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OBJECTIVE: Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes. METHODS: A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores. RESULTS: Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by > 0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains. CONCLUSION: Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.
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BACKGROUND: Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis. METHODS: Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day. RESULTS: Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (ORadj = 3.71 [95%CI = 1.34-10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (ORadj = 2.61 [95%CI = 1.07-6.41]; p = 0.036), lower chronicity index (ORadj = 1.33 per unit decrease [95%CI = 1.10-1.62]; p = 0.003), and positive anti-dsDNA antibody (ORadj = 2.61 [95%CI = 0.93-7.33]; p = 0.069). CONCLUSIONS: CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.
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Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Estudios Prospectivos , Creatinina , Prednisona/uso terapéutico , Resultado del Tratamiento , Inducción de Remisión , Estudios Retrospectivos , RiñónRESUMEN
Lupus nephritis (LN) is a pathologically heterogenous autoimmune disease linked to end-stage kidney disease and mortality. Better therapeutic strategies are needed as only 30%-40% of patients completely respond to treatment. Noninvasive biomarkers of intrarenal inflammation may guide more precise approaches. Because urine collects the byproducts of kidney inflammation, we studied the urine proteomic profiles of 225 patients with LN (573 samples) in the longitudinal Accelerating Medicines Partnership in RA/SLE cohort. Urinary biomarkers of monocyte/neutrophil degranulation (i.e., PR3, S100A8, azurocidin, catalase, cathepsins, MMP8), macrophage activation (i.e., CD163, CD206, galectin-1), wound healing/matrix degradation (i.e., nidogen-1, decorin), and IL-16 characterized the aggressive proliferative LN classes and significantly correlated with histological activity. A decline of these biomarkers after 3 months of treatment predicted the 1-year response more robustly than proteinuria, the standard of care (AUC: CD206 0.91, EGFR 0.9, CD163 0.89, proteinuria 0.8). Candidate biomarkers were validated and provide potentially treatable targets. We propose these biomarkers of intrarenal immunological activity as noninvasive tools to diagnose LN and guide treatment and as surrogate endpoints for clinical trials. These findings provide insights into the processes involved in LN activity. This data set is a public resource to generate and test hypotheses and validate biomarkers.
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Nefritis Lúpica , Humanos , Nefritis Lúpica/tratamiento farmacológico , Proteómica , Proteinuria , Inflamación , AgresiónRESUMEN
Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based pathologic immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation in patients with LN and to identify correlates of renal parameters and treatment response. Unbiased analysis identified 3 immunologically distinct groups of patients with LN that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells at baseline showed more severe disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized primarily by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive by immunophenotyping at enrollment but with chronic renal injuries. Main immune profiles could be distilled down to 5 simple cytometric parameters that recapitulate several of the associations, highlighting the potential for blood immune profiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
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OBJECTIVE: Delayed detection of LN associates with worse outcomes. There are conflicting recommendations regarding a threshold level of proteinuria at which biopsy will likely yield actionable management. This study addressed the association of urine protein:creatinine ratios (UPCR) with clinical characteristics and investigated the incidence of proliferative and membranous histology in patients with a UPCR between 0.5 and 1. METHODS: A total of 275 SLE patients (113 first biopsy, 162 repeat) were enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership across 15 US sites at the time of a clinically indicated renal biopsy. Patients were followed for 1 year. RESULTS: At biopsy, 54 patients had UPCR <1 and 221 had UPCR ≥1. Independent of UPCR or biopsy number, a majority (92%) of patients had class III, IV, V or mixed histology. Moreover, patients with UPCR <1 and class III, IV, V, or mixed had a median activity index of 4.5 and chronicity index of 3, yet 39% of these patients had an inactive sediment. Neither anti-dsDNA nor low complement distinguished class I or II from III, IV, V or mixed in patients with UPCR <1. Of 29 patients with baseline UPCR <1 and class III, IV, V or mixed, 23 (79%) had a UPCR <0.5 at 1 year. CONCLUSION: In this prospective study, three-quarters of patients with UPCR <1 had histology showing class III, IV, V or mixed with accompanying activity and chronicity despite an inactive sediment or normal serologies. These data support renal biopsy at thresholds lower than a UPCR of 1.
