Clinicopathological and prognostic significance of programmed cell death ligand 1 expression in patients diagnosed with breast cancer: meta-analysis.

BACKGROUND: Uncertainty exists regarding the clinical relevance of programmed cell death ligand 1 (PD-L1) expression in breast cancer. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Observational studies that compared high versus low expression of PD-L1 on breast cancer cells were identified. Log hazard ratios (HRs) for disease-free and overall survival and their standard errors were calculated from Kaplan-Meier curves or Cox regression analyses, and pooled using the inverse-variance method. Dichotomous variables were pooled as odds ratios (ORs) using the Mantel-Haenszel method. RESULTS: Sixty-five studies with 19 870 patients were included; 14 404 patients were classified as having low and 4975 high PD-L1 expression. High PD-L1 was associated with achieving a pathological complete response following neoadjuvant chemotherapy (OR 3.30, 95 per cent confidence interval 1.19 to 9.16; P < 0.01; I2 = 85 per cent). Low PD-L1 expression was associated with human epidermal growth factor receptor 2 (OR 3.98, 1.81 to 8.75; P < 0.001; I2 = 96 per cent) and luminal (OR 14.93, 6.46 to 34.51; P < 0.001; I2 = 99 per cent) breast cancer subtypes. Those with low PD-L1 had favourable overall survival rates (HR 1.30, 1.05 to 1.61; P = 0.02; I2 = 85 per cent). CONCLUSION: Breast cancers with high PD-L1 expression are associated with aggressive clinicopathological and immunohistochemical characteristics and are more likely to achieve a pathological complete response following neoadjuvant chemotherapy. These breast cancers are, however, associated with worse overall survival outcomes.

July 2012 Greenland melt extent enhanced by low-level liquid clouds.

Melting of the world's major ice sheets can affect human and environmental conditions by contributing to sea-level rise. In July 2012, an historically rare period of extended surface melting was observed across almost the entire Greenland ice sheet, raising questions about the frequency and spatial extent of such events. Here we show that low-level clouds consisting of liquid water droplets ('liquid clouds'), via their radiative effects, played a key part in this melt event by increasing near-surface temperatures. We used a suite of surface-based observations, remote sensing data, and a surface energy-balance model. At the critical surface melt time, the clouds were optically thick enough and low enough to enhance the downwelling infrared flux at the surface. At the same time they were optically thin enough to allow sufficient solar radiation to penetrate through them and raise surface temperatures above the melting point. Outside this narrow range in cloud optical thickness, the radiative contribution to the surface energy budget would have been diminished, and the spatial extent of this melting event would have been smaller. We further show that these thin, low-level liquid clouds occur frequently, both over Greenland and across the Arctic, being present around 30-50 per cent of the time. Our results may help to explain the difficulties that global climate models have in simulating the Arctic surface energy budget, particularly as models tend to under-predict the formation of optically thin liquid clouds at supercooled temperatures--a process potentially necessary to account fully for temperature feedbacks in a warming Arctic climate.

A review of question prompt lists used in the oncology setting with comparison to the Patient Concerns Inventory.

A question prompt list (QPL) is a simple and inexpensive communication tool used to facilitate patient participation in medical consultations. The QPL is composed of a structured list of questions and has been shown to be an effective way of helping ensure patients' individual information needs are appropriately met. This intervention has been investigated in a variety of settings but not specifically head and neck cancer (HNC). The aim of this paper was to perform a narrative review of literature reporting the use of a QPL for oncology patients and to draw comparison to the Patient Concerns Inventory (PCI-HN). The databases Scopus, PubMed and MEDLINE were searched using the key terms 'question prompt list', 'question prompt sheet', 'cancer' and 'oncology'. Of 98 articles hand searched, 30 of which were found to meet all inclusion criteria, and described in a tabulated summary. The studies concluded that the QPL was an effective intervention, enabling active patient participation in medical consultations. The PCI-HN is specific for HNC and differs from many QPLs, which are more general cancer tools. The QPL approach should prove to be a useful intervention for HNC sufferers, however further research into the clinical utility is required.

