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Single-phase Hf2Al4C5 ternary carbide was fabricated from Hf/Al/C powder mixtures by pressure assisted sintering techniques such as hot pressing and spark plasma sintering at 1900 °C for 3 h and 10 min, respectively. XRD confirmed that the ternary carbide started to form at temperatures as low as 1500 °C and with total formation of Hf2Al4C5 after reactive sintering for 1 h at 1900 °C. It is evident from HRTEM that two Hf-C layers were sandwiched with 4 Al-C layers (Al4C3) in the Hf2Al4C5 ternary carbide. Tight interlocking of grains, faceted grains and stacking faults were occasionally observed. Thermal conductivity of Hf2Al4C5 is measured to be 14 w m−1k−1 from room temperature to 1300 °C. The oxidation studies carried out at 1300 °C for 3 h reveal that the oxidation layer thickness is around 220 μm and it contains microcracks closer to sample surface whereas the interface looks seamless without any cracking or spallation of the oxide layer.

In this work we present the results of experiments aimed at comparing the performances of various techniques for the detection of metal contamination in the silicon technology. Techniques for the measurement of surface contamination such as Total Reflection X-Ray Fluorescence (TXRF) and Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) are compared with techniques for the measurement of contamination in the silicon volume, specifically the Deep Level Transient Spectroscopy and techniques for the measurement of carrier lifetime. Carrier lifetime measurements were obtained by photocurrent measurements and by Surface Photovoltage measurements. In a first experiment, Synchrotron-Radiation TXRF (SR-TXRF) was used as the reference technique to assess the sensitivity of a commercial TXRF instrument and of carrier lifetime measurements to detect iron contamination in wafers cleaned by ordinary cleaning processes. Samples intentionally contaminated by spinning with various elements were used for another experiment comparing TXRF and ToF-SIMS measurements of surface contamination. Then, a few case studies are discussed, specifically tungsten contamination by sputtering in ion-implanted samples and palladium contamination due to contact with a contaminated chuck. In all these experiments, advantages and disadvantages of the different techniques are discussed. The results of this study clearly show that it is not possible to define a unique recipe that can be applied in all cases. The maximum tolerated contaminant concentration per unit area depends on the contaminant diffusivity, and is much lower for slow diffusers. The contaminant diffusivity and solid solubility in silicon determine the in-depth distribution of the contaminant, and hence the most effective approach.

PI3K/Akt/mTOR pathway activation is common in GH-secreting pituitary tumours, and a target for treatment with mTOR inhibitors, including everolimus (EVE). The current study aimed to evaluate the efficacy of two PI3K inhibitors (PI3Ki), NVP-BKM120 and NVP-BYL719, alone and in combination with EVE in rat GH-secreting pituitary tumour cell line (GH3) and human GH-secreting pituitary tumour cell cultures. In GH3 cell line and in six GH-secreting tumour cell cultures, the effects of PI3Ki and EVE, as single agents and in combination, were tested on cell viability and colony survival, by MTT and clonogenic assay, respectively, whereas western blot was performed to evaluate the underlying intracellular signalling pathways. PI3Ki and EVE showed a dose-dependent inhibition of cell viability in GH3 cell line, with PI3Ki displaying a synergistic effect when combined with EVE. PI3Ki and EVE inhibited colony survival in GH3 cell line with no further improvement in combination. In GH-secreting pituitary tumour cell cultures PI3Ki are effective in inhibiting cell viability increasing the slight and non significant inhibition induced by EVE as single agent, generally showing a synergistic effect. Despite in both GH3 cell line and GH-secreting pituitary tumour cell cultures combination of PI3Ki enhanced EVE effect, the study of intracellular signalling pathways revealed a different regulation of PI3K/Akt/mTOR and MAPK between the two models. The results of the current study demonstrated that PI3Ki, especially in combination with EVE, are effective in inhibiting cell proliferation, therefore representing a promising therapeutic tool for the treatment of aggressive GH-secreting pituitary tumours, not responsive to standard medical therapies.

