An Adaptive Low-Rank Modeling-Based Active Learning Method for Medical Image Annotation.

Active learning is an effective solution to interactively select a limited number of informative examples and use them to train a learning algorithm that can achieve its optimal performance for specific tasks. It is suitable for medical image applications in which unlabeled data are abundant but manual annotation could be very time-consuming and expensive. However, designing an effective active learning strategy for informative example selection is a challenging task, due to the intrinsic presence of noise in medical images, the large number of images, and the variety of imaging modalities. In this study, a novel low-rank modeling-based multi-label active learning (LRMMAL) method is developed to address these challenges and select informative examples for training a classifier to achieve the optimal performance. The proposed method independently quantifies image noise and integrates it with other measures to guide a pool-based sampling process to determine the most informative examples for training a classifier. In addition, an automatic adaptive cross entropy-based parameter determination scheme is proposed for further optimizing the example sampling strategy. Experimental results on varied medical image datasets and comparisons with other state-of-the-art multi-label active learning methods illustrate the superior performance of the proposed method.

Earth-like Habitable Environments in the Subsurface of Mars.

In Earth's deep continental subsurface, where groundwaters are often isolated for >106 to 109 years, energy released by radionuclides within rock produces oxidants and reductants that drive metabolisms of non-photosynthetic microorganisms. Similar processes could support past and present life in the martian subsurface. Sulfate-reducing microorganisms are common in Earth's deep subsurface, often using hydrogen derived directly from radiolysis of pore water and sulfate derived from oxidation of rock-matrix-hosted sulfides by radiolytically derived oxidants. Radiolysis thus produces redox energy to support a deep biosphere in groundwaters isolated from surface substrate input for millions to billions of years on Earth. Here, we demonstrate that radiolysis by itself could produce sufficient redox energy to sustain a habitable environment in the subsurface of present-day Mars, one in which Earth-like microorganisms could survive wherever groundwater exists. We show that the source localities for many martian meteorites are capable of producing sufficient redox nutrients to sustain up to millions of sulfate-reducing microbial cells per kilogram rock via radiolysis alone, comparable to cell densities observed in many regions of Earth's deep subsurface. Additionally, we calculate variability in supportable sulfate-reducing cell densities between the martian meteorite source regions. Our results demonstrate that martian subsurface groundwaters, where present, would largely be habitable for sulfate-reducing bacteria from a redox energy perspective via radiolysis alone. We present evidence for crustal regions that could support especially high cell densities, including zones with high sulfide concentrations, which could be targeted by future subsurface exploration missions.

Clinical Outcomes and Prognostic Features of Angiosarcoma: Significance of Prior Radiation Therapy.

AIMS: Angiosarcoma is a rare and aggressive malignancy with a poor prognosis. There is limited literature describing prognostic factors and guidelines for treatment. We aim to describe outcomes in angiosarcoma, including the impact of patient-, tumour- and treatment-related factors on prognosis. MATERIALS AND METHODS: Patients with non-metastatic angiosarcoma diagnosed between 2008 and 2017 were retrospectively reviewed. Univariable and multivariable Cox proportional hazards methods were used to evaluate factors associated with locoregional recurrence, distant failure and overall survival. The Kaplan-Meier method and log-rank statistics were used to compare outcomes among patients with and without a history of prior radiation therapy. RESULTS: The cohort included 65 patients. The median age at diagnosis was 68 years (35-93). Nineteen patients had a history of receiving prior radiation therapy at the anatomic location of their angiosarcoma. Treatment modalities included surgery (n = 19), surgery + radiation therapy (n = 12), surgery + chemotherapy (n = 8), chemotherapy + radiation therapy (n = 7) and all three modalities (n = 14). The median follow-up was 18 (2-192) months. The 2-year locoregional control, distant control and overall survival were 61.8, 63.6 and 58.9%, respectively. On multivariable analysis, a history of previous radiation therapy was associated with inferior outcomes with respect to locoregional recurrence (hazard ratio 89.67, 95% confidence interval 8.45-951.07, P < 0.001), distant failure (hazard failure 3.74, 95% confidence interval 1.57-8.91, P = 0.003) and overall survival (hazard ratio 3.89, 95% confidence interval 1.56-9.60, P = 0.003). In patients with primary angiosarcoma, the rates of locoregional control, distant control and overall survival were 72.4, 73.4 and 65.1%, respectively, compared with 31.9, 41.1 and 45.1% in patients with radiation therapy-induced angiosarcoma (P = 0.001). CONCLUSION: Angiosarcomas that arise as a result of previous radiation therapy have worse outcomes compared with primary angiosarcomas. Although selection bias and compromise of clinical care in radiation therapy-induced angiosarcoma are partially to blame, differences in genomic profiles of the tumours need to be characterised to evaluate the underlying biological differences, as this may guide future treatment management. This study adds to the existing body of literature on angiosarcoma. Results from the current study are presented alongside previously published data to further characterise outcomes and prognostic factors on this rare and aggressive malignancy.

