective therapeutic agent in preventing tumor progression and inducing apoptosis in human glioblastoma in vivo, without impairing hepatic function.
Assuntos
Compostos Alílicos/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , Histona Desacetilases/metabolismo , Sulfetos/uso terapêutico , Análise de Variância , Animais , Proteínas Reguladoras de Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Marcação In Situ das Extremidades Cortadas , Fígado/patologia , Camundongos , Camundongos SCID , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Melatonin has shown particular promise as a neuroprotective agent to prevent motoneuron death in animal models of both amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI). However, an understanding of the roles of endogenous melatonin receptors including MT1, MT2, and orphan G-protein receptor 50 (GPR50) in neuroprotection is lacking. To address this deficiency, we utilized plasmids for transfection and overexpression of individual melatonin receptors in the ventral spinal cord 4.1 (VSC4.1) motoneuron cell line. Receptor-mediated cytoprotection following exposure to glutamate at a toxic level (25 µm) was determined by assessing cell viability, apoptosis, and intracellular free Ca(2+) levels. Our findings indicate a novel role for MT1 and MT2 for increasing expression of the calcium-binding proteins calbindin D28K and parvalbumin. Increased levels of calbindin D28K and parvalbumin in VSC4.1 cells overexpressing MT1 and MT2 were associated with cytoprotective effects including inhibition of proapoptotic signaling, downregulation of inflammatory factors, and expression of prosurvival markers. Interestingly, the neuroprotective effects conferred by overexpression of MT1 and/or MT2 were also associated with increases in the estrogen receptor ß (ERß): estrogen receptor α (ERα) ratio and upregulation of angiogenic factors. GPR50 did not exhibit cytoprotective effects. To further confirm the involvement of the melatonin receptors, we silenced both MT1 and MT2 in VSC4.1 cells using RNA interference technology. Knockdown of MT1 and MT2 led to an increase in glutamate toxicity, which was only partially reversed by melatonin treatment. Taken together, our findings suggest that the neuroprotection against glutamate toxicity exhibited by melatonin may depend on MT1 and MT2 but not GPR50.
Assuntos
Ácido Glutâmico/toxicidade , Neurônios Motores/efeitos dos fármacos , Receptores de Melatonina/biossíntese , Animais , Apoptose/efeitos dos fármacos , Calbindinas/biossíntese , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Camundongos , Neurônios Motores/metabolismo , Proteínas do Tecido Nervoso/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Parvalbuminas/biossíntese , RNA Interferente Pequeno/farmacologia , Receptor MT1 de Melatonina/genética , Receptor MT2 de Melatonina/genética , Receptores Acoplados a Proteínas G/efeitos dos fármacosRESUMO
Spinal cord injury (SCI), depending on the severity of injury, leads to neurological dysfunction and paralysis. Methylprednisolone, the only currently available therapy renders limited protection in SCI. Therefore, other therapeutic agents must be tested to maximize neuroprotection and functional recovery. Previous data from our laboratory indicate that estrogen (17ß-estradiol) at a high dose may attenuate multiple damaging pathways involved in SCI and improve locomotor outcome. Since use of high dose estrogen may have detrimental side effects and therefore may never be used in the clinic, the current study investigated the efficacy of this steroid hormone at very low doses in SCI. In particular, we tested the impact of dosing (1-10 µg/kg), mode of delivery (intravenous vs. osmotic pump), and delay in estrogen application (15 min-4 h post-SCI) on microgliosis and neuronal death in acute SCI in rats. Treatment with 17ß-estradiol (1-10 µg/kg) significantly reduced microglial activation and also attenuated apoptosis of neurons compared to untreated SCI animals. The attenuation of cell death and inflammation by estrogen was observed regardless of mode and time of delivery following injury. These findings suggest estrogen as a potential agent for the treatment of individuals with SCI.
