Pigment Epithelium Macroadenoma Mimicking Iris or Ciliary Body Melanoma

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Preconditioned iterative methods for convection diffusion and related boundary value problems

AbstractWe develop and analyze preconditioners for the iterative solution of the system of equations arising from the discretization of multi-dimensional singularity perturbed boundary value problems. This includes a class of convection diffusion models. The choice of preconditioner is crucial for the efficient solution of the system of equations. In particular, it is necessary to choose a preconditioner that substantially reduces the condition number κ both for small grid size h and for large values of the parameter K multiplying the convection terms. A class of preconditioners is analyzed that is inexpensive to implement and for which κ = 0(1) as h→0 and κ = (1 + K12) as K → ∞ for some convection diffusion problems with positive definite symmetric part. This result is then used to develop an algorithm with work estimate 0(1 + K12as K → ∞ for a more general class of convection diffusion problems including those with indefinite symmetric part. Numerical experiments using a symmetric multigrid preconditioner demonstrate the effectiveness of the numerical method even for large problems

Phenotypic profile of expanded NK cells in chronic lymphoproliferative disorders: a surrogate marker for NK-cell clonality

Currently, the lack of a universal and specific marker of clonality hampers the diagnosis and classification of chronic expansions of natural killer (NK) cells. Here we investigated the utility of flow cytometric detection of aberrant/altered NK-cell phenotypes as a surrogate marker for clonality, in the diagnostic work-up of chronic lymphoproliferative disorders of NK cells (CLPD-NK). For this purpose, a large panel of markers was evaluated by multiparametric flow cytometry on peripheral blood (PB) CD56low NK cells from 60 patients, including 23 subjects with predefined clonal (n = 9) and polyclonal (n = 14) CD56low NK-cell expansions, and 37 with CLPD-NK of undetermined clonality; also, PB samples from 10 healthy adults were included. Clonality was established using the human androgen receptor (HUMARA) assay. Clonal NK cells were found to show decreased expression of CD7, CD11b and CD38, and higher CD2, CD94 and HLADR levels vs. normal NK cells, together with a restricted repertoire of expression of the CD158a, CD158b and CD161 killer-associated receptors. In turn, NK cells from both clonal and polyclonal CLPD-NK showed similar/overlapping phenotypic profiles, except for high and more homogeneous expression of CD94 and HLADR, which was restricted to clonal CLPD-NK. We conclude that the CD94hi/HLADR+ phenotypic profile proved to be a useful surrogate marker for NK-cell clonality

Incidence of chromosome numerical changes in multiple myeloma: fluorescence in situ hybridization analysis using 15 chromosome-specific probes

Fue el primer trabajo precursor de los estudios con FISH en pacientes con Mieloma múltiple continuando la exitosa línea de investigación en mieloma del grupo de Salamanca, y por añadidura, del Grupo español de mieloma. La metodología FISH es hoy en día la principal herramienta de pronóstico en mieloma múltiple en todo el mundo.[EN]The presence of complex karotypes with frequent numerical and structural abnormalities has been reported in 20 to 50% of multiple myeloma (MM) patients. This variability is mainly due to the difficulty of conventional cytogenetics to obtain tumor metaphases representative of all possible neoplastic clones in MM. To gain insight into the real incidence of numerical chromosome changes in MM we have studied by fluorescence in situ hybridization technique 15 different human chromosomes, 1, 3, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, X, and Y, in a series of 52 MM patients. In all cases, the DNA index assessed by a propidium iodide/CD38 double-staining technique with flow cytometry was simultaneously investigated for correlation, with fluorescence in situ hybridization results. Additional aims of this study were 1) to analyze whether the abnormalities detected were common to all plasma cells or were present in only a subpopulation of tumor cells, 2) to explore changes caused by disease progression, and 3) to establish possible associations among the altered chromosomes. Although the overall incidence of numerical abnormalities was 67%, this frequency increased to 80% in the 41 cases in which 7 or more chromosomes were analyzed. Trisomies were significantly more common than monosomies (84% versus 16%). Chromosomes 9 and 15 were the most frequently altered (52% and 48% of cases, respectively), with all of their abnormalities corresponding to trisomies. The most frequent losses involved chromosomes 13 (26%) and X in females (32%). Other common numerical changes corresponded to chromosomes 1 (39%), 11 (37%), 6 (32%), 3 (31%), 18 (29%), 7 (28%), and 17 (22%). By contrast, chromosomes 8(13%), 10(8%), and 12(3%) were rarely altered. DNA aneuploidy by flow cytometry was detected in 67% of patients, and a high degree of correlation was observed between the DNA index obtained by flow cytometry and the chromosome index derived from fluorescence in situ hybridization studies, calculated according to two mathematical formulas (coefficient of correlation of 0.82 and 0.91 when at least 7 or 12 chromosomes were considered, respectively). The frequency of numeric chromosome aberrations was higher in those patients with progressive disease and, interestingly, trisomy of chromosome 8 was exclusively detected in this latter group of patients. Our study shows that, with the exception of chromosome 8, a possible marker of clonal evolution, the numeric chromosome changes are present in nearly all malignant plasma cells (r > 0.84). Finally, frequent associations between chromosomal aberrations were observed (ie, chromosomes 6, 7, 9, and 17; 7 and 15; and 11 and 17). By excluding them, it was found that two triple combinations of chromosome-specific probes, chromosomes 1 and 9 together with either chromosome 13 or 15, could be a useful marker for detection of residual disease, as it permits the identification of most MM patients displaying numerical changes.University Hosptial of Salamanca Universidad de SalamancaHospital Universitario de Salamanc

