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Cancer diagnosis and treatment often produce psychologic stresses resulting from the actual symptoms of the disease, as well as from perceptions of the disease and its stigma. Depression is seen in many cancer patients. Depression occurs in approximately 25% of palliative care patients. It is widely recognised by clinicians that depression is a difficult symptom to identify amongst patients with advanced illness. The study is aimed for screening of depression among palliative care female patients. This study was local, prospective and cross-sectional. It was carried at Department of Clinical Oncology and Radiation Therapy of Charles University Hospital in Hradec Kralove, Czech Republic. Dates were obtained during year 2007 - 2008 in 64 palliative care female patients. The mean age for all 64 subjects was 60,5 years old (aged 29 - 88 years old). The Czech version of Zung self-rating depression scale was performed. The statistical evaluation presents that mean SDS (self-rating depression score) certifies the presence of signs of mildly depression among palliative care female patients (SDS range was 50-59). The mean SDS in all subjects was 56. The mean SDS in group of healthy females was 38,9 (normal range). The incidence of depression is 71,8% (46 of all 64 subjects). The relevance of depression is characterized: severely depressed was proved in 8 of all 46 subjects, the moderately depressed in 21 subjects of all 46 subjects and mildly depressed in 17 of all 46 subjects. The statistical evaluation not presents statistically significant dependence of SDS on smoking abuse, marital status, age, number of associated diseases and type of palliative care. The statistical evaluation presents that patients with cancer of lung, with cancer of endometrium, with cancer of gallbladder and with melanomas are moderately depressed (SDS 60-69), patients with cancer of ovary, with cancer of breast, with primary brain tumour, with cancer of ventricle, with cancer of pancreas head and with cancer of bucall cavity are mildly depressed (SDS 50-59). The results show that subsists clear association between oncological disease in palliative care and depression.

Large cross section libraries, such as EAF-2007 used for activation calculations, need to be validated. A traditional approach employs simple systematic formulae based on experimental data and derived at energies such as 14.5 MeV. Such systematics are also used for renormalization of cross sections during library preparation. This approach is gradually being replaced by using results of sophisticated nuclear model calculations. As the energy range of EAF libraries has expanded from 20 to 60 MeV an additional approach is required and the method of ‘statistical analysis of cross sections’ (SACS) has proved to be useful. SACS analyses are carried out for the important charged particle reactions (n,p) and (n,α) in the EAF-2007 and TALYS-6 libraries. TALYS-6 is a calculational library generated by the TALYS model code Version 0.72. SACS considers various reaction statistics such as σmax, Emax and Δ1/2 and plots scatter plots against a parameter such as the asymmetry (s). Trend lines using simple algebraic formulae can be fitted to the data and points discrepant from the trends correspond to reactions that require improvement. A new observation is a ‘step’ in the Δ1/2(s) plot for (n,p) reactions and this has been interpreted as due to competition between (n,p) and (n,n′p) reaction channels. Equations for the various trend curves for EAF-2007 are given.

We examined the prognostic impact of cytogenetics on the outcome of 200 acute lymphoblastic leukemia (ALL) patients 15 to 65 years of age enrolled in Southwest Oncology Group (SWOG)–9400 study. Evaluable cytogenetics or fluorescence in situ hybridization studies were available in 140 (70%) patients. Four karyotype categories (normal [n = 31, 22%], t(9;22)/BCR/ABL1 [n = 36, 26%], other unfavorable [−7, +8, or 11q23 rearrangement, n = 19, 13%], and miscellaneous [n = 54, 39%]) and the biologically and clinically relevant ALL ploidy subgroups were prospectively defined. Overall survival (OS) decreased significantly with increasing age (P = .009) and varied with karyotype category (P < .001). OS was worst for t(9;22)/BCR/ABL1 followed by other unfavorable karyotypes, with hazard ratios (HR) of 3.45 (95% confidence interval [CI], 1.88-6.31) and 2.14 (95% CI, 1.04-4.04), respectively, compared with normal diploid group. OS of the miscellaneous group was similar to that of the normal diploid group (HR = 0.82; 95% CI, 0.44-1.53). Relapse-free survival (RFS) was not significantly associated with age (P = .30) but was heterogeneous among karyotype categories (P < .001) primarily because of poor RFS in t(9;22)/BCR/ABL1 (HR = 3.49; 95% CI, 1.80-6.75) compared with the normal diploid group. After accounting for the variation among karyotype groups, age was not a significant prognostic factor for OS or RFS, highlighting cytogenetics as the most important prognostic factor in adult ALL. This trial was registered at www.ClinicalTrials.gov as #NCT00002665.

Acute myeloid leukemia (AML) is one of the most common and deadly forms of hematopoietic malignancies. We hypothesized that microarray studies could identify previously unrecognized expression changes that occur only in AML blasts. We were particularly interested in those genes with increased expression in AML, believing that these genes may be potential therapeutic targets. To test this hypothesis, we compared gene expression profiles between normal hematopoietic cells from 38 healthy donors and leukemic blasts from 26 AML patients. Normal hematopoietic samples included CD34+ selected cells (N = 18), unselected bone marrows (N = 10), and unselected peripheral bloods (N = 10). Twenty genes displayed AML-specific expression changes that were not found in the normal hematopoietic cells. Subsequent analyses using microarray data from 285 additional AML patients confirmed expression changes for 13 of the 20 genes. Seven genes (BIK, CCNA1, FUT4, IL3RA, HOMER3, JAG1, WT1) displayed increased expression in AML, while 6 genes (ALDHA1A, PELO, PLXNC1, PRUNE, SERPINB9, TRIB2) displayed decreased expression. Quantitative RT/PCR studies for the 7 over-expressed genes were performed in an independent set of 9 normal and 21 pediatric AML samples. All 7 over-expressed genes displayed an increased expression in the AML samples compared to normals. Three of the 7 over-expressed genes (WT1, CCNA1, and IL3RA) have already been linked to leukemogenesis and/or AML prognosis, while little is known about the role of the other 4 over-expressed genes in AML. Future studies will determine their potential role in leukemogenesis and their clinical significance.

The European Activation System (EASY) has been developed for activation calculations within the Fusion Technology programme. It comprises the EAF nuclear data libraries and the FISPACT inventory code. EASY-2005 contains about five times more neutron-induced reactions (62,637) than the previous version; due to an increase in the upper energy limit from 20 to 60MeV. Many measurements of activation in well-defined neutron spectra have been made; these integral results are used to validate EAF. Details of the validation covering 453 reactions are given. Model calculations were used to produce the majority of the data, and the large number of reactions, and the lack of experimental data, make it necessary to develop new checking tools. Within the SAFEPAQ-II code, the new methodology of statistical analysis of cross sections (SACS) has been developed. This enables various quantities such as maximum cross section (σ max ) to be plotted as a function of asymmetry parameter (s) for each reaction type. Such plots show well-defined trends and inconsistent data for a particular reaction can readily be identified. The use of integral data and SACS for improvement are discussed, in relation to the maintenance version, EASY-2005. 1 and the planned new version, EASY-2007.

