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1.
J Neurooncol ; 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38740672

RESUMEN

BACKGROUND: Breast cancer (BC) is the second most common etiology of brain metastases (BrM). We aimed to examine the incidence of BrM among all BC patients presenting to a large tertiary cancer centre over one decade. METHODS: We included all BC patients presenting consecutively between 2009 and 2019 and cross referenced that cohort to a radiotherapy database, identifying patients treated for BrM at any time following their initial presentation. Cumulative incidences (CI) of BrM diagnoses were calculated using death as a competing risk and compared using the Fine-Gray method. Overall survival was estimated using the Kaplan Meier method. RESULTS: We identified 12,995 unique patients. The CI of BrM in patients who initially presented with Stage 0-4 disease was 2.1%, 3.7%, 9.4%, 10.6%, and 28.7%, respectively at 10 years. For 8,951 patients with available molecular subtype data, 6,470 (72%), 961 (11%), 1,023 (11%), and 497 (6%) had hormone-receptor (HR)-positive/ERBB2-, HR-negative/ERBB2-, HR-positive/ERBB2 + , and HR-negative/ERBB2 + disease, respectively; the CI of BrM in each was 7.6%, 25.3%, 24.1%, and 26.6%, at 10 years following BC diagnosis, respectively. Median overall survival (OS) following BC diagnosis and BrM diagnosis was 28 years 95% CI [25, 32] and 10 months 95% CI [9, 12], respectively. CONCLUSIONS: From a large, registry-based study, we observed that patients with ERBB2 + and triple negative BC have the highest incidence of BrM. Our data supports prospective surveillance brain MRI studies. Given advancements in BrM treatment, clinicians should have a low threshold for brain imaging in BC patients with high risk subtypes.

2.
Support Care Cancer ; 32(6): 381, 2024 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-38787434

RESUMEN

PURPOSE: Patients with lung cancer can experience significant psychological morbidities including depression. We characterize patterns and factors associated with interventions for symptoms of depression in stage IV non-small cell lung cancer (NSCLC). METHODS: We conducted a population-based cohort study using health services administrative data in Ontario, Canada of stage IV NSCLC diagnosed from January 2007 to September 2018. A positive symptom of depression score was defined by reporting at least one ESAS (Edmonton Symptom Assessment System) depression score ≥ 2 following diagnosis until the end of follow-up (September 2019). Patient factors included age, sex, comorbidity burden, rurality of residence, and neighbourhood income quintile. Interventions included psychiatry assessment, psychology referral, social work referral and anti-depressant medical therapy (for patients ≥ 65 years with universal drug coverage). Multivariable modified Poisson regression models were used to examine the association between patient factors and intervention use for patients who reported symptoms of depression. RESULTS: In the cohort of 13,159 patients with stage IV NSCLC lung cancer, symptoms of depression were prevalent (71.4%, n = 9,397). Patients who reported symptoms of depression were more likely to receive psychiatry assessment/psychology referral (7.8% vs 3.5%; SD [standardized difference] 0.19), social work referral (17.4% vs 11.9%; SD 0.16) and anti-depressant prescriptions (23.8% vs 13.8%; SD 0.26) when compared to patients who did not report symptoms of depression respectively. In multivariable analyses, older patients were less likely to receive any intervention. Females were more likely to obtain a psychiatry assessment/psychology referral or social work referral. In addition, patients from non-major urban or rural residences were less likely to receive psychiatry assessment/psychology referral or social work referral, however patients from rural residences were more likely to be prescribed anti-depressants. CONCLUSIONS: There is high prevalence of symptoms of depression in stage IV NSCLC. We identify patient populations, including older patients and rural patients, who are less likely to receive interventions that will help identifying and screening for symptoms of depression.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Depresión , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Ontario/epidemiología , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/psicología , Neoplasias Pulmonares/terapia , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Anciano , Persona de Mediana Edad , Depresión/epidemiología , Depresión/etiología , Estudios de Cohortes , Estadificación de Neoplasias , Anciano de 80 o más Años , Antidepresivos/uso terapéutico , Adulto , Prevalencia
3.
J Neurooncol ; 162(1): 119-128, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36914878