Nonrhabdomyosarcoma soft-tissue sarcomas (STSs) are a class of 50+ cancers arising in muscle and soft tissues of children, adolescents, and adults. Rarity of each subtype often precludes subtype-specific preclinical research, leaving many STS patients with limited treatment options should frontline therapy be insufficient. When clinical options are exhausted, personalized therapy assignment approaches may help direct patient care. Here, we report the results of an adult female STS patient with relapsed undifferentiated pleomorphic sarcoma (UPS) who self-drove exploration of a wide array of personalized Clinical Laboratory Improvement Amendments (CLIAs) level and research-level diagnostics, including state of the art genomic, proteomic,ex vivolive cell chemosensitivity testing, a patient-derived xenograft model, and immunoscoring. Her therapeutic choices were also diverse, including neoadjuvant chemotherapy, radiation therapy, and surgeries. Adjuvant and recurrence strategies included off-label and natural medicines, several immunotherapies, and N-of-1 approaches. Identified treatment options, especially those validated during thein vivostudy, were not introduced into the course of clinical treatment but did provide plausible treatment regimens based on FDA-approved clinical agents.

Acromegaly is associated with an enhanced mortality, with cardiovascular and respiratory complications representing not only the most frequent comorbidities but also two of the main causes of deaths, whereas a minor role is played by metabolic complications, and particularly diabetes mellitus. The most prevalent cardiovascular complications of acromegaly include a cardiomyopathy, characterized by cardiac hypertrophy and diastolic and systolic dysfunction together with arterial hypertension, cardiac rhythm disorders and valve diseases, as well as vascular endothelial dysfunction. Biochemical control of acromegaly significantly improves cardiovascular disease, albeit completely recovering to normal mainly in young patients with short disease duration. Respiratory complications, represented mainly by sleep-breathing disorders, particularly sleep apnea, and respiratory insufficiency, frequently occur at the early stage of the disease and, although their severity decreases with disease control, this improvement does not often change the indication for a specific therapy directed to improve respiratory function. Metabolic complications, including glucose and lipid disorders, are variably reported in acromegaly. Treatments of acromegaly may influence glucose metabolism, and the presence of diabetes mellitus in acromegaly may affect the choice of treatments, so that glucose homeostasis is worth being monitored during the entire course of the disease. Early diagnosis and prompt treatment of acromegaly, aimed at obtaining a strict control of hormone excess, are the best strategy to limit the development or reverse the complications and prevent the premature mortality.

Up to date, it is commonly reported in literature that the amount of copper hillocks is dependent on a) the total amount of residual Cu oxide after Cu CMP, and b) the Cu nitridation. The present work describes how that is only partially true: hillocks depend also on the kind of oxide and on the roughness of the surface after wet treatment. This contribution is even more important than what reported in literature. A tentative model for this behavior is proposed.

In this paper, we review the results of some studies addressing the problem of tungsten contamination in implantation processes. For some tests, the implanter was contaminated by implantation of wafers with an exposed tungsten layer, resulting in critical contamination conditions. First, DLTS (deep level transient spectroscopy) measurements were calibrated to measure tungsten contamination in ion-implanted samples. DLTS measurements of tungsten-implanted samples showed that the tungsten concentration increases linearly with the dose up to a rather low dose (5×1010 cm–2). Tungsten deactivation was observed when the dose was further increased. Under these conditions, ToF-SIMS revealed tungsten at the wafer surface, showing that deactivation was due to surface segregation. DLTS calibration could therefore be obtained in the linear dose regime only. This calibration was used to evaluate the tungsten contamination in arsenic implantations. Ordinary operating conditions and critical contamination conditions of the equipment were compared. A moderate tungsten contamination was observed in samples implanted under ordinary operating conditions. This contamination was easily suppressed by a thin screen oxide. On the contrary, implantations in critical conditions of the equipment resulted in a relevant tungsten contamination, which could be reduced but not suppressed even by a relatively thick screen oxide (up to 150 A). A decontamination process consisting of high dose implantations of dummy wafers was tested for its efficiency to remove tungsten and titanium contamination. This process was found to be much more effective for titanium than for tungsten. Finally, DLTS proved to be much more sensitive that TXRF (total reflection X-ray fluorescence) in detecting tungsten contamination. (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

SUMMARY: We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFNγ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFNγ in vitro exposure leads to a conserved transcriptome response unless cells have IFNγ receptor alterations. This conserved IFNγ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFNγ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy. ETOC BLURB: Analyzing the transcriptome of biopsies of patients during immune checkpoint blockade therapy, Grasso et al. show that the increase of T cell infiltration and the downstream IFNγ signaling drive clinical responses.