Repair of damage to DNA resulting from chemotherapy may influence drug toxicity and survival in response to treatment. We evaluated the role of polymorphisms in DNA repair genes APE1, XRCC1, ERCC1, XPD, and XRCC3 in predicting therapeutic outcomes of older adults with acute myeloid leukemia (AML) from 2 Southwest Oncology Group (SWOG) clinical trials. All patients received standard chemotherapy induction regimens. Using logistic and proportional hazards regression models, relationships between genotypes, haplotypes, and toxicities, response to induction therapy, and overall survival were evaluated. Patients with XPD Gln751C/Asp312G (‘D’) haplotype were more likely to have complete response (OR = 3.06; 95% CI, 1.44-6.70) and less likely to have resistant disease (OR = 0.32; 95%CI, 0.14-0.72) than patients with other haplotypes. ERCC1 polymorphisms were significantly associated with lung (P = .037) and metabolic (P = .041) toxicities, and patients with the XRCC3 241Met variant had reduced risk of liver toxicity (OR = 0.32; 95%CI, 0.11-0.95). Significant associations with other toxicities were also found for variant XPD genotypes/haplotypes. These data from clinical trials of older patients treated for AML indicate that variants in DNA repair pathways may have an impact on both outcomes of patients and toxicities associated with treatments. With validation of results in larger samples, these findings could lead to optimizing individual chemotherapy options.

Several neutron activation cross section libraries have been produced recently with data above the energy of 20 MeV. These are needed because of new applications, such as the International Fusion Material Irradiation Facility (IFMIF) and Accelerator Driven Systems (ADS). A standard validation procedure for such libraries is a comparison with differential and integral experimental data. However, the number of differential data above 20 MeV is relatively small and there are very few integral experiments with neutron spectra dominated by high-energy (>20 MeV) neutrons. Furthermore the size of these libraries (about 775 targets and >60,000 reactions) favours global test procedures. It is shown that the method of ‘Statistical analysis of cross sections’ (SACS) can be used for this purpose. This is based on the assumptions that cross section excitation curves for all targets have a similar (bell) shape shifted by differences in Q -value, and that their properties, such as the maximum of the excitation curve ( σ max ), the incident neutron energy at which σ max occurs ( E max ) and the width of the excitation curve at half its maximum ( Δ 1/2 ) have a pronounced smooth trend as a function of A or s . It will be demonstrated that this method of analysis is a very effective and novel way to validate reaction cross section data, both for their shape and their magnitude. This will be illustrated using the recent European Activation Library EAF-2005, produced within the EFDA Fusion Technology Programme. The majority of the cross section data in the library are based on calculations with the nuclear reaction code TALYS.

Pancreatic amyloid formation by islet amyloid polypeptide (IAPP) is a hallmark pathological feature of type 2 diabetes. IAPP is stored in the secretory granules of pancreatic beta-cells and co-secreted with insulin to maintain glucose homeostasis. IAPP is innocuous under homeostatic conditions but imbalances in production or processing of IAPP may result in homodimer formation leading to the rapid production of cytotoxic oligomers and amyloid fibrils. The consequence is beta-cell dysfunction and the accumulation of proteinaceous plaques in and around pancreatic islets. Beta-site APP-cleaving enzyme 2, BACE2, is an aspartyl protease commonly associated with BACE1, a related homolog responsible for amyloid processing in the brain and strongly implicated in Alzheimer’s disease. Herein, we identify two distinct sites of the mature human IAPP sequence that are susceptible to BACE2-mediated proteolytic activity. The result of proteolysis is modulation of human IAPP fibrillation and human IAPP protein degradation. These results suggest a potential therapeutic role for BACE2 in type 2 diabetes-associated hyperamylinaemia.

This paper develops a banking-sector framework with heterogeneous loan monitoring costs. Banks are exposed to the moral hazard behavior of borrowers and endogenously choose whether to monitor their loans to eliminate this exposure. After analyzing an unregulated banking system, we examine several cases in which regulatory capital requirements bind the notional loan supplies of various subsets of banks. To gauge the impact of capital requirements, we define loan ‘quality’ in terms of either the ratio of monitored to total loans or the ratio of monitoring banks to total bank population. Under the assumption of a specific cross-sectional distribution of banks, our simulations show that the imposition of binding capital requirements on a previously unregulated banking system unambiguously increases the market loan rate and reduces aggregate lending, but has an ambiguous effect on loan ‘quality’. Nevertheless, once capital requirements are in place, the simulations indicate that regulators can contribute to higher overall loan ‘quality’ by toughening capital requirements.

A population-based case-control study was conducted to estimate the radiation-related risk of thyroid cancer in persons who were exposed in childhood to (131)I from the Chernobyl accident of April 26, 1986 and to investigate the impact of uncertainties in individual dose estimates. Included were all 66 confirmed cases of primary thyroid cancer diagnosed from April 26, 1986 through September 1998 in residents of Bryansk Oblast, Russia, who were 0-19 years old at the time of the accident, along with two individually matched controls for each case. Thyroid radiation doses, estimated using a semi-empirical model based on environmental contamination data and individual characteristics, ranged from 0.00014 Gy to 2.73 Gy and had large uncertainties (median geometric standard deviation 2.2). The estimated excess relative risk (ERR) associated with radiation exposure, 48.7/Gy, was significantly greater than 0 (P = 0.00013) but had an extremely wide 95% confidence interval (4.8 to 1151/Gy). Adjusting for dose uncertainty nearly tripled the ERR to 138/Gy, although this was likely an overestimate due to limitations in the modeling of dose uncertainties. The radiation-related excess risk observed in this study is quite large, especially if the uncertainty of dose estimation is taken into account, but is not inconsistent with estimates previously reported for risk after (131)I exposure or acute irradiation from external sources.

Background There is little evidence regarding the risk of leukaemia in children following exposure to radionuclides from the Chernobyl Nuclear Power Plant explosion on April 26, 1986. Methods This population-based case-control study investigated whether acute leukaemia is increased among children who were in utero or

Approximately 740,000 Ci of 131I were released into the atmosphere from the Hanford Nuclear Site in Washington State during 1944-1957. The Hanford Thyroid Disease Study (HTDS), conducted to determine if thyroid disease is increased among persons exposed as children to that 131I, also investigated whether thyroid ultrasound (US) abnormalities might be increased. The HTDS cohort (n = 5199) was selected from 1940-1946 births to mothers with usual residence in seven Washington counties. Of these, 4350 were located alive, 3447 attended HTDS clinics (1992-1997), and 3440 (1747 females) had evaluable clinical results and sufficient data to characterize their Hanford 131I exposures. US abnormalities were observed in 55.5% of women and 37.4% of men. Thyroid radiation doses from Hanford 131I, which could be estimated for 3191 evaluable participants, ranged from 0.0029 to 2823 mGy (mean, 174 mGy). Estimated dose was not significantly associated with the prevalence of any US abnormality (p = 0.21), US nodules with maximum dimension 5 mm or more (p = 0.64), or average number of US nodules per person (p = 0.80 for nodules with maximum dimension 5 mm or more). These results remained unchanged after accounting for factors that might confound or modify dose-response relationships and for uncertainty of the dose estimates. This study does not support the hypothesis that 131I exposure at Hanford's dose levels and dose rates during infancy and childhood increases the prevalence of adult thyroid US abnormalities.