RESUMEN

INTRODUCTION: Various treatment options exist to salvage stereotactic radiosurgery (SRS) failures for brain metastases, including repeat SRS and hypofractionated SRS (HSRS). Our objective was to report outcomes specific to salvage HSRS for brain metastases that failed prior HSRS/SRS. METHODS: Patients treated with HSRS to salvage local failures (LF) following initial HSRS/SRS, between July 2010 and April 2020, were retrospectively reviewed. The primary outcomes were the rates of LF, radiation necrosis (RN), and symptomatic radiation necrosis (SRN). Univariable (UVA) and multivariable (MVA) analyses using competing risk regression were performed to identify predictive factors for each endpoint. RESULTS: 120 Metastases in 91 patients were identified. The median clinical follow up was 13.4 months (range 1.1-111.1), and the median interval between SRS courses was 13.1 months (range 3.0-56.5). 115 metastases were salvaged with 20-35 Gy in 5 fractions and the remaining five with a total dose ranging from 20 to 24 Gy in 3-fractions. 67 targets (56%) were postoperative cavities. The median re-treatment target volume and biological effective dose (BED10) was 9.5 cc and 37.5 Gy, respectively. The 6- and 12- month LF rates were 18.9% and 27.7%, for RN 13% and 15.6%, and for SRN were 6.1% and 7.0%, respectively. MVA identified larger re-irradiation volume (hazard ratio [HR] 1.02, p = 0.04) and shorter interval between radiosurgery courses (HR 0.93, p < 0.001) as predictors of LF. Treatment of an intact target was associated with a higher risk of RN (HR 2.29, p = 0.04). CONCLUSION: Salvage HSRS results in high local control rates and toxicity rates that compare favorably to those single fraction SRS re-irradiation experiences reported in the literature.


Asunto(s)
Neoplasias Encefálicas , Traumatismos por Radiación , Radiocirugia , Humanos , Radiocirugia/efectos adversos , Radiocirugia/métodos , Estudios Retrospectivos , Terapia Recuperativa , Neoplasias Encefálicas/secundario , Traumatismos por Radiación/etiología , Necrosis/etiología , Resultado del Tratamiento
4.
J Neurooncol ; 159(3): 705-712, 2022 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-35999435

RESUMEN

OBJECTIVE: Gamma Knife Icon-based hypofractionated stereotactic radiosurgery (GKI-HSRS) is a novel technical paradigm in the treatment of brain metastases that allows for both the dosimetric benefits of the GKI stereotactic radiosurgery (SRS) platform as well as the biologic benefits of fractionation. We report mature local control and adverse radiation effect (ARE) outcomes following 5 fraction GKI-HSRS for intact brain metastases. METHODS: Patients with intact brain metastases treated with 5-fraction GKI-HSRS were retrospectively reviewed. Survival, local control, and adverse radiation effect rates were determined. Univariable and multivariable regression (MVA) were performed on potential predictive factors. RESULTS: Two hundred and ninety-nine metastases in 146 patients were identified. The median clinical follow-up was 10.7 months (range 0.5-47.6). The median total dose and prescription isodose was 27.5 Gy (range, 20-27.5) in 5 daily fractions and 52% (range, 45-93), respectively. The median overall survival (OS) was 12.7 months, and the 1-year local failure rate was 15.2%. MVA identified a total dose of 27.5 Gy vs. ≤ 25 Gy (hazard ratio [HR] 0.59, p = 0.042), and prior chemotherapy exposure (HR 1.99, p = 0.015), as significant predictors of LC. The 1-year ARE rate was 10.8% and the symptomatic ARE rate was 1.8%. MVA identified a gross tumor volume of ≥ 4.5 cc (HR 7.29, p < 0.001) as a significant predictor of symptomatic ARE. CONCLUSION: Moderate total doses in 5 daily fractions of GKI-HSRS were associated with high rates of LC and a low incidence of symptomatic ARE.


Asunto(s)
Productos Biológicos , Neoplasias Encefálicas , Radiocirugia , Fraccionamiento de la Dosis de Radiación , Humanos , Radiocirugia/efectos adversos , Estudios Retrospectivos , Resultado del Tratamiento
5.
Infection ; 50(5): 1067-1109, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35750943

RESUMEN

OBJECTIVE: Although complications and clinical symptoms of COVID-19 have been elucidated, the prevalence of long-term sequelae of COVID-19 is less clear in previously hospitalized COVID-19 patients. This review and meta-analysis present the occurrence of different symptoms up to 1 year of follow-up for previously hospitalized patients. METHODS: We performed a systematic review from PubMed and Web of Science using keywords such as "COVID-19", "SARS-CoV-2", "sequelae", "long-term effect" and included studies with at least 3-month of follow-up. Meta-analyses using random-effects models were performed to estimate the pooled prevalence for different sequelae. Subgroup analyses were conducted by different follow-up time, regions, age and ICU admission. RESULTS: 72 articles were included in the meta-analyses after screening 11,620 articles, identifying a total of 167 sequelae related to COVID-19 from 88,769 patients. Commonly reported sequelae included fatigue (27.5%, 95% CI 22.4-33.3%, range 1.5-84.9%), somnipathy (20.1%, 95% CI 14.7-26.9%, range 1.2-64.8%), anxiety (18.0%, 95% CI 13.8-23.1%, range 0.6-47.8%), dyspnea (15.5%, 95% CI 11.3-20.9%, range 0.8-58.4%), PTSD (14.6%, 95% CI 11.3-18.7%, range 1.2-32.0%), hypomnesia (13.4%, 95% CI 8.4-20.7%, range 0.6-53.8%), arthralgia (12.9%, 95% CI 8.4-19.2%, range 0.0-47.8%), depression (12.7%, 95% CI 9.3-17.2%, range 0.6-37.5%), alopecia (11.2%, 95% CI 6.9-17.6%, range 0.0-47.0%) over 3-13.2 months of follow-up. The prevalence of most symptoms reduced after > 9 months of follow-up, but fatigue and somnipathy persisted in 26.2% and 15.1%, respectively, of the patients over a year. COVID-19 patients from Asia reported a lower prevalence than those from other regions. CONCLUSIONS: This review identified a wide spectrum of COVID-19 sequelae in previously hospitalized COVID-19 patients, with some symptoms persisting up to 1 year. Management and rehabilitation strategies targeting these symptoms may improve quality of life of recovered patients.