Assuntos
Estradiol/farmacologia , Estradiol/uso terapêutico , Microglia/efeitos dos fármacos , Degeneração Neural/tratamento farmacológico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia , Animais , Morte Celular/efeitos dos fármacos , Estrogênios/farmacologia , Estrogênios/uso terapêutico , Inflamação/tratamento farmacológico , Inflamação/fisiopatologia , Masculino , Metilprednisolona/farmacologia , Metilprednisolona/uso terapêutico , Microglia/patologia , Microglia/fisiologia , Degeneração Neural/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismoRESUMO
BACKGROUND: Dural reconstruction to achieve expansion duraplasty is important in suboccipital decompression for Chiari malformation type 1 (CM1). Although various dural substitutes are available, including synthetic collagen matrix grafts and dural xenografts, they have the potential to induce an inflammatory response. In this case series, the authors present their experience and discuss the incidence and possible mechanism of aseptic meningitis after the use of bovine collagen matrix graft as a dural substitute in patients with CM1 after suboccipital decompression. OBSERVATIONS: Three consecutive adult female patients who underwent suboccipital decompression at a single institution by a single neurosurgeon were retrospectively reviewed. They all presented with signs of aseptic meningitis in a delayed fashion, responded well to steroid administration, but had recurrence of their symptoms. Bovine collagen dural substitutes are resorbed in a process that induces an inflammatory response manifesting with signs of aseptic meningitis and is only alleviated with removal of the dural substitute. LESSONS: DuraMatrix Suturable, a dural xenograft derived from bovine dermis, though a viable choice for dural repair, is a potential cause of chemical meningitis after duraplasty in Chiari decompression surgery. In patients presenting with delayed and persistent aseptic meningitis after intervention, removal of this dural substitute led to improved symptomatology.
RESUMO
Loss of motoneurons may underlie some of the deficits in motor function associated with the central nervous system (CNS) injuries and diseases. We tested whether melatonin, a potent antioxidant and free radical scavenger, would prevent motoneuron apoptosis following exposure to toxins and whether this neuroprotection is mediated by melatonin receptors. Exposure of VSC4.1 motoneurons to either 50 microm H(2)O(2), 25 microm glutamate (LGA), or 50 ng/mL tumor necrosis factor-alpha (TNF-alpha) for 24 h caused significant increases in apoptosis, as determined by Wright staining and ApopTag assay. Analyses of mRNA and proteins showed increased expression and activities of stress kinases and cysteine proteases and loss of mitochondrial membrane potential during apoptosis. These insults also caused increases in intracellular free [Ca(2+)] and activities of calpain and caspases. Cells exposed to stress stimuli for 15 min were then treated with 200 nm melatonin. Post-treatment of cells with melatonin attenuated production of reactive oxygen species (ROS) and phosphorylation of p38, MAPK, and JNK1, prevented cell death, and maintained whole-cell membrane potential, indicating functional neuroprotection. Melatonin receptors (MT1 and MT2) were upregulated following treatment with melatonin. To confirm the involvement of MT1 and MT2 in providing neuroprotection, cells were post-treated (20 min) with 10 microm luzindole (melatonin receptor antagonist). Luzindole significantly attenuated melatonin-induced neuroprotection, suggesting that melatonin worked, at least in part, via its receptors to prevent VSC4.1 motoneuron apoptosis. Results suggest that neuroprotection rendered by melatonin to motoneurons is receptor mediated and melatonin may be an effective neuroprotective agent to attenuate motoneuron death in CNS injuries and diseases.