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Nefritis Lúpica , Humanos , Estudios Prospectivos , Incidencia , Proteinuria/diagnóstico , Pruebas de Función Renal , Riñón/patologíaRESUMEN
Type I IFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant nucleic acid-sensing pathways, leading to autoantibody production. Type III IFN (IFN-λ) is now appreciated to have a nonredundant role in viral infection, but few studies have addressed the effects of IFN-λ on immune cells given the more restricted expression of its receptor primarily to the epithelium. In this study, we demonstrate that B cells display a prominent IFN gene expression profile in patients with lupus. Serum levels of IFN-λ are elevated in SLE and positively correlate with B cell subsets associated with autoimmune plasma cell development, including CD11c+T-bet+CD21- B cells. Although B cell subsets express all IFN receptors, IFNLR1 strongly correlates with the CD11c+CD21- B cell expansion, suggesting that IFN-λ may be an unappreciated driver of the SLE IFN signature and B cell abnormalities. We show that IFN-λ potentiates gene transcription in human B cells typically attributed to type I IFN as well as expansion of T-bet-expressing B cells after BCR and TLR7/8 stimulation. Further, IFN-λ promotes TLR7/8-mediated plasmablast differentiation and increased IgM production. CD11c+ B cells demonstrate IFN-λ hyperresponsive signaling compared with other B cell subsets, suggesting that IFN-λ accelerates plasma cell differentiation through this putative extrafollicular pathway. In summary, our data support type III IFN-λ as a cytokine promoting the Ab-secreting cell pool in human viral and autoimmune disease.
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Linfocitos B/inmunología , Interferones/inmunología , Lupus Eritematoso Sistémico/inmunología , Células Plasmáticas/inmunología , Adulto , Anciano , Diferenciación Celular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
PURPOSE OF REVIEW: FDA-approved B cell-targeted therapy has expanded to a multitude of autoimmune diseases ranging from organ specific diseases, like pemphigus and multiple sclerosis, to systemic diseases such as ANCA-associated vasculitis, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In this review, we discuss the variability in response to B cell-targeted therapies with a focus on the diversity of human B cells and plasma cells, and will discuss several of the promising new B cell-targeted therapies. RECENT FINDING: The pathogenic roles for B cells include autoantibody-dependent and autoantibody-independent functions whose importance may vary across diseases or even in subsets of patients with the same disease. Recent data have further demonstrated the diversity of human B cell subsets that contribute to disease as well as novel pathways of B cell activation in autoimmune disease. The importance of eliminating autoreactive B cells and plasma cells will be discussed, as well as new approaches to do so. SUMMARY: The past several years has witnessed significant advances in our knowledge of human B cell subsets and function. This has created a nuanced picture of the diverse ways B cells contribute to autoimmunity and an ever-expanding armamentarium of B cell-targeted therapies.
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Enfermedades Autoinmunes/etiología , Enfermedades Autoinmunes/terapia , Autoinmunidad , Linfocitos B/inmunología , Terapia Molecular Dirigida , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Autoanticuerpos/inmunología , Enfermedades Autoinmunes/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Biomarcadores , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Depleción Linfocítica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Systemic lupus (SLE) is characterized by a break of B cell tolerance that plays a central role in disease pathophysiology. An early checkpoint defect occurs at the transitional stage leading to the survival of autoreactive B cells and consequently the production of pathogenic autoantibodies. The main purpose of our work was to determine whether transitional B cells, as the most immature naïve B cell subset upstream of pathogenic B cells, display specific features compared to healthy non SLE subjects. Through extensive analysis of transitional B cells from untreated or low treated, mostly Caucasian, SLE patients, we demonstrated that transitional (T1 and T2) B cell frequencies were increased in SLE and positively correlated with disease activity. SLE transitional B cells displayed defects in two closely inter-related molecules (i.e. TLR9 defective responses and CD19 downregulation). RNA sequencing of sorted transitional B cells from untreated patients revealed a predominant overexpression of interferon stimulated genes (ISGs) even out of flares. In addition, early transitional B cells from the bone marrow displayed the highest interferon score, reflecting a B cell interferon burden of central origin. Hence, the IFN signature in transitional B cells is not confined to African American SLE patients and exists in quiescent disease since the medullary stage. These results suggest that in SLE these 3 factors (i.e. IFN imprintment, CD19 downregulation and TLR9 responses impairment) could take part at the early transitional B cell stage in B cell tolerance by-pass, ultimately leading in periphery to the expansion of autoantibodies-secreting cells.
