gebhart/patrepeval huggingface dataset:
Deep learning to achieve clinically applicable segmentation of head and neck anatomy for radiotherapy (2018)

Over half a million individuals are diagnosed with head and neck cancer each year worldwide. Radiotherapy is an important curative treatment for this disease, but it requires manual time consuming delineation of radio-sensitive organs at risk (OARs). This planning process can delay treatment, while also introducing inter-operator variability with resulting downstream radiation dose differences. While auto-segmentation algorithms offer a potentially time-saving solution, the challenges in defining, quantifying and achieving expert performance remain. Adopting a deep learning approach, we demonstrate a 3D U-Net architecture that achieves expert-level performance in delineating 21 distinct head and neck OARs commonly segmented in clinical practice. The model was trained on a dataset of 663 deidentified computed tomography (CT) scans acquired in routine clinical practice and with both segmentations taken from clinical practice and segmentations created by experienced radiographers as part of this research, all in accordance with consensus OAR definitions. We demonstrate the model's clinical applicability by assessing its performance on a test set of 21 CT scans from clinical practice, each with the 21 OARs segmented by two independent experts. We also introduce surface Dice similarity coefficient (surface DSC), a new metric for the comparison of organ delineation, to quantify deviation between OAR surface contours rather than volumes, better reflecting the clinical task of correcting errors in the automated organ segmentations. The model's generalisability is then demonstrated on two distinct open source datasets, reflecting different centres and countries to model training. With appropriate validation studies and regulatory approvals, this system could improve the efficiency, consistency, and safety of radiotherapy pathways.
Thermodynamic contributions of single internal rA·dA, rC·dC, rG·dG and rU·dT mismatches in RNA/DNA duplexes (2010)

The thermodynamic contributions of rA·dA, rC·dC, rG·dG and rU·dT single internal mismatches were measured for 54 RNA/DNA duplexes in a 1 M NaCl buffer using UV absorbance thermal denaturation. Thermodynamic parameters were obtained by fitting absorbance versus temperature profiles using the curve-fitting program Meltwin. The weighted average thermodynamic data were fit using singular value decomposition to determine the eight non-unique nearest-neighbor parameters for each internal mismatch. The new parameters predict the ΔG°(37), ΔH° and melting temperature (T(m)) of duplexes containing these single mismatches within an average of 0.33 kcal/mol, 4.5 kcal/mol and 1.4°C, respectively. The general trend in decreasing stability for the single internal mismatches is rG·dG > rU·dT > rA·dA > rC·dC. The stability trend for the base pairs 5' of the single internal mismatch is rG·dC > rC·dG > rA·dT > rU·dA. The stability trend for the base pairs 3' of the single internal mismatch is rC·dG > rG·dC >> rA·dT > rU·dA. These nearest-neighbor values are now a part of a complete set of single internal mismatch thermodynamic parameters for RNA/DNA duplexes that are incorporated into the nucleic acid assay development software programs Visual oligonucleotide modeling platform (OMP) and ThermoBLAST.
A Gene Co-Expression Network in Whole Blood of Schizophrenia Patients Is Independent of Antipsychotic-Use and Enriched for Brain-Expressed Genes (2012)

Despite large-scale genome-wide association studies (GWAS), the underlying genes for schizophrenia are largely unknown. Additional approaches are therefore required to identify the genetic background of this disorder. Here we report findings from a large gene expression study in peripheral blood of schizophrenia patients and controls. We applied a systems biology approach to genome-wide expression data from whole blood of 92 medicated and 29 antipsychotic-free schizophrenia patients and 118 healthy controls. We show that gene expression profiling in whole blood can identify twelve large gene co-expression modules associated with schizophrenia. Several of these disease related modules are likely to reflect expression changes due to antipsychotic medication. However, two of the disease modules could be replicated in an independent second data set involving antipsychotic-free patients and controls. One of these robustly defined disease modules is significantly enriched with brain-expressed genes and with genetic variants that were implicated in a GWAS study, which could imply a causal role in schizophrenia etiology. The most highly connected intramodular hub gene in this module (ABCF1), is located in, and regulated by the major histocompatibility (MHC) complex, which is intriguing in light of the fact that common allelic variants from the MHC region have been implicated in schizophrenia. This suggests that the MHC increases schizophrenia susceptibility via altered gene expression of regulatory genes in this network.
Mechanobiology of force transduction in dermal tissue (2003)