Incorporating BEAMing technology as a liquid biopsy into clinical practice for the management of colorectal cancer patients : an expert taskforce review

The importance of mutation identification for advanced colorectal cancer treatment with anti-epidermal growth factor receptor agents is well established. However, due to delays in turnaround time, low-quality tissue samples, and/or lack of standardization of testing methods a significant proportion of patients are being treated without the information that Kirsten rat sarcoma and neuroblastoma rat sarcoma (RAS) testing can provide. The detection of mutated circulating tumor DNA by BEAMing technology addresses this gap in care and allows these patients to receive international guideline-recommended expanded RAS testing with rapid turnaround times. Furthermore, the overall concordance between OncoBEAM RAS colorectal cancer testing and standard of care tissue testing is very high (93.3%). This article presents an overview of the clinical utility and potential applications of this minimally invasive method, such as early detection of emergent resistance to anti-epidermal growth factor receptor therapy. If appropriately implemented, BEAMing technology holds considerable promise to enhance the quality of patient care and improve clinical outcomes

Development of a thermosensitive hydrogel based on Polaxamer 407 and gellan gum with inclusion complexes (Sulfobutylated-β-cyclodextrin-Farnesol) as a local drug delivery system

This work proposes the development of a thermosensitive local drug release system based on Polaxamer 407, also known as Pluronic® F-127 (PF-127), Gellan Gum (GG) and the inclusion complex Sulfobutylated-β-cyclodextrin (CD) with Farnesol (FOH). Rheological properties of the hydrogels and their degradation were studied. According to the rheological results, a solution of 20% w/v of PF-127 forms a strong gel with a gelling temperature of about 25 °C (storage modulus of 15,000 Pa). The addition of the GG increased the storage modulus (optimal concentration of 0.5 % w/v) twofold without modifying the gelling temperature. Moreover, including 0.5% w/v of GG also increased 6 times the degradation time of the hydrogel. Regarding the inclusion complex, the addition of free CD decreased the viscosity and the gel strength since polymer chains were included in CD cavity without affecting the gelling temperature. Contrarily, the inclusion complex CD-FOH did not significantly modify any property of the formulation because the FOH was hosted in the CD. Furthermore, a mathematical model was developed to adjust the degradation time. This model highlights that the addition of the GG decreases the number of released chains from the polymeric network (which coincides with an increase in the storage modulus) and that the free CD reduces the degradation rate, protecting the polymeric chains. Finally, FOH release was quantified with a specific device, that was designed and printed for this type of system, observing a sustainable drug release (similar to FOH aqueous solubility, 8 μM) dependent on polymer degradation

Skeletal anomalies in the Neandertal family of El Sidron (Spain) support a role of inbreeding in Neandertal extinction

Neandertals disappeared from the fossil record around 40,000 bp, after a demographic history of small and isolated groups with high but variable levels of inbreeding, and episodes of interbreeding with other Paleolithic hominins. It is reasonable to expect that high levels of endogamy could be expressed in the skeleton of at least some Neandertal groups. Genetic studies indicate that the 13 individuals from the site of El Sidrón, Spain, dated around 49,000 bp, constituted a closely related kin group, making these Neandertals an appropriate case study for the observation of skeletal signs of inbreeding. We present the complete study of the 1674 identified skeletal specimens from El Sidrón. Altogether, 17 congenital anomalies were observed (narrowing of the internal nasal fossa, retained deciduous canine, clefts of the first cervical vertebra, unilateral hypoplasia of the second cervical vertebra, clefting of the twelfth thoracic vertebra, diminutive thoracic or lumbar rib, os centrale carpi and bipartite scaphoid, tripartite patella, left foot anomaly and cuboid-navicular coalition), with at least four individuals presenting congenital conditions (clefts of the first cervical vertebra). At 49,000 years ago, the Neandertals from El Sidrón, with genetic and skeletal evidence of inbreeding, could be representative of the beginning of the demographic collapse of this hominin phenotype

