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Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells. Cancer Res; 72(23); 6227–35. ©2012 AACR.

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INTRODUCTION: Physiological episodes are an issue in military aviation. Some non-pressure-related in-flight symptoms are proved to be due to hyperventilation rather than hypoxia. The aim of this study was to validate a new training method provoking hyperventilation during normobaric hypoxia (NH) training in an F/A-18 Hornet simulator.METHODS: In a double-blind setting, 26 fighter pilots from the Finnish Air Force performed 2 setups in a WTSAT simulator in randomized order with full flight gear. Without the pilot's knowledge, 6% O2 in nitrogen or 6% O2 + 4% CO2 in nitrogen was turned on. Ventilation (VE) was measured before, during, and after hypoxia. Spo2 and ECG were monitored and symptoms documented. The subjects performed a tactical identification flight until they recognized symptoms of hypoxia. Thereafter, they performed hypoxia emergency procedures with 100% O2 and returned to the base with a GPS malfunction and executed an instrument landing system (ILS) approach with the waterline HUD mode evaluated by the flight instructor on a scale of 1 to 5.RESULTS: Ventilation increased during normobaric hypoxia (NH) from 12 L · min−1 to 19 L · min−1 at Spo2 75% with 6% O2, and from 12 L · min−1 to 26 L · min−1 at Spo2 77% with 6% O2 + 4% CO2. ILS flight performance was similar 10 min after combined hyperventilation and hypoxia (3.1 with 6% O2 + 4% CO2 and 3.2 with 6% O2). No adverse effects were reported during the 24-h follow-up.DISCUSSION: Hyperventilation-provoking normobaric hypoxia training is a new and well-tolerated method to meet NATO Standardization Agreement hypoxia training requirements.Leinonen AM, Varis NO, Kokki HJ, Leino TK. A new method for combined hyperventilation and hypoxia training in a tactical fighter simulator. Aerosp Med Hum Perform. 2022; 93(9):681–687.

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Accumulating evidence suggests that constitutively active Nrf2 has a pivotal role in cancer as it induces pro-survival genes that promote cancer cell proliferation and chemoresistance. The mechanisms of Nrf2 dysregulation and functions in cancer have not been fully characterized. Here, we jointly analyzed the Broad-Novartis Cancer Cell Line Encyclopedia (CCLE) and the Cancer Genome Atlas (TCGA) multi-omics data in order to identify cancer types where Nrf2 activation is present. We found that Nrf2 is hyperactivated in a subset of glioblastoma (GBM) patients, whose tumors display a mesenchymal subtype, and uncover several different mechanisms contributing to increased Nrf2 activity. Importantly, we identified a positive feedback loop between SQSTM1/p62 and Nrf2 as a mechanism for activation of the Nrf2 pathway. We also show that autophagy and serine/threonine signaling regulates p62 mediated Keap1 degradation. Our results in glioma cell lines indicate that both Nrf2 and p62 promote proliferation, invasion and mesenchymal transition. Finally, Nrf2 activity was associated with decreased progression free survival in TCGA GBM patient samples, suggesting that treatments have limited efficacy if this transcription factor is overactivated. Overall, our findings place Nrf2 and p62 as the key components of the mesenchymal subtype network, with implications to tumorigenesis and treatment resistance. Thus, Nrf2 activation could be used as a surrogate prognostic marker in mesenchymal subtype GBMs. Furthermore, strategies aiming at either inhibiting Nrf2 or exploiting Nrf2 hyperactivity for targeted gene therapy may provide novel treatment options for this subset of GBM.

BACKGROUND: Little is known about the factors that predict for gastrointestinal stromal tumor (GIST) recurrence in patients treated with adjuvant imatinib. METHODS: Risk factors for GIST recurrence were identified, and 2 risk stratification scores were developed using the database of the Scandinavian Sarcoma Group (SSG) XVIII trial, where 358 patients with high-risk GIST with no overt metastases were randomly assigned to adjuvant imatinib 400 mg/day either for 12 or 36 months after surgery. The findings were validated in the imatinib arm of the American College of Surgeons Oncology Group Z9001 trial, where 359 patients with GIST were randomized to receive imatinib and 354 were to receive placebo for 12 months. RESULTS: Five factors (high tumor mitotic count, nongastric location, large size, rupture, and adjuvant imatinib for 12 months) were independently associated with unfavorable recurrence-free survival (RFS) in a multivariable analysis in the SSGXVIII cohort. A risk score based on these 5 factors had a concordance index with GIST recurrence of 78.9%. When a simpler score consisting of the 2 strongest predictive factors (mitotic count and tumor site) was devised, the groups with the lowest, intermediate high, and the highest risk had 5-year RFS of 76.7%, 47.5%, and 8.4%, respectively. Both scores were strongly associated with RFS in the validation cohort (P