Background/aims: The influence of mechanical forces on skin has been examined since 1861 when Langer first reported the existence of lines of tension in cadaver skin. Internal tension in the dermis is not only passively transferred to the epidermis but also gives rise to active cell‐extracellular matrix and cell–cell mechanical interactions that may be an important part of the homeostatic processes that are involved in normal skin metabolism. The purpose of this review is to analyse how internal and external mechanical loads are applied at the macromolecular and cellular levels in the epidermis and dermis. Methods: A review of the literature suggests that internal and external forces applied to dermal cells appear to be involved in mechanochemical transduction processes involving both cell–cell and cell–extra‐cellular matrix (ECM) interactions. Internal forces present in dermis are the result of passive tension that is incorporated into the collagen fiber network during development. Active tension generated by fibroblasts involves specific interactions between cell membrane integrins and macromolecules found in the ECM, especially collagen fibrils. Forces appear to be transduced at the cell–ECM interface via re‐arrangement of cytoskeletal elements, activation of stretch‐induced changes in ion channels, cell contraction at adherens junctions, activation of cell membrane‐associated secondary messenger pathways and through growth factor‐like activities that influence cellular proliferation and protein synthesis. Conclusions: Internal and external mechanical loading appears to affect skin biology through mechanochemical transduction processes. Further studies are needed to understand how mechanical forces, energy storage and conversion of mechanical energy into changes in chemical potential of small and large macromolecules may occur and influence the metabolism of dermal cells.
Mechanistic Study of the sPLA2-Mediated Hydrolysis of a Thio-ester Pro Anticancer Ether Lipid (2009)

Secretory phospholipase A(2) (sPLA(2)) is an interesting enzyme for triggered liposomal drug delivery to tumor tissue due the overexpression of sPLA(2) in cancerous tissue. A drug delivery system based on the triggered release of therapeutics from sPLA(2)-sensitive liposomes constituted of pro anticancer ether lipids, which become cytotoxic upon sPLA(2)-catalyzed hydrolysis has previously been established. To optimize the hydrolysis rate of the lipids and thereby optimizing the release profile of the drugs from the liposomes, we have synthesized a thio-ester pro anticancer ether lipid. Liposomes constituted of this lipid showed an altered rate of hydrolysis by sPLA(2). We have tested the cytotoxicity of the thio-ester pro anticancer ether lipids toward cancer cells, and the results showed that the cytotoxicity is indeed maintained upon sPLA(2) exposure. To further understand the origin for the observed different hydrolysis rates for the esters, we have applied molecular dynamics simulations and density functional theory. The combination of these theoretical methods has given valuable insight into the molecular mechanism for sPLA(2) action on sulfur-containing phospholipids. It appears that the enzyme-catalyzed hydrolysis of thio-esters follow a different pathway compared to the hydrolysis pathway of the free thio-ester.
Integrin α3β1-mediated interaction with laminin-5 stimulates adhesion, migration and invasion of malignant glioma cells (1998)

Gliomas, characterized by their progressively invasive phenotype, express integrin alpha3beta1 as a major receptor for the extracellular matrix both in vivo and in vitro. Since the integrin alpha3beta1 has been shown to be a specific receptor for laminin-5 (alpha3beta3gamma2), we examined the effects of purified human laminin-5 on adhesion, migration and invasion of human glioma cells. Among different types of laminin variants and other matrix proteins including fibronectin and vitronectin, laminin-5 was most potent in promoting adhesion and migration of different kinds of glioma cells. Laminin-5-mediated adhesion and migration were specifically inhibited by monoclonal antibodies against integrin alpha3 and beta1 chains, confirming the role of integrin alpha3beta1 as the major laminin-5 receptor. Invasion of the reconstituted basement membrane (i.e., Matrigel) by glioma cells was also selectively stimulated by laminin-5. Out results show that laminin-5 is the major extracellular stimulant for glioma cell adhesion, migration and invasion. The immunohistochemical distribution of laminin gamma2 chain, a laminin subunit unique to laminin-5, showed that it was expressed in the tumor parenchyma of human glioma tissues. Expression of laminin alpha3, beta3 and gamma2 chains in glioma tissues and in glioma cell lines was also demonstrated at the messenger RNA level by reverse transcription polymerase chain reaction. Our results, taken together, show that laminin-5 may be involved in the invasive phenotype of malignant gliomas both in vitro and in vivo.
The safety and efficacy of osimertinib for the treatment ofEGFRT790M mutation positive non-small-cell lung cancer (2016)

First- and second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the evidence-based first-line treatment for metastatic non-small-cell lung cancers (NSCLCs) that harbor sensitizing EGFR mutations (i.e. exon 19 deletions or L858R). However, acquired resistance to EGFR TKI monotherapy occurs invariably within a median time frame of one year. The most common form of biological resistance is through the selection of tumor clones harboring the EGFR T790M mutation, present in >50% of repeat biopsies. The presence of the EGFR T790M mutation negates the inhibitory activity of gefitinib, erlotinib, and afatinib. A novel class of third-generation EGFR TKIs has been identified by probing a series of covalent pyrimidine EGFR inhibitors that bind to amino-acid residue C797 of EGFR and preferentially inhibit mutant forms of EGFR versus the wild-type receptor. We review the rapid clinical development and approval of the third-generation EGFR TKI osimertinib for treatment of NSCLCs with EGFR-T790M.
Dimerization and activation of the kit receptor by monovalent and bivalent binding of the stem cell factor. (1992)