Asunto(s)
COVID-19 , COVID-19/epidemiología , Fatiga/epidemiología , Humanos , Alta del Paciente , Calidad de Vida , SARS-CoV-2
6.
Cereb Cortex ; 29(7): 3168-3181, 2019 07 05.
Artículo en Inglés | MEDLINE | ID: mdl-30169596

RESUMEN

Neural responses to small manipulable objects ("tools") in high-level visual areas in ventral temporal cortex (VTC) provide an opportunity to test how anatomically remote regions modulate ventral stream processing in a domain-specific manner. Prior patient studies indicate that grasp-relevant information can be computed about objects by dorsal stream structures independently of processing in VTC. Prior functional neuroimaging studies indicate privileged functional connectivity between regions of VTC exhibiting tool preferences and regions of parietal cortex supporting object-directed action. Here we test whether lesions to parietal cortex modulate tool preferences within ventral and lateral temporal cortex. We found that lesions to the left anterior intraparietal sulcus, a region that supports hand-shaping during object grasping and manipulation, modulate tool preferences in left VTC and in the left posterior middle temporal gyrus. Control analyses demonstrated that neural responses to "place" stimuli in left VTC were unaffected by lesions to parietal cortex, indicating domain-specific consequences for ventral stream neural responses in the setting of parietal lesions. These findings provide causal evidence that neural specificity for "tools" in ventral and lateral temporal lobe areas may arise, in part, from online inputs to VTC from parietal areas that receive inputs via the dorsal visual pathway.


Asunto(s)
Vías Nerviosas/fisiología , Lóbulo Parietal/fisiología , Reconocimiento Visual de Modelos/fisiología , Lóbulo Temporal/fisiología , Adulto , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Neuroimagen/métodos , Desempeño Psicomotor/fisiología , Vías Visuales/fisiología
7.
PLoS Pathog ; 13(8): e1006545, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28806780

RESUMEN

The AraC Negative Regulators (ANR) comprise a large family of virulence regulators distributed among diverse clinically important Gram-negative pathogens, including Vibrio spp., Salmonella spp., Shigella spp., Yersinia spp., Citrobacter spp., and pathogenic E. coli strains. We have previously reported broad effects of the ANR members on regulators of the AraC/XylS family. Here, we interrogate possible broader effects of the ANR members on the bacterial transcriptome. Our studies focused on Aar (AggR-activated regulator), an ANR family archetype in enteroaggregative E. coli (EAEC) isolate 042. Transcriptome analysis of EAEC strain 042, 042aar and 042aar(pAar) identified more than 200 genes that were differentially expressed (+/- 1.5 fold, p<0.05). Most of those genes are located on the bacterial chromosome (195 genes, 92.85%), and are associated with regulation, transport, metabolism, and pathogenesis, based on the predicted annotation; a considerable number of Aar-regulated genes encoded for hypothetical proteins (46 genes, 21.9%) and regulatory proteins (25, 11.9%). Notably, the transcriptional expression of three histone-like regulators, H-NS (orf1292), H-NS homolog (orf2834) and StpA, was down-regulated in the absence of aar and may explain some of the effects of Aar on gene expression. By employing a bacterial two-hybrid system, LacZ reporter assays, pull-down and electrophoretic mobility shift assay (EMSA) analysis, we demonstrated that Aar binds directly to H-NS and modulates H-NS-induced gene silencing. Importantly, Aar was highly expressed in the mouse intestinal tract and was found to be necessary for maximal H-NS expression. In conclusion, this work further extends our knowledge of genes under the control of Aar and its biological relevance in vivo.


