GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15.

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.

More skin, more sun, more tan, more melanoma.

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.

GPX3 supports ovarian cancer tumor progression in vivo and promotes expression of GDF15.

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.

Is chronic cutaneous discoid lupus protective against severe renal disease in patients with systemic lupus erythematosus?

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.

Using Vaginal Impedance Measurement to Identify Proestrus in Rats Given Luteinizing Hormone Releasing Hormone (LHRH) Agonist.

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.

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer.

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.

Ty1 copy number dynamics in Saccharomyces.

To understand long terminal repeat (LTR)-retrotransposon copy number dynamics, Ty1 elements were reintroduced into a "Ty-less" Saccharomyces strain where elements had been lost by LTR-LTR recombination. Repopulated strains exhibited alterations in chromosome size that were associated with Ty1 insertions, but did not become genetically isolated. The rates of element gain and loss under genetic and environmental conditions known to affect Ty1 retrotransposition were determined using genetically tagged reference elements. The results show that Ty1 retrotransposition varies with copy number, temperature, and cell type. In contrast to retrotransposition, Ty1 loss by LTR-LTR recombination was more constant and not markedly influenced by copy number. Endogenous Ty1 cDNA was poorly utilized for recombination when compared with LTR-LTR recombination or ectopic gene conversion. Ty1 elements also appear to be more susceptible to copy number fluctuation in haploid cells. Ty1 gain/loss ratios obtained under different conditions suggest that copy number oscillates over time by altering the rate of retrotransposition, resulting in the diverse copy numbers observed in Saccharomyces.

Racial disparity of epidermal growth factor receptor expression in prostate cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) plays a critical role in prostate cancer (PC) signal transduction and is the target of a novel class of anticancer agents. Despite recent reports of interethnic variation in response to EGFR inhibitors, limited information exists regarding differences in expression of EGFR in PC patients. This has therapeutic relevance because a better understanding of the molecular basis underlying the ethnic variability will help in the design of individualized treatment regimens using EGFR inhibitors. PATIENTS AND METHODS: We investigated EGFR expression in a well-characterized cohort of PC patients to determine the association between EGFR expression and race. Tumor tissues from 202 radical prostatectomies performed between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) were studied (142 African Americans, 60 whites; median age, 67 years; stage T2, n = 130; stage > or = T3, n = 72; Gleason score < 7, n = 110; Gleason score > or = 7, n = 92). Membrane-specific EGFR expression was evaluated immunohistochemically. RESULTS: EGFR overexpression, defined as complete membrane staining in more than 10% of tumor cells, was observed in 75 of 202 patients (37%). There was a significant association between EGFR overexpression and African American race (P = .0006), higher pretreatment prostate-specific antigen (PSA; P = .02), and stage (P = .02), but not Gleason score (P = .33). The association between African American race and EGFR overexpression remained significant in a multivariate model after controlling for grade, stage, and pretreatment PSA simultaneously (P = .003). CONCLUSION: Our data demonstrate that race contributes significantly to variability of EGFR expression in prostate cancer. Racial background may have an impact on the design of clinical trials to test the efficacy of anti-EGFR agents.

Altered N-myc downstream-regulated gene 1 protein expression in African-American compared with caucasian prostate cancer patients.

PURPOSE: The protein encoded by N-myc downstream-regulated gene 1 (NDRG1) is a recently discovered protein whose transcription is induced by androgens and hypoxia. We hypothesized that NDRG1 expression patterns might reveal a biological basis for the disparity of clinical outcome of prostate cancer patients with different ethnic backgrounds. EXPERIMENTAL DESIGN: Patients who underwent radical prostatectomy between 1990 and 2000 at Veterans Administration Medical Center of New York were examined. We studied 223 cases, including 157 African Americans and 66 Caucasians (T2, n = 144; >/=T3, n = 79; Gleason <7, n = 122; >/=7, n = 101). Three patterns of NDRG1 expression were identified in prostate cancer: (a) intense, predominately membranous staining similar to benign prostatic epithelium; (b) intense, nucleocytoplasmic localization; and (c) low or undetectable expression. We then examined the correlations between patients' clinicopathological parameters and different NDRG1 expression patterns. RESULTS: In this study of patients with equal access to care, African-American ethnic origin was an independent predictor of prostate-specific antigen recurrence (P < 0.05). We also observed a significant correlation between different patterns of NDRG1 expression and ethnic origin. Pattern 2 was less frequent in African Americans (21% versus 38%), whereas the reverse was observed for pattern 3 (60% in African Americans versus 44% in Caucasians; P = 0.03). This association remained significant after controlling for both grade and stage simultaneously (P = 0.02). CONCLUSIONS: Our data suggest that different NDRG1 expression patterns reflect differences in the response of prostatic epithelium to hypoxia and androgens in African-American compared with Caucasian patients. Further studies are needed to determine the contribution of NDRG1 to the disparity in clinical outcome observed between the two groups.

Neutral endopeptidase protein expression and prognosis in localized prostate cancer.