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Antígenos CD19/biosíntesis , Interferones/inmunología , Lupus Eritematoso Sistémico/inmunología , Células Precursoras de Linfocitos B/inmunología , Receptor Toll-Like 9/inmunología , Adulto , Anciano , Autoanticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Femenino , Humanos , Persona de Mediana Edad , Transcriptoma/genéticaRESUMEN
The original version of this article unfortunately contained mistakes.
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PURPOSE OF REVIEW: The concept of cellular senescence has been evolving. Although originally proposed based on studies of serum-driven replication of cell lines in vitro, it is now clear that cellular senescence occurs in vivo. It has also become clear that cellular senescence can be triggered by a number of stimuli such as radiation, chemotherapy, activation of oncogenes, metabolic derangements, and chronic inflammation. RECENT FINDINGS: As we learn more about the mechanisms of cellular aging, it has become important to ask whether accelerated cellular senescence occurs in lupus and other systemic rheumatologic diseases. Accelerated cellular aging may be one explanation for some of the excess morbidity and mortality seen in lupus patients. If so, drugs targeting cellular senescence may provide new options for preventing long-term complications such as organ failure in systemic lupus erythematosus patients.
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Senescencia Celular/fisiología , Lupus Eritematoso Sistémico/fisiopatología , Humanos , Lupus Eritematoso Sistémico/patologíaRESUMEN
The current model of psoriatic arthritis implicates both the IL-23/IL-17 axis and the tumor necrosis factor (TNF) pathways in disease pathogenesis. Although specific major histocompatibility complex class I molecules are associated with the psoriatic disease phenotype, no specific antigen or autoantibody has been identified. Instead, an array of genes may code for an autoinflammatory loop, potentially activated by mechanical stress and dysbiosis in the skin or gut. Danger signals released by innate immune cells activate a Th1 and Th17 response that leads to synovitis, enthesitis, axial inflammation, and altered bone homeostasis characterized by pathologic bone resorption and new bone formation.
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Artritis Psoriásica , Exposición a Riesgos Ambientales/efectos adversos , Predisposición Genética a la Enfermedad , Inmunidad Innata , Artritis Psoriásica/etiología , Artritis Psoriásica/genética , Artritis Psoriásica/inmunología , Humanos , Factores de RiesgoRESUMEN
Human memory T cells present in ovarian tumor ascites fluids fail to respond normally to stimulation via the T cell receptor (TCR). This immunosuppression is manifested by decreases in NF-κB and NFAT activation, IFN-γ production, and cell proliferation in response to TCR stimulation with immobilized antibodies to CD3 and CD28. The anergy of the tumor-associated T cells (TATs) is mediated by soluble factors present in ovarian tumor ascites fluids. The non-responsiveness of the T cells is quickly reversed when the cells are assayed in the absence of the ascites fluid, and is rapidly reestablished when a cell-free ascites fluid is added back to the T cells. Based upon the observed normal phosphorylation patterns of the TCR proximal signaling molecules, the inhibition of NF-κB, and NFAT activation in response to TCR stimulation, as well as the ability of the diacylglycerol analog PMA and the ionophore ionomycin to bypass the ascites fluid-induced TCR signaling arrest, the site of the arrest in the activation cascade appears to be at or just upstream of PLC-γ. An identical TCR signaling arrest pattern was observed when T cells derived from normal donor peripheral blood were incubated with either malignant or nonmalignant (cirrhotic) ascites fluids. The immunosuppressive activity of ascites fluids reported here suggests that soluble factors acting directly or indirectly upon T cells present within tumors contribute to the anergy that has previously been observed in T cells derived from malignant and nonmalignant inflammatory microenvironments. The soluble immunosuppressive factors represent potential therapeutic targets for ovarian cancer.
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FN-kappa B/inmunología , Factores de Transcripción NFATC/inmunología , Neoplasias Ováricas/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Ascitis/inmunología , Ascitis/patología , Femenino , Humanos , FN-kappa B/metabolismo , Factores de Transcripción NFATC/metabolismo , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de SeñalRESUMEN
Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγ(null) (NSG) mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts) i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.