A randomised phase 2 study comparing different dose approaches of induction treatment of regorafenib in previously treated metastatic colorectal cancer patients (REARRANGE trial)

Altres ajuts: Bayer HealthCare Pharmaceuticals Inc.Purpose: The purpose of this article is to evaluate the safety of two regorafenib dose-escalation approaches in refractory metastatic colorectal cancer (mCRC) patients. Patients and methods: Patients with mCRC and progression during or within 3 months following their last standard chemotherapy regimen were randomised to receive the approved dose of regorafenib of 160 mg QD (arm A) or 120 mg QD (arm B) administered as 3 weeks of treatment followed by 1 week off, or 160 mg QD 1 week on/1 week off (arm C). The primary end-point was the percentage of patients with G3/G4 treatment-related adverse events (AEs) in each arm. Results: There were 299 patients randomly assigned to arm A (n = 101), arm B (n = 99), or arm C (n = 99); 297 initiated treatments (arm A n = 100, arm B n = 98, arm C n = 99: population for safety analyses). G3/4 treatment-related AEs occurred in 60%, 55%, and 54% of patients in arms A, B, and C, respectively. The most common G3/4 AEs were hypertension (19, 12, and 20 patients), fatigue (20, 14, and 15 patients), hypokalemia (11, 7, and 10 patients), and hand-foot skin reaction (8, 7, and 3 patients). Median overall survival was 7.4 (IQR 4.0-13.7) months in arm A, 8.6 (IQR 3.8-13.4) in arm B, and 7.1 (IQR 4.4-12.4) in arm C. Conclusions: The alternative regorafenib dosing schedules were feasible and safe in patients with mCRC who had been previously treated with standard therapy. There was a higher numerical improvement on the most clinically relevant AEs in the intermittent dosing arm, particularly during the relevant first two cycles. Clinicaltrials.gov identifier: NCT02835924

Response to Comment on "The growth pattern of Neandertals, reconstructed from a juvenile skeleton from El Sidrón (Spain)".

This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Rosas, A., et al. (2018). "Response to Comment on “The growth pattern of Neandertals, reconstructed from a juvenile skeleton from El Sidrón (Spain)”." Science 359(6380). on Science 09 Mar 2018: Vol. 359, Issue 6380, eaar3820, DOI: 10.1126/science.aar3820The comment by DeSilva challenges our suggestion that brain growth of the El Sidrón J1 Neandertal was still incomplete at 7.7 years of age. Evidence suggests that endocranial volume is likely to represent less than 90% adult size at El Sidrón as well as Neandertal male plus Krapina samples, in line with further evidence from endocranial surface histology and dural sinus groove size

The CARMENES search for exoplanets around M dwarfs -- A deep learning approach to determine fundamental parameters of target stars

Existing and upcoming instrumentation is collecting large amounts of astrophysical data, which require efficient and fast analysis techniques. We present a deep neural network architecture to analyze high-resolution stellar spectra and predict stellar parameters such as effective temperature, surface gravity, metallicity, and rotational velocity. With this study, we firstly demonstrate the capability of deep neural networks to precisely recover stellar parameters from a synthetic training set. Secondly, we analyze the application of this method to observed spectra and the impact of the synthetic gap (i.e., the difference between observed and synthetic spectra) on the estimation of stellar parameters, their errors, and their precision. Our convolutional network is trained on synthetic PHOENIX-ACES spectra in different optical and near-infrared wavelength regions. For each of the four stellar parameters, $T_{\rm eff}$, $\log{g}$, [M/H], and $v \sin{i}$, we constructed a neural network model to estimate each parameter independently. We then applied this method to 50 M dwarfs with high-resolution spectra taken with CARMENES (Calar Alto high-Resolution search for M dwarfs with Exo-earths with Near-infrared and optical Echelle Spectrographs), which operates in the visible (520-960 nm) and near-infrared wavelength range (960-1710 nm) simultaneously. Our results are compared with literature values for these stars. They show mostly good agreement within the errors, but also exhibit large deviations in some cases, especially for [M/H], pointing out the importance of a better understanding of the synthetic gap