PURPOSE: Neutral endopeptidase (NEP) is a cell-surface peptidase that inactivates neuropeptide growth factors implicated in prostate cancer progression. The clinical significance of decreased NEP expression observed in prostate cancer is unclear. We investigated whether decreased NEP expression in localized prostate cancers is associated with prostate-specific antigen (PSA) relapse after radical prostatectomy. EXPERIMENTAL DESIGN: NEP expression patterns were examined by immunohistochemistry in 223 men, who underwent radical prostatectomy between 1990 and 2000 at the Veterans Administration Medical Center (New York, NY) with available representative tissues and adequate follow up. We also examined whether hypermethylation of the NEP promoter contributes to down-regulation of NEP protein expression in a subset of patients that showed decreased NEP expression (n = 22). RESULTS: Three patterns of NEP expression were observed: (a) membranous expression similar to benign prostate epithelium (n = 82; 37%); (b) complete loss of NEP expression in prostate cancer compared with adjacent benign prostate glands (n = 105; 47%); and (c) heterogeneous NEP expression (n = 36; 16%). In a multivariate analysis, complete loss of NEP expression was associated with PSA relapse after controlling for grade, stage, pretreatment PSA, and race simultaneously (hazard ratio, 1.99; 95% confidence interval, 1.13-3.52; two-sided chi(2) P = 0.017). In addition, DNA hypermethylation of the NEP promoter was frequently (73%) identified in a subset of 22 of cases that showed decreased NEP expression. CONCLUSION: Our data suggest that decreased NEP expression might contribute to progression of localized prostate cancer after surgery. Data also suggest that methylation is an important mechanism of NEP protein silencing. Larger prospective studies are required for confirmation.

Benign pneumatosis intestinalis in a pediatric patient with multiple risk factors including granulomatosis with polyangiitis: a case report and review of the literature.

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.

Impact of medication withdrawal method on flare-free survival in patients with juvenile idiopathic arthritis on combination therapy.

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.

Defining an acceptable period of time from melanoma biopsy to excision.

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.

Management of psoriatic arthritis from the view of the dermatologist.

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.

Epiglottic abscess in an HIV-positive patient.

Coalescence of infection of the epiglottis, or epiglottic abscess, is a rare manifestation of epiglottitis. We report the case of a 49-year-old Hispanic man with HIV (CD4 count 243 [16.2%]), HIV viral load 175,689 copies per milliliter, antiretroviral-naive) contracted from his wife who presented to the emergency department with a 3-week history of sore throat, odynophagia, left temporal headache, left neck pain, and occasional blood-streaked sputum. This case represents the first reported case of epiglottic abscess in an HIV-positive individual. Epiglottic abscess formation is associated with potentially rapid airway compromise and carries a high mortality rate. The diagnosis of epiglottic abscess is often difficult. In HIV-infected individuals, a variety of infectious and oncologic sources of respiratory compromise should be considered in addition to epiglottic abscesses. Prompt diagnosis and treatment of this condition is crucial for ensuring optimal outcomes in this rare but often lethal infection.

Analysis of a Ty1-less variant of Saccharomyces paradoxus: the gain and loss of Ty1 elements.

Because Ty elements transpose through an RNA intermediate, element accumulation through retrotransposition must be regulated or offset by element loss to avoid uncontrolled genome expansion. Here we examine the fate of Ty sequences in Saccharomyces strain 337, a strain that is reported to lack Ty1 and Ty2 elements, but contains remnant solo long terminal repeats (LTRs). Although strain 337 was initially classified as Saccharomyces cerevisiae, our work indicates that this strain is more closely related to S. paradoxus. Several degenerate Ty1 and Ty2 LTRs were mapped to the same insertion sites as full-length Ty1 and Ty2 elements in S. cerevisiae, suggesting that this strain lost Ty elements by LTR-LTR recombination. Southern analysis indicates that strain 337 also lacks Ty4 and Ty5 elements. We estimated the rates of element gain and loss in this strain by introducing a single transposition-competent Ty1 element. The results indicate that Ty1 retrotransposition occurs at a much higher rate than elimination, suggesting that copy-number-dependent co-factors or environmental conditions contribute to the loss of Ty elements in this genome.

Detection of circulating cancer cells expressing uroplakins and epidermal growth factor receptor in bladder cancer patients.

Our purpose was to determine the clinical relevance of the detection of circulating tumor cells (CTCs) expressing urothelial and epithelial markers in bladder cancer patients. Sixty-two patients who presented to Memorial Sloan-Kettering Cancer Center between July 2000 and September 2001 were studied. Peripheral blood was tested by nested RT-PCR assay for uroplakins (UPs) Ia, Ib, II and III as well as for epidermal growth factor receptor (EGFR). We determined the sensitivity and specificity of each individual marker and the combinations of UPIa/UPII and UPIb/UPIII. The latter strategy was based on our data, which showed that UPIa and UPIb form heterodimers with UPII and UPIII, respectively. Forty patients had clinically advanced bladder cancer and 22 had no evidence of disease at the time of assay. Eight of the 22 patients recurred during the follow-up period. All 8 patients were positive at presentation for UPIa/UPII. The combination of UPIa/UPII provided the best sensitivity (75%) of detecting CTCs, with a specificity of 50%. The combination of UPIb/UPIII was the most specific (79%) but had modest sensitivity (31%). Detection of EGFR-positive cells alone and in combination with UPs was inferior to that for UPIa/UPII. Combinations of urothelial markers are superior to single urothelial or epithelial markers in detecting CTCs in bladder cancer patients. Further efforts are under way to confirm the potential predictive value of these markers in a prospectively designed study of a larger cohort of patients.

Política andina de salud intercultural / Andean intercultural health policy

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