Quantitative trait locus mapping and functional genomics of an organophosphate resistance trait in the western corn rootworm, Diabrotica virgifera virgifera.

The western corn rootworm, Diabrotica virgifera virgifera, is an insect pest of corn and population suppression with chemical insecticides is an important management tool. Traits conferring organophosphate insecticide resistance have increased in frequency amongst D. v. virgifera populations, resulting in the reduced efficacy in many corn-growing regions of the USA. We used comparative functional genomic and quantitative trait locus (QTL) mapping approaches to investigate the genetic basis of D. v. virgifera resistance to the organophosphate methyl-parathion. RNA from adult methyl-parathion resistant and susceptible adults was hybridized to 8331 microarray probes. The results predicted that 11 transcripts were significantly up-regulated in resistant phenotypes, with the most significant (fold increases ≥ 2.43) being an α-esterase-like transcript. Differential expression was validated only for the α-esterase (ST020027A20C03), with 11- to 13-fold greater expression in methyl-parathion resistant adults (P < 0.05). Progeny with a segregating methyl-parathion resistance trait were obtained from a reciprocal backcross design. QTL analyses of high-throughput single nucleotide polymorphism genotype data predicted involvement of a single genome interval. These data suggest that a specific carboyxesterase may function in field-evolved corn rootworm resistance to organophosphates, even though direct linkage between the QTL and this locus could not be established.

WASP-12b as a prolate, inflated and disrupting planet from tidal dissipation.

The class of exotic Jupiter-mass planets that orbit very close to their parent stars were not explicitly expected before their discovery. The recently discovered transiting planet WASP-12b has a mass M = 1.4 +/- 0.1 Jupiter masses (M(J)), a mean orbital distance of only 3.1 stellar radii (meaning it is subject to intense tidal forces), and a period of 1.1 days. Its radius 1.79 +/- 0.09R(J) is unexpectedly large and its orbital eccentricity 0.049 +/- 0.015 is even more surprising because such close orbits are usually quickly circularized. Here we report an analysis of its properties, which reveals that the planet is losing mass to its host star at a rate of about 10(-7)M(J) per year. The planet's surface is distorted by the star's gravity and the light curve produced by its prolate shape will differ by about ten per cent from that of a spherical planet. We conclude that dissipation of the star's tidal perturbation in the planet's convective envelope provides the energy source for its large volume. We predict up to 10 mJy CO band-head (2.292 mum) emission from a tenuous disk around the host star, made up of tidally stripped planetary gas. It may also contain a detectable resonant super-Earth, as a hypothetical perturber that continually stirs up WASP-12b's eccentricity.

[Artificial Feedback for Invasive Brain-Computer Interfaces].

During the last two decades, considerable progress has been made in the studies of brain-computer interfaces (BCIs)--devices in which motor signals from the brain are registered by multi-electrode arrays and transformed into commands for articial actuators such as cursors and robotic devices. This review is focused on one problem. Voluntary motor control is based on neurophysiological processes which depend heavily on the afferent innervation of skin, muscles and joints. Thus, invasive BCI has to be based on a bidirectional system in which motor control signals are registered by multi-channel micro-electrodes implanted in motor areas, while tactile, proprioceptive and other useful signals are transported back to the brain through spatial-temporal patterns of intracortical microstimulation (ICMS) delivered to sensory areas. In general, the studies of invasive BCIs have advanced in several directions. The progress of BCIs with articial sensory feedback will not only help patients, but will also expand knowledge base in the field of human cortical functions.

FGF receptor genes and breast cancer susceptibility: results from the Breast Cancer Association Consortium.