Modulated chlorophyll fluorescence was used to compare dissipation of light energy as heat in photosystem II of homoiohydric and poikilohydric photosynthetic organisms which were either hydrated or dehydrated. In hydrated chlorolichens with an alga as the photobiont, fluorescence quenching revealed a dominant mechanism of energy dissipation which was based on a protonation reaction when zeaxanthin was present. CO2 was effective as a weak protonating agent and actinic light was not necessary. In a hydrated cyanobacterial lichen, protonation by CO2 was ineffective to initiate energy dissipation. This was also true for leaves of higher plants. Thus, regulation of zeaxanthin-dependent energy dissipation by protonation was different in leaves and in chlorolichens. A mechanism of energy dissipation different from that based on zeaxanthin became apparent on dehydration of both lichens and leaves. Quenching of maximum or Fm fluorescence increased strongly during dehydration. In lichens, this was also true for so-called basal or Fo fluorescence. In contrast to zeaxanthin-dependent quenching, dehydration-induced quenching could not be inhibited by dithiothreitol. Both zeaxanthin-dependent and dehydration-induced quenching cooperated in chlorolichens to increase thermal dissipation of light energy if desiccation occurred in the light. In cyanolichens, which do not possess a zeaxanthin cycle, only desiccation-induced thermal energy dissipation was active in the dry state. Fluorescence emission spectra of chlorolichens revealed stronger desiccation-induced suppression of 685-nm fluorescence than of 720-nm fluorescence. In agreement with earlier reports of Bilger et al. (1989), fluorescence excitation data showed that desiccation reduced flow of excitation energy from chlorophyll b of the light harvesting complex II to emitting centres more than flow from chlorophyll a of core pigments. The data are discussed in relation to regulation and localization of thermal energy dissipation mechanisms. It is concluded that desiccation-induced fluorescence quenching of lichens results from the reversible conversion of energy-conserving to energy-dissipating photosystem II core complexes.

Seven morphologists examined 382 slide and 82 non-slide, post-Chernobyl pediatric acute leukemia (AL) cases in radiation-exposed areas of Belarus, Russia and Ukraine; part of a case-control study by the International Consortium for Research on the Health Effects of Radiation. Among the slide cases, 99% were confirmed as AL: 92% acute lymphoid leukemia (ALL) and 86% acute myeloid leukemia (AMD demonstrating the utility of FAB classification for distinguishing ALL and AML. Among the non-slide cases, 79% were confirmed as AL: 84% ALL, and 71% AML. This study affirms AL diagnostic accuracy during a time of social upheaval in the former Soviet Union.

Bank equity is exogenous in the standard deposit-and-loan-expansion multiplier model, so that model is inappropriate for analyzing the interaction between monetary and bank regulatory policies. This paper examines the effect of a binding capital requirement on the loan expansion process. We evaluate how the conflict between the monetary and regulatory authorities evolves when bank equity adjusts to a binding capital requirement. We find that capital requirements are not innocuous for monetary policy. Nevertheless, the monetary authority can assert control over the loan expansion process in the long run, although multiplier values will differ considerably from those in the standard multiplier model.

Background: Little is known about the joint effect of iodine deficiency and radiation exposure on the risk of thyroid cancer. No epidemiological studies have been published assessing the modifying effect of iodine deficiency on radiation-induced thyroid cancer following the Chernobyl accident. Methods: A population sample of 3070 individuals (2590 ages 6–18 and 480 adults) from 75 settlements in the most highly contaminated regions of the Bryansk Oblast of Russia was identified and sampled for urinary iodine measurements in 1996 and iodine deficiency in each geopolitical unit (raion) was estimated. All cases of thyroid cancer were identified in those born 1968–1986 who were resident in the study area in May–June 1986 (34 histologically confirmed cases). The risk of thyroid cancer was examined in relation to population estimates of thyroid radiation dose and urinary iodine excretion level. Results: The excess relative risk (ERR) of thyroid cancer was significantly associated with increasing thyroid radiation dose and was inversely associated with urinary iodine excretion levels. There was a joint effect of radiation exposure and iodine deficiency. At 1 gray (Gy) the ERR in territories with severe iodine deficiency was approximately two times that in areas of normal iodine intake. Conclusions: These findings suggest that elimination of iodine deficiency in areas affected by Chernobyl may be important in reducing the effects of radiation exposure on the thyroid. If confirmed by studies based on individuals they may have implications for the use of stable iodine in the case of population exposure to radioactive iodine. (authors)

CD38 expression on chronic lymphocytic leukaemia (CLL) cells is a poor prognostic factor, however, methods for measuring this vary. The QuantiBRITETM flow cytometry (FC) system yields an absolute antigen expression value (antibodies bound/cell, ABC) and may be useful in standardizing CD38 expression analysis. We evaluated cryopreserved pretreatment CLL cells for CD20 ABC, CD38 ABC, and percentage of CD38+ B cells from 131 patients requiring therapy. The 92 patients (70%) with >/= 100 CD38 ABC had worse overall survival (OS; 34% at 5 years) compared with those with /= 100 ABC was worse than that of the 39 with /= 100 ABC was actually similar to that of patients with >/= 30% CD38+ cells. BrightCD20 expression (>/= 20 000 ABC) was not associated with a worse OS (P = 0.10). The presence of >/= 100 CD38 ABC in CLL patients requiring therapy is an unfavourable prognostic factor for OS and quantitative FC may be superior to percentage CD38+ cell assessment. Prospective trials are required to determine more precisely the prognostic significance of absolute expression levels in fresh CLL cells.

The transfer of laboratory cultures of H. pluvialis to high irradiance outdoors caused a substantial decline in the maximum quantum yield of photosystem II (PSII), from 0.65 in the morning to 0.45 at midday, as measured by the ratio of variable to maximum fluorescence yields (Fv/Fm), and a steep rise in non-photochemical quenching (NPQ). Chlorophyll fluorescence induction curves of morning samples showed a clear I-step, reflecting a certain PSII heterogeneity. Single turnover flash measurements on samples taken from the outdoor photobioreactor in the middle of day showed an increase in the reoxidation time constant of the reduced plastoquinone QA −, i.e., the time required for electron transfer from the primary plastoquinone acceptor of PSII QA − to the secondary plastoquinone acceptor QB. Photosynthesis rates were almost constant during the day. Along with the increase in non-photochemical quenching, there was a slight increase in zeaxanthin and antheraxanthin contents and decrease in violaxanthin, showing the presence of an operative xanthophyll cycle in this microalga. A marked increase of secondary carotenoids was found at the end of the first day of exposure to sunlight, mainly astaxanthin monoester, which reached 15.5% of the total carotenoid content. Though cells turned reddish during the second day, the decline in the fluorescence parameter Fv/Fm in the middle of the day was less than during the first day, and there was no further increase in the value for NPQ. Similar behaviour was observed during the third day when the culture was fully red. After four days of exposure to sunlight, the dry weight reached 800 mg L−1 and the concentration of secondary carotenoids (81% astaxanthin monoester) reached 4.4% dry weight.

The ability to predict the effects of neutron irradiation on an arbitrary material is a fundamental need of fusion technology. The European Fusion Technology Programme has long recognised this fact...

Important neutron reactions relevant to the generation of medium and long-lived radionuclides of significance to waste management in a fusion power plant have been identified. Cross sections from EAF-2001 were used to calculate the concentrations of these significant induced radionuclides. The concentrations of these radionuclides, namely A126, Co60, Nb94, and Agl08m, and the corresponding contact dose rates, due to 1 ppm of their parent impurities in the blanket and hot shield components made of vanadium based structural alloy, were calculated. The concentration of induced Ar42 in the V-4Cr-4Ti alloy was also calculated after the respective lifetime of the power plant components. A review was made of the important transmutation and activation cross sections.