Background: Tumor immune cell infiltrates influence prognosis of node negative breast cancer (BC), and intratumoral B-cells and T-cells are of importance for achieving response to chemotherapy in triple negative BC. The role of tumor infiltrating macrophages remains unclear, but they might promote tumorigenesis. We investigated the prognostic value of CD68 mRNA levels within the luminal, HER2-positive and triple negative subtypes in the FinHer trial patient population, and evaluated their predictive value on survival outcomes achieved with adjuvant trastuzumab and chemotherapy in early breast cancer. Methods: RNA was extracted from formalin-fixed paraffin-embedded (FFPE) tumor tissue of 917 (90.8%) patients out of the 1010 patients who participated in the FinHer trial. Intratumoral macrophage infiltration was assessed by measuring breast tumor CD68 mRNA content using RT-qPCR from representative FFPE tissue samples. Breast cancer molecular subtypes (luminal, HER2 positive and triple-negative) were approximated using immunohistochemistry (IHC) and central CISH testing data obtained from the FinHer trial datafile. Prognostic significance of CD68 on distant disease-free survival (DDFS) was assessed using Kaplan-Meyer analysis and log-rank test. Results: Tumor CD68 mRNA expression was normally distributed with median expression of 33.56 (dCt). CD68 mRNA levels correlated weakly with estrogen receptor (ER) mRNA expression and ER protein levels (r = 0.11 and r = 0.15, respectively; p Conclusions: The study validates tumor CD68 concentration as a prognostic biomarker in HER2-positive early breast cancer. Patients with HER2-positive cancer and few tumor macrophages (low tumor CD68 mRNA content) benefitted from addition of trastuzumab to chemotherapy, whereas patients with HER2-positive BC with high tumor macrophage content derived no benefit from adjuvant trastuzumab. Trastuzumab may be effective only for macrophage-poor HER2-positive cancers that are prone to antibody-dependent cellular cytotoxicity (ADCC), whereas it may have little efficacy for cancers that progress despite or due to high intratumoral macrophage content that interferes with ADCC. Other agents, such as T-DM1, might work better than trastuzumab in the subset of women who have HER2-positive BC with a high tumor macrophage content. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-06.

Background. Little information is available about survival outcomes of patients with HER2-positive early breast cancer treated with adjuvant capecitabine-containing chemotherapy with or without trastuzumab. Patients and methods. One thousand and five hundred patients with early breast cancer were entered to the Finland Capecitabine trial (FinXX) between January 2004 and May 2007, and were randomly assigned to receive either three cycles of adjuvant TX (docetaxel, capecitabine) followed by three cycles of CEX (cyclophosphamide, epirubicin, capecitabine; TX-CEX) or three cycles of docetaxel followed by three cycles of CEF (cyclophosphamide, epirubicin, fluorouracil; T-CEF). The primary endpoint was recurrence-free survival (RFS). The study protocol was amended in May 2005 while study accrual was ongoing to allow adjuvant trastuzumab for patients with HER2-positive cancer. Of the 284 patients with HER2-positive cancer accrued to FinXX, 176 (62.0%) received trastuzumab after amending the study protocol, 131 for 12 months and 45 for nine weeks. The median follow-up time was 6.7 years. Results. Patients with HER2-positive cancer who received trastuzumab had better RFS than those who did not (five-year RFS 89.2% vs. 75.9%; HR 0.41, 95% CI 0.23–0.72; p = 0.001). Patients treated with trastuzumab for 12 months or nine weeks had similar RFS. There was no significant interaction between trastuzumab administration and the type of chemotherapy. Four (2.3%) patients treated with trastuzumab had heart failure or left ventricular dysfunction, three of these received capecitabine. Conclusion. Adjuvant trastuzumab improves RFS of patients treated with TX-CEX or T-CEF. Few patients had cardiac failure.

Background: Presence of immune cell infiltrates in tumor may influence outcome of patients with node negative breast cancer (BC) (Schmidt et al 2008). High expression of CXCL13 (B lymphocyte chemoattractant chemokine) was strongly associated with favorable survival in one recent series consisting of BC patients treated with adjuvant chemotherapy (Razis et al. 2012). Here we examined the clinical significance of breast tumor CXCL13 mRNA levels within the context of the FinHer trial, where patients were randomly assigned to receive 3 cycles of either docetaxel or vinorelbine followed by 3 cycles of FEC. Patients with HER2-positive BC had a second randomization for trastuzumab vs. control. Since intratumoral B cells are of particular importance for obtaining response to chemotherapy in triple negative BC (TNBC) and of limited value in luminal BC (Schmidt et al. 2012), and trastuzumab treatment is a confounding factor in HER2+ BC, we focused on TNBC. Methods: RNA was extracted from FFPE tumor tissue of 917 (90.8%) out of the 1010 patients who participated in the FinHer trial. CXCL13 mRNA expression was measured using RT-qPCR. The molecular subtypes (luminal, HER2-enriched and triple-negative) were determined using IHC and central chromogenic in situ hybridization (CISH) testing. Prognostic significance of factors was assessed using univariate and multivariate analyses. Distant disease-free survival (DDFS) between groups was compared using the log-rank test. Results: Tumor CXCL13 mRNA expression showed a bimodal distribution and correlated negatively with tumor ESR1 mRNA levels (r = −0,31; p < 0.0001). 146 (15.9%) out of the 917cancers were classified as TNBC. High tumor CXCL13 mRNA levels above the median were strongly associated with favorable 5-yr DDFS in TNBC compared to low levels (85% vs. 60%; p < 0.0001). The prognostic value of tumor CXCL13 was evident in the subset of women with TNBC treated with vinorelbine (5-year DDFS 90% vs. 40%; p < 0.0001), whereas no significant association was found in the docetaxel arm (5-year DDFS 80% vs. 80%; p = 0.76). When only patients with TNBC and low CXCL13 mRNA levels were assessed, patients treated with docetaxel had better DDFS compared to those treated with vinorelbine (5-year DDFS 80% versus 40%; p < 0.0064). There was no DDFS difference between treatment arms in patients exhibiting high CXCL13 expression. Conclusions: Tumor CXCL13 mRNA expression is a favorable prognostic factor for women with TNBC treated with adjuvant chemotherapy providing further evidence that the host immune response may influence outcome of patients with early BC. The clinical significance of the host B cell immune response may vary substantially pending on the type of chemotherapy administered. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD10-06.