Asunto(s)
Factor de Transcripción de AraC/metabolismo , Escherichia coli Enteropatógena/metabolismo , Infecciones por Escherichia coli/metabolismo , Regulación Bacteriana de la Expresión Génica/fisiología , Virulencia/fisiología , Animales , Ensayo de Cambio de Movilidad Electroforética , Escherichia coli Enteropatógena/patogenicidad , Proteínas de Escherichia coli/metabolismo , Histonas/metabolismo , Ratones , Ratones Endogámicos BALB C , Reacción en Cadena de la Polimerasa
8.
J Cell Mol Med ; 22(1): 261-276, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-28805297

RESUMEN

Although mesenchymal stem cells (MSCs) transplantation into the IVD (intervertebral disc) may be beneficial in inhibiting apoptosis of nucleus pulposus cells (NPCs) and alleviating IVD degeneration, the underlying mechanism of this therapeutic process has not been fully explained. The purpose of this study was to explore the protective effect of MSC-derived exosomes (MSC-exosomes) on NPC apoptosis and IVD degeneration and investigate the regulatory effect of miRNAs in MSC-exosomes and associated mechanisms for NPC apoptosis. MSC-exosomes were isolated from MSC medium, and its anti-apoptotic effect was assessed in a cell and rat model. The down-regulated miRNAs in apoptotic NPCs were identified, and their contents in MSC-exosomes were detected. The target genes of eligible miRNAs and possible downstream pathway were investigated. Purified MSC-exosomes were taken up by NPCs and suppressed NPC apoptosis. The levels of miR-21 were down-regulated in apoptotic NPCs while MSC-exosomes were enriched in miR-21. The exosomal miR-21 could be transferred into NPCs and alleviated TNF-α induced NPC apoptosis by targeting phosphatase and tensin homolog (PTEN) through phosphatidylinositol 3-kinase (PI3K)-Akt pathway. Intradiscal injection of MSC-exosomes alleviated the NPC apoptosis and IVD degeneration in the rat model. In conclusion, MSC-derived exosomes prevent NPCs from apoptotic process and alleviate IVD degeneration, at least partly, via miR-21 contained in exosomes. Exosomal miR-21 restrains PTEN and thus activates PI3K/Akt pathway in apoptotic NPCs. Our work confers a promising therapeutic strategy for IVD degeneration.


Asunto(s)
Apoptosis , Exosomas/metabolismo , Degeneración del Disco Intervertebral/patología , Células Madre Mesenquimatosas/metabolismo , MicroARNs/administración & dosificación , Núcleo Pulposo/metabolismo , Adulto , Animales , Apoptosis/efectos de los fármacos , Medios de Cultivo Condicionados/farmacología , Exosomas/ultraestructura , Femenino , Humanos , Masculino , Células Madre Mesenquimatosas/efectos de los fármacos , MicroARNs/genética , Persona de Mediana Edad , Núcleo Pulposo/efectos de los fármacos , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/farmacología , Adulto Joven
9.
J Neuroinflammation ; 15(1): 145, 2018 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-29764444

RESUMEN

BACKGROUND: Immune checkpoint inhibitors have been shown to promote antitumor immunity and achieve durable tumor remissions. However, certain tumors are refractory to current immunotherapy. These negative results encouraged us to uncover other therapeutic targets and strategies. PTPN2 (protein tyrosine phosphatase, non-receptor type 2) has been newly identified as an immunotherapy target. Loss of PTPN2 sensitizes the tumor to immunotherapy via IFNγ signaling. METHODS: Here, we investigated the relationship between PTPN2 mRNA levels and clinical characteristics in gliomas. RNA-seq data of a cohort of 325 patients with glioma were available from the Chinese Glioma Genome Atlas and 671 from The Cancer Genome Atlas. R language, GraphPad Prism 5, and SPSS 22.0 were used to analyze data and draw figures. RESULTS: PTPN2 transcript levels increased significantly with higher grades of glioma and in isocitrate dehydrogenase (IDH) wild-type and mesenchymal subtype gliomas. A comprehensive biological analysis was conducted, which indicated a crucial role of PTPN2 in the immune and inflammation responses in gliomas. Specifically, PTPN2 was positively associated with HCK, LCK, MHC II, and STAT1 but negatively related to IgG and interferon. Moreover, canonical correlation analysis showed a positive correlation of PTPN2 with infiltrating immune cells, such as macrophages, neutrophils, and CD8+ T cells. Clinically, higher levels of PTPN2 were associated with a worse overall survival both in patients with gliomas and glioblastomas. CONCLUSION: PTPN2 expression level was increased in glioblastomas and associated with gliomas of the IDH wild-type and mesenchymal subtype. There was a close correlation between PTPN2 and the immune response and inflammatory activity in gliomas. Our results show that PTPN2 is a promising immunotherapy target and may provide additional treatment strategies.


