OBJECTIVE: We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. METHODS: GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. RESULTS: GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-ß growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. CONCLUSIONS: We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.
Objective: We previously reported that high expression of the extracellular glutathione peroxidase GPX3 is associated with poor patient outcome in ovarian serous adenocarcinomas, and that GPX3 protects ovarian cancer cells from oxidative stress in culture. Here we tested if GPX3 is necessary for tumor establishment in vivo and to identify novel downstream mediators of GPX3's pro-tumorigenic function. Methods: GPX3 was knocked-down in ID8 ovarian cancer cells by shRNA to test the role of GPX3 in tumor establishment using a syngeneic IP xenograft model. RNA sequencing analysis was carried out in OVCAR3 cells following shRNA-mediated GPX3 knock-down to identify GPX3-dependent gene expression signatures. Results: GPX3 knock-down abrogated clonogenicity and intraperitoneal tumor development in vivo, and the effects were dependent on the level of GPX3 knock-down. RNA sequencing showed that loss of GPX3 leads to decreased gene expression patterns related to pro-tumorigenic signaling pathways. Validation studies identified GDF15 as strongly dependent on GPX3. GDF15, a member of the TGF-ß growth factor family, has known oncogenic and immune modulatory activities. Similarly, GPX3 expression positively correlated with pro-tumor immune cell signatures, including regulatory T-cell and macrophage infiltration, and displayed significant correlation with PD-L1 expression. Conclusions: We show for the first time that tumor produced GPX3 is necessary for ovarian cancer growth in vivo and that it regulates expression of GDF15. The immune profile associated with GPX3 expression in serous ovarian tumors suggests that GPX3 may be an alternate marker of ovarian tumors susceptible to immune check-point inhibitors.
Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.
Vaginal cytology is the most common method of monitoring the estrous cycle in rats; however, this test requires specific technical training and can be subject to interpretation. Vaginal impedance offers a quicker and less technically challenging alternative and has been used successfully to identify estrus in normally cycling breeder rats. We hypothesize that vaginal impedance can also be used to stage the estrous cycle in rats that have been given luteinizing hormone releasing hormone (LHRH) for timed mating. Vaginal impedance measurements and vaginal cytology were performed in LHRH-primed female rats (n = 36) at the expected peak of proestrus and paired with proven stud males. Breeding success was determined by gross necropsy to detect embryo implantation sites in the female rats. We found that the predictive rates of vaginal cytology and impedance measurement for proestrus were similar; however, both methods resulted in high proportions of false positive and false negative determinations (28% and 31%, respectively). We further hypothesized that females respond to LHRH at variable rates, resulting in variable times of peak proestrus. To test this, vaginal impedance measurements were performed multiple times throughout the expected day of proestrus in LHRH-primed female rats (n = 36). Females were either paired with a male 24 h after reaching the proestrus threshold (n = 18) or paired according to our standard protocol at 1300 h on the day after the expected proestrus (n = 18). Sequential measurements reduced false positive and negative rates (14% and 8%, respectively). Pregnancy rates did not differ based on the time of pairing during expected estrus. Overall, we determined vaginal impedance can be more successful than vaginal cytology at identifying proestrus in the rat, but only if multiple measurements are taken.