Purpose Capecitabine is an active agent in the treatment of breast cancer. It is not known whether integration of capecitabine into an adjuvant regimen that contains a taxane, an anthracycline, and cyclophosphamide improves outcome in early breast cancer. Patients and Methods Women with axillary node–positive or high-risk node-negative breast cancer were randomly assigned to receive either three cycles of docetaxel and capecitabine (TX) followed by three cycles of cyclophosphamide, epirubicin, and capecitabine (CEX; n = 753) or three cycles of docetaxel (T) followed by three cycles of cyclophosphamide, epirubicin, and fluorouracil (CEF; n = 747). The primary end point was recurrence-free survival (RFS). Results During a median follow-up time of 59 months, 214 RFS events occurred (local or distant recurrences or deaths; TX/CEX, n = 96; T/CEF, n = 118). RFS was not significantly different between the groups (hazard ratio [HR], 0.79; 95% CI, 0.60 to 1.04; P = .087; 5-year RFS, 86.6% for TX/CEX v 84.1% for T/CEF). Fifty-six patients assigned to TX/CEX died during the follow-up compared with 75 of patients assigned to T/CEF (HR, 0.73; 95% CI, 0.52 to 1.04; P = .080). In exploratory analyses, TX/CEX improved breast cancer–specific survival (HR, 0.64; 95% CI, 0.44 to 0.95; P = .027) and RFS in women with triple-negative disease and in women who had more than three metastatic axillary lymph nodes at the time of diagnosis. We detected little severe late toxicity. Conclusion Integration of capecitabine into a regimen that contains docetaxel, epirubicin, and cyclophosphamide did not improve RFS significantly compared with a similar regimen without capecitabine.

Background: Molecular subtyping of breast cancer has become an integral part of standard evaluation of breast cancer patients. Their assessment requires combining data from analyses on ER, PR, HER2 and cell proliferation markers. However, their immunohistochemical (IHC) testing carries an up to 20% risk of erroneous results. Similarly, assessment of cell proliferation by Ki-67 staining is hampered by lack of standardization of laboratory methods and agreement on cut-offs. Here we tested the prognostic value of objective quantitation of ESR1, PgR, HER2 and the proliferation markers RACGAP1 using RT-qPCR and compared the results with local and central IHC assessments. Methods: RNA was extracted from FFPE tumor tissue of 917 patients who participated in the FinHer trial. ESR1, PgR, HER2 and RACGAP1 mRNA expression were measured using RT-qPCR. The molecular subtypes (luminal, HER2−enriched and triple-negative) were determined. Prognostic significance of proliferation markers was assessed using univariate and multivariate analyses. The RT-qPCR results were compared with local and central IHC results. Results: HER2 mRNA showed a bimodal distribution with 197 (21.4%) out of the 917 tumors being above the predefined cut-off. HER2 mRNA expression increased in parallel with HER protein expression. Overall concordance of HER2 mRNA testing with central IHC and CISH was good, while local IHC testing suffered higher false positive rates. RACGAP1 mRNA expression was the greater the higher the histological grade. ESR1 and PgR mRNA correlated negatively with the histological grade (r=-0.38 and r=-0.33; p Conclusions: Molecular subtyping of breast cancer by RT-qPCR using RNA isolated from FFPE tissue proved successfully in this large patient cohort. RACGAP1 mRNA expression distinguished high and low risk luminal breast cancers. In a multivariate analysis mRNA-based molecular markers outperformed the immunohistochemical markers ER, PgR and Ki-67. Of note, quantitative assessment of the proliferation marker RACGAP1 was superior to semiquantitative assessment of Ki-67 from routine FFPE tissues using IHC. We conclude that quantitative assessment of ESR1, PgR, HER2 and RACGAP1 mRNA by RT-qPCR is a robust and reproducible method to assess these key tumor biological factors from archival FFPE tumor tissue. RACGAP1 is novel cell proliferation marker in breast cancer that warrants further validation. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-04.