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Modelos Animales de Enfermedad , Neoplasias Ováricas/patología , Animales , Ascitis/metabolismo , Antígeno Ca-125/sangre , Antígeno Ca-125/metabolismo , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoensayo , Inmunohistoquímica , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Ratones , Metástasis de la Neoplasia/patología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/metabolismoRESUMEN
OBJECTIVE ⢠To evaluate the impact of p53-associated Parkin-like cytoplasmic protein (Parc) short-interfering RNA (siRNA) on the location of p53 as well as the biology of Peyronie's disease (PD) plaque-derived fibroblasts after Parc knockdown. PATIENTS AND METHODS ⢠Plaque tissue was excised from men with stable PD undergoing penile reconstructive surgery and used to produce cultured PD plaque-derived fibroblasts. ⢠Immunofluorescence (IF) and reverse transcription-polymerase chain reaction (RT-PCR) were then used to define the location of p53 and Parc before and after siRNA. ⢠Nuclear fractionation studies were used to assess the chronology of translocation of p53 from cytoplasm to nucleus on Parc knockdown. ⢠The terminal transferase dUTP Nick end labelling (TUNEL) assay was used to assess the apoptotic indices of the PD fibroblasts after Parc knockdown. RESULTS ⢠IF and PCR showed high cytoplasmic levels of p53 and Parc before siRNA. On IF, there was little or no p53 present within the nucleus before Parc knockdown. ⢠After Parc siRNA, IF showed translocation of p53 to the fibroblast nucleus, while Parc levels dropped significantly, but what Parc remained was confined to the cytoplasm with none present in the nucleus. ⢠Nuclear fractionation studies using RT-PCR confirmed this translocation phenomenon and showed the chronology of the event. All p53 had moved from the cytoplasm to the nucleus within 16 h of Parc siRNA. ⢠On TUNEL assay, apoptotic indices increased dramatically after Parc siRNA. CONCLUSIONS ⢠These data prove that Parc is a cytoplasmic anchor for p53 in PD plaque-derived fibroblasts and may be the primary cause of the stabilization and defunctionalization of p53 in these cells. ⢠These findings support Parc as a novel target for PD pharmacotherapy, perhaps using human siRNA technologies once commercially available.
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Proteínas Portadoras/metabolismo , Fibroblastos/metabolismo , Induración Peniana/metabolismo , ARN Interferente Pequeño/metabolismo , Citoplasma , Electroforesis en Gel Bidimensional , Humanos , Immunoblotting , Etiquetado Corte-Fin in Situ , Masculino , Induración Peniana/etiología , Induración Peniana/patología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , TransferasasRESUMEN
Fibroblasts are a dominant cell type in most human solid tumors. The possibility that fibroblasts have the capacity to interact with and modulate the function of tumor-associated T lymphocytes makes them a potential therapeutic target. To address this question, primary cultures of fibroblasts derived from human lung tumors were established and cultured with T cells derived from the same tumor. The tumor fibroblasts significantly enhance the production of IFN-gamma and IL-17A by the tumor-associated T cells following a CD3/CD28-induced activation of the T cells. This enhancement was fibroblast cell dose-dependent and did not require direct contact between the two cell types. Tumor-associated fibroblast-conditioned media similarly enhanced both IFN-gamma and IL-17A in activated T cells, and this enhancement was significantly reduced by Abs to IL-6. Conditioned media derived from activated lymphocyte cultures significantly enhanced IL-6 production by tumor fibroblasts. A similar enhancement of IFN-gamma and IL-17A was observed when activated T cells from a normal donor were cultivated with skin fibroblasts derived from the same donor. These results establish that fibroblasts and autologous lymphocytes, whether derived from the tumor microenvironment or from nonmalignant tissues, have the capacity to reciprocally interact and modulate function. In contrast to other reports, fibroblasts are shown to have an immunostimulatory effect upon activated T lymphocytes. The ability of fibroblasts to enhance two T cell cytokines known to have an impact upon tumor progression suggests that fibroblasts play an important role in tumor pathogenesis that could be exploited therapeutically.