Cyclosporine A (CsA) inhibits P-glycoprotein (Pgp)–mediated cellular export of anthracyclines at clinically achievable concentrations. This randomized controlled trial was performed to test the benefit of CsA addition to treatment with cytarabine and daunorubicin (DNR) in patients with poor-risk acute myeloid leukemia (AML). A total of 226 patients were randomly assigned to sequential treatment with cytarabine and infusional DNR with or without intravenous CsA. Remitting patients received one course of consolidation chemotherapy that included DNR with or without CsA as assigned during induction. Addition of CsA significantly reduced the frequency of resistance to induction chemotherapy (31% versus 47%,P = .0077). Whereas the rate of complete remission was not significantly improved (39% versus 33%, P = .14), relapse-free survival (34% versus 9% at 2 years,P = .031) and overall survival (22% versus 12%,P = .046) were significantly increased with CsA. The effect of CsA on survival was greatest in patients with moderate or bright Pgp expression (median 12 months with CsA versus 4 months for controls) compared to patients with absent or low Pgp expression (median 6 months in both arms). The frequency of induction deaths was 15% with CsA and 18% in controls. Steady-state serum concentrations of DNR (P = .0089) and daunorubicinol (P

INTRODUCTION. Most studies of AML biomarkers have examined cryopreserved mononuclear cells (MNCs) obtained from repositories. These MNCs typically include non-leukemic cells (e.g., lymphocytes) and heterogeneous populations of viable and nonviable AML blasts at various stages of differentiation. We hypothesize that these variables negatively impact the prognostic power of current biomarkers. In an attempt to improve the prognostic power of such biomarkers, we examined enriched populations of viable AML blasts from 190 randomly selected AML patients on SWOG trials. To our knowledge, this study represents the largest examination of the quality of cryopreserved AML blasts and the potential prognostic benefit of enriching for viable leukemic blasts. METHODS. Cryopreserved bone marrow (BM, N=124) and peripheral blood (PB, N=116) samples from 190 AML patients on SWOG trials (SWOG-9031, SWOG-9333, S0106, and S0112) were randomly selected. The samples were thawed and sorted for viable AML blasts using a combination of fluorochrome-conjugated antibodies and DAPI. DNA and RNA were extracted and evaluated from both the unsorted AML samples (A-MNCs) and viable AML blasts (A-Blasts). FLT3-ITD allelic ratio (AR) was quantified by fragment analyses. Expression of 13 potentially prognostic transcripts was quantified via quantitative RT/PCR: BAALC, CCNA1, CEBPA, ERG1, EVI1, FLT3, GATA2, IL3RA, JAG1, KIT, MN1, RUNX1, and WT1. Fold expression differences were computed by the comparative CT method. Associations between quantitative biomarkers (FLT3-ITD AR and transcript expression) and survival (overall, OS and relapse-free, RFS) were analyzed using Cox proportional hazards regression, with interaction terms for biomarker by cell population (A-MNCs vs. A-Blasts) or CD34 expression (separately for A-MNCs and A-Blasts). A predetermined FLT3-ITD AR cutoff of 0.5 was utilized based on results by Schneider et al. (Blood, 2012) and others. For paired samples, BM was used. RESULTS. Lymphocyte percentage varied (median 7.1%, range 0.4 - 70.1%) and was correlated with patients' pre-treatment blast percentages (rs = -0.29, P = 0.0002). Viability by DAPI varied widely (median 66.5%, range 5.2 - 95.6%), and AML blasts displayed inter- and intra-sample immunophenotypic heterogeneity, with the slight majority expressing CD34 (54%) using a predetermined immunofluorescence cut-off > 104. For OS, there was no significant difference (P=0.67) in the effect of FLT3-ITD AR between A-Blasts (HR=0.91, P=0.78) and A-MNCs (HR=1.05, P=0.88). However, for RFS, the effect of FLT3/ITD AR differed significantly (P=0.025) between A-Blasts (HR=1.93, P=0.14) and A-MNCs (HR=0.87, P=0.73). Kaplan-Meier curves of RFS by FLT3-ITD AR for A-MNCs (Figure 1A) and A-Blasts (Figure 1B) also suggest this trend. A similar, but nonsignificant, trend towards higher HRs in A-Blasts was displayed in analyses restricted to NPM1 mutated patients (Table 1). Similar analyses did not show such a striking interaction between cell population and transcript biomarkers, but we found that most transcripts displayed significant associations with immunophenotype (data not shown). Therefore, we examined if CD34 expression might impact the prognostic value of transcripts, separately by cell population. The expression of two genes (CCNA1 and GATA2) displayed significant interactions with CD34 expression in relation to clinical outcomes (Table 1). Moreover, the interaction between biomarker and CD34 expressions differed depending on which cell population was examined, such that the interaction was significant in the A-Blasts but not A-MNCs. CONCLUSION. Cryopreserved samples vary widely in percentages of non-leukemic, dying cells and differentiation stage of leukemic blasts. These factors impact the measurement of quantitative biomarkers and may also impact the significance and prognostic value of these biomarkers. Future studies must consider the effects that sample viability, composition, and differentiation stage may have on quantitative biomarkers. In addition, we are examining the potential impact that mutations in other genes (e.g., ASXL1, DNMT3A, RUNX1, etc.) may have on our results. ACKNOWLEDGEMENT. The authors wish to gratefully acknowledge the important contributions of the late Dr. Stephen H. Petersdorf to SWOG and to study S0106. SUPPORT. NIH/NCI grants CA160872,CA180819, CA180828, and CA180888. Disclosures Wood: Seattle Genetics: Honoraria, Other: Laboratory Services Agreement; Amgen: Honoraria, Other: Laboratory Services Agreement; Pfizer: Honoraria, Other: Laboratory Services Agreement; Juno: Other: Laboratory Services Agreement. Erba:Jannsen: Consultancy, Research Funding; Sunesis: Consultancy; Gylcomimetics: Other: DSMB; Agios: Research Funding; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Incyte: Consultancy, DSMB, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Ariad: Consultancy; Astellas: Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Celator: Research Funding; Juno: Research Funding. Othus:Celgene: Consultancy; Glycomimetics: Consultancy. Radich:Incyte: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy; Gilliad: Consultancy.

Increasing evidence suggests that the biology of acute myeloid leukemia (AML) may differ between older and younger patients, with a higher incidence of antecedent myelodysplasia, unfavorable cytogenetic abnormalities, and multidrug resistance seen in the elderly. Abrogation of apoptosis in response to cytotoxic medications is associated with drug resistance in AML, as is expression of bcl-2, an important anti-apoptotic protein. We hypothesized that blasts from elderly (≥55 years) and young adult AML patients might have different levels of apoptotic and cell cycle responses to chemotherapeutic agents, as well as different levels of proliferation and of bcl-2 protein expression. Therefore, we cultured bone marrow leukemia samples from previously untreated elderly (n=33) and young (n=21) AML patients for 48 h and then measured apoptosis, bcl-2 protein levels, cell cycle distributions, and expression of a proliferation marker, proliferating cellular nuclear antigen (PCNA) in multi-parametric flow cytometry assays. In some experiments, leukemia samples were exposed to cytarabine (Ara-C) or daunomycin (DNR) for the last 16–18 h of the culture period. In comparison to samples from young patients, cultured samples from elderly AML patients had a higher fraction of viable cells, as measured by Trypan blue exclusion, higher PCNA expression, and significantly less culture-induced and drug-induced apoptosis. The mean apoptosis after culture was 13% for elderly AML samples, versus 20% for young AML samples (P=0.009). Similarly, the mean apoptosis after Ara-C was lower in elderly than in young AML samples, 13 versus 28% (P=0.001), as was the mean apoptosis after DNR, 15 versus 26% (P=0.012). Diminished apoptotic responses in elderly AML cells were not consistently associated with high bcl-2 levels at thaw or bcl-2 levels increased by culture. These data suggest that new therapies should be developed to overcome abrogated apoptosis, particularly in elderly AML patients.