BACKGROUND: Breast cancer is one of the most common malignancies in women. Genome-wide association studies have identified FGFR2 as a breast cancer susceptibility gene. Common variation in other fibroblast growth factor (FGF) receptors might also modify risk. We tested this hypothesis by studying genotyped single-nucleotide polymorphisms (SNPs) and imputed SNPs in FGFR1, FGFR3, FGFR4 and FGFRL1 in the Breast Cancer Association Consortium. METHODS: Data were combined from 49 studies, including 53 835 cases and 50 156 controls, of which 89 050 (46 450 cases and 42 600 controls) were of European ancestry, 12 893 (6269 cases and 6624 controls) of Asian and 2048 (1116 cases and 932 controls) of African ancestry. Associations with risk of breast cancer, overall and by disease sub-type, were assessed using unconditional logistic regression. RESULTS: Little evidence of association with breast cancer risk was observed for SNPs in the FGF receptor genes. The strongest evidence in European women was for rs743682 in FGFR3; the estimated per-allele odds ratio was 1.05 (95% confidence interval=1.02-1.09, P=0.0020), which is substantially lower than that observed for SNPs in FGFR2. CONCLUSION: Our results suggest that common variants in the other FGF receptors are not associated with risk of breast cancer to the degree observed for FGFR2.

Phase II study of everolimus-erlotinib in previously treated patients with advanced non-small-cell lung cancer.

BACKGROUND: Preclinical data suggest combining a mammalian target of rapamycin inhibitor with erlotinib could provide synergistic antitumor effects in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: In this multicenter, open-label, phase II study, patients with advanced NSCLC that progressed after one to two previous chemotherapy regimens were randomized 1:1 to erlotinib 150 mg/day±everolimus 5 mg/day. Primary end point was the disease control rate (DCR) at 3 months; secondary end points included progression-free survival (PFS) and safety. RESULTS: One hundred thirty-three patients received everolimus-erlotinib (n=66) or erlotinib alone (n=67). The DCR at 3 months was 39.4% and 28.4%, respectively. The probability for the difference in disease control at 3 months to be ≥15% was estimated to be 29.8%, which was below the prespecified probability threshold of ≥40%. Median PFS was 2.9 and 2.0 months, respectively. Grade 3/4 adverse events occurred in 72.7% and 32.3% of patients, respectively. Grade 3/4 stomatitis was observed in 31.8% of combination therapy recipients. CONCLUSIONS: Everolimus 5 mg/day plus erlotinib 150 mg/day was not considered sufficiently efficacious per the predefined study criteria. The combination does not warrant further investigation based on increased toxicity and the lack of substantial improvement in disease stabilization.

A phase Ib dose-escalation study of everolimus combined with cisplatin and etoposide as first-line therapy in patients with extensive-stage small-cell lung cancer.

BACKGROUND: This phase Ib study aimed to establish the feasible everolimus dose given with standard-dose etoposide plus cisplatin (EP) for extensive-stage small-cell lung cancer (SCLC). PATIENTS AND METHODS: An adaptive Bayesian dose-escalation model and investigator opinion were used to identify feasible daily or weekly everolimus doses given with EP in adults with treatment-naive extensive-stage SCLC. A protocol amendment mandated prophylactic granulocyte colony-stimulating factor (G-CSF). Primary end point was cycle 1 dose-limiting toxicity (DLT) rate. Secondary end points included safety, relative EP dose intensity, pharmacokinetics, and tumor response. RESULTS: Patients received everolimus 2.5 or 5 mg/day without G-CSF (n=10; cohort A), 20 or 30 mg/week without G-CSF (n=18; cohort B), or 2.5 or 5 mg/day with G-CSF (n=12; cohort C); all received EP. Cycle 1 DLT rates were 50.0%, 22.2%, and 16.7% in cohorts A, B, and C, respectively. Cycle 1 DLTs were neutropenia (cohorts A and B), febrile neutropenia (all cohorts), and thrombocytopenia (cohorts A and C). The most common grade 3/4 adverse events were hematologic. Best overall response was partial response (40.0%, 61.1%, and 58.3% in cohorts A, B, and C, respectively). CONCLUSIONS: Everolimus 2.5 mg/day plus G-CSF was the only feasible dose given with standard-dose EP in untreated extensive-stage SCLC.

Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations.

Morquio A (Mucopolysaccharidosis IVA; MPS IVA) is an autosomal recessive lysosomal storage disorder caused by partial or total deficiency of the enzyme galactosamine-6-sulfate sulfatase (GALNS; also known as N-acetylgalactosamine-6-sulfate sulfatase) encoded by the GALNS gene. Patients who inherit two mutated GALNS gene alleles have a decreased ability to degrade the glycosaminoglycans (GAGs) keratan sulfate and chondroitin 6-sulfate, thereby causing GAG accumulation within lysosomes and consequently pleiotropic disease. GALNS mutations occur throughout the gene and many mutations are identified only in single patients or families, causing difficulties both in mutation detection and interpretation. In this study, molecular analysis of 163 patients with Morquio A identified 99 unique mutations in the GALNS gene believed to negatively impact GALNS protein function, of which 39 are previously unpublished, together with 26 single-nucleotide polymorphisms. Recommendations for the molecular testing of patients, clear reporting of sequence findings, and interpretation of sequencing data are provided.

Measurement of the cosmic microwave background polarization lensing power spectrum with the POLARBEAR experiment.

Gravitational lensing due to the large-scale distribution of matter in the cosmos distorts the primordial cosmic microwave background (CMB) and thereby induces new, small-scale B-mode polarization. This signal carries detailed information about the distribution of all the gravitating matter between the observer and CMB last scattering surface. We report the first direct evidence for polarization lensing based on purely CMB information, from using the four-point correlations of even- and odd-parity E- and B-mode polarization mapped over ∼30 square degrees of the sky measured by the POLARBEAR experiment. These data were analyzed using a blind analysis framework and checked for spurious systematic contamination using null tests and simulations. Evidence for the signal of polarization lensing and lensing B modes is found at 4.2σ (stat+sys) significance. The amplitude of matter fluctuations is measured with a precision of 27%, and is found to be consistent with the Lambda cold dark matter cosmological model. This measurement demonstrates a new technique, capable of mapping all gravitating matter in the Universe, sensitive to the sum of neutrino masses, and essential for cleaning the lensing B-mode signal in searches for primordial gravitational waves.

Evidence for gravitational lensing of the cosmic microwave background polarization from cross-correlation with the cosmic infrared background.

We reconstruct the gravitational lensing convergence signal from cosmic microwave background (CMB) polarization data taken by the Polarbear experiment and cross-correlate it with cosmic infrared background maps from the Herschel satellite. From the cross spectra, we obtain evidence for gravitational lensing of the CMB polarization at a statistical significance of 4.0σ and indication of the presence of a lensing B-mode signal at a significance of 2.3σ. We demonstrate that our results are not biased by instrumental and astrophysical systematic errors by performing null tests, checks with simulated and real data, and analytical calculations. This measurement of polarization lensing, made via the robust cross-correlation channel, not only reinforces POLARBEAR auto-correlation measurements, but also represents one of the early steps towards establishing CMB polarization lensing as a powerful new probe of cosmology and astrophysics.

[Quality of neuronal signal registered in the monkey motor cortex with chronically implanted multiple microwires].

Disconnection of central and peripheral parts of motor system leads to severe forms of disability. However, current research of brain-computer interfaces will solve the problem of rehabilitation of patients with motor disorders in future. Chronic recordings of single-unit activity in specialized areas of cerebral cortex could provide appropriate control signal for effectors with multiple degrees of freedom. In present article we evaluated the quality of chronic single-unit recordings in the primary motor cortex of awake behaving monkeys obtained with bundles of multiple microwires. Action potentials of proper quality were recorded from single units during three months. In some cases up to 7 single units could be extracted on a channel. Recording quality stabilized after 40 days since electrodes were implanted. Ultimately, functionality of multiple electrodes bundle makes it highly usable and reliable instrument for obtaining of control neurophysiologic signal from populations of neurons for brain-computer interfaces.