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Carcinoma de Pulmón de Células no Pequeñas/inmunología , Comunicación Celular/inmunología , Fibroblastos/inmunología , Fibroblastos/patología , Neoplasias Pulmonares/inmunología , Activación de Linfocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Separación Celular , Técnicas de Cocultivo , Relación Dosis-Respuesta Inmunológica , Fibroblastos/metabolismo , Humanos , Interferón gamma/biosíntesis , Interleucina-17/biosíntesis , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/patología , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/patología , Células Tumorales CultivadasRESUMEN
The immune system of cancer patients recognizes tumor-associated antigens expressed on solid tumors and these antigens are able to induce tumor-specific humoral and cellular immune responses. Diverse immunotherapeutic strategies have been used in an attempt to enhance both antibody and T cell responses to tumors. While several tumor vaccination strategies significantly increase the number of tumor-specific lymphocytes in the blood of cancer patients, most vaccinated patients ultimately experience tumor progression. CD4+ and CD8+ T cells with an effector memory phenotype infiltrate human tumor microenvironments, but most are hyporesponsive to stimulation via the T cell receptor (TCR) and CD28 under conditions that activate memory T cells derived from the peripheral blood of the cancer patients or normal donors. Attempts to identify cells and molecules responsible for the TCR signaling arrest of tumor-infiltrating T cells have focused largely upon the immunosuppressive effects of tumor cells, tolerogenic dendritic cells and regulatory T cells. Here we review potential mechanisms by which human T cell function is arrested in the tumor microenvironment with a focus on the immunomodulatory effects of stromal fibroblasts. Determining in vivo which cells and molecules are responsible for the TCR arrest in human tumor-infiltrating T cells will be necessary to formulate and test strategies to prevent or reverse the signaling arrest of the human T cells in situ for a more effective design of tumor vaccines. These questions are now addressable using novel human xenograft models of tumor microenvironments.
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INTRODUCTION: Erectile dysfunction (ED) and atherosclerotic vascular disease have the same risk factors; furthermore, endothelial dysfunction has been shown to be a common link between these conditions. A high prevalence of silent coronary artery disease (CAD) in patients with ED has been observed. AIMS: The aims of this article were to define the prevalence and identify predictors of occult obstructive CAD in patients with documented vasculogenic ED. MAIN OUTCOME MEASURES: Duplex Doppler penile ultrasonography (DUS); exercise stress echocardiography; IIEF; CAD risk factors. Methods. Patients presenting with ED who had penile vascular insufficiency documented by DUS and who had no history of diabetes or symptoms of CAD were prospectively enrolled for noninvasive cardiac stress testing using exercise stress echocardiography. RESULTS: Forty-nine men (mean age 517 years) with an average duration of ED of 2.52 years were evaluated. Penile arterial insufficiency was present in 94%, and venous leak in 20% of patients. Comorbidities included hypertension (51%), hyperlipidemia (41%), and smoking (35%). All patients had at least one vascular risk factor, with 40% having two, 15% three, and 15% four risk factors. Ten patients (20%) had abnormal cardiac stress test. On univariate analysis, age, IIEF-EF domain score, cavernosal artery insufficiency, presence of venous leak, and history of a first-degree relative with CAD were significant predictors. On multivariate analysis, cavernosal artery insufficiency, venous leak, and family history of CAD continued to be predictors of an abnormal stress test. CONCLUSIONS: A significant proportion of men with vasculogenic ED have abnormal cardiac stress test. The greatest chance for abnormal cardiac stress test was observed in those with corporo-venocclusive dysfunction or family history of CAD. In some men presenting with ED, even without a CAD history, performing penile DUS or cardiology referral for stress testing should be considered.
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Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/epidemiología , Ecocardiografía , Impotencia Vasculogénica/epidemiología , Estrés Fisiológico , Adulto , Comorbilidad , Humanos , Hiperlipidemias/epidemiología , Hipertensión/epidemiología , Impotencia Vasculogénica/diagnóstico , Masculino , Persona de Mediana Edad , Pene/diagnóstico por imagen , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Factores de Riesgo , Fumar/epidemiología , Encuestas y Cuestionarios , Ultrasonografía Doppler DúplexRESUMEN
Mild hemophilia A (factor VIII deficiency) was diagnosed in Golden Retrievers and pedigree studies were undertaken to test the cosegregation of an intragenic factor VIII marker with the disease phenotype. The study population consisted of 30 client-owned dogs (22 males and 8 females). Hemophilic males (n = 12) typically demonstrated prolonged bleeding after trauma or surgery rather than spontaneous hemorrhagic events. The affected males had a proportionate reduction in factor VIII coagulant activity (mean FVIII:C = 4%) and factor VIII protein concentration (mean FVIII:Ag = 3%). Twenty-five dogs (10 affected males, 8 clear males, 2 obligate carrier dams, and 5 suspect carrier daughters) were genotyped for a factor VIII microsatellite marker, with allele size assigned by an automated capillary electrophoresis system. Five distinct marker alleles were present in the study pedigree and a 300-base pair allele was found to segregate with the hemophilia A phenotype. The inheritance of the hemophilia-associated allele defined carrier status for 5 suspect daughters of obligate carrier dams. The limitations inherent to linkage analyses (i.e., lack of access to key family members and homozygosity at the marker locus) did not preclude carrier detection in this pedigree. We conclude that genotype analysis for the intragenic factor VIII marker can aid in control of canine hemophilia A through enhanced carrier detection.