The present study seeks to elucidate the interactions between the "competence" growth factor basic fibroblast growth factor (bFGF) and/or estrogen 17β-estradiol and the "progression" growth factors epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and insulin (INS) on DNA labeling and also cyclin D1, extracellular signal-related kinase 1/2 (ERK1/2), glial fibrillary acidic protein (GFAP), and vimentin expression in astroglial cultures under different experimental conditions. Pretreatment for 24 hr with bFGF and subsequent exposure for 36 hr to estradiol (E2 ) and EGF, IGF-I, or INS stimulated DNA labeling in the last 12 hr, especially when the cultures were treated with progression growth factors. bFGF pretreatment and subsequent treatment with E2 for 36 hr stimulated DNA labeling. The 36-hr E2 treatment alone did not significantly decrease DNA labeling, but contemporary addition of E2 with two or three growth factors stimulated DNA labeling remarkably. When E2 was coadded with growth factors, a significantly increased DNA labeling was observed, demonstrating an astroglial synergistic mitogenic effect evoked by contemporary treatment with growth factors in the presence of estrogens. Cyclin D1 expression was markedly increased when astrocyte cultures were pretreated for 36 hr with E2 and subsequently treated with two or three competence and progression growth factors. A highly significant increase of ERK1/2 expression was observed after all the treatments (EGF, bFGF, INS, IGF-I alone or in combination with two or three growth factors). GFAP and vimentin expression was markedly increased when the cultures were treated with two or three growth factors. In conclusion, our data demonstrate estradiol-growth factor cross-talk during astroglial cell proliferation and differentiation in culture.

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi-histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

Inverted urothelial papilloma (IUP) is an uncommon neoplasm of the urinary bladder with distinct morphological features. Studies regarding the role of human papillomavirus (HPV) in the etiology of IUP have provided conflicting evidence of HPV infection. Additionally, little is known regarding the molecular alterations present in IUP or other urothelial neoplasms which might demonstrate inverted growth pattern like low-grade or high-grade urothelial carcinoma. Here, we evaluated for the presence of common driving somatic mutations and HPV within a cohort of inverted urothelial papillomas, (n=7) non-invasive low-grade papillary urothelial carcinomas with inverted growth pattern (n=5,) and non-invasive high-grade papillary urothelial carcinomas with inverted growth pattern (n=8). HPV was not detected in any case of inverted urothelial papilloma or inverted urothelial carcinoma by either ISH or by PCR. Next generation sequencing identified recurrent mutations in HRAS (Q61R) in 3 of 5 inverted urothelial papillomas, described for the first time in this neoplasm. Additional mutations of Ras pathway members were detected including HRAS, KRAS, and BRAF. The presence of Ras pathway member mutations at a relatively high rate suggests this pathway may contribute to pathogenesis of inverted urothelial neoplasms. Additionally, we did not find any evidence supporting a role for HPV in the etiology of inverted urothelial papilloma.

Laser Thermal Processing (LTP) both at silicon melting and sub-melting powers have been studied for many years in order to achieve high levels of dopant activation and abrupt junctions thanks to extremely short annealing times with potential elimination of transient-enhanced diffusion. However, its introduction in a CMOS-like process is not achieved yet, since the laser energy can be destructive to other parts of the device, integration issues related to the introduction of effective reflecting layers to protect devices from laser have not been solved yet. In the present work we present a preliminary characterization in order to identify the most promising implantations and LTP process for both standard and emerging device. Both melting and sub-melting regime was investigated. A first characterization by transmission electron microscopy (TEM), time of flight secondary ion mass spectroscopy (TOF-SIMS) and sheet resistance measurements of LTP performances allowed to identify Boron as preferable to BF2 as doping species and to exclude non melting regime from further investigations. Indeed, in Boron implanted samples sheet resistance is found to be lower than in BF2 implanted samples for almost all energy densities, suggesting better activation. In both BF2 and B implants sheet resistance in sub-melted samples is too high to allow measurements. Junction depth seems to be steady in Boron implanted sample whereas it increases at BF2 implanted ones during thermal treatment. So Boron implanted samples show better control of diffusion with no drift of the profile at concentrations below 2 * 10 19 cm −3 . This result is rather surprising, because dopant diffusion takes a large amount of doping at concentration below the solid solubility, so a lower sheet resistance is generally associated with a more diffused profile. In terms of silicon defectivity the Boron implanted sample treated with the highest laser energy is the only one where no dislocations rich layer is observed, on the contrary the silicon close to the surface appears perfectly crystalline.