[Long-term recording of single unit activity and criteria for estimation of stability].

Stable single-unit recording in the brain of vertebrates allows to investigate processes underlying neural plasticity. In applied aspect long-term single-unit recording can be useful for development of invasive brain--computer interface. Here we propose a criterion for identification of neurons that were recorded for more than one day. Based only on the spike forms classification yields ambiguous result. Additional parameters (such as form of interspike interval histogram or certain parameters of that histogram) decreased misclassification probability considerably. Using proposed criterion we were able to identify 82 neurons that were recoded for more than one day. In extreme case activity of one neuron was observed for 94 days.

NLC-Based Sunscreen Formulations with Optimized Proportion of Encapsulated and Free Filters Exhibit Enhanced UVA and UVB Photoprotection.

The topical use of sunscreens is recommended for avoiding the damaging effects of UV radiation. However, improvements are still needed in the existing products to enhance their photoprotection effectiveness and safety. This involves minimizing the use of chemical UV filters while providing enhanced and prolonged photoprotection. This work investigated novel sunscreen formulations and their UV protection effects by encapsulating Uvinul® A, Tinosorb® S, and Uvinul® T150 into nanostructured lipid carriers (NLCs) based on bacuri butter and raspberry seed oil. First, the impact of critical formulation and process parameters on NLCs' particle size was evaluated using a 22 Face Centered Central Composite Design. Then, formulations were evaluated in terms of critical quality factors, in vitro skin permeation, and in vitro and in vivo photoprotection activities. The developed NLCs-containing formulations exhibited appropriate size (122-135 nm), PdI (<0.3), encapsulation efficiency (>90%), and drug content (>80%), which were preserved for at least 90 days under different stability conditions. Moreover, these NLCs-based formulations had equivalent skin permeation to emulsion-based controls, and the addition of NLCs into sunscreen cream bases in the optimum proportion of 20% (w/w) resulted in enhanced UVA and UVB photoprotection levels, despite a 10% reduction in the total filters content. Altogether, these results describe the application of nanoencapsulated organic UV filters in innovative sunscreen formulations to achieve superior photoprotection and cosmeceutical properties.

Systemic mirnas as potential biomarkers for malignancy.

MiRNAs are a class of short, endogenous, single-stranded RNA molecules that play a role in the regulation of gene expression. They have been shown to modulate a number of cellular processes including cell differentiation, growth and apoptosis and as a result have been implicated in carcinogenesis. They are detectable in tumour tissue, and altered expression levels have been identified in various cancer types. Of interest, miRNAs have recently been detected and identified to be dysregulated in the circulation of patients with breast cancer. The fact that a minimally invasive test can distinguish the presence or absence of disease illustrates the immense potential these molecules hold as predictive markers. This review serves to identify those systemic miRNAs that are upregulated or downregulated in malignancy and how treatment impacts on their circulating levels. In addition, this review questions the source of these small molecules in the bloodstream and how they may possibly play a role in the future detection of cancer as either prognostic or predictive markers.

Incidence and prevalence of copper deficiency following roux-en-y gastric bypass surgery.