Background: Accurate assessment of the HER2 status is essential for identifying patients who may benefit from HER2 targeted therapy. The current methods, immunohistochemistry (IHC) and in situ hybridization (ISH), determine HER2 status semi-quantitatively as positive (+), equivocal (+/−) and negative (−) with predefined cutoff values. Recent studies have suggested that current HER2 cutoffs may not be optimal for all clinical settings of HER2 targeted therapy. In a small subset of adjuvant NCCTG N9831 patients confirmed as HER2−normal by round-robin review of HER2 testing, trastuzumab benefit was observed (Perez et al, SABCS 2010). Quantification of HER2 as continuous variable may enable a more accurate optimization of HER2 cutoffs for various HER2 targeted therapies. In this study, we measured continuous HER2 protein expression by the HERmark™ assay and continuous mRNA expression by quantitative real time polymerase chain reaction (qPCR), and compared these results with central IHC and central chromogenic in situ hybridization (CISH) results of FinHer. Methods: Total HER2 protein expression (H2T) was quantified using the HERmark assay as previously described (Huang et al. Am J Clin Pathol 2010;134:303). HER2 mRNA expression (H2N) was measured by qPCR as previously published (Noske et al. Br Cancer Res Treat 2011;126:109). The results of H2T and H2N as continuous variables and as predefined categories were compared with central CISH results from FinHer (Joensuu et al, N Engl J Med 2006;354), and central IHC retesting. Results: H2T in 899 evaluable samples described a continuum of 0.4 to 721.2 (relative HERmark unit); while H2N in 915 evaluable samples showed a continuum of 31.4 to 42.8 (delta-Ct). Significant correlation between H2T and H2N as continuous variable was found (R2= 0.56, P< .0001). Paired method comparison was performed for samples with valid results in any two of the four testing methods. Overall concordance of H2T and H2N with predefined categories (+, +/−, -) was 81%, and concordance of (+) and (−) subsets was 95% when (+/−) cases (H2T 11%; H2N 6%) were excluded. Overall concordance of central IHC and H2T categories (+, +/−, -) was 75%, and concordance of (+) and (−) subsets was 96% when (+/−) cases (IHC 16%; H2T 11%) were excluded. Overall concordance of IHC and H2N categories (+, +/−, -) was 84%, and concordance of (+) and (−) subsets was 99% when (+/−) cases (IHC 16%; H2N 6%) were excluded. Concordance of central CISH (+, -) with H2T and H2N categories (+, -) was 89% and 91%, respectively, when (+/−) cases were excluded from H2T (13%) and H2N (8%), respectively. Conclusions: All four methods identified HER2−positive breast cancers. The discordance rate between the methods tested was approximately 10 to 20% despite careful delineation of cancerous tissue in the sample and analysis of adjacent tumor sections. No combination of assays could be identified with concordance rate >95% when the equivocal subsets were included in comparisons. Exclusion of the equivocal subsets (about 10% of samples) yielded high concordance rates of approximately 95% or higher. H2T and H2N showed comparable continuous distribution patterns and significant concordance with standard HER2 status by central IHC and CISH. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-07-01.

The purpose of this study was to examine the association between bacterial colonization/infection and respiratory outcomes in children younger than 3 years old who were hospitalized for their first wheezing episode. This was an observational study. The primary outcome was hospitalization time and the secondary outcomes included relapses within 2 months and time to recurrent wheezing (i.e. three physician confirmed wheezing episodes) within 12 months. Bacterial antibody assays for Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae and Chlamydia pneumoniae were studied as well as nasopharyngeal bacterial culture for the three former and urine pneumococcal antigen. Nasopharyngeal bacterial culture was positive in 31/52 (60%) children, serologic evidence of bacterial infection was found in 17/96 (18%) children, urine pneumococcal antigen was positive in 24/101 (24%), and any bacterial detection method was positive in 53/106 (50%) children. The children with positive nasopharyngeal bacterial culture had longer duration of hospitalization (hazard ratio 2.4) and more often relapsed within two months than those with negative culture (odds ratio 7.3). In this study, half of the first time wheezing children had bacterial colonization or symptomatic or asymptomatic bacterial infection. The bacterial colonization (i.e. positive nasopharyngeal bacterial culture) was associated with longer duration of hospitalization and higher risk of recurrent wheezing.

Background: Alternating administration of docetaxel and gemcitabine might result in improved time-to-treatment failure (TTF) and fewer adverse events compared with single-agent docetaxel as treatment of advanced breast cancer. Patients and methods: Women diagnosed with advanced breast cancer were randomly allocated to receive 3-weekly docetaxel (group D) or 3-weekly docetaxel alternating with 3-weekly gemcitabine (group D/G) until treatment failure as first-line chemotherapy. The primary end point was TTF. Results: Two hundred and thirty-seven subjects were assigned to treatment (group D, 115; group D/G, 122). The median TTF was 5.6 and 6.2 months in groups D and D/G, respectively (hazard ratio 0.85, 95% confidence interval 0.63–1.16; P = 0.31). There was no significant difference in time-to-disease progression, survival, and response rate between the groups. When adverse events were evaluated for the worst toxicity encountered during treatment, there was little difference between the groups, but when they were assessed per cycle, alternating treatment was associated with fewer severe (grade 3 or 4) adverse effects (P = 0.013), and the difference was highly significant for cycles when gemcitabine was administered in group D/G (P < 0.001). Conclusion: The alternating regimen was associated with a similar TTF as single-agent docetaxel but with fewer adverse effects during gemcitabine cycles.

and Summary This report describes factors influencing the attainment of orgasm in the stump-tailed macaque in the laboratory. In the male, penile stimulation during copulation was not a sufficient condition for orgasm to occur; successful copulation had to be preceded by a high level of excitement triggered by various psychosocial factors. In the female, stereotypic signs of high sexual excitement were invariably displayed during copulation at the time of male orgasm and also during homosexual interactions which did not provide genital stimulation. The observations suggest that female orgasm results from high responsiveness to the overall behaviour of the excited partner. Zusammenfassung Dieser Bericht beschreibt Faktoren, die bei im Labor lebenden Stummelschwanz-Makaken (Macaca arctoides) zum Orgasmus fuhren. Beim Mannchen war die Penisreizung wahrend der Kopulation keine ausreichende Bedingung fur das Auftreten eines Orgasmus; einer erfolgreichen Kopulation mus ein hoher Grad an Erregung, ausgelost durch verschiedene psychosoziale Faktoren, vorausgehen. Das Weibchen zeigte gleichbleibend stereotype Zeichen hoher sexueller Erregung wahrend der Kopulation zum Zeitpunkt des mannlichen Orgasmus und ebenso wahrend homosexueller Interaktionen ohne genitale Reizung. Die Beobachtungen scheinen darauf hinzuweisen, das das Weibchen wahrend der Kopulation infolge seiner hohen Empfanglichkeit fur das Gesamtverhalten des erregten Partners mit der Ejakulation des Mannchens einen Orgasmus erfahrt.