Assuntos
Apoptose/efeitos dos fármacos , Ácido Glutâmico/toxicidade , Melatonina/farmacologia , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/metabolismo , Estresse Oxidativo , Receptores de Melatonina/fisiologia , Fator de Necrose Tumoral alfa/toxicidade , Animais , Proteína Agonista de Morte Celular de Domínio Interatuante com BH3/metabolismo , Cálcio/metabolismo , Caspase 8/metabolismo , Células Cultivadas , Peróxido de Hidrogênio/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Receptor MT1 de Melatonina/metabolismo , Receptor MT2 de Melatonina/metabolismo , Triptaminas/farmacologiaRESUMO
Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Preparações Farmacêuticas , Antineoplásicos Alquilantes/farmacologia , Antineoplásicos Alquilantes/uso terapêutico , Benzamidas , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Linhagem Celular Tumoral , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Glioblastoma/tratamento farmacológico , Glioblastoma/genética , Humanos , Imidazóis , Fosfatidilinositol 3-Quinases , Pirimidinas , Sulfonas , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Triazinas , Proteínas Supressoras de Tumor/genéticaRESUMO
BACKGROUND: We aim to assess the long-term trend of and identify risk factors for traumatic spinal cord injury (TSCI) mortality from 1981 through 1998 in the state of South Carolina (SC). METHODS: We analyzed data from the TSCI surveillance system in SC. Poisson regression analyses were used to examine trends in TSCI mortality rates across subpopulations of interest. Multiple logistic regression was used to identify risk factors for TSCI mortality. RESULTS: The rate of TSCI mortality was 27.4 per million population between 1981 and 1998. A significant 3% annual decrease in the TSCI mortality rate was found from 1981 through 1998. Specifically, TSCI mortality rates declined the most per year in motor vehicle crashes, males, and whites. Adjusted for covariates, individuals of older ages, black race, with a cervical TSCI, and with a more severe injury, as defined by both Frankel grade and Abbreviated Injury Scale, were associated with higher odds of in-hospital mortality. Females had lower odds of in-hospital mortality than males. CONCLUSION: Although mortality rate is decreasing, TSCI remains a significant public health problem, with SC having higher rates of TSCI mortality than the United States. The association between gender and in-hospital mortality needs further exploration.
Assuntos
Traumatismos da Medula Espinal/mortalidade , Adolescente , Adulto , Idoso , Distribuição de Qui-Quadrado , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Distribuição de Poisson , Vigilância da População , Fatores de Risco , South Carolina/epidemiologiaRESUMO
BACKGROUND: In an RCT of PDT in the treatment of malignant gliomas, 3 patients developed cranial neuropathies after photoillumination. We are aware of no previous reports on cranial neuropathy after intracranial PDT. METHODS: In a cohort of 80 patients, there were 41 men and 39 women; 47 were newly diagnosed and 33 had recurrent tumors. All patients underwent surgical tumor extirpation. There were 77 malignant gliomas, 2 meningiomas, and 1 metastatic tumor. The tumor locations were as follows: 39 frontal, 25 temporal, 12 parietal, and 4 occipital. Of the 25 patients with temporal lobe tumors, 18 received PDT. RESULTS: Three of the 18 patients with temporal lobe tumors developed cranial neuropathies after PDT. The floor of the middle fossa received photoillumination in all 3 patients. This complication was not seen in any other patient with tumors in the frontal, parietal, or occipital regions, or patients with temporal lobe tumors who did not receive PDT. The first patient developed seventh nerve paresis and hypoesthesia in fifth nerve distribution, which resolved only partially. The second patient developed a seventh nerve paresis that resolved completely. The third patient developed transient neuralgic pain in the trigeminal nerve distribution. CONCLUSIONS: Cranial neuropathies could be the result of photoillumination of fifth and seventh cranial nerves during PDT of the temporal fossa. We recommend shielding of the middle fossa floor during PDT.
Assuntos
Doenças dos Nervos Cranianos/induzido quimicamente , Éter de Diematoporfirina/efeitos adversos , Glioma/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Fotoquimioterapia/efeitos adversos , Neoplasias Supratentoriais/tratamento farmacológico , Idoso , Antineoplásicos/efeitos adversos , Fossa Craniana Média/patologia , Doenças dos Nervos Cranianos/metabolismo , Doenças dos Nervos Cranianos/fisiopatologia , Nervo Facial/anatomia & histologia , Nervo Facial/efeitos dos fármacos , Nervo Facial/fisiopatologia , Doenças do Nervo Facial/induzido quimicamente , Doenças do Nervo Facial/metabolismo , Doenças do Nervo Facial/fisiopatologia , Feminino , Glioma/metabolismo , Humanos , Luz/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/fisiopatologia , Estimulação Luminosa/efeitos adversos , Cuidados Pré-Operatórios/normas , Neoplasias Supratentoriais/metabolismo , Lobo Temporal/patologia , Lobo Temporal/fisiopatologia , Nervo Trigêmeo/anatomia & histologia , Nervo Trigêmeo/efeitos dos fármacos , Nervo Trigêmeo/fisiopatologia , Doenças do Nervo Trigêmeo/induzido quimicamente , Doenças do Nervo Trigêmeo/metabolismo , Doenças do Nervo Trigêmeo/fisiopatologiaRESUMO
BACKGROUND: The authors report the case of a 76-year-old woman presenting with leg pain, numbness, and weakness mimicking a lumbosacral radiculopathy. CASE DESCRIPTION: Initial lumbar spine magnetic resonance imaging demonstrated mild root compression, but lumbar decompression afforded only transient symptomatic relief. Postoperative magnetic resonance imaging of the lumbosacral plexus and sciatic nerve revealed a gluteal venous varix compressing the sciatic nerve just distal to the piriformis muscle. Neurolysis and surgical resection of the offending varix resulted in resolution of her symptoms. CONCLUSIONS: Variceal compression is a rare cause of extraspinal origin of lower extremity radicular pain. It should be considered if there is lack of correlation between radiologic findings and the clinical picture or if there is a failure of response to treatment of the assumed spinal cause.