Asunto(s)
Neoplasias Encefálicas/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Glioma/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 2/metabolismo , ARN Mensajero/metabolismo , Área Bajo la Curva , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Estudios de Cohortes , Correlación de Datos , Bases de Datos Genéticas , Femenino , Regulación Neoplásica de la Expresión Génica/inmunología , Glioma/inmunología , Glioma/mortalidad , Glioma/patología , Humanos , Isocitrato Deshidrogenasa/genética , Isocitrato Deshidrogenasa/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Macrófagos/patología , Masculino , Mutación/genética , Neutrófilos/patología , Proteínas Proto-Oncogénicas c-hck/metabolismo , Factor de Transcripción STAT1/metabolismo
10.
Ann Rheum Dis ; 77(5): 770-779, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29343508

RESUMEN

OBJECTIVES: Circular RNAs (circRNAs) have been proven to function as competing endogenous RNAs to interact with microRNAs (miRNAs) and influence the expression of miRNA target mRNAs. In this study, we investigated whether circRNAs could act as competing endogenous RNAs to regulate the pathological process of intervertebral disc degeneration (IVDD). METHODS: The role and mechanism of a circRNA, circVMA21, in IVDD were explored in nucleus pulposus (NP) cells and degenerative NP tissues from patients and rat models. The interaction between circVMA21 and miR-200c as well as the target mRNA, X linked inhibitor-of-apoptosis protein (XIAP), was examined. RESULTS: The decreased expression of XIAP in the inflammatory cytokines-treated NP cells and the degenerative NP tissues was directly associated with excessive apoptosis and imbalance between anabolic and catabolic factors of extracellular matrix. miR-200c regulated NP cell viability and functions through inhibiting XIAP. circVMA21 acted as a sponge of miR-200c and functioned in NP cells through targeting miR-200c and XIAP. Intradiscal injection of circVMA21 alleviated IVDD in the rat model. CONCLUSIONS: CircVMA21 could alleviate inflammatory cytokines-induced NP cell apoptosis and imbalance between anabolism and catabolism of extracellular matrix through miR-200c-XIAP pathway. It provides a potentially effective therapeutic strategy for IVDD.


Asunto(s)
Degeneración del Disco Intervertebral/genética , MicroARNs/genética , ARN/genética , ATPasas de Translocación de Protón Vacuolares/genética , Proteína Inhibidora de la Apoptosis Ligada a X/genética , Animales , Apoptosis/genética , Supervivencia Celular/genética , Matriz Extracelular/metabolismo , Humanos , Núcleo Pulposo/metabolismo , ARN Circular , Ratas , Transducción de Señal/genética
11.
J Neurooncol ; 139(1): 89-95, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-29680903

RESUMEN

BACKGROUND: Pituitary adenomas (PAs) are the second most common brain tumors, and mostly are benign tumors. However, there exists subtypes of PAs refractory to common treatments, and need novel therapy. Programmed death 1 (PD-1) blockade has shown durable objective response in a variety of malignancies, and the key predictive markers for this immunotherapy were PD-L1 and CD8+ tumor-infiltrating lymphocyte (TILs) expression. To evaluate the potential immunotherapy for PAs, we investigated the expression of these two immune markers in PAs. METHODS: Immunohistochemistry (IHC) was performed to detect the expression of PD-L1 and CD8+ TILs in PAs. The ratio of positive expression of PD-L1 and CD8+ TILs was compared with chi-squared tests among different subtypes of PAs. The association between their expression profile and clinical parameters was analyzed using a chi-squared test, or Fisher's exact probability test when appropriate. RESULTS: One hundred and ninety one patients with PAs were retrospectively involved in this study, consisting of 106 non-functioning PAs (NF-PAs, 55.5%), 40 PRL-secreting PAs (PRL-PAs, 20.9%), 31 GH-secreting PAs (GH-PAs, 16.2%), 9 ACTH-secreting PAs (ACTH-PAs, 4.7%) and 5 plurihormonal adenomas (2.6%) respectively. 36.6% of them were PD-L1 positive and 86.9% were CD8+ TILs positive. The positive PD-L1 immunostaining presented more frequently in functioning PAs (58.8%), compared with that (34.3%) in nonfunctioning group (p = 0.000). Moreover, the rates of PD-L1 expression were more associated with increased blood levels of PRL, GH, ACTH and cortisol. Contrastly, positive CD8+ TILs immunostaining was only correlated with elevated blood level of GH. For the analysis of immune markers with pathological results, PD-L1 expression was associated with PRL and GH immunostaining and higher Ki-67 index. But CD8+ TILs was only correlated with PRL immunostaining. CONCLUSION: Our results showed that PD-L1 was frequently expressed in functioning PAs with association of aggressive behaviors in PAs. The immunotherapy could be a promising treatment option of PAs.


Asunto(s)
Adenoma/inmunología , Antígeno B7-H1/metabolismo , Linfocitos T CD8-positivos/inmunología , Inmunoterapia , Neoplasias Hipofisarias/inmunología , Adenoma/patología , Adenoma/terapia , Adolescente , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Linfocitos T CD8-positivos/patología , Niño , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Neoplasias Hipofisarias/patología , Neoplasias Hipofisarias/terapia , Estudios Retrospectivos , Adulto Joven
12.
Mol Microbiol ; 101(2): 314-32, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27038276