Crystal structure, vibrational and optic properties of 2-N-methylamino-3-methylpyridine N-oxide - Its X-ray and spectroscopic studies as well as DFT quantum chemical calculations.

The crystal and molecular structure and physicochemical properties of 2-N-methylamino-3-methylpyridine N-oxide (MA3MPO) have been studied. MA3MPO was synthesized from 2-amino-3-methylpyridine by several steps to form colorless crystals suitable for crystallographic analysis. The data reveal that MA3MPO crystallizes in the monoclinic space group P21/n. The studied compound contains a nearly flat triply substituted pyridine skeleton whose structure is stabilized by an intramolecular N-H⋅⋅⋅O hydrogen bond. The N-oxide molecules are connected together by weak C-H⋯O hydrogen bonds, an acceptor of which is the oxygen atom from the N-oxide group. This leads to creation of two-dimensional network of hydrogen bonds. Its IR, Raman, UV-Vis and luminescence spectra have been measured and analyzed on the basis of DFT and NBO quantum chemical calculations in which the B3LYP/6-311++G(d,p) approach was applied. The distribution of the electron levels in the studied compound has been analyzed in terms of the possibility of its participation in the ligand-to-lanthanide ion energy transfer.

Magnetic Resonance Image-Guided Radiotherapy (MRIgRT): A 4.5-Year Clinical Experience.

AIMS: Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. MATERIALS AND METHODS: We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014-2018) to identify shifts in institutional practice patterns. RESULTS: Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. DISCUSSION: MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

Conformation of the azo bond and its influence on the molecular and crystal structures, IR and Raman spectra, and electron properties of 6-methyl-3,5-dinitro-2-[(E)-phenyldiazenyl]pyridine - Quantum chemical DFT calculations.

The crystal and molecular structures of 6-methyl-3,5-dinitro-2-[(E)-phenyldiazenyl]pyridine have been determined by X-ray diffraction and quantum chemical DFT calculations. The crystal is monoclinic, space group Cc (No. 9) with Z=4 with the unit cell parameters: a=12.083(7), b=12.881(6), c=8.134(3) Å and ß=97.09(5)°. The azo-bridge appears in the trans conformation in which C2-N2-N2'-C1' torsion angle takes a value -178.6(3)°, whereas the dihedral angle between the planes of the phenyl and pyridine rings is 3.5(2)°. The IR and Raman spectra measured in the temperature range 80-350K and quantum chemical calculations with the use of B3LYP/6-311G(2d,2p) approach confirmed the trans configuration of the azo-bridge as the most stable energetically and allowed determination of the energy other virtual structures. The observed effects were used in the discussion of vibrational dynamics of the studied compound. The energy gap between cis and trans conformers equals to 1.054eV (0.03873 Hartree). The electron absorption and emission spectra have been measured and analyzed on the basis of DFT calculations. The life time of the excited state is 12µs and the Stokes shift is close to 5470cm-1.

Structure, vibrational spectra and DFT characterization of the intra- and inter-molecular interactions in 2-hydroxy-5-methylpyridine-3-carboxylic acid--normal modes of the eight-membered HB ring.

Fourier transform IR and Raman spectra, XRD studies and DFT quantum chemical calculations have been used to characterize the structural and vibrational properties of 2-hydroxy-5-methylpyridine-3-carboxylic acid. In the unit-cell of this compound two molecules related by the inversion center interact via OH⋯N hydrogen bonds. The double hydrogen bridge system is spaced parallel to the (102) crystallographic plane forming eight-membered arrangement characteristic for pyridine derivatives. The six-membered ring is the second characteristic unit formed via the intramolecular OH⋯O hydrogen bond. The geometry optimization of the monomer and dimer have been performed applying the Gaussian03 program package. All calculations were performed in the B3LYP/6-31G(d,p) basis set using the XRD data as input parameters. The relation between the molecular and crystal structures has been discussed in terms of the hydrogen bonds formed in the unit cell. The vibrations of the dimer have been discussed in terms of the resonance inside the system built of five rings coupled via hydrogen bonds.