We report on 348 patients ≥ 70 years (median age 78 years) with acute myeloid leukemia (> 50% with secondary AML) randomized to receive either 600 mg or 300 mg of tipifarnib orally twice daily on days 1–21 or days 1–7 and 15–21, repeated every 28 days (4 treatment regimens). Responses were seen in all regimens, with overall response rate (CR + CRi + PR) highest (20%) among patients receiving tipifarnib 300 mg twice daily on days 1–21. Toxicities were acceptable. Unless predictors of response to tipifarnib are identified, further study as a single agent in this population is unwarranted.

The associations of cytogenetics with complete remission (CR) rates, overall survival (OS), and outcomes after CR were studied in 609 previously untreated AML patients younger than 56 years old in a clinical trial comparing 3 intensive postremission therapies: intensive chemotherapy, autologous transplantation (ABMT), or allogeneic bone marrow transplantation (alloBMT) from matched related donors. Patients were categorized into favorable, intermediate, unfavorable, and unknown cytogenetic risk groups based on pretreatment karyotypes. CR rates varied significantly (P

Older patients with acute myelogenous leukemia (AML) have overexpression of P-glycoprotein (Pgp+), and this has been shown to correlate quantitatively with therapeutic outcome. Since Pgp-mediated efflux of cytotoxic drugs can be inhibited by the cyclosporine analogue, PSC 833, we investigated the use of this agent with a 5-day mitoxantrone/etoposide regimen in patients over age 55 with newly diagnosed AML. Previous studies suggested a 33% incidence of grade IV/V non-hematologic toxicity with the use of mitoxantrone 10 mg/M(2) and etoposide 100 mg/M(2), each for 5 days, in this patient population. Since PSC 833 alters the pharmacokinetic excretion of MDR-related cytotoxins, this phase I dose-finding study was performed to identify doses of mitoxantrone/etoposide associated with a similar 33% incidence of grade IV/V non-hematologic toxicity, when given with PSC 833. Mitoxantrone/etoposide (M/E) doses were escalated in fixed ratio from a starting dose of M: 4 mg/M(2) and E: 40 mg/M(2), to M: 7 mg/M(2) and E: 70 mg/M(2), in successive cohorts of eight patients each. PSC 833 was well tolerated and the MTD of this M/E regimen with PSC 833 in this population was M: 6 mg/M(2) and E: 60 mg/M(2). The complete response (CR) rate for all patients was 50% (15/30) and was considerably higher for de novo than for secondary AML. These data suggest that the addition of PSC 833 to an M/E regimen for older patients with untreated AML is well tolerated but requires a reduction in M/E dosing to avoid increased toxicity.

The main secondary carotenoids used in food industries are astaxanthin and β-carotene. Microalgae are one of the best sources for these compounds. Only two taxa i.e. Dunaliella and Haematococcus are used for industrial purposes. In this contribution, we report results about the secondary carotenoid synthesis capacity of 25 different green algal strains. The different strains were cultivated in standard conditions. Their growth rates were monitored and were used as a first selection parameter, Significant differences were found between the different species. In order to estimate the capacity to synthesize secondary carotenoids, the algae were subjected to a combination of light and nitrogen-starvation stresses. Under these conditions, dramatic changes in the pigment composition were triggered: chlorophyll amount dramatically decreased while secondary carotenoids synthesis occurred. As a consequence, a change in the culture colour from green to orange or red was visually observed. The modifications in the pigment composition during this process were further analyzed by thin-layer and diode-array reversed-phase high-performance liquid chromatographies. The analysis revealed that most of the strains accumulated more than one astaxanthin form except Ankistrodesmus sp., Mychonastes zofingiensis, Chlorella fusca and Pleurastrum sarcinoideum strain LUKESOVA 23/87 which preferentially accumulated free astaxanthin, astaxanthin monoester and astaxanthin diester, respectively.

The European Activation File (EAF) project has been an ongoing process performed through European and world-wide cooperation that has led to the creation of succeeding EAF versions. The latest release, EAF-99, has benefited from the generation and maintenance of comprehensive activation files and the maturing of the processing code SYMPAL. Recently, for the first time, results of integral experiments have been used to adjust data. Validation of activation code predictions, and thereby of cross section and decay data, has been performed by means of direct comparison with measurements of sample structural material under fusion-relevant neutron spectra. The EAF-99 library contains 12,468 excitation functions involving 766 different targets from 1H to 257Fm, atomic numbers 1 to 100, in the energy range 10−5 eV to 20 MeV. The 1,500,000 lines that make up the pointwise file are then processed into numerous groupwise files with different micro-flux weighting spectra to meet various user needs. Uniquely, an uncer...

Multicolor spectral karyotyping allows simultaneous visualization of all human chromosomes and screening for chromosomal rearrangements without a priori knowledge of any abnormalities involved. Based on this potentially increased sensitivity, we investigated, in a preliminary manner, whether spectral karyotyping could detect cytogenetic aberrations in karyotypically normal leukemia. The test population was comprised of 28 cryopreserved, cytogenetically normal acute myeloid leukemia (AML) samples from patients registered to a randomized trial for previously untreated AML (SWOG 9031). Two normal and 12 samples with known cytogenetic aberrations were used to validate and establish the diagnostic accuracy of the spectral karyotyping assay and instrumentation in a clinical setting. Enumeration and region-specific DNA fluorescence in situ hybridization (FISH) probes verified discrepant results. In the validation data set, spectral karyotyping refined complex karyotypic rearrangements in six cases and defined the chromosomal origin of a “jumping” homogeneously staining region; however, the technology was less sensitive in the detection of subtelomeric rearrangements and double minute chromosomes. In the test population, spectral karyotyping identified previously undetected cytogenetic aberrations in two cases (7%) of karyotypically normal AML: a cryptic 11q23 translocation in 20/20 cells and a minor monosomy 7 clone in 3/21 cells (FISH, 10.5%). Both of these abnormalities are considered to confer a poor prognosis when based on classical cytogenetic prognostic criteria. As an adjunct to classical cytogenetics and standard FISH analyses, the additive resolution of spectral karyotyping, in particular, with chromosome paints spiked with subtelomeric and/or locus-specific probes, may allow significant gains to be made in diagnostic accuracy and recognition of genotype/phenotype prognostic relationships, and in defining underlying biologic mechanisms in cancer. Genes Chromosomes Cancer 28:318 ‐328, 2000. © 2000 Wiley-Liss, Inc.

This paper extends one aspect of the US stock market study of Fama (1990) and Schwert (1990). We examine the relationship between industrial production (IP) growth rates and lagged real stock returns for the G-7 countries using both in-sample cointegration and error-correction models and the out-of-sample forecast-evaluation procedure of Ashley et al. (1980). The cointegration tests show a long-run equilibrium relationship between the log levels of IP and real stock prices, while the error-correction models indicate a correlation between IP growth and lagged real stock returns for all countries except Italy. The out-of-sample tests show that in several sub-periods the US, UK, Japanese, and Canadian stock markets enhance predictions of future IP. ” 1999 Elsevier Science B.V. All rights reserved.