RESUMEN

AraC Negative Regulators (ANR) suppress virulence genes by directly down-regulating AraC/XylS members in Gram-negative bacteria. In this study, we sought to investigate the distribution and molecular mechanisms of regulatory function for ANRs among different bacterial pathogens. We identified more than 200 ANRs distributed in diverse clinically important gram negative pathogens, including Vibrio spp., Salmonella spp., Shigella spp., Yersinia spp., Citrobacter spp., enterotoxigenic (ETEC) and enteroaggregative E. coli (EAEC), and members of the Pasteurellaceae. By employing a bacterial two hybrid system, pull down assays and surface plasmon resonance (SPR) analysis, we demonstrate that Aar (AggR-activated regulator), a prototype member of the ANR family in EAEC, binds with high affinity to the central linker domain of AraC-like member AggR. ANR-AggR binding disrupted AggR dimerization and prevented AggR-DNA binding. ANR homologs of Vibrio cholerae, Citrobacter rodentium, Salmonella enterica and ETEC were capable of complementing Aar activity by repressing aggR expression in EAEC strain 042. ANR homologs of ETEC and Vibrio cholerae bound to AggR as well as to other members of the AraC family, including Rns and ToxT. The predicted proteins of all ANR members exhibit three highly conserved predicted α-helices. Site-directed mutagenesis studies suggest that at least predicted α-helices 2 and 3 are required for Aar activity. In sum, our data strongly suggest that members of the novel ANR family act by directly binding to their cognate AraC partners.


Asunto(s)
Factor de Transcripción de AraC/genética , Genes araC/genética , Factor de Transcripción de AraC/metabolismo , Proteínas Bacterianas/metabolismo , Proteínas de Unión al ADN/metabolismo , Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Regulación Bacteriana de la Expresión Génica/genética , Genes araC/fisiología , Bacterias Gramnegativas/genética , Mutagénesis Sitio-Dirigida , Filogenia , Relación Estructura-Actividad , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Virulencia/genética
13.
Toxicol Appl Pharmacol ; 288(3): 453-62, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26341291

RESUMEN

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cells to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death.


Asunto(s)
Productos Biológicos/farmacología , Neoplasias de la Mama/genética , Señalización del Calcio , Proteínas de Unión al GTP/metabolismo , Regulación Neoplásica de la Expresión Génica , Proteína p53 Supresora de Tumor/metabolismo , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Femenino , Humanos , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína p53 Supresora de Tumor/genética
14.
Hum Mol Genet ; 21(9): 1931-44, 2012 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-22228096

RESUMEN

The leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of autosomal-dominant Parkinson disease (PD). Mitochondrial dysfunction represents a critical event in the pathogenesis of PD. We demonstrated that wild-type (WT) LRRK2 expression caused mitochondrial fragmentation along with increased mitochondrial dynamin-like protein (DLP1, also known as DRP1), a fission protein, which was further exacerbated by expression of PD-associated mutants (R1441C or G2019S) in both SH-SY5Y and differentiated primary cortical neurons. We also found that LRRK2 interacted with DLP1, and LRRK2-DLP1 interaction was enhanced by PD-associated mutations that probably results in increased mitochondrial DLP1 levels. Co-expression of dominant-negative DLP1 K38A or WT Mfn2 blocked LRRK2-induced mitochondrial fragmentation, mitochondrial dysfunction and neuronal toxicity. Importantly, mitochondrial fragmentation and dysfunction were not observed in cells expressing either GTP-binding deficient mutant LRRK2 K1347A or kinase-dead mutant D1994A which has minimal interaction with DLP1 and did not increase the mitochondrial DLP1 level. We concluded that LRRK2 regulates mitochondrial dynamics by increasing mitochondrial DLP1 through its direct interaction with DLP1, and LRRK2 kinase activity plays a critical role in this process.


Asunto(s)
GTP Fosfohidrolasas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Sustitución de Aminoácidos , Animales , Línea Celular , Dinaminas , GTP Fosfohidrolasas/genética , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina , Microscopía Electrónica de Transmisión , Proteínas Asociadas a Microtúbulos/genética , Mitocondrias/ultraestructura , Proteínas Mitocondriales/genética , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación Missense , Neuronas/metabolismo , Neuronas/ultraestructura , Enfermedad de Parkinson/genética , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Ratas , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Estrés Fisiológico , Transfección
15.
Artículo en Inglés | MEDLINE | ID: mdl-38244875