Parameningeal rhabdomyosarcoma in pediatric age: results of a pooled analysis from North American and European cooperative groups.

BACKGROUND: Parameningeal (PM) site is a well-known adverse prognostic factor in children with localized rhabdomyosarcoma (RMS). To identify risk factors associated with outcome at this site, we pooled data from 1105 patients treated in 10 studies conducted by European and North American cooperative groups between 1984 and 2004. PATIENTS AND METHODS: Clinical factors including age, histology, size, invasiveness, nodal involvement, Intergroup Rhabdomyosarcoma Study (IRS) clinical group, site, risk factors for meningeal involvement (MI), study group, and application of radiotherapy (RT) were studied for their impact on event-free and overall survival (EFS and OS). RESULTS: Ten-year EFS and OS were 62.6 and 66.1% for the whole group. Patients without initial RT showed worse survival (10-year OS 40.8% versus 68.5% for RT treated patients). Multivariate analysis focusing on 862 patients who received RT as part of their initial treatment revealed four unfavorable prognostic factors: age <3 or >10 years, signs of MI, unfavorable site, and tumor size. Utilizing these prognostic factors, patients could be classified into different risk groups with 10-year OS ranging between 51.1 and 80.9%. CONCLUSIONS: While, in general, PM localization is regarded as an adverse prognostic factor, the current analysis differentiates those with good prognosis (36% patients with 0-1 risk factor: 10-year OS 80.9%) from high-risk PM patients (28% with 3-4 factors: 10-year OS 51.1%). Furthermore, this analysis reinforces the necessity for RT in PM RMS.

Intra- and inter-molecular hydrogen bonds, conformation and vibrational characteristics of hydrazo-group in 5-nitro-2-(2-phenylhydrazinyl)pyridine and its 3-, 4- or 6-methyl isomers.

Syntheses of 5-nitro-2-(2-phenylhydrazinyl)pyridine (5-nitro-2-phenylhydrazopyridine), 3-methyl-5-nitro-2-(2-phenylhydrazinyl)pyridine (3-methyl-5-nitro-2-phenylhydrazopyridine), 4-methyl-5-nitro-2-(2-phenylhydrazinyl)pyridine (4-methyl-5-nitro-2-phenylhydrazopyridine) and 6-methyl-5-nitro-2-(2-phenylhydrazinyl)pyridine (6-methyl-5-nitro-2-phenylhydrazopyridine) have been described. Their IR and Raman spectra have been measured and analyzed in terms of DFT quantum chemical calculations. The 6-311G(2d,2p) basis set with the B3LYP functional has been used to discuss the optimized structure and vibrational spectra. The vibrational characteristics of the hydrazo-bond have been reported with their relation to the inter- and intra-molecular hydrogen bonds formed in the studied systems. The role and influence of substitution position of the methyl chromophore on the structure and vibrational data have been discussed.

Vibrational spectra, crystal structure, DFT quantum chemical calculations and conformation of the hydrazo-bond in 6-methyl-3-nitro-2-(2-phenylhydrazinyl)pyridine.

The crystal and molecular structures of 6-methyl-3-nitro-2-(2-phenylhydrazinyl)pyridine (6-methyl-3-nitro-2-phenylhydrazopyridine) have been determined by X-ray diffraction and quantum chemical DFT analysis. The crystal is monoclinic, space group C2/c, with Z=8 formula units in the elementary unit cell of dimensions a=16.791(4), b=6.635(2), c=21.704(7)Å, ß=100.54(3)°. The molecule consists of two nearly planar pyridine subunits. A conformation of the linking hydrazo-bridge CNHNHC is bend and the dihedral angle between the planes of the phenyl and pyridine rings is 88.2(5)°. The hydrogen bonding of the type NH···N and possibly also CH···O favors a dimer formation in the crystal structure. The dimers are further linked by a NH···O hydrogen bond, so forming a layer parallel to the ab plane. The molecular structure of the studied compound has been determined using the DFT B3LYP/6-311G(2d,2p) approach and compared to that derived from X-ray studies. The IR and Raman wavenumbers have been calculated for the optimized geometry of a possible monomer structural model but the possibility of the dimer formation through the NH···N hydrogen bond has also been considered. The structural and vibrational properties of the intra-molecular NH···O interaction are described.