INTRODUCTION AND OBJECTIVES: The frequency of copper deficiency and clinical manifestations following roux-en-y gastric bypass (RYGB) surgery is not yet clear. Objectives were to determine the prevalence and incidence of copper deficiency in patients who have undergone RYGB. DESIGN AND METHODS: We sought to determine the number of RYGB patients undergoing medical and nutritional follow-up visits at the Emory Bariatric Center who experienced copper deficiency and associated hematological and neurological complaints (n=136). Separately, in patients followed longitudinally before and during 6 and 24 months following RYGB surgery, we obtained measures of copper status (n=16). Systemic blood cell counts and measures of copper, zinc and ceruloplasmin were determined using standardized assays in reference laboratories including atomic absorption spectrometry and immunoassays. RESULTS: Thirteen patients were identified to have copper deficiency suggesting a prevalence of copper deficiency of 9.6%, and the majority of these had concomitant complications including anemia, leukopenia and various neuro-muscular abnormalities. In the longitudinal study, plasma copper concentrations and ceruloplasmin activity decreased over 6 and 24 months following surgery, respectively (P<0.05), but plasma zinc concentrations did not change. A simultaneous decrease in white blood cells was observed (P<0.05). The incidence of copper deficiency in these subjects was determined to be 18.8%. CONCLUSIONS: The prevalence and incidence of copper deficiency following RYGB surgery was determined to be 9.6% and 18.8%, respectively, with many patients experiencing mild-to-moderate symptoms. Given that copper deficiency can lead to serious and irreversible complications if untreated, frequent monitoring of the copper status of RYGB patients is warranted.

Expert recommendations for the laboratory diagnosis of MPS VI.

Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 4-sulfatase (arylsulfatase B, ASB). This enzyme is required for the degradation of dermatan sulfate. In its absence, dermatan sulfate accumulates in cells and is excreted in large quantities in urine. Specific therapeutic intervention is available; however, accurate and timely diagnosis is crucial for maximal benefit. To better understand the current practices for diagnosis and to establish diagnostic guidelines, an international MPS VI laboratory diagnostics scientific summit was held in February of 2011 in Miami, Florida. The various steps in the diagnosis of MPS VI were discussed including urinary glycosaminoglycan (uGAG) analysis, enzyme activity analysis, and molecular analysis. The following conclusions were reached. Dilute urine samples pose a significant problem for uGAG analysis and MPS VI patients can be missed by quantitative uGAG testing alone as dermatan sulfate may not always be excreted in large quantities. Enzyme activity analysis is universally acknowledged as a key component of diagnosis; however, several caveats must be considered and the appropriate use of reference enzymes is essential. Molecular analysis supports enzyme activity test results and is essential for carrier testing, subsequent genetic counseling, and prenatal testing. Overall the expert panel recommends caution in the use of uGAG screening alone to rule out or confirm the diagnosis of MPS VI and acknowledges enzyme activity analysis as a critical component of diagnosis. Measurement of another sulfatase enzyme to exclude multiple sulfatase deficiency was recommended prior to the initiation of therapy. When feasible, the use of molecular testing as part of the diagnosis is encouraged. A diagnostic algorithm for MPS VI is provided.

Circulating miR-34a levels are reduced in colorectal cancer.

INTRODUCTION: MicroRNAs (miRNAs) are small, non-coding RNA segments that regulate gene expression via post-transcriptional inhibition and have roles in cell differentiation, proliferation, and apoptosis. Expression differs between tumor and normal tissue in several malignancies. Most work has focused on tissue and cell expression with few reports of circulating miRNAs in colorectal cancer. Available biomarkers for colorectal cancer have limited sensitivity and specificity, thus there is a need for new markers. AIMS: This study aimed to identify miRNAs that are differentially expressed in the blood of colorectal cancer patients compared to controls and to establish if this is specific to colorectal cancer and thus could be utilized as potential tumor markers. METHODS: Blood samples were collected from 63 colorectal cancer patients and 45 controls. Expression of 7 target miRNAs (miR-143, miR-145, miR-21, miR-30a-3p, miR-31, miR-34a, and miR-92) was measured using RQ-PCR. Results were correlated with clinicopathological data and analyzed. Analysis of differentially expressed circulating miRNAs was expanded to include 62 patients with prostate, renal, breast, and melanoma cancers. RESULTS: Analysis of the relative quantification of the target miRNAs showed significantly reduced expression (P = 0.004) of miR-34a in colorectal cancer. MiR-34a was also significantly reduced in breast cancer (P = 0.019). CONCLUSION: This study demonstrates significantly reduced expression of circulating miR-34a in colorectal and breast cancer. This may have future application as part of a biomarker profile.