Among the transparent conductor, one of the most interesting is the Al doped MgxZn1−xO films for their electrical properties that make it very attracting for solar cell application. In this work, the Mg distribution in Al doped MgxZn1−xO films was investigated in order to find a reliable methods to determine Mg distribution. In particular, X-ray diffraction, Auger electron spectroscopy and time of flight secondary ion mass spectrometry were used to characterize the film. Time of flight secondary ion mass spectrometry MCs+ results appear to be the most promising analytical technique. Copyright © 2014 John Wiley & Sons, Ltd.

OBJECTIVE: The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment. PATIENTS: Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20-82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients. DESIGN: The design of the study was analytical, observational, open, and retrospective. OUTCOME MEASURES: Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months. RESULTS: The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2-95.4); specificity = 83.3% (65.3-94.3)], whereas that of GH levels after 3 months was 7.8 microg/liter [sensitivity = 70.3% (53.0-84.1); specificity = 93.3% (79.0-99.0)]. CONCLUSION: Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.

Motivation: Tumors acquire many chromosomal amplifications, and those acquired early in the lifespan of the tumor may be not only important for tumor growth but also can be used for diagnostic purposes. Many methods infer the order of the accumulation of abnormalities based on their occurrence in a large cohort of patients. Recently, Durinck et al. (2011) and Greenman et al. (2012) developed methods to order a single tumor’s chromosomal amplifications based on the patterns of mutations accumulated within those regions. This method offers an unprecedented opportunity to assess the etiology of a single tumor sample, but has not been widely evaluated. Results: We show that the model for timing chromosomal amplifications is limited in scope, particularly for regions with high levels of amplification. We also show that the estimation of the order of events can be sensitive for events that occur early in the progression of the tumor and that the partial maximum likelihood method of Greenman et al. (2012) can give biased estimates, particularly for moderate read coverage or normal contamination. We propose a maximum-likelihood estimation procedure that fully accounts for sequencing variability and show that it outperforms the partial maximum-likelihood estimation method. We also propose a Bayesian estimation procedure that stabilizes the estimates in certain settings. We implement these methods on a small number of ovarian tumors, and the results suggest possible differences in how the tumors acquired amplifications. Availability and implementation: We provide implementation of these methods in an R package cancerTiming, which is available from the Comprehensive R Archive Network (CRAN) at http://CRAN.R-project.org/. Contact: epurdom@stat.Berkeley.edu Supplementary information: Supplementary data are available at Bioinformatics online.

Summary Background Acromegaly results from increased growth hormone and its target insulin-like growth factor-1, most commonly due to a pituitary tumour. As it is frequently accompanied by infertility, little is known about the course of this disease in pregnancy. Objective We describe 13 new pregnancies in acromegalic women and compare their outcomes in a systematic review of the literature. Methods We collected clinical, biochemical, imaging, and outcomes data during and following pregnancy and performed a systematic review for a total of 47 pregnancies. An extended analysis of 106 pregnancies was also performed. Results In 13 newly described cases, pregnancy was un-complicated without need for additional surgical intervention. In these pregnancies, adjunctive medical therapy was required in three patients. This was in the form of somatostatin analogs (SA) (3/13) as well as pegvisomant in 1/13 to control symptomatic and biochemical progression. One 37-year-old female succeeded in having two separate pregnancies 2 years apart both without need for any form of medical therapy. Review of an additional 34 published reports allowed for an analysis of outcomes in 47 pregnancies. Adjunctive medical therapy during pregnancy was required in 15 of these cases where 12 received SA and an additional three received dopamine agonists. None of these patients developed endocrine or neurologic complications during pregnancy. In an extended analysis of 106 pregnancies, treatment during pregnancy appears to be associated with good disease control but increased risk of microsomic or macrosomic newborns depending on the medical agent used. Conclusions In 13 newly described pregnancies along with systematic review of an additional 34 cases indicate that pregnancy in treated acromegalic women can proceed without significant complications or teratogenicity. Medical treatment during pregnancy with DA or SA appears to be associated with altered neonatal weight. Nevertheless, gestation may have a beneficial impact on acromegaly control both during and following pregnancy.