Purpose Docetaxel has not been compared with vinorelbine as adjuvant treatment of early breast cancer. Efficacy and long-term safety of a short course of adjuvant trastuzumab administered concomitantly with chemotherapy for human epidermal growth factor receptor 2 (HER2) –positive cancer are unknown. Patients and Methods One thousand ten women with axillary node–positive or high-risk node-negative breast cancer were randomly assigned to receive three cycles of docetaxel or vinorelbine, followed in both groups by three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Women with HER2-positive cancer (n = 232) were further assigned to either receive or not receive trastuzumab for 9 weeks with docetaxel or vinorelbine. The median follow-up time was 62 months after random assignment. Results Women assigned to docetaxel had better distant disease–free survival (DDFS) than those assigned to vinorelbine (hazard ratio [HR] = 0.66; 95% CI, 0.49 to 0.91; P = .010). In the subgroup of HER2-positive disease, patients treated with trastuzumab tended to have better DDFS than those treated with chemotherapy only (HR = 0.65; 95% CI, 0.38 to 1.12; P = .12; with adjustment for presence of axillary nodal metastases, HR = 0.57; P = .047). In exploratory analyses, docetaxel, trastuzumab, and FEC improved DDFS compared with docetaxel plus FEC (HR = 0.32; P = .029) and vinorelbine, trastuzumab, and FEC (HR = 0.31; P = .020). The median left ventricular ejection fraction of trastuzumab-treated patients remained unaltered during the 5-year follow-up; only one woman treated with trastuzumab was diagnosed with a heart failure. Conclusion Adjuvant treatment with docetaxel improves DDFS compared with vinorelbine. A brief course of trastuzumab administered concomitantly with docetaxel is safe and effective and warrants further evaluation.

Background: We analysed data from three clinical trials in Parkinson’s disease (PD) patients with wearing-off to determine whether early enhancement of levodopa therapy with entacapone can lead to better long-term outcomes than delayed entacapone treatment. Methods: Post-hoc analysis of pooled data from three randomized, double-blind, placebo-controlled studies and their long-term, open-label extension phases. In all three studies, patients on levodopa/dopa-decarboxylase inhibitor (DDCI) were first randomized to entacapone (‘early-start’ group) or placebo (‘delayed-start’ group) for the initial 6-month double-blind phase, after which all patients received open-label levodopa/DDCI and entacapone treatment for up to 5 years. Results: A total of 488 PD patients with wearing-off were included in the analysis. A statistically significant benefit of early initiation of levodopa/DDCI and entacapone was found, with an improvement in Unified Parkinson’s Disease Rating Scale Part III (motor) score of −1.66 (95% confidence intervals [−3.01, −0.31]) points compared with the delayed-start treatment group (P

Purpose: Preoperative percutaneous transabdominal wall biopsy may be considered to diagnose gastrointestinal stromal tumour (GIST) and plan preoperative treatment with tyrosine kinase inhibitors when an endoscopic biopsy is not possible. Hypothetically, a transabdominal wall biopsy might lead to cell seeding and conversion of a local GIST to a disseminated one. We investigated the influence of preoperative needle biopsy on survival outcomes. Methods: We collected the clinical data from hospital case records of the 397 patients who participated in the Scandinavian Sarcoma Group (SSG) XVIII/Arbeitsgemeinschaft Internistische Onkologie (AIO) randomised trial and who had a transabdominal fine needle and/or core needle biopsy carried out prior to study entry. The SSG XVIII/AIO trial compared 1 and 3 years of adjuvant imatinib in a patient population with a high risk of GIST recurrence after macroscopically radical surgery. The primary end-point was recurrence-free survival (RFS), and the secondary end-points included overall survival (OS). Results: A total of 47 (12.0%) out of the 393 patients with data available underwent a percutaneous biopsy. No significant difference in RFS or OS was found between the patients who underwent or did not undergo a percutaneous biopsy either in the entire series or in subpopulation analyses, except for a statistically significant RFS advantage for patients who had a percutaneous biopsy and a tumour >= 10 cm in diameter. Conclusion: A preoperative diagnostic percutaneous biopsy of a suspected GIST may not increase the risk for GIST recurrence in a patient population who receive adjuvant imatinib after the biopsy. (C) 2016 Elsevier Ltd. All rights reserved.