The protooncogene c-kit encodes a tyrosine kinase receptor for the stem cell factor (SCF). Mutants of c-kit were shown to confer a pleiotropic defective phenotype and often display negative dominance in heterozygous mice. To explore the involvement of receptor dimerization in this genetic phenomenon, we employed both a human ligand, which does not recognize the murine receptor, and a rodent SCF, which binds to the human receptor with 100-fold reduced affinity as compared with human SCF. SCF binding to living cells was found to induce rapid and complete receptor dimerization that involved activation of the catalytic tyrosine kinase function. Although receptor dimerization can be attributed to the dimeric nature of the ligand, no dissociation of Kit dimers occurred at high excess of SCF, suggesting that receptor-receptor interactions are also involved in dimer stabilization. This was supported by in vitro formation of heterodimers between the human and murine Kit proteins through monovalent binding of species-specific human SCF. By coexpression of human and mouse Kit in murine fibroblasts, we found that receptor heterodimerization in living cells involved an increase in the affinity of human Kit for rat SCF and also an accelerated rate of receptor down-regulation. When a human Kit mutant lacking the kinase insert domain was coexpressed with the murine wild-type receptor, we observed a significant decrease in both the activation of the intact tyrosine kinase and its coupling to an effector protein, namely phosphatidylinositol 3'-kinase. Our results favor a receptor activation model that assumes an initial step of monovalent ligand binding, followed by an intermediate receptor dimer bound by one arm of the ligand molecule. This model predicts the existence of an intrinsic receptor dimerization site and provides a structural basis for genetic dominance of mutant SCF receptors.
Use of androgens in postmenopausal women (1997)

Serum androgen levels decline with age in women, a decline already demonstrable prior to menopause. Oestrogen administration is associated with a decrease in bioavailable testosterone. Testosterone administration can lead to increases in a number of parameters of sexuality, probably by direct neural effects. Androgens also have anabolic effects on bone, and do not adversely affect lipids, especially when given parenterally.
Common-channel soft handoff in cdma2000. The paging channel (2000)

cdma2000 has been proposed as the standard in the US for next-generation (3G) mobile phones. This paper describes the proposed paging channel of the cdma2000. It provides both the physical layer details of operation, and the signaling and network issues required to support these new channels. The new paging channel significantly improves the standby times of the phones for the 3G systems. This paper looks at a way to put this common channel in soft handoff, thereby improving the reliability of call setup, and leading to a better standby time for the cdma2000 phones. It is shown that the method does not affect the call setup time, and causes no significant impact on the power budget of the base stations. Furthermore, it is completely backward compatible.
Nanosecond-to-femtosecond laser-induced breakdown in dielectrics (1996)

We report extensive laser-induced damage threshold measurements on dielectric materials at wavelengths of 1053 and 526 nm for pulse durations $\ensuremath{\tau}$ ranging from 140 fs to 1 ns. Qualitative differences in the morphology of damage and a departure from the diffusion-dominated ${\ensuremath{\tau}}^{\frac{1}{2}}$ scaling of the damage fluence indicate that damage occurs from ablation for $\ensuremath{\tau}&lt;~10$ ps and from conventional melting, boiling, and fracture for $\ensuremath{\tau}&gt;50$ ps. We find a decreasing threshold fluence associated with a gradual transition from the long-pulse, thermally dominated regime to an ablative regime dominated by collisional and multiphoton ionization, and plasma formation. A theoretical model based on electron production via multiphoton ionization, Joule heating, and collisional (avalanche) ionization is in quantitative agreement with the experimental results.
Hierarchical porous/hollow tin oxide nanostructures mediated by polypeptide: surface modification, characterization, formation mechanism and gas-sensing properties (2006)

Successful synthesis of silica shells templated by polypeptide spheres stabilized by citric acid inspired us to explore the possibility of realizing aqueous self-assembly of metal oxides using the same template. As a specific case in the present study, we have begun with tin (IV) oxide. Initially, we failed to control the assembly process due to strong hydrolysis of Sn4+ ions and agglomeration of tin hydrates. After modification by a proper amount of citric acid which was trapped onto the surface of the tin hydrates through the chelating bond between RCOO− groups and Sn4+ ions, finely dispersed and stabilized tin oxide precursors have been obtained through electrostatic repulsion or/and steric hindrance. As a result, aqueous self-assembly of surface functional SnO2 building blocks mediated by the pre-formed polypeptide templates has been successfully achieved through interfacial columbic forces (COO−/NH3+). Samples fabricated from systematic processing control were characterized by thermogravimetric (TG) analysis, field-emission scanning electron microscopy (SEM), x-ray powder diffraction, high-resolution transmission electron microscopy (HRTEM), infrared (IR) absorption and N2 gas sorption experiments. Unique coral- and sea worm-like multilevel porous/hollow frameworks consisting of SnO2 nanocrystallites (4–5 nm) were synthesized. The samples also demonstrated improved H2 gas sensing property due to the large specific surface area (180–210 m2 g−1) as well as easy gas diffusion.
Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines (1992)

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
Differential