Breast cancer is a heterogeneous disease, exhibiting a wide range of molecular aberrations and clinical outcomes. Here we employed paired-end transcriptome sequencing to explore the landscape of gene fusions in a panel of breast cancer cell lines and tissues. We observed that individual breast cancers harbor an array of expressed gene fusions. We identified two classes of recurrent gene rearrangements involving microtubule associated serine-threonine kinase (MAST) and Notch family genes. Both MAST and Notch family gene fusions exerted significant phenotypic effects in breast epithelial cells. Breast cancer lines harboring Notch gene rearrangements are uniquely sensitive to inhibition of Notch signaling, and over-expression of MAST1 or MAST2 gene fusions had a proliferative effect both in vitro and in vivo. These findings illustrate that recurrent gene rearrangements play significant roles in subsets of carcinomas and suggest that transcriptome sequencing may serve to identify patients with rare, actionable gene fusions.

The research community at large is expending considerable resources to sequence the coding region of the genomes of tumors and other human diseases using targeted exome capture (i.e., “whole exome sequencing”). The primary goal of targeted exome sequencing is to identify nonsynonymous mutations that potentially have functional consequences. Here, we demonstrate that whole-exome sequencing data can also be analyzed for comprehensively monitoring somatic copy number alterations (CNAs) by benchmarking the technique against conventional array CGH. A series of 17 matched tumor and normal tissues from patients with metastatic castrate-resistant prostate cancer was used for this assessment. We show that targeted exome sequencing reliably identifies CNAs that are common in advanced prostate cancer, such as androgen receptor (AR) gain and PTEN loss. Taken together, these data suggest that targeted exome sequencing data can be effectively leveraged for the detection of somatic CNAs in cancer.

Summary Objective (i) To analyse the predictors of GH suppression after standard glucose load (oGTT) in the healthy population and (ii) to establish the 97th percentile of GH nadir post-oGTT according to these variables. Design Analytical, retrospective. Measurements GH nadir after oGTT. Subjects Two hundred and thirty-one healthy subjects (113 women, 118 men 15–80 years) were studied. Results The GH nadir after glucose load ranged from 0·01 ( 88 cm in women and 102 cm in men (97th percentile 0·16 μg/l). Conclusions The results of this study show that GH nadir after oGTT should be analysed according to gender, menopausal status and waist circumference. The GH cut-off should be limited to the assay used.

In the present study, we evaluated the expression of some proliferation and differentiation markers in 15 DIV astrocyte cultures pretreated or not with 0.5 mM glutamate for 24 h and than maintained under chronic or acute treatment with 50 μM R(+)enantiomer or raceme alpha-lipoic acid (ALA). GFAP expression significantly increased after (R+)enantiomer acute-treatment and also in glutamate-pretreated ones. Vimentin expression increased after R(+)enantiomer acute-treatment, but it decreased after raceme acute-treatment. Nestin expression drastically increased after acute raceme-treatment in glutamate-pretreated or not cultures, but significantly decreased after (R+)enantiomer acute and chronic-treatments. Cyclin D1 expression increased in raceme acute-treated cultures pretreated with glutamate. MAP-kinase expression slightly increased after (R+)enantiomer acute treatment in glutamate-pretreated or unpretreated ones. These preliminary findings may better clarify antioxidant and metabolic role played by ALA in proliferating and differentiating astrocyte cultures suggesting an interactive cross-talk between glial and neuronal cells, after brain lesions or damages.

BackgroundSomatostatin analogs (SA) are the cornerstone in the medical treatment of acromegaly, used as either primary or adjunctive therapy. In particular, SA are effective in inducing the biochemical remission of the disease and tumor shrinkage, although only few cases of complete disappearance of the pituitary tumor in patients treated with SA as long-acting formulations have been reported. SA withdrawal has been demonstrated to keep safe levels of GH and IGF1 at least in a small subset of patients well responsive to SA, although it is generally followed by disease recurrence after several months.Case reportA 61-year-old female patient bearing a very large GH-secreting pituitary macroadenoma was treated with 12-month lanreotide Autogel (ATG), at the initial dose of 120 mg/28 days. After 3 months, GH and IGF1 levels were fully normalized, to prolong the administration interval from 28 to 56 days. After 6 months of treatment, a significant tumor shrinkage (90% of baseline size) was observed, whereas GH and IGF1 excess was still well controlled. After 12-month therapy, a complete disappearance of the pituitary tumor was observed, and the hormonal evaluation confirmed the complete biochemical remission of acromegaly. Lanreotide ATG treatment was withdrawn. The clinical, biochemical, and radiological remission of acromegaly was maintained 24 months after lanreotide ATG treatment discontinuation, without evidence of disease recurrence.ConclusionsThis report represents an exemplary case of the potentiality of treatment with lanreotide ATG in inducing a complete remission of acromegalic disease, persistent after a long period of time from treatment withdrawal.