RESUMEN

PURPOSE: The efficacy and safety of stereotactic body radiation (SBRT) for patients with non-spine bone metastases (NSBM) remains in question. A systematic review and meta-analysis was performed to evaluate SBRT treatment outcomes in NSBM. METHODS AND MATERIALS: Eligible studies were retrieved from Medline, Embase, Scielo, the Cochrane Library, and annual meeting proceedings until July 6, 2023. We adhered to the PRISMA and MOOSE guideline recommendations. Quantitative synthesis was performed using a random effects model. RESULTS: Seven retrospective studies, with a total of 807 patients (1048 lesions) treated with stereotactic body radiation were included, with median follow-up ranging from 7.6-26.5 months. The most common stereotactic body radiation sites were pelvis (39.2%), ribs (25.8%), femur (16.7%), and humerus/shoulder region (8.7%). At 1-year, the LF and FR were 7% (95%CI 5.5-8.5%; I2=0, n= 75/1048), and 5.3% (95%CI 3-7.5%;I2=0, n= 65/1010). The 2-year cumulative LF incidence was 12.1% (95% CI: 10-15.5%). The OS and PFS at 1-year were 82% (95%CI 75-88%;I2=82%, n= 746/867), and 33.5%(95%CI 26-41%;I2=0%, n= 51/152), with a median of 20.2 months (95%CI: 10.9-49.1 months) and 8.3 months (95% CI: 6.3-10.3%) for OS and PFS, respectively. Meta-regression analysis revealed a significant relationship between planning target volume and fracture rate (p<0.05). Ribs 2.5% followed by the femur 1.9% (95%CI:0-6.1%) were the most common fracture sites. The occurrence of pain flare, fatigue and dermatitis were 7 %, 5.4 %, and 0.65 %, respectively. CONCLUSIONS: Stereotactic body radiation proves both safety and efficacy for non-spine bone metastases and serious complications (grade 3) are infrequent. Careful consideration of target volume is crucial due to its link with a higher fracture risk.

16.
J Neurosurg Spine ; : 1-8, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38848586

RESUMEN

OBJECTIVE: Spinal chordoma treatment guidelines recommend resection. However, in patients in whom gross-total resection (GTR) is achieved, the benefits of radiation therapy (RT) are unclear. Therefore, the authors performed a systematic review to determine if RT is associated with postoperative progression-free survival (PFS) or overall survival (OS) after achieving GTR of spinal chordoma. METHODS: The PubMed database was searched for studies including individualized data of patients undergoing GTR with or without RT for spinal chordoma. Patients < 18 years of age or those who underwent stereotactic body RT were excluded. Qualitative assessment was performed using Newcastle-Ottawa Scale guidelines. Log-rank tests for time-to-event data and a Cox proportional-hazards model were generated for a multivariable statistical model. RESULTS: Complete data of 132 patients were retrieved, with 37 (28%) patients receiving adjuvant RT and 95 (72%) not receiving adjuvant RT. The mean follow-up was not statistically significantly different between those undergoing RT and not undergoing RT (54.02 months and 65.43 months, respectively). Patients were more likely not to undergo RT if their disease was located in the sacrum versus the mobile spine (p < 0.001). When controlling for age ≥ 65 years, male sex, disease location, and treatment year ≥ 2010, patients undergoing RT had similar PFS and OS when compared with those not undergoing RT on multivariable survival analysis (HR 0.935 [95% CI 0.703-2.340], p = 0.844 and HR 2.078 [95% CI 0.848-5.090], p = 0.110, respectively). However, age ≥ 65 years was associated with poorer OS in adjusted analyses (HR 2.761 [95% CI 1.185-6.432], p = 0.018) relative to patients < 65 years of age. CONCLUSIONS: After achieving GTR of spinal chordoma, the utility of RT on PFS and OS remains unclear. Age ≥ 65 years appears to be associated with OS in spinal chordoma patients. Additional multicenter prospective studies are needed to determine the utility of RT in this patient population.

17.
Artículo en Inglés | MEDLINE | ID: mdl-38445180

RESUMEN

Purpose: An integrated magnetic resonance scanner and linear accelerator (MR-linac) was implemented with daily online adaptive radiation therapy (ART). This study evaluated patient-reported experiences with their overall hospital care as well as treatment in the MR-linac environment. Methods: Patients pre-screened for MR eligibility and claustrophobia were referred to simulation on a 1.5 T MR-linac. Patient-reported experience measures were captured using two validated surveys. The 15-item MR-anxiety questionnaire (MR-AQ) was administered immediately after the first treatment to rate MR-related anxiety and relaxation. The 40-item satisfaction with cancer care questionnaire rating doctors, radiation therapists, the services and care organization and their outpatient experience was administered immediately after the last treatment using five-point Likert responses. Results were analyzed using descriptive statistics. Results: 205 patients were included in this analysis. Multiple sites were treated across the pelvis and abdomen with a median treatment time per fraction of 46 and 66 min respectively. Patients rated MR-related anxiety as "not at all" (87%), "somewhat" (11%), "moderately" (1%) and "very much so" (1%). Positive satisfaction responses ranged from 78 to 100% (median 93%) across all items. All radiation therapist-specific items were rated positively as 96-100%. The five lowest rated items (range 78-85%) were related to general provision of information, coordination, and communication. Overall hospital care was rated positively at 99%. Conclusion: In this large, single-institution prospective cohort, all patients had low MR-related anxiety and completed treatment as planned despite lengthy ART treatments with the MR-linac. Patients overall were highly satisfied with their cancer care involving ART using an MR-linac.