Assuntos
Síndromes de Compressão Nervosa/etiologia , Ciática/etiologia , Varizes/complicações , Idoso , Descompressão Cirúrgica , Diagnóstico Diferencial , Feminino , Humanos , Vértebras Lombares/diagnóstico por imagem , Vértebras Lombares/cirurgia , Síndromes de Compressão Nervosa/diagnóstico por imagem , Síndromes de Compressão Nervosa/cirurgia , Reoperação , Nervo Isquiático/diagnóstico por imagem , Ciática/diagnóstico por imagem , Ciática/cirurgia , Varizes/diagnóstico por imagem , Varizes/cirurgiaRESUMO
Polymeric nanoparticles have been extensively studied as drug delivery vehicles both in vitro and in vivo for the last two decades. In vitro methods to assess drug release profiles usually utilize degradation of nanoparticles in aqueous medium, followed by the measurement of the concentration of the released drug. This method, however, is difficult to use for drugs that are poorly water soluble. In this study, a protocol for measuring drug release kinetic using albumin solution as the medium is described. Albumin is a major blood transport protein, which mediates transport of many lipid soluble compounds including fatty acids, hormones, and bilirubin. The use of a dialysis-based system utilizing albumin dialysate solution allows hydrophobic drug release from a diverse set of drug delivery modalities is demonstrated. The method using liposomes and PLGA nanoparticles as drug carriers, and two model hydrophobic drugs, 17ß-estradiol, and dexamethasone is validated.
Assuntos
Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Nanopartículas/química , Albuminas/química , Dexametasona/química , Portadores de Fármacos/uso terapêutico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cinética , Lipídeos/química , Lipossomos/química , Nanopartículas/uso terapêutico , Polímeros/química , Soluções/química , Água/químicaRESUMO
PURPOSE/INTRODUCTION: Glioblastoma (GB) remains incurable despite aggressive chemotherapy, radiotherapy, and surgical interventions; immunotherapies remain experimental in clinical practice. Relevant preclinical models that can accurately predict tumor response to therapy are equally challenging. This study aimed to validate the effect of the naturally occurring agent diallyl trisulfide (DATS) in human GB in relevant pre-clinical models. METHODS: Ex vivo slice culture, in vivo cell line derived orthotopic xenograft and patient-derived orthotopic xenograft (PDX) animal models of GB were utilized to assess efficacy of treatment with DATS. RESULTS: Our results showed 72-h treatments of 25 µM DATS induced cell death in ex vivo human GB slice culture. We treated U87MG orthotopic xenograft models (U87MGOX) and patient-derived orthotopic xenograft models (PDX) with daily intraperitoneal injections of DATS for 14 days. Magnetic resonance (MR) imaging of mice treated with DATS (10 mg/kg) demonstrated reduced tumor size at 5 weeks when compared with saline-treated U87MGOX and PDX controls. Hematoxylin (H&E) staining demonstrated dose-dependent reduction in gross tumor volume with decreased proliferation and decreased angiogenesis. Western blotting showed that DATS was associated with increases in histone acetylation (Ac-Histone H3/H4) and activated caspase-3 in this novel preclinical model. Histological assessment and enzyme assays showed that even the highest dose of DATS did not negatively impact hepatic function. CONCLUSIONS: DATS may be an effective and well-tolerated therapeutic agent in preventing tumor progression and inducing apoptosis in human GB.