Estrous Cycle , Rats/physiology , Reproductive Techniques/veterinary , Vagina/physiology , Animal Technicians , Animals , Electric Impedance , Female , Luteinizing Hormone/agonists , Male , Pregnancy , Proestrus/physiology
OBJECTIVE: To determine whether order of medication withdrawal in children with juvenile idiopathic arthritis (JIA) taking methotrexate (MTX) and tumor necrosis factor inhibitor (TNFi) combination therapy (CBT) affects flare-free survival (FFS). METHODS: This retrospective observational study of 335 patients with polyarticular JIA or enthesitis-related arthritis analyzed FFS off medications in 4 withdrawal arms: 1) TNFi plus MTX, off MTX first, 2) TNFi plus MTX, off TNFi first, 3) MTX monotherapy, or 4) TNFi monotherapy. Outcomes were evaluated based on order of medication withdrawal, clinical presentation, serologic parameters, and duration of clinically inactive disease (CID) while taking medications. RESULTS: Sixty-four percent of all patients achieved CID. However, 89% of patients on CBT who withdrew TNFi first flared within 12 months despite continuing MTX, compared to 12% of those who withdrew MTX and continued TNFi (P < 0.0005). Twenty-seven percent of patients discontinued all medications, but 63% flared within 12 months, and only 49% of these regained CID within 12 months of restarting therapy. Patients on MTX monotherapy had the best FFS after medication withdrawal. FFS was independent of disease subtype, rheumatoid factor status, initial erythrocyte sedimentation rate, initial joint count, corticosteroid exposure, time in CID, and method of medication discontinuation. CONCLUSION: This study confirms that flare rates in JIA are high, and discontinuing medications is challenging. Withdrawal of TNFi from CBT first carries a significantly higher risk of disease flare than withdrawing MTX first. The high relapse rate after discontinuation of TNFi suggests that these medications may not modify the underlying disease process.
Antirheumatic Agents/administration & dosage , Arthritis, Juvenile/drug therapy , Biological Products/administration & dosage , Methotrexate/administration & dosage , Adolescent , Arthritis, Juvenile/diagnosis , Arthritis, Juvenile/immunology , Child , Child, Preschool , Disease-Free Survival , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Infant , Kaplan-Meier Estimate , Los Angeles , Male , Recurrence , Remission Induction , Retrospective Studies , Risk Factors , Time Factors , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitors
OBJECTIVE: To describe the first reported case of pneumatosis intestinalis (PI) in a pediatric patient with granulomatosis with polyangiitis (GPA) and multiple other risk factors and review the literature for PI in adult and pediatric rheumatologic conditions. METHODS: A PubMed search was completed using the search phrase "pneumatosis intestinalis." Searches were limited to humans and the English language, and remaining articles involving patients with rheumatologic diagnoses were identified and included in our discussion. RESULTS: This is the first reported of case of PI in a patient with underlying GPA or antineutrophil cytoplasmic antibody-associated vasculitides. Out of 90 previously reported cases of PI in patients with rheumatologic conditions, 79 cases were in adults and 11 in children. There were 30 patients with systemic sclerosis, 18 with MCTD/overlap syndrome, 18 with dermatomyositis or polymyositis, 16 with SLE, and 8 with other diagnoses. Overall, 81% of the patients were on corticosteroids or other immunosuppressants prior to development of PI. The most common presenting symptom was abdominal pain, and 51% of patients had associated pneumoperitoneum. CONCLUSIONS: PI can be associated with a broad spectrum of rheumatic diseases, including GPA, and should be included in the differential diagnosis of patients with rheumatologic conditions and nonspecific gastrointestinal symptoms.
Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/epidemiology , Pneumatosis Cystoides Intestinalis/diagnosis , Pneumatosis Cystoides Intestinalis/epidemiology , Adolescent , Anti-Bacterial Agents/therapeutic use , Antifungal Agents/therapeutic use , Comorbidity , Drug Therapy, Combination , Female , Granulomatosis with Polyangiitis/drug therapy , Humans , Methotrexate/therapeutic use , Pneumatosis Cystoides Intestinalis/drug therapy , Prednisone/therapeutic use , Risk Factors , Treatment Outcome
Although personal melanoma risk factors are well established, the contribution of socioeconomic factors, including clothing styles, social norms, medical paradigms, perceptions of tanned skin, economic trends, and travel patterns, to melanoma incidence has not been fully explored. We analyzed artwork, advertisements, fashion trends, and data regarding leisure-time activities to estimate historical changes in UV skin exposure. We used data from national cancer registries to compare melanoma incidence rates with estimated skin exposure and found that they rose in parallel. Although firm conclusions about melanoma causation cannot be made in an analysis such as this, we provide a cross-disciplinary, historical framework in which to consider public health and educational measures that may ultimately help reverse melanoma incidence trends.