Lysosomal dysfunction causes neurodegeneration in mucolipidosis II 'knock-in' mice.

Mucolipidosis II is a neurometabolic lysosomal trafficking disorder of infancy caused by loss of mannose 6-phosphate targeting signals on lysosomal proteins, leading to lysosomal dysfunction and accumulation of non-degraded material. However, the identity of storage material and mechanisms of neurodegeneration in mucolipidosis II are unknown. We have generated 'knock-in' mice with a common mucolipidosis II patient mutation that show growth retardation, progressive brain atrophy, skeletal abnormalities, elevated lysosomal enzyme activities in serum, lysosomal storage in fibroblasts and brain and premature death, closely mimicking the mucolipidosis II disease in humans. The examination of affected mouse brains at different ages by immunohistochemistry, ultrastructural analysis, immunoblotting and mass spectrometric analyses of glycans and anionic lipids revealed that the expression and proteolytic processing of distinct lysosomal proteins such as α-l-fucosidase, ß-hexosaminidase, α-mannosidase or Niemann-Pick C2 protein are more significantly impacted by the loss of mannose 6-phosphate residues than enzymes reaching lysosomes independently of this targeting mechanism. As a consequence, fucosylated N-glycans, GM2 and GM3 gangliosides, cholesterol and bis(monoacylglycero)phosphate accumulate progressively in the brain of mucolipidosis II mice. Prominent astrogliosis and the accumulation of organelles and storage material in focally swollen axons were observed in the cerebellum and were accompanied by a loss of Purkinje cells. Moreover, an increased neuronal level of the microtubule-associated protein 1 light chain 3 and the formation of p62-positive neuronal aggregates indicate an impairment of constitutive autophagy in the mucolipidosis II brain. Our findings demonstrate the essential role of mannose 6-phosphate for selected lysosomal proteins to maintain the capability for degradation of sequestered components in lysosomes and autophagolysosomes and prevent neurodegeneration. These lysosomal proteins might be a potential target for a valid therapeutic approach for mucolipidosis II disease.

Proteomic characterization in the hippocampus of prenatally stressed rats.

Rats exposed to early life stress are considered as a valuable model for the study of epigenetic programming leading to mood disorders and anxiety in the adult life. Rats submitted to prenatal restraint stress (PRS) are characterized by an anxious/depressive phenotype associated with neuroadaptive changes in the hippocampus. We used the model of PRS to identify proteins that are specifically affected by early life stress. We therefore performed a proteomic analysis in the hippocampus of adult male PRS rats. We found that PRS induced changes in the expression profile of a number of proteins, involved in the regulation of signal transduction, synaptic vesicles, protein synthesis, cytoskeleton dynamics, and energetic metabolism. Immunoblot analysis showed significant changes in the expression of proteins, such as LASP-1, fascin, and prohibitin, which may lie at the core of the developmental programming triggered by early life stress.

Serum-stimulated cell cycle entry promotes ncOGT synthesis required for cyclin D expression.

Nuclear and cytoplasmic O-GlcNAc transferase (OGT) is a unique and universally expressed enzyme catalyzing O-GlcNAcylation of thousands of proteins. Although OGT interferes with many crucial intracellular processes, including cell cycle, only few studies have focused on elucidating the precise role of the glycosyltransferase during cell cycle entry. We first demonstrated that starved MCF7 cells reincubated with serum quickly induced a significant OGT increase concomitantly to activation of PI3K and MAPK pathways. Co-immunoprecipitation experiments performed upon serum stimulation showed a progressive interaction between OGT and ß-catenin, a major factor in the regulation of cell cycle. OGT expression was also observed in starved HeLa cells reincubated with serum. In these cells, the O-GlcNAcylation status of the ß-catenin-2XFLAG was increased following stimulation. Moreover, ß-catenin-2XFLAG was heavily O-GlcNAcylated in exponentially proliferating HeLa cells when compared to confluent cells. Furthermore, blocking OGT activity using the potent inhibitor Ac-5SGlcNAc prevented serum-stimulated cyclin D1 synthesis and slightly delayed cell proliferation. At last, interfering with OGT expression (siOGT) blocked cyclin D1 expression and decreased PI3K and MAPK activation. Together, our data indicate that expression and catalytic activity of OGT are necessary and essential for G0/G1 transition.