Conditions for the primary culture of branching scleractinian coral (Acropora micropthalma and Pocillopora damicornis) cells were established with a calcium-free seawater cell dissociation method. Cells were isolated and cultured in supplemented Dulbecco's modified Eagle media with heat-inactivated fetal bovine serum, antibiotics, and sterile seawater. Among the isolated cell types, large (60-100 microm) multicellular endothelial isolates (MEIs) were seen in high numbers. These isolates were observed to continually spin for up to 300 h without media change. The following parameters were optimized: media, serum, light, trace elements, and growth factor supplements. Rotations per minute were calculated to determine MEI motility in relation to size. Finally, analyses of external and internal structures were conducted with scanning electron microscopy, transmission electron microscopy, and fluorescence microscopy. Additional coral species, Montipora digitata, Stylophora pistillata, Seriatopora hystrix and Porites sp. were also cultured to determine the applicability of isolation techniques. The relatively long survival time of MEIs in primary culture makes them ideal candidates for in vitro studies examining coral disease processes (e.g., mode of infection and intracellular effects of disease-causing agents) as well as aspects of general coral growth and health (e.g., trace element requirements and transfer of products between host cell and zooxanthellae).

The aim of this study is to determine whether the addition of mitoxantrone to high dose cytarabine improves the outcome of treatment in patients with relapsed or refractory acute myeloid leukemia (AML). One hundred and sixty-two eligible patients, 14-76 years of age, with AML either in first relapse or that failed to respond to initial remission induction therapy, with no CNS involvement were randomized to receive therapy with cytarabine 3 gm/M2 i.v. over 2 h every 12 h for 12 doses on days 1-6 (Arm I) (HIDAC); or HIDAC plus mitoxantrone 10 mg/M2 i.v. daily on days 7 9 (Arm II) (HIDAC + M). Patients achieving complete remission were treated with three courses of consolidation including HIDAC (Ara-C 3 gm/M2 i.v. 12 h days 1 3; 2 gm/M2 over age 50) alone (ARM I) or with mitoxantrone (10 mg/M2 i.v. day 1) (ARM II). Among 162 patients (81 HIDAC, 81 HIDAC + M) evaluated for induction toxicity, there were 10 (12%) induction deaths with HIDAC and 13 (17%) with HIDAC + M (2-tailed P = 0.65). Most early deaths were due to infection and/or hemorrhage. Among 162 patients evaluated for responses to induction therapy, 26/81 (32%) HIDAC and 36/81 (44%) HIDAC + M patients achieved complete remission (two-tailed P = 0.15). Although this difference was not statistically significant in univariate analysis, it was after adjusting for the effects of WBC and PMN percentage in multivariate analysis (P=0.013). Median survivals from study entry were 8 months (HIDAC) and 6 months (HIDAC + M); 2-tailed logrank P = 0.58. Among 48 patients registered for consolidation, the median disease-free survivals from that registration were 8 months with HIDAC and 11 months with HIDAC + M (P = 0.60). There were three treatment-related deaths during consolidation (1 HIDAC, 2 HIDAC + M), all due to infections. In this randomized trial, the addition of mitoxantrone to high-dose cytarabine was associated with a trend toward a higher CR rate. There was less evidence for an advantage in disease-free or overall survival, although any such conclusion is limited by the size of the study.

The cytomorphological features (cell morphology, type of cell division, cell structure, structure of photosynthetic apparatus) were studied in the type strains of the cyanoprokaryotic genera Cyanobium and Cyanobacterium , and in the reference strain of the traditional genus Synechococcus ( Synechococcus PCC 6301; = “ Anacystis nidulans ” sensu auct.). They were originally described by Rippka & Cohen-Bazire, based on the mean DNA-base composition (moles % G + C) and on the resistance to various cyanophages. The phenotypic diacritical characters were found to coincide well with the molecular markers, and thus, the genera Cyanobium and Cyanobacterium are acceptable also according to the traditional (botanical) taxonomic criteria. The integrated molecular, cytomorphological and ecophysiological approaches to the solution of taxonomic problems in cyanobacteria are therefore inevitable for taxonomic evaluation, from the methodological point of view. The lists of species within the revised genera Cyanobium and Cyanobacterium are reviewed.

I. INTRODUCTION This paper presents a finite-life model of human capital acquisition. Time is continuous and individuals have lifespan T. Technological progress has two components, an ease-of-learning parameter and a knowledge frontier. The first reflects the rate of knowledge acquisition for a given amount of learning time, and the second reflects the limit on what can be learned. We obtain three main results. The first is that as lifespan increases, output per person-hour rises. The increase is nearly linear for short lifespans, but diminishes at higher lifespans as the knowledge frontier becomes binding. An increase in lifespan causes individuals to opt for more pre-work learning, higher skill levels at the beginning of the working phase, and, for sufficiently long lifespans, more learning during the work-phase. Thus, an increase in lifespan raises the skill level and thereby the total human capital and labor supply of a country, and consequently its per capita capital stock and output levels.(1) The data are consistent with a lifespan impact on output that is positive and diminishes as lifespan increases.(2) The second result concerns the technology adoption behavior of working individuals. We find that workers will only adopt new technology after they begin working if they have sufficiently long lifespans so that reaching the knowledge frontier is in their interest. When lifespans are short, individuals begin to work before they reach the knowledge frontier and never attempt to learn anything after that point. This aspect of optimal behavior is important because if there is a surge in worldwide technological progress, current workers will not adopt the new knowledge in a country characterized by short lifespans. Rates of transition will therefore be slower for short-lifespan countries. The final result is that when lifespans differ among countries, international differences in output per person can persist even in the presence of perfect markets. Goods can trade freely. Capital can move across borders without any borrowing or lending impediments. The only restriction is that individuals cannot migrate freely. The per capita differences persist because countries that differ in skill levels, real wages and per capita output levels will nevertheless have similar per skill-unit wages. Human capital accumulation has received renewed attention in the growth literature.(3) Prominent examples are Jones, Manuelli and Rossi [1993] and Caballe and Santos [1993]. These authors study models in which individuals have infinite lifespans, which contrasts with ours where lifespans are finite. The finite-life behavior of our model reflects the earlier work of Ryder, Stafford, and Stephan [1976] and has been reviewed in Blinder and Weiss [1976]. In particular, these authors describe a four-stage sequence (learning, work and learning, learning only and retirement) that is also central to our analysis. O'Neill [1995] studies the role of the returns to human capital accumulation in explaining transitional growth rates. Parente and Prescott [1994] study the acquisition of knowledge and also assume an exogenously decreasing cost of knowledge acquisition, although in their model firms, not individuals, engage in the acquisition of knowledge. Moreover, our paper assumes two forms of technology, a knowledge frontier and an ease of acquiring it, whereas Parente and Prescott only have the second. The present paper builds on Swanson, Kopecky, and Tucker [1997], who study the business cycle effects of different adoption rates at different ages. In this paper we focus on the lifespan effects of a similar model. The paper is organized as follows. Section II describes the nature of the correlations of lifespan with both current output and future growth. Section III develops the finite lifetime model. Section IV characterizes the behavior of the model and compares it with the evidence provided in section II. …