The objective of the study was to investigate the impact of first-line somatostatin analogs (SSAs) on glucose tolerance (GT) in acromegaly.The design was open and prospective.One hundred twelve patients [63 with normal GT (56.2%), 24 with impaired GT (21.4%), and 25 with diabetes (22.3%)] were treated with depot SSAs for 12 months: 54 patients (48.2%) achieved mean fasting GH levels less than 2.5 microg/liter in presence of normal IGF-I levels (controlled) during SSA.Fasting glucose and glycosylated hemoglobin levels were measured.At study end, 57 patients had normal GT (50.1% vs. baseline; P = 0.55), 30 had impaired fasting glucose or impaired GT (26.8%, P =0.43) and 25 had diabetes (22.3%; P = 1.0). Twenty-eight patients (25.0%), modified their GT [11 improved (9.8%), 17 worsened (15.2%)]: 90% of the patients with GT improvement achieved control of acromegaly and 89% of those having GT worsening did not (P0.0001). The major predictors of GT changing were disease control (t = -4.99; P0.0001), baseline GT (t = -2.84; P = 0.0054), and GH levels (t = 2.70; P = 0.008). Fasting glucose levels were predicted by patients' age (t = 2.74; P = 0.0071) and IGF-I levels (t = 2.14; P = 0.035). Glycosylated hemoglobin levels were predicted by disease duration (t = 3.53; P = 0.0006), GH levels (t = 2.70; P = 0.0071), and IGF-I levels (t = 2.11; P = 0.037).This study showed a similar prevalence of deterioration and improvement of GT 12 months after first-line SSA treatment. Uncontrolled acromegaly during SSA treatment and abnormal GT at baseline were associated with GT worsening.

The human mesonephros is currently regarded as a simplified version of the foetal metanephros, primarily due to the close morphological resemblance between these two structures. The aim of the present study was to define whether human mesonephric and foetal metanephric nephrons share immunophenotypical traits in their corresponding structures (glomeruli, proximal and distal tubules). For this purpose we first investigated immunohistochemically the overall expression and topographical distribution of cytokeratins 7, 8, 18, 19, and 20, vimentin and α-smooth muscle actin in mature mesonephric nephrons and compared the results with those obtained in maturing-stage foetal metanephric nephrons. No expression of cytokeratins 7 and 20 was found. Cytokeratins 8, 18, and 19 and vimentin showed a restricted and basically coincident expression along the different components of both mesonephric and metanephric nephrons. These findings indicate that the intermediate filament protein profile of human mature mesonephric nephrons closely recapitulates that observed in developing metanephros and thereby strengthens the concept that human mesonephros, a transient ontogenic structure, is largely similar to the foetal metanephros.

The US Navy is striving to reduce total ownership costs of the Fleet, The operational and safety issues associated with several cases of loss or damage to AOE 6 class accommodation ladders, provided the opportunity to demonstrate the effectiveness of a Government-Industry partnership and the application of proven commercial technology in reducing manpower requirements and life cycle cost, while maintaining mission capabilities of an existing U.S. Navy replenishment ship.

This paper focuses on material handling as a “system of systems”. U.S. Navy material handling issues are large, global and complex. These issues greatly affect ship interoperability and mission now and in the future. Following a discussion of current material handling methods, future Fleet logistic system needs will be addressed. Additionally, the paper will show the requirement for considering material handling early in the ship's design phase and from a global perspective.

Systemic lupus erythematosus (SLE)-prone female MRL-lpr / lpr (MRL-lpr) mice were treated with mouse or rat IFN-gamma under different experimental conditions, both prophylactically in 6- to 8 week-old animals and therapeutically in 12- to 18-week-old SLE-affected mice. It was found that IFN-gamma heterogeneously modulated the course of the disease in MRL-lpr mice. When administered prophylactically, IFN-gamma favorably modulated the histological, serological and clinical signs of the disease. Relative to untreated or PBS-treated control animals, the MRL-lpr mice which received IFN gamma were virtually free of inflammatory infiltration of the kidneys and the lungs, had lower levels of azotemia with reduction of both circulating IgG1, IgG2a and IgG3 and anti-double strand (ds) and single strand (ss) DNA antibodies, milder skin vasculitis, significantly reduced enlargement of their lymph nodes and lower weight of the spleens. IFN-gamma also lowered the rate of mortality of MRL-lpr mice. In contrast to these findings, therapeutically administered IFN-gamma worsened the course of the disease in MRL-lpr mice, which exhibited increased proteinuria, higher levels of IgG2a and IgG3 and anti-ds and -ss DNA antibodies, more aggressive nephritis and died at an earlier age than PBS-treated control mice. The dichotomic effect of IFN-gamma on disease manifestation in MRL-lpr mice offers new insights into the complex role of this cytokine in the regulation of systemic autoimmunity such as SLE.