Melanoma/epidemiology , Sunbathing/statistics & numerical data , Adolescent , Adult , Clothing/history , Culture , Female , Health Knowledge, Attitudes, Practice , History, 20th Century , Humans , Incidence , Male , Melanoma/etiology , Skin/radiation effects , Sunbathing/history , Suntan , United States , Young Adult
Este documento permitirá de modo consensuado orientar una ruta hacia el futuro y reforzar las estrategias desarrolladas en cada país en materia de elaboración de políticas públicas en salud basadas en amplios procesos participativos con los pueblos involucrados. Ese es el sustento principal del camino recorrido: nada sin los pueblos. Los contenidos expuestos, se basan en la contribución de los países miembros del ORAS - CONHU, quienes han aportado experiencia y facilitado materiales relacionados con documentos sobre políticas públicas y regulaciones en salud intercultural vigentes
Culturally Competent Care , Health Policy
El documento técnico ha sido elaborado por los expertos en ASIS de los seis países integrantes del ORAS-CONHU (Bolivia, Chile, Colombia, Ecuador, Perú y Venezuela), está conformado por cuatro capítulos; el primero, de información contextual abordándose la situación social, política, económica y demográfica del país, esto es Perú y Chile; para el caso de Perú se utilizan datos e indicadores del año 2012, mientras que para Chile los datos corresponden a las proyecciones del INE de la población según el Censo del 2002. El segundo, corresponde al análisis de la información de los componentes sociodemográfico, Salud-Enfermedad, de morbilidad, de mortalidad y de respuesta organizada a la sociedad, cada uno de estos componentes ha sido abordado de manera organizada por las Nute 4 Tacna y Arica. El tercero, trata sobre el análisis de información del 2012 correspondiente a la priorización, criterios utilizados para la selección, la respuesta social organizada en salud, la información se aborda por Nute 4 y se consolida por eje fronterizo; y, por último, el cuarto capítulo, busca proponer las principales intervenciones que se requieren para el eje
Health Surveillance , Diagnosis of Health Situation
Este documento está conformado por cuatro capítulos: el primero, de información contextual abordándose la situación social, política, económica y demográfica de país, Perú y Bolivia; para el caso de Perú se utilizan datos e indicadores según las proyecciones del Censo del año 2007 del INEI, mientras que para Bolivia los datos corresponden al censo del INE 2012. El Segundo, corresponde al análisis de la información de los componentes sociodemográfico, Salud-Enfermedad, de morbilidad, de mortalidad y de respuesta organizada a la sociedad, cada uno de estos componentes ha sido abordado de manera organizada, por las Nute 4 Paica y Charaña. El tercero, trata sobre el análisis de información del 2013 correspondiente a la priorización, criterios utilizados para la selección; la respuesta social organizada en salud, la información se aborda por Nute 4 y se consolida por eje fronterizo, y por último, el cuarto capítulo busca proponer las principales intervenciones que se requieren para el eje.