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Enfermedades de los Perros/genética , Factor VIII/genética , Hemofilia A/veterinaria , Repeticiones de Microsatélite/genética , Animales , Perros , Genotipo , Hemofilia A/genética , LinajeRESUMEN
INTRODUCTION: Orgasmic pain is an infrequently reported but distressing problem for the patients who experience it. No consensus exists as to its etiology however bladder neck/pelvic floor spasm may play a role. This analysis was conducted to assess the effect of the alpha-blocking medication, tamsulosin on post-orgasmic pain. METHODS: In a prospective, non-placebo controlled study, patients with orgasmic pain were interviewed and administered tamsulosin 0.4 mg po qhs for at least 4 weeks. Outcome measures included libido, pain and continence and these were evaluated using the International Index of Erectile Function (IIEF), a visual analog scale (VAS) for pain and an incontinence scale respectively pre and post treatment. Patients were separated into groups based on etiology of the problem (radical prostatectomy, radiation therapy, and other) for statistical analysis. RESULTS: 98 patients were enrolled. Pain was located predominantly in the penis (72%), with other sites including testis, rectum and abdomen. Most patients (52%) experienced pain for less than 5 minutes post-orgasm. 76/98 (77%) patients reported significant improvement in pain (>/=2 points on pain VAS) and 12/98 (12%) noted complete resolution of their pain. The VAS for pain reflected a statistically significant decrease in pain for all groups in response to tamsulosin treatment. The entire group had a decrease of 2.7 points between pre and post-treatment phases. The IIEF libido domain increased significantly (mean of 2.4 points) for all treatment groups. CONCLUSION: Tamsulosin decreases orgasmic pain intensity in patients with orgasmic pain. These data support the hypothesis that orgasmic pain is related to bladder neck and/or pelvic floor muscle spasm.
Asunto(s)
Antagonistas Adrenérgicos alfa/uso terapéutico , Orgasmo/fisiología , Dolor/tratamiento farmacológico , Dolor/fisiopatología , Sulfonamidas/uso terapéutico , Abdomen , Humanos , Libido/efectos de los fármacos , Masculino , Persona de Mediana Edad , Dimensión del Dolor/efectos de los fármacos , Pene , Proyectos Piloto , Estudios Prospectivos , Prostatectomía/efectos adversos , Radioterapia/efectos adversos , Recto , Tamsulosina , Testículo , Resultado del TratamientoRESUMEN
INTRODUCTION: Sildenafil citrate is a highly effective erectogenic agent. However, predicting which patients will respond to this agent is often difficult. While the patient response to this agent is dependent on the nitric oxide-guanylate cyclase-cyclic guanosine monophosphate cascade, the integrity of penile arterial flow and venocclusive mechanism is also important. Duplex Doppler penile ultrasonography can reliably document penile hemodynamics. This study aimed at defining response rates based on degree of penile vascular sufficiency. METHODS: This study enrolled patients who met strict criteria for sildenafil citrate response who had also undergone penile ultrasound. Correlation was drawn between the nature and the severity of the vascular insufficiency and the response rate to sildenafil citrate. RESULTS: The distribution of vascular diagnoses was arteriogenic 64%, venogenic 6%, mixed vascular insufficiency 18%, and normal 12%. The best response was seen in those men with normal vascular studies, 80% responding. Fifty-three percent of all men with any abnormality on penile ultrasound responded; 65% of men with arteriogenic erectile dysfunction (ED), 25% of patients with venogenic ED, and 6% of men with a mixed vascular insufficiency were responders. There was a correlation between the degree of vascular impairment and the response rate. All men with venogenic ED who responded had mild leak. CONCLUSION: These data demonstrate a correlation between the nature and severity of penile vascular disease and the ability to respond to sildenafil citrate. These data may be useful to the sexual medicine practitioner when counseling patients regarding oral erectogenic therapy.