Purpose. To assess the response rate, survival, and toxicity of Taxol®(paclitaxel) as 1‐h infusion plus doxorubicin as first‐line treatment for patients with metastatic breast cancer (MBC). Patients and methods. Seventy‐six patients with untreated MBC were recruited. All of them had measurable disease and were evaluable for toxicity. Fifty‐five percent of the patients had visceral involvement. The dose of doxorubicin was fixed at 50 mg/m2 as a short intravenous infusion, followed by 200 mg/m2 of Taxol as a 1‐h intravenous infusion. Doxorubicin was administered during the first seven cycles, continuing with Taxol only up to a maximum of ten cycles. Results. Neutropenia was the most important toxicity: 30% grade 3 and 18% grade 4. Only 2 patients showed a decrease in the left ventricular ejection fraction (LVEF) which caused discontinuing the treatment. No clinical congestive heart failure (CHF) was observed. Seventy‐four patients were eligible for response evaluation: 10 (14%) achieved complete response (CR) and 46 (62%) achieved partial response (PR). The mean duration of response was 13.47± 1.35 months (95% confidence interval (CI): 10.82; 16.12) and the mean survival was 21.50± 1.42 months (95% CI: 18.72; 24.29). Conclusion. The overall response (OR) rate was 76%. No CHF was assessed and 2 patients stopped treatment due to LVEF decrease. Although doxorubicin 50 mg/m2 followed by Taxol 200 mg/m2 in 1‐h intravenous infusion presents a toxicity profile which demands a close follow‐up, it represents a convenient outpatient schedule with similar activity rate compared to longer Taxol infusions.

A toxicity identification evaluation (TIE) was conducted on the effluent from a petrochemical plant which discharges into an estuary. The effluent had been consistently toxic to mysid shrimp (Mysidopsis bahia) but not toxic to sheepshead minnows (Cyprinodon variegatus). Phase I effluent toxicity characterization tests revealed that treatment of the effluent with a cation exchange resin (Amberlite(R) IR-120 Plus) was partially effective at reducing, but not removing, toxicity. Phase II characterization tests revealed that four cations varied with toxicity: Ca and Sn were positively correlated with increasing toxicity; Mg and K were negatively correlated with increasing toxicity. Toxicity tests with SnCl2 revealed that the toxicity threshold for Sn was far above the concentrations present in the raw effluent. Reduction of Ca was shown to result in a significant improvement in survival, but some toxicity still remained. Further augmentation of the treated effluent with CaCl2, MgCl2, and KBr to restore the concentrations of Ca, Mg, K, and Br to natural seawater concentrations resulted in survival of all exposed organisms. Repeated success of this treatment regime on additional samples of the effluent as well as "mock effluent" studies confirmed that ion imbalance was the sole source of toxicity in this effluent. Process source water composition and essential ion balance are discussed as important components of marine effluent TIEs.

Summary: POAVIZ creates a visualization of a multiple sequence alignment that makes clear the overall structure of how sequences match and diverge in the alignment. POAVIZ can construct visualizations from any multiple sequence alignment source (e.g. PIR and CLUSTAL formats), and is valuable for revealing complex branching structure (such as domains, large-scale insertions / deletions or recombinations), especially in partnership with the Partial Order Alignment (POA) multiple sequence alignment program. Availability: The Partial Order multiple sequence Alignment Visualizer (POAVIZ) program is available at http://www.bioinformatics.ucla.edu/poa Contact: leec@mbi.ucla.edu * To whom correspondence should be addressed.

Polycystic ovary syndrome (PCOS) is a multifactorial syndrome affecting 10% of women in reproductive age. Insulin sensitizer agents are the best therapeutic option for PCOS patients; among which there is Inositol. Inositol is a polyalcohol existing as nine different stereoisomers, two of which have been shown to be insulin mediators: myo-inositol (MI) and D-chiro-inositol (DCI). So far only MI have been show to be present in the follicular fluid and in a direct comparison between MI and DCI only MI was able to improve oocyte and embryo quality. Therefore, Could we say "bye-bye D-chiro-Inositol" in the practice of clinical gynecology and reproductive medicine?