PDE4: a novel target in the treatment of chronic obstructive pulmonary disease.

Phosphodiesterases (PDEs) are important modulators of inflammation and wound healing. In this capacity, specific targeting of PDEs for the treatment of many diseases, including chronic obstructive pulmonary disease (COPD), has been investigated. Currently, treatment of COPD is suboptimal. PDE4 modulates the inflammatory response of the lung, and inhibition of PDE4 may be a novel, COPD-specific approach toward more effective treatment strategies. This review describes the state of PDE4-inhibitor therapy for use in COPD treatment.

Early toxicity predicts long-term survival in high-grade glioma.

BACKGROUND: Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known. METHODS: Acute and late ≥ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable. RESULTS: There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2-4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months). INTERPRETATION: Acute NT is significantly associated with both late NT and overall survival.

Molecular structure, IR and Raman spectra as well as DFT chemical calculations for alkylaminoacetylureas: vibrational characteristics of dicarbonylimide bridge.

The present work reports room temperature IR and Raman study of R-NH-CH2-CO-NH-CO-NH2 alkylaminoacetylureas (R=C3H7, C4H9, C5H11, C6H13, C7H15, C8H17, C9H19, C10H21, C12H25, C14H29, C16H33 and C18H37). The experimental energy levels have been compared to those obtained from DFT chemical quantum calculations performed with the use of B3LYP/6-31G (d,p) basis for the R=C3H7 derivative. Energies of 66 vibrational states have been calculated for this molecule. Its molecular symmetry was taken as C1 and was optimized in the both quantum models applied. The role of the hydrogen bond in the stabilization of the structure has been analyzed.

DMBT1 expression and glycosylation during the adenoma-carcinoma sequence in colorectal cancer.

The gene DMBT1 (deleted in malignant brain tumour-1) has been proposed to play a role in brain and epithelial cancer, but shows unusual features for a classical tumour-suppressor gene. On the one hand, DMBT1 has been linked to mucosal protection, whereas, on the other, it potentially plays a role in epithelial differentiation. Thus its function in a particular tissue is of mechanistic importance for its role in cancer. Because the former function requires secretion to the lumen and the latter function may depend on its presence in the extracellular matrix, we decided to investigate DMBT1 expression, location and its mode of secretion during malignant transformation in colorectal cancer. Using human colorectal PC/AA cell lines and tissue sections from individual patients, we have examined the expression of DMBT1 and its glycosylation in the adenoma-carcinoma sequence leading to the adenocarcinoma phenotype.

Second-generation recombination-based in vivo expression technology for large-scale screening for Vibrio cholerae genes induced during infection of the mouse small intestine.

We have constructed an improved recombination-based in vivo expression technology (RIVET) and used it as a screening method to identify Vibrio cholerae genes that are transcriptionally induced during infection of infant mice. The improvements include the introduction of modified substrate cassettes for resolvase that can be positively and negatively selected for, allowing selection of resolved strains from intestinal homogenates, and three different tnpR alleles that cover a range of translation initiation efficiencies, allowing identification of infection-induced genes that have low-to-moderate basal levels of transcription during growth in vitro. A transcriptional fusion library of 8,734 isolates of a V. cholerae El Tor strain that remain unresolved when the vibrios are grown in vitro was passed through infant mice, and 40 infection-induced genes were identified. Nine of these genes were inactivated by in-frame deletions, and their roles in growth in vitro and fitness during infection were measured by competition assays. Four mutant strains were attenuated >10-fold in vivo compared with the parental strain, demonstrating that infection-induced genes are enriched in genes essential for virulence.

The SPASIBA force field as an essential tool for studying the structure and dynamics of saccharides.

The SPASIBA force field has been applied to the determination of the structure and dynamical properties of various disaccharides. It has been shown that the experimental properties (structure, dipole moment, conformational relative energies) are satisfactorily predicted. The anomeric and exo-anomeric effects are confidently reproduced without specific terms for the alpha and beta anomers and the type of glycosidic linkages.