Diagnosis of Health Situation , Sanitary Control of Borders
La guía plantea una metodología para el análisis de los datos que parte de una sensibilización de las autoridades y el compromiso de ellas con la comunidad que va a ser beneficiada, luego la organización del cronograma de actividades, de los aspectos administrativos, la identificación de los indicadores a ser trabajados, de los instrumentos para la recolección de los datos y del flujo de la información para su validación binacional. Finalmente, se procede a la socialización de la información, a su difusión para elaborar un plan operativo frente a la información conocida
Delivery of Health Care , Sanitary Control of Borders
El documento está conformado por cuatro capítulos, el primero de información contextual abordándose la situación social, política, económica y demográfica de país, esto es Perú y Ecuador; para el caso de Perú se utilizan datos e indicadores del año 2012, mientras que para el Ecuador los datos corresponden a los resultados del Censo Nacional de 2010. El segundo, corresponde al análisis de la información de los componentes sociodemográfico, de morbilidad y de mortalidad y de respuesta organizada a la sociedad, cada uno de estos componentes ha sido abordado de manera organizada, se abordan los territorios de la zona fronteriza del Eje Tumbes El Oro, con sus cantones: Huaquillas, Arenillas y Las Lajas (Nute 3) para la provincia de El Oro (Ecuador) y la provincia de Zarumilla (Nute 3) del departamento de Tumbes (Perú). El tercero, trata sobre el análisis de información del 2012 correspondiente a la priorización, criterios utilizados para la selección; la respuesta social organizada en salud, la información se aborda por Nute 3 y se consolida por cordón; y por último el cuarto, busca proponer las principales intervenciones que se requieren para el eje
Diagnosis of Health Situation , Sanitary Control of Borders
Melanoma is the most lethal form of skin cancer and it is the second most common cancer among adolescents and young adults. The aim of this work is to determine if surgical intervals differ between four different clinics and between departments within the hospitals, and to compare these to industry standards. Surgical intervals were measured through retrospective chart review at four dermatology clinics. Of 205 melanoma cases, clinic and departmental median surgical intervals ranged 15-36.5 days and 26-48 days, respectively. There was significant association between clinic and time between biopsy and pathology report, time between pathology report and excision, and total surgical interval (P<0.0001, P=0.03, and P<0.0001 respectively). There was significant association between department and time between pathology report and excision, and surgical interval (P<0.0001, and P=0.003 respectively). Pair-wise comparisons detected significantly longer intervals between some clinics and departments (maximum difference 67.3%, P<0.0001). Hypothesis-based, informal guidelines recommend treatment within 4-6 weeks. In this study, median surgical intervals varied significantly between clinics and departments, but nearly all were within a 6-week frame.
Los cuarenta años del ORAS-CONHU constituyen un hito en el proceso de integración andina y un referente en la salud de nuestros países, siendo este documento una recopilación de hechos históricos relacionados a la situación política y social vinculados a la integración andina y a la salud, los cuales han incidido desde la creación del Convenio Hipólito Unanue hasta lo que hoy es el Organismo Andino de Salud. Contiene temas sobre: 1. Los procesos de integración y la Subregión andina, 2. Del Acuerdo de Cartagena a la Comunidad Andina, 3. La creación del Convenio Hipólito Unanue, 4. La primera década del Convenio Hipólito Unanue, 5. Los años 80 y los límites del Convenio Hipólito Unanue, 6. Los años 90: la década de las reformas, 7. Nuevas orientaciones del Convenio Hipólito Unanue, 8. La reorganización del CONHU y la adscripción al Sistema Andino de Integración, 9. El nuevo milenio: el ORAS-CONHU, 10. Nuevos retos para la Salud Andina
Intersectoral Collaboration , Annual Report , Health , Health Care Reform
OBJECTIVE: The aim was to assess the level of systemic involvement and character of renal disease in patients with chronic cutaneous lupus erythematosus of the discoid lupus variety (hereafter referred to as 'discoid lupus') and features of systemic lupus erythematosus (SLE). Clinical confusion with other types of cutaneous lupus erythematosus complicates interpretation of some previously reported studies. METHODS: Over three years, sixteen patients met the diagnostic criteria of discoid lupus, positive anti-nuclear-antibody, and at least one extracutaneous manifestation. RESULTS: Most patients (14/16) were female, between 26 to 66 years old. Arthritis was the most common extracutaneous manifestation followed by Raynaud's phenomenon. The anti-nuclear-antibody was speckled in ten patients with titers ranging from 1:40 to 1:1280 IU/mL. Elevated levels of double-stranded-DNA in low titers were found in four patients, anti-Smith-antibody in four; anti-Sjogren-syndrome-A-antibody in seven, and anti-ribonucleoprotein-antibody in seven. Renal function markers were transiently high in some patients but normalized over time. Hematuria and/or proteinuria were present at some time in seven patients. The highest BUN and creatinine levels were 42 mg/dL and 1.5 mg/dL, respectively. One patient had membranous glomerulonephropathy class 5; however, discoid lupus developed well after the onset of renal disease during a time when renal function had returned to normal. CONCLUSION: Our observational data supports previous reports suggesting that patients with active discoid lupus rarely have progressive renal insufficiency. The mechanism for the development of discoid lupus may involve an immunologic mechanism that differs from that which produces severe organ involvement, especially advanced immune-complex-mediated renal disease. Patients with discoid lupus rarely have sustained high levels of antibodies to double-stranded-DNA. Discoid lupus appears to be a marker for a more benign lupus course. This clinical observation lays the groundwork for a larger prospective, longitudinal cohort study for further validation.