The effect of various fungicides on Glomerella cingulata, the causal agent of a serious rot of olive fruits, was evaluated both in vitro and in the field. The following fungicides were tested: copper oxychloride, Bordeaux mixture, ziram, myclobutanil, hexaconazole, metiram, bitertanol and benomyl. Field trials were carried out in Calabria (southern Italy) for 2 years on two olive cultivars, Ottobratica (susceptible) and Sinopolese (resistant). The minimum effective concentrations of bitertanol, hexaconazole, myclobutanil, benomyl, metiram, ziram, and copper oxychloride on mycelial growth in vitro were < 5, < 50, < 50, < 1000, < 1000, < 1000, < 1000 μg ml−1, respectively. The ED90 values for conidial germination were 0.01, 0.02, 50, 50, 1000, 1000, and 1000 μg ml−1 of benomyl, ziram, myclobutanil, copper oxychloride, bitertanol, hexaconazole and metiram, respectively. In field trials, Bordeaux mixture and copper oxychloride proved to be the most effective products; however ziram, myclobutanil, bitertanol, metiram, and hexaconazole reduced the incidence of fruit rot significantly.

One-lung ventilation (OLV) affects respiratory mechanics and ventilation/perfusion matching, reducing functional residual capacity of the ventilated lung. While the application of a lung-recruiting manoeuvre (RM) on the ventilated lung has been shown to improve oxygenation, data regarding the impact of RM on respiratory mechanics are not available.Thirteen patients undergoing lung resection in lateral decubitus were studied. During OLV, a lung-recruiting strategy consisting in a RM lasting 1 min followed by the application of positive end-expiratory pressure 5 cmH(2)O was applied to the ventilated lung. Haemodynamics, gas exchange and respiratory mechanics parameters were recorded on two-lung ventilation (TLV(baseline)), OLV before and 20 min after the RM (OLV(pre-RM), OLV(post-RM), respectively) and TLV(end). Haemodynamics parameters were also recorded during the RM.The PaO(2)/FiO(2) ratio was 358+/-126 on TLV(baseline); it decreased to 235+/-113 on OLV(pre-RM) (P0.01) increased to 351+/-120 on OLV(post-RM) (P0.01 vs. OLV(pre-RM)), and remain stable thereafter. During the RM, CI decreased from 3.04+/-0.7 l/m(2) OLV(pre-RM) to 2.4+/-0.6 l/m(2) (P0.05), and returned to baseline on OLV(post-RM) (3.1+/-0.7 l/m(2), NS vs. OLV(pre-RM)). The RM resulted in alveolar recruitment and caused a significant decrease in static elastance of the dependent lung (16.6+/-8.9 cmH(2)O/ml OLV(post-RM) vs. 22.3+/-8.1 cmH(2)O/ml OLV(pre-RM)) (P0.01).During OLV in lateral decubitus for thoracic surgery, application to the dependent lung a recruiting strategy significantly recruits the dependent lung, improving arterial oxygenation and respiratory mechanics until the end of surgery. However, the transient haemodynamic derangement occurring during the RM should be taken into account.

Motivation: Partial order alignment (POA) has been proposed as a new approach to multiple sequence alignment (MSA), which can be combined with existing methods such as progressive alignment. This is important for addressing problems both in the original version of POA (such as order sensitivity) and in standard progressive alignment programs (such as information loss in complex alignments, especially surrounding gap regions). Results: We have developed a new Partial Order–Partial Order alignment algorithm that optimally aligns a pair of MSAs and which therefore can be applied directly to progressive alignment methods such as CLUSTAL. Using this algorithm, we show the combined Progressive POA alignment method yields results comparable with the best available MSA programs (CLUSTALW, DIALIGN2, T-COFFEE) but is far faster. For example, depending on the level of sequence similarity, aligning 1000 sequences, each 500 amino acids long, took 15 min (at 90% average identity) to 44 min (at 30% identity) on a standard PC. For large alignments, Progressive POA was 10–30 times faster than the fastest of the three previous methods (CLUSTALW). These data suggest that POA-based methods can scale to much larger alignment problems than possible for previous methods. Availability: The POA source code is available at http://www.bioinformatics.ucla.edu/poa