Older age is a poor prognosis factor in acute myeloid leukemia (AML). This double-blind trial was designed to test the hypothesis that granulocyte colony-stimulating factor (G-CSF) used as supportive care could improve the treatment of elderly AML patients. Two hundred thirty-four patients 55 or more years of age with a morphologic diagnosis of de novo or secondary AML, French-American-British (FAB) M0-M7, excluding M3, were randomly assigned to a standard induction regimen (daunorubicin at 45 mg/m2 intravenously [IV] on days 1 through 3 and Ara-C at 200 mg/m2 IV continuous infusion on days 1 through 7) plus either placebo or G-CSF (400 μg/m2 IV over 30 minutes once daily). Results are reported here for 211 centrally confirmed cases of non-M3 AML. The two groups were well balanced in demographic, clinical, and hematological parameters, with median ages of 68 years in the G-CSF and 67 years in the placebo groups. The complete response (CR) rate was not significantly better in the G-CSF group: 50% in the placebo and 41% in the G-CSF group (one-tailedP = .89). Median overall survival was also similar, 9 months (95% confidence interval [CI], 7 to 10 months) in the placebo and 6 months (95% CI, 3 to 8 months) in the G-CSF arms (P = .71). We found a significant 15% reduction in the time to neutrophil recovery in the G-CSF group (P = .014). G-CSF had no impact on recovery from thrombocytopenia (P = .80) or duration of first hospitalization (P = .27). When infection complications were evaluated, G-CSF had a beneficial effect on the duration but not on incidence of infection. G-CSF patients had fewer days with fever and shorter duration of antibiotic use. However, there was no difference in the frequency of total documented infections or in the number of fatal infections (19% placebo v 20% G-CSF). In this study of elderly AML patients, G-CSF improved clinical parameters of duration of neutropenia and antibiotic use, but did not change CR rate or survival or shorten hospitalization.

An instrument, that validly and reliably identifies and measures agitation is required to evaluate environmental modifications, interpersonal strategies, psychopharmacological interventions, directed toward managing these commonly occurring and highly-disabling emotions and behavior. The conceptualization of agitation on a continuum from anxiety to aggression provides a practical framework for guiding clinical practice toward the early identification and intervention of agitation. The results of this study established the reliability and validity of the Overt Agitation Severity Scale (OASS) in measuring agitation severity in young adult psychiatric inpatients based on objectifiable vocalizations and motoric upper and lower body behaviors. The OASS differs from other agitation scales in its ability to capture both the intensity and frequency of observable behavioral manifestations of agitation, as opposed to subjective interpretations and a diffuse range of symptoms and problem behaviors.

FLT3 internal tandem duplications (FLT3/ITDs) in the juxtamembrane domain are found in approximately 25% of acute myeloid leukemia (AML) patients, ranging in size from 3 to hundreds of nucleotides. We examined whether the sizes of FLT3/ITDs were associated with clinical outcomes in 151 AML patients enrolled in Southwest Oncology Group studies: S9333 and S9500. FLT3/ITDs were identified in 32% of patients (median ITD size = 39 nucleotides; range, 15-153 nucleotides). The CR rates were 35%, 67%, and 52% for patients with large (≥ 40), small (< 40), and no ITDs, respectively (P = .19). Increasing ITD size was associated with decreasing OS (estimated 5-year OS: large = 13%, small = 26%, and no ITD = 21%, P = .072) and RFS (estimated 5-year RFS: large = 13%, small = 27%, and no ITD = 34%, P = .017). These studies suggest that ITD size may have prognostic significance.

BACKGROUND Reports on outcomes of chemotherapy trials in acute myeloid leukemia (AML) have rarely included results of long-term follow-up beyond 10 years. The authors therefore chose to review long-term follow-up data from 3 studies conducted by the Southwest Oncology Group (SWOG) between 1978 and 1990. METHODS The analysis included data on 2083 patients enrolled in SWOG studies S7823, S8124, and S8600. The results were based on data available as of November 15, 1996. RESULTS The probability of survival 8 years after entry was 9% in Study S7823, 14% in S8124, and 15% in S8600. For patients age < 50 years, the probabilities were 14%, 24%, and 20%, respectively. For patients ages 50-64 years, the probabilities were 7%, 8%, and 8%, respectively. For those age < 50 years who achieved complete remission, the 8-year probability of disease free survival was 17% in Study S7823, 28% in S8124, 17% with standard dose cytarabine in S8600, and 26% with high dose cytarabine in S8600. Relapse was the major reason for failure after complete remission in all three studies. When the results of the 3 studies were combined, most of the 743 relapses had occurred by Year 3 and nearly all the rest by Year 5. Among the prognostic factors universally available for study, three were highly associated with survival in all three studies: age, French-American-British disease classification, and white blood cell count at diagnosis. CONCLUSIONS In view of the fact that most deaths occurred during the first 3 years, it is appropriate to report the results of clinical trials after patients have been followed for 4 years. Despite modest gains, the results of chemotherapy for AML remain disappointing, especially in the treatment of older patients. Cancer 1997; 80:2199-204. © 1997 American Cancer Society.

Two studies tested the reliability and validity of the Overt Agitation Severity Scale (OASS), a new instrument developed to define and objectively rate the severity of agitated behavior. The authors postulate that agitation should be conceptualized as vocal and motor behaviors on a continuum of expressions that extends from anxiety to aggression. Content validity through expert agreement was achieved in the development of test construction over a 2-year period. Results of two pilot studies (n = 25 and n = 14 subjects) established the reliability and validity of the OASS to measure agitation severity. The OASS differs from other agitation scales in that it confines its rating exclusively to observable behavioral manifestations of agitation.

The processing code SYMPAL is used to perform the necessary data treatment involved in the creation of a version of the European Activation File (EAF). The entire process is handled by different modules of the code in a sequential and orderly manner. Two major data bases are accessed and merged so as to create a new library level. The Master Data File (MDF) contains the original cross-section data extracted, unmodified but reformatted, from numerous sources. The Master Parameter File (MPF) contains a compilation of all physical information necessary to renormalise, split and internally validate any particular type of cross-section. The combination of the two Master files generates a new activation file in a pointwise and various groupwise formats. An uncertainty file, reporting information and validation plots, is also produced.

The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is described in full. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, aldehydes, and ketones.

Compared with younger patients, elderly patients with acute myeloid leukemia (AML) respond poorly to conventional chemotherapy. To determine if this poor response is due to differences in the biologic characteristics of AML in the elderly, we studied 211 patients (161 de novo, 50 secondary AML) over 55 years of age (median, 68 years) registered to a single clinical trial for previously untreated AML (SWOG 9031, Phase III randomized trial of standard dose cytosine arabinoside and daunomycin ± rhG-CSF ). Pretreatment leukemic blasts were karyotyped and were also analyzed for intrinsic drug resistance by quantitating expression of the multidrug resistance glycoprotein MDR1 and functional drug efflux using sensitive flow cytometric techniques. Results were correlated with clinical variables and outcome. These elderly AML patients had a high frequency of unfavorable cytogenetics (32%), MDR1 protein expression (71%), and functional drug efflux (58%); each of these factors occurred at high frequencies in both de novo and secondary AML patients and was associated with a significantly poorer complete remission (CR) rate. In multivariate analysis, secondary AML (P = .0035), unfavorable cytogenetics (P = .0031), and MDR1 (P = .0041) were each significantly and independently associated with lower CR rates. Resistant disease was associated with unfavorable cytogenetics (P = .017) and MDR1 expression (P = .0007). Strikingly, elderly MDR1(−) de novo AML patients with favorable/intermediate cytogenetics had a CR rate of 81%; with increasing MDR1 expression, CR rate decreased in this cytogenetic group. MDR1(+) secondary AML patients with unfavorable cytogenetics had a CR rate of only 12%. Thus, AML in the elderly is associated with an increased frequency of unfavorable cytogenetics and MDR1 expression, both of which independently contribute to poor outcomes. The high frequencies of these features in both de novo and secondary elderly AML patients suggest a common biologic mechanism for these leukemias distinct from that in younger patients. Investigation of biologic parameters at diagnosis in AML in the elderly may help identify patients with a high likelihood of achieving CR with conventional regimens, as well as those who may require alternate regimens designed to overcome therapy resistance.