Lupus Erythematosus, Discoid/immunology , Lupus Erythematosus, Systemic/complications , Renal Insufficiency/etiology , Adult , Aged , Antibodies, Antinuclear/blood , Biomarkers/blood , Female , Humans , Lupus Erythematosus, Discoid/complications , Lupus Nephritis/etiology , Male , Middle Aged , Severity of Illness Index
Psoriatic arthritis (PsA) is an inflammatory seronegative spondyloarthropathy associated with psoriasis. Although the main assessment measures for PsA are borrowed from the standard criteria used to assess rheumatoid arthritis, a number of new criteria such as the PsAJAI and CPDAI are being developed specifically for PsA. Long-term consequences of untreated PsA include persistent inflammation, progressive joint damage and, in many cases, substantial functional limitations, pain and disability. Moreover, patients with PsA have an increased mortality risk and an increased risk of developing cardiovascular disease and metabolic syndrome. Both GRAPPA and the AAD have developed treatment guidelines, which are discussed here. Psoriasis commonly precedes arthritic symptoms; thus, dermatologists are ideally placed to make the initial diagnosis of PsA and treat it appropriately, affording the opportunity to slow disease progression, improve physical function and enhance quality of life. This Review explores the management of patients with PsA, with a particular emphasis on assessment tools, long-term consequences and treatment issues from the viewpoint of the dermatologist.
Arthritis, Psoriatic/drug therapy , Arthritis, Psoriatic/diagnosis , Dermatology , Disease Progression , Humans , Practice Guidelines as Topic
Esta valiosa herramienta está orientada a fortalecer la capacidad de gestión y respuesta de los países de la Subregión Andina, para enfrentar adecuadamente la problemática de las discapacidades, así como al diseño y ejecución de acciones conjuntas dirigidas a construir una subregión sin barreras, incluyente y equitativa, en la que la población en su conjunto incluidas las personas con discapacidad puedan ser parte del desarrollo de sus países y actores directos de su progreso y realización. Esta Política recoge el fruto de una experiencia que ha sido exitosa a través de las distintas Misiones y programas que los 6 países han desarrollado. Corresponde a los Ministerios de Salud la gran responsabilidad de implementar las acciones derivadas de la aplicación de la Política Andina y cumplir de esa manera con el compromiso asumido por sus máximas autoridades
Este documento de política andina de evaluación de tecnologías sanitarias (PAETS), se enmarca en tres ejes estratégicos: 1. El fortalecimiento del rol rector de la autoridad sanitaria de los países andinos mediante la ETS, que constituye la valiosa fuente de información para la toma de decisiones de las mencionadas autoridades sanitarias; 2. La implementación de la ETS en la Subregión Andina, utilizando diferentes estrategias; creando las Unidades de ETS en cada uno de los países con sus respectivas redes locales, nacionales, subregionales y regionales; 3. La transversalidad en la PAETS
Biomedical Technology