18.
JCO Oncol Pract ; : OP2300576, 2024 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-38442311

RESUMEN

PURPOSE: Randomized controlled trials have demonstrated that palliative care (PC) can improve quality of life and survival for outpatients with advanced cancer, but there are limited population-based data on the value of inpatient PC. We assessed PC as a component of high-value care among a nationally representative sample of inpatients with metastatic cancer and identified hospitalization characteristics significantly associated with high costs. METHODS: Hospitalizations of patients 18 years and older with a primary diagnosis of metastatic cancer from the National Inpatient Sample from 2010 to 2019 were analyzed. We used multivariable mixed-effects logistic regression to assess medical services, patient demographics, and hospital characteristics associated with higher charges billed to insurance and hospital costs. Generalized linear mixed-effects models were used to determine cost savings associated with provision of PC. RESULTS: Among 397,691 hospitalizations from 2010 to 2019, the median charge per admission increased by 24.9%, from $44,904 in US dollars (USD) to $56,098 USD, whereas the median hospital cost remained stable at $14,300 USD. Receipt of inpatient PC was associated with significantly lower charges (odds ratio [OR], 0.62 [95% CI, 0.61 to 0.64]; P < .001) and costs (OR, 0.59 [95% CI, 0.58 to 0.61]; P < .001). Factors associated with high charges were receipt of invasive medical ventilation (P < .001) or systemic therapy (P < .001), Hispanic patients (P < .001), young age (18-49 years, P < .001), and for-profit hospitals (P < .001). PC provision was associated with a $1,310 USD (-13.6%, P < .001) reduction in costs per hospitalization compared with no PC, independent of the receipt of invasive care and age. CONCLUSION: Inpatient PC is associated with reduced hospital costs for patients with metastatic cancer, irrespective of age and receipt of aggressive interventions. Integration of inpatient PC may de-escalate costs incurred through low-value inpatient interventions.

19.
Adv Sci (Weinh) ; : e2404275, 2024 Jul 08.
Artículo en Inglés | MEDLINE | ID: mdl-38973294

RESUMEN

Intervertebral disc degeneration (IVDD) is a chronic degenerative disease involving the aging and loss of proliferative capacity of nucleus pulposus cells (NPCs), processes heavily dependent on mitochondrial dynamics and autophagic flux. This study finds that the absence of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) is associated with senescence-related NPC degeneration, disrupting mitochondrial quality control. Bone marrow mesenchymal stem cells (BMSCs) have multidirectional differentiation potential and produce extracellular vesicles containing cellular activators. Therefore, in this study, BMSCs are induced under hypoxic stimulation to deliver BNIP3-rich extracellular vesicles to NPCs, thereby alleviating aging-associated mitochondrial autophagic flux, promoting damaged mitochondrial clearance, and restoring mitochondrial quality control. Mechanistically, BNIP3 is shown to interact with the membrane-bound protein annexin A2 (ANXA2), enabling the liberation of the transcription factor EB (TFEB) from the ANXA2-TFEB complex, promoting TFEB nuclear translocation, and regulating autophagy and lysosomal gene activation. Furthermore, a rat model of IVDD is established and verified the in vivo efficacy of the exosomes in repairing disc injuries, delaying NPC aging, and promoting extracellular matrix (ECM) synthesis. In summary, hypoxia-induced BMSC exosomes deliver BNIP3-rich vesicles to alleviate disc degeneration by activating the mitochondrial BNIP3/ANXA2/TFEB axis, providing a new target for IVDD treatment.

20.
J Neurooncol ; 114(2): 155-64, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23695514

RESUMEN

Targeted toxins (TT) are molecules that bind cell surface antigens or receptors such as the transferrin or interleukin-13 receptor that are overexpressed in cancer. After internalization, the toxin component kills the cell. These recombinant proteins consist of an antibody or carrier ligand coupled to a modified plant or bacterial toxin such as diphtheria toxin (DT). These fusion proteins are very effective against brain cancer cells that are resistant to radiation therapy and chemotherapy. TT have shown an acceptable profile for toxicity and safety in animal studies and early clinical trials have demonstrated a therapeutic response. This review summarizes the characteristics of DT-based TT, the animal studies in malignant brain tumors and early clinical trial results. Obstacles to the successful treatment of brain tumors include poor penetration into tumor, the immune response to DT and cancer heterogeneity.


Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Toxina Diftérica/uso terapéutico , Inmunotoxinas/uso terapéutico , Animales , Antineoplásicos/efectos adversos , Antineoplásicos/química , Toxinas Bacterianas/efectos adversos , Toxinas Bacterianas/química , Toxinas Bacterianas/uso terapéutico , Neoplasias Encefálicas/inmunología , Toxina Diftérica/efectos adversos , Toxina Diftérica/química , Humanos , Inmunotoxinas/administración & dosificación , Inmunotoxinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proteínas Recombinantes de Fusión/efectos adversos , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/uso terapéutico , Transferrina/efectos adversos , Transferrina/química , Transferrina/uso terapéutico
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