A total of 105 patients (age ≥ 18 years) with newly diagnosed low or intermediate risk acute promyelocytic leukaemia (APL) were treated with a standard induction and consolidation regimen including arsenic trioxide (ATO). Sixty-eight patients who were polymerase chain reaction (PCR) negative for PML-RARA post-consolidation were randomized to either one year of maintenance with tretinoin, mercaptopurine and methotrexate, or observation. Enrollment in this non-inferiority trial was stopped prematurely due to slow accrual. With a median follow up of 36.1 months, the overall survival of the 105 patients was 93%, and there have been no relapses in the patients randomized to maintenance or observation. These results demonstrate that cures can be expected in >90% of patients with low and intermediate risk APL and suggest that maintenance therapy may not be needed if patients are treated with an intensive post-remission regimen including ATO. This trial was registered at clinicaltrials.gov as #{"type":"clinical-trial","attrs":{"text":"NCT00492856","term_id":"NCT00492856"}}NCT00492856.

Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1β, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNγ and GM-CSF, were measured using a Luminex suspension bead-based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL.

To determine whether standard evaluations of pain distinguish subjects with no pain from those with myofascial pain syndromes (MPS) and active myofascial trigger points (MTrPs) and to assess whether self-reports of mood, function, and health-related quality of life differ between these groups.A prospective, descriptive study.University.Adults with and without neck pain.We evaluated adults with MPS and active (painful) MTrPs and those without pain. Subjects in the "active" (A) group had at least one active MTrP with spontaneous pain that was persistent, lasted longer than 3 months, and had characteristic pain on palpation. Subjects in the "no pain" (NP) group had no spontaneous pain. However, some of these subjects had discomfort upon MTrP palpation (latent MTrP), whereas others in the NP group had no discomfort upon palpation of nodules or had no nodules.Each participant underwent range of motion measurement, a 10-point manual muscle test, and manual and algometric palpation. The latter determined the pain/pressure threshold using an algometer of 4 predetermined anatomic sites along the upper trapezius. Participants rated pain using a verbal analog scale (0-10) and completed the Brief Pain Inventory and Oswestry Disability Scale (which included a sleep subscale), the Short -Form 36 Health Survey, and the Profile of Mood States.The A group included 24 subjects (mean age 36 years; 16 women), and the NP group included 26 subjects (mean age 26 years; 12 women). Group A subjects differed from NP subjects in the number of latent MTrPs (P = .0062), asymmetrical cervical range of motion (P = .01 for side bending and P = .002 for rotation), and in all pain reports (P.0001), algometry (P.03), Profile of Mood States (P.038), Short Form 36 Health Survey (P.01), and Oswestry Disability Scale (P.0001).A systematic musculoskeletal evaluation of people with MPS reliably distinguishes them from subjects with no pain. The 2 groups are significantly different in their physical findings and self-reports of pain, sleep disturbance, disability, health status, and mood. These findings support the view that a "local" pain syndrome has significant associations with mood, health-related quality of life, and function.

The tetrapod auditory system transmits sound through the outer and middle ear to the organ of Corti or other sound pressure receivers of the inner ear where specialized hair cells translate vibrations of the basilar membrane into electrical potential changes that are conducted by the spiral ganglion neurons to the auditory nuclei. In other systems, notably the vertebrate limb, a detailed connection between the evolutionary variations in adaptive morphology and the underlying alterations in the genetic basis of development has been partially elucidated. In this review, we attempt to correlate evolutionary and partially characterized molecular data into a cohesive perspective of the evolution of the mammalian organ of Corti out of the tetrapod basilar papilla. We propose a stepwise, molecularly partially characterized transformation of the ancestral, vestibular developmental program of the vertebrate ear. This review provides a framework to decipher both discrete steps in development and the evolution of unique functional adaptations of the auditory system. The combined analysis of evolution and development establishes a powerful cross-correlation where conclusions derived from either approach become more meaningful in a larger context which is not possible through exclusively evolution or development centered perspectives. Selection may explain the survival of the fittest auditory system, but only developmental genetics can explain the arrival of the fittest auditory system. [Modified after (Wagner 2011)].

An overview was given on the recent progress of nuclear data development for fusion reactor technology. The status of an international nuclear data library, FENDL, was reviewed. Recent requests for...

Interest in high-dose cytarabine (HDAC) for both induction and postremission therapy for acute myeloid leukemia (AML) prompted the Southwest Oncology Group (SWOG) to initiate a randomized trial comparing HDAC with standard-dose cytarabine (SDAC) for remission induction of previously untreated AML and to compare high-dose treatment versus conventional doses for consolidation therapy. Patients less than 65 years of age with de novo or secondary AML were randomized for induction between SDAC 200 mg/ m2/d for 7 days by continuous infusion or HDAC at 2 g/ m2 intravenously every 12 hours for 12 doses; both groups received daunorubicin (DNR) at 45 mg/m2/d intravenously for 3 days. Complete responders to SDAC were randomized to receive either two additional courses of SDAC plus DNR or one course of HDAC plus DNR. Complete responders to HDAC were nonrandomly assigned to receive one additional course of HDAC plus DNR. Of patients randomized between SDAC (n = 493) and HDAC (n = 172) induction, 361 achieved complete remission (CR). The CR rate was slightly poorer with HDAC: 55% versus 58% with SDAC for patients aged less than 50, and 45% (HDAC) versus 53% (SDAC) for patients aged 50 to 64 (age-adjusted one-tailed P = .96). With a median follow-up time of 51 months, survival was not significantly better with HDAC (P = .41); the estimated survival rate at 4 years was 32% (HDAC) versus 22% (SDAC) for those aged less than 50, and 13% (HDAC) versus 11% (SDAC) for those aged 50 to 64. However, relapse-free survival was somewhat better following HDAC Induction (P = .049): 33% (HDAC) versus 21% (SDAC) at 4 years for those aged less than 50, and 21% (HDAC) versus 9% (SDAC) for those aged 50 to 64. Induction with HDAC was associated with a significantly increased risk of fatal (P = .0033) and neurologic (P < .0001) toxicity. Among patients who achieved CR with SDAC, survival and disease-free survival (DFS) following consolidation randomization were not significantly better with HDAC compared with SDAC (P = .77 and .46, respectively). Patients who received both HDAC induction and consolidation had the best postremission outcomes; however, the proportion of CR patients who did not go on to protocol consolidation therapy was more than twice as high after HDAC induction compared with SDAC. Induction therapy with HDAC plus DNR was associated with greater toxicity than SDAC plus DNR, but with no improvement in CR rate or survival. Following CR induction with SDAC, consolidation with HDAC increased toxicity but not survival or DFS. In a nonrandomized comparison, patients who received both HDAC induction and consolidation had superior survival and DFS compared with those who received SDAC induction with either SDAC or HDAC consolidation.