Purpose The ability to make eye movements to point the fovea toward object perceived in peripheral visual field is a fundamental feature of human visual system. We studied if reaction time (RT) in visual search task can be used for deciding if a peripheral visual field stimulus is visible when measuring visual field thresholds. Methods Ocusweep™ ambient light perimeter was programmed to display peripheral 0.2° stimulus of 100 ms duration for triggering a reflex saccade to point the fovea towards the location of the stimulus which was replaced with a faint arrow figure for reporting its direction with a button press and thus confirming foveal fixation. Next peripheral stimulus followed by a new arrow was then displayed. RT between button presses were recorded. Thresholds of the right eye of eight experienced healthy persons (mean age 43, range 22–58 years) using Humphrey 30–2 grid were measured with a staircase algorithm adjusting the intensity of the stimulus in response to the RT. Measurement reliability was estimated with catch trials, viewing distance controlled using ultrasonic rangers and variation in ambient room lighting (94–240 cd/m²) compensated using ambient light sensors of Ocusweep™. Results Thresholds measured with RT perimetry were close to normal age corrected values of Octopus perimeter: mean MD was 0.7 dB and mean sLV 2.5 dB. The RT difference between positive (no stimulus, pure visual search, mean RT 1980 ms) and negative catch trials (suprathreshold stimulus, reflex saccade, mean RT 649 ms) was 1331 ms (SD 369 ms). Conclusions Reaction time perimetry can be used to measure visual field thresholds and also to assess reflex saccades.

The prevalence and persistence of antibodies against cytomegalovirus (CMV), herpes simplex virus types 1 (HSV1) and 2 (HSV2), Helicobacter pylori and Chlamydia pneumoniae were determined in Alaskan Eskimos. The study included 610 individuals (mean age 43 ± 15 years; 45% males) participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. Archived serum samples and those collected during the GOCADAN study were analysed for antibodies against the above pathogens by ELISA. The current prevalence of antibody seropositivity was 94% to CMV, 90% to HSV1, 38% to HSV2, 80% to H. pylori, and 42% to C. pneumoniae. The persistence of antibodies (in both archived and current samples) against CMV, HSV1 and H. pylori was high (83%, 84% and 67%, respectively) compared with those against HSV2 (26%) and C. pneumoniae (29%). Moreover, the seroconversion rates to these organisms were low. Most individuals acquired CMV, HSV1 and H. pylori antibodies by the age of 24 years (94%, 90% and 72%, respectively), and >50% carried HSV2 and C. pneumoniae antibodies by the age of 45 years. There were gender differences in antibody seropositivity rates. Over 70% of individuals had antibodies to at least three of the five pathogens tested. The study demonstrated the high prevalence and lifelong persistence of multiple antibodies, suggesting chronic infections among Alaskan Eskimos.

Purpose: To evaluate whether radiological findings and healing time in children with pneumonia are correlated to etiologic agent.Material and Methods: A total of 346 children with radiologically verified acute pneumonia, and with accomplished serological tests for bacteria and viruses, were included in the study. Five etiological groups were analysed: children with bacterial etiology only, with viral etiology only, with mixed bacterial and viral etiology, with Mycoplasma only, and children with no etiology.Results: The chest films of each etiological group were analysed and the findings were correlated to the children's age. The radiological findings did not differ between the etiological groups. Radiological findings correlated significantly with the patient's age. The radiological healing frequency at check‐up X‐ray was found to be significantly lower in children with mixed bacterial and viral etiology compared to children in each of the other groups and to the material as a whole.Conclusion: Conclusions about the etiology could not be drawn from the chest X‐ray findings.

Entacapone is a catechol-O-methyltransferase (COMT) inhibitor used as an adjunct to levodopa/dopa decarboxylase inhibitors in the treatment of Parkinson's disease. Entacapone increases the bioavailability and reduces the daily variation of plasma levodopa when administered with standard levodopa preparations. These parameters were studied when entacapone was administered with a controlled-release levodopa preparation after repeated administrations throughout the day in 16 healthy male volunteers. On 2 test days, 200 mg entacapone or placebo was administered 4 times during the day at 4-hour intervals concomitantly with a single dose of controlled-release levodopa/carbidopa 100 mg/25 mg (Sinemet CR). Plasma levodopa, 3-O-methyldopa (3-OMD), and carbidopa concentrations were measured before intake of the medication and then every 30 minutes for 16 hours (until midnight), and less frequently up to 24 hours after the first levodopa dose. The minimum, maximum, and average concentration of levodopa; the daily variation of levodopa concentration; and the area under the time concentration curve (AUC) were calculated. The mean (+/-SD) plasma levodopa AUC was 39% (P = 0.0001) higher with entacapone (11,802 +/- 1454 ng/hour/mL) compared with placebo (8465 +/- 927 ng/hour/mL). The daily variation of plasma levodopa was reduced by about 25% with entacapone (P < 0.01). Entacapone significantly reduced plasma 3-OMD concentration by about 50% (P = 0.0001), indicating marked COMT inhibiting activity. There were no differences in plasma carbidopa concentrations. Entacapone significantly increased the bioavailability of levodopa and reduced its daily variation when administered concomitantly with a controlled-release levodopa preparation.

The long-term safety and efficacy of the catechol-O-methyltransferase (COMT) inhibitor entacapone was investigated in a 3-year open-label extension of the 6-month double-blind placebo-controlled Nordic (NOMECOMT) study. After a wash-out following this study, 132 patients with Parkinson's disease (PD) experiencing motor fluctuations treated with levodopa/dopa decarboxylase (DDC) inhibitor received additional therapy with entacapone 200 mg, administered with each dose of levodopa. The most common adverse events (AEs) were insomnia (30%), dizziness (20%), nausea (20%), aggravated parkinsonism (17%) and hallucinations (14%). Only 19 (14%) patients discontinued because of AEs. Most dopaminergic AEs occurred shortly after initiation of entacapone, and these could be managed by levodopa down-adjustment. The mean duration of benefit of a single dose of levodopa increased significantly from 2.1 to 2.8 h (P < 0.01) at 3 months and remained prolonged for the whole study. At the end of the study, the mean daily dose of levodopa was significantly decreased from baseline (from 737 to 696 mg; P < 0.05). The patients' global assessment indicated that 69% of patients improved when given entacapone and this proportion was maintained until the end of the study (64%). There was a significant worsening of disability upon withdrawal of entacapone. In conclusion, entacapone given in combination with levodopa, has a good long-term safety profile and a sustained beneficial effect in patients with PD with motor fluctuations.