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Compostos Alílicos/uso terapêutico , Glioblastoma/tratamento farmacológico , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/metabolismo , Sulfetos/uso terapêutico , Compostos Alílicos/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Astrócitos/efeitos dos fármacos , Astrócitos/patologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Glioblastoma/enzimologia , Glioblastoma/patologia , Inibidores de Histona Desacetilases/administração & dosagem , Humanos , Masculino , Camundongos SCID , Neurônios/efeitos dos fármacos , Neurônios/patologia , Sulfetos/administração & dosagem , Ensaios Antitumorais Modelo de XenoenxertoAssuntos
Vértebras Cervicais/cirurgia , Meningocele/etiologia , Complicações Pós-Operatórias/etiologia , Quadriplegia/etiologia , Compressão da Medula Espinal/cirurgia , Humanos , Masculino , Meningocele/patologia , Pessoa de Meia-Idade , Complicações Pós-Operatórias/patologia , Quadriplegia/patologia , Compressão da Medula Espinal/patologiaRESUMO
The treatment of malignant gliomas has advanced significantly in the past 15 years. The simultaneous development of new targeting agents and techniques to deliver these high-molecular-weight compounds has led to improved efficacy and promising results in Phase III trials. Convection-enhanced delivery (CED) of macromolecules has emerged as the leading delivery technique for the treatment of malignant gliomas. A summary of the basic principles of CED and a review of the current human trials of protein targeting agents are provided.
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Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Glioma/tratamento farmacológico , Glioma/radioterapia , Imunotoxinas/administração & dosagem , Radioisótopos/administração & dosagem , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Terapia Combinada/métodos , Terapia Combinada/tendências , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Humanos , Bombas de Infusão/tendênciasRESUMO
Peripheral nerve involvement may be the first sign of systemic amyloid light-chain (AL) amyloidosis, a rare disease. Physical examination and electrodiagnostic testing are the mainstays of peripheral neuropathy evaluation at presentation. Sural nerve biopsy is performed in conjunction with serum and urine protein evaluation to differentiate between focal and systemic disease. Systemic disease is treated with a combination of chemotherapy, steroids, and stem cell transplantation. Isolated peripheral nerve disease is extremely rare. The authors here report the case of an 80-year-old woman who presented with progressive right upper-extremity weakness due to right radial neuropathy discovered upon electrodiagnostic testing. Magnetic resonance neurography (MRN) revealed a focal lesion within the right radial nerve. She underwent radial nerve exploration and excision of an intraneural mass consisting of amyloid on histopathology, with mass spectrometry analysis diagnostic for AL amyloidosis. Noninvasive testing and clinical history did not suggest systemic involvement. This unique case of isolated peripheral nerve AL amyloidosis in the absence of signs and symptoms of systemic disease is described, and the literature demonstrating peripheral nerve involvement in AL amyloidosis is reviewed.
Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina/diagnóstico , Neuropatia Radial/diagnóstico , Idoso de 80 Anos ou mais , Feminino , HumanosRESUMO
Glioblastoma is the most common and deadliest of malignant primary brain tumors (Grade IV astrocytoma) in adults. Current standard treatments have been improving but patient prognosis still remains unacceptably devastating. Glioblastoma recurrence is linked to epigenetic mechanisms and cellular pathways. Thus, greater knowledge of the cellular, genetic and epigenetic origin of glioblastoma is the key for advancing glioblastoma treatment. One rapidly growing field of treatment, epigenetic modifiers; histone deacetylase inhibitors (HDACis), has now shown much promise for improving patient outcomes through regulation of the acetylation states of histone proteins (a form of epigenetic modulation) and other non-histone protein targets. HDAC inhibitors have been shown, in a pre-clinical setting, to be effective anticancer agents via multiple mechanisms, by up-regulating expression of tumor suppressor genes, inhibiting oncogenes, inhibiting tumor angiogenesis and up-regulating the immune system. There are many HDAC inhibitors that are currently in pre-clinical and clinical stages of investigation for various types of cancers. This review will explain the theory of epigenetic cancer therapy, identify HDAC inhibitors that are being investigated for glioblastoma therapy, explain the mechanisms of therapeutic effects as demonstrated by pre-clinical and clinical studies and describe the current status of development of these drugs as they pertain to glioblastoma therapy.