Reunanen A, Roivainen M, Kleemola M, Saikku P, Leinonen M, Hovi T, Knekt P, Leino A, Aromaa A (National Public Health Institute, Helsinki and Oulu; Social Insurance Institution, Turku; University Hospital, Turku, Finland). Enterovirus, mycoplasma and other infections as predictors for myocardial infarction. Journal of Intern Med 2002; 252: 421–429. Objectives. To study antibodies against five infectious agents for their prediction of major coronary events in men with and without evidence of coronary heart disease at baseline. Design. A case–control study nested within a prospective population study. Subjects. The study cases included 441 men 45–64 years old with nonfatal myocardial infarction or coronary death within a mean follow-up time of 10 years. A total of 165 men had already signs of heart disease at baseline, whilst 276 were apparently healthy at the beginning of the study. Two controls for each case were matched for age, heart disease status and place of residence. Antibodies against enterovirus, Mycoplasma pneumoniae, Chlamydia pneumoniae, cytomegalovirus and adenovirus were determined. Results. Men without reported baseline heart disease, but not those with heart disease, showing the highest quartile of antibodies to enterovirus and mycoplasma or increased levels of immune complex-bound antibodies to chlamydia had a significantly higher risk of coronary events than men with lower level of antibodies. The increased risk demonstrated in men with high levels of antibodies to enterovirus and mycoplasma remained significant after adjustment for other antibodies, acute-phase reactant and conventional risk factors. Serological evidence of infection by multiple agents was also significantly associated with coronary events. Conclusions. Serological evidence for several infectious agents is associated with the risk of coronary heart disease, but only in men without baseline history of heart disease.

Objectives– To determine the efficacy and safety of the catechol-O-methyltransferase (COMT) inhibitor entacapone, used as an adjunct to levodopa, in Parkinson's disease (PD) patients. Patients and methods– In this parallel group, randomized, double-blind study, 301 PD patients, the majority with motor fluctuations, received entacapone (200 mg) or placebo with each daily dose of standard or controlled-release (CR) levodopa. The 24-week treatment period was followed by 2 weeks of entacapone withdrawal. Efficacy was determined by home diaries (`on' and `off' times), Unified Parkinson's Disease Rating Scale (UPDRS) and changes in levodopa dosage, and safety by adverse-event inquiry, vital signs, electro cardiography (ECG) and laboratory tests. Results– In the total population, the UPDRS activities of daily living and motor scores were significantly improved (P

Purpose To validate a novel perimetry method (Visual Search Test, VST) which is based on reaction times in visual decision-making task, where the subject is allowed to move eyes and where the fixation is verified by the subject himself in contrast to standard automatic perimetry (SAP) where prolonged stationary fixation and external fixation monitoring apparatus is required. Methods Device (Ocusweep prototype, Ocuspecto Ltd, Turku, Finland) consisting of 35° arc (radius 54 cm) was constructed with six 3x5 LED arrays displaying 0.4°, 100 ms suprathreshold stimulus (Saccade Triggering Stimulus, STS) followed by an arrow ( ) as a fixation object (FO) the recognition of which was reported by pressing a correct button. The intensity of FO was 3-5 dB above the foveal threshold. With a correct button press a new peripheral STS & FO stimulus sequence was displayed in order to initiate a reflex saccade towards the STS. The time periods between button presses were recorded. 18 locations (up to 28° temporal, 20° nasal) along the meridians 0° and 8° of the visual field of left eye were tested. The center of the physiological blind spot of 11 healthy volunteers was measured with Octopus perimeter by custom program (1° oval grid of 139 test points). Reaction times within the blind spot area were compared to other locations. Results Reaction times within the blind spot area were slower compared to other locations in 10 of 11 subjects (AOV, p < 0.001 in 9 subjects, p < 0.006 in one subject). Conclusion Visual Search Test (VST) can be used to detect visual field defects. Commercial interest

The Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor E2-related factor 2 (Nrf2) pathway is one of the major signaling cascades involved in cell defense and survival against endogenous and exogenous stress. While Nrf2 and its target genes provide protection against various age-related diseases including tumorigenesis, constitutively active Nrf2 in cancer cells increases the expression of cytoprotective genes and, consequently, enhances proliferation via metabolic reprogramming and inhibition of apoptosis. Herein, we review the current understanding of the regulation of Nrf2 in normal cells as well as its dual role in cancer. Furthermore, the mechanisms of Nrf2 dysregulation in cancer, consequences of unchecked Nrf2 activity, and therapies targeting the Keap1-Nrf2 system are discussed.

BACKGROUND—Since the last British study of the microbial aetiology of community acquired pneumonia (CAP) about 20 years ago, new organisms have been identified (for example, Chlamydia pneumoniae), new antibiotics introduced, and fresh advances made in microbiological techniques. Pathogens implicated in CAP in adults admitted to hospital in the UK using modern and traditional microbiological investigations are described. METHODS—Adults aged 16 years and over admitted to a teaching hospital with CAP over a 12 month period from 4 October 1998 were prospectively studied. Samples of blood, sputum, and urine were collected for microbiological testing by standard culture techniques and new serological and urine antigen detection methods. RESULTS—Of 309 patients admitted with CAP, 267 fulfilled the study criteria; 135 (50.6%) were men and the mean (SD) age was 65.4 (19.6) years. Aetiological agents were identified from 199 (75%) patients (one pathogen in 124 (46%), two in 53 (20%), and three or more in 22 (8%)): Streptococcus pneumoniae 129 (48%), influenza A virus 50 (19%), Chlamydia pneumoniae 35 (13%), Haemophilus influenzae 20 (7%), Mycoplasma pneumoniae 9 (3%), Legionella pneumophilia 9 (3%), other Chlamydia spp 7 (2%), Moraxella catarrhalis 5 (2%), Coxiella burnetii 2 (0.7%), others 8 (3%). Atypical pathogens were less common in patients aged 75 years and over than in younger patients (16% v 27%; OR 0.5, 95% CI 0.3 to 0.9). The 30 day mortality was 14.9%. Mortality risk could be stratified by the presence of four "core" adverse features. Three of 60 patients (5%) infected with an atypical pathogen died. CONCLUSION—S pneumoniae remains the most important pathogen to cover by initial antibiotic therapy in adults of all ages admitted to hospital with CAP. Atypical pathogens are more common in younger patients. They should also be covered in all patients with severe pneumonia and younger patients with non-severe infection.

BACKGROUND—Acute lower respiratory tract illness in previously well adults is usually labelled as acute bronchitis and treated with antibiotics without establishing the aetiology. Viral infection is thought to be the cause in most cases. We have investigated the incidence, aetiology, and outcome of this condition. METHODS—Previously well adults from a stable suburban population consulting over one year with a lower respiratory tract illness were studied. For the first six months detailed investigations identified predetermined direct and indirect markers of infection. Evidence of infection was assessed in relation to presenting clinical features, indirect markers of infection, antibiotic use, and outcome. RESULTS—Consultations were very common, particularly in younger women (70/1000 per year in previously well women aged 16-39 years), mainly in the winter months; 638 patients consulted, of whom 316were investigated. Pathogens were identified in 173 (55%) cases: bacteria in 82 (Streptococcus pneumoniae 54, Haemophilus influenzae 31, Moraxella catarrhalis 7), atypical organisms in 75 (Chlamydia pneumoniae 55, Mycoplasma pneumoniae 23), and viruses in 61 (influenza 23). Seventy nine (24%) had indirect evidence of infection. Bacterial and atypical infection correlated with changes in the chest radiograph and high levels of C reactive protein but not with (a) the GP's clinical assessment of whether infection was present, (b) clinical features other than focal chest signs, and (c) outcome, whether or not appropriate antibiotics were prescribed. CONCLUSIONS—Over 50% of patients have direct and/or indirect evidence of infection, most commonly bacterial and atypical pathogens, but the outcome is unrelated to the identified pathogens. Many patients improve without antibiotics and investigations do not help in the management of these patients. GPs can reassure patients of the causes and usual outcome of this self-limiting condition.

An enzyme-linked immunoassay (EIA) is described and evaluated which quantitates human antibodies to serotype specific S. pneumoniae polysaccharide (PnPs) in human sera. Based on the observations previously described by Koskela (1), native PnPs are used as coating antigens and sera are absorbed with a soluble pneumococcal absorbant material containing C-polysaccharide (CPs) to ensure measurement of serotype specific anti-PnPs antibodies. The robustness of this method was evaluated by ten laboratories using the same reagents, protocol, and five human serum samples. Reproducible antibody values were obtained for IgM, IgG, and IgA antibodies to five different PnPs serotypes, 3, 6B, 14, 19F, and 23F. The overall mean percent coefficients of variation in this interlaboratory study for all five selotype specific anti-PnPs determinations with the five coded sera were 30% for IgG, 3/% for IgM, and 36% for IgA. This assay can be standardized for quantitation of serotype specific anti-PnPs antibodies, allowing comparison of antibody values in vaccine trials evaluating pneumococcal vaccines.

Objective: The objective of the study was to compare the clinical efficacy and acceptability of inhaling a single 100μg dose of salbutamol via either an Easyhaler® multidose dry powder inhaler or a pressurised metered-dose inhaler (pMDI) in the treatment of histamine-induced bronchoconstriction.

Nickel(II) acetylacetonate bound to polybenzimidazole has been shown to be an efficient catalyst for the aerobic epoxidation of alkenes with an aldehyde as co-reactant. Rates of reaction and yields of epoxide are higher with this system than with dissolved Ni(II) acetylacetonate under otherwise identical conditions. The polymer-bound complex acts as a heterogeneous catalyst and can be recovered from the reaction mixture. Some loss of activity is observed upon re-use of the catalyst due to leaching of the metal complexes.

An easy and convenient method for the preparation of functionalised porous polymer films (∼76 × 14 mm) of uniform thickness (∼60–120 µm) has been developed using microscope slides stacked together as a mould for UV-initiated polymerisation of comonomer mixtures. Both gel-type and macroporous styrene and methacrylate-based species have been prepared by appropriate choice of crosslinker (%) and porogen. The incorporation of functional comonomers: 4-vinylpyridine, vinylbenzyl chloride or glycidyl methacrylate allows ready further chemical modification of the films for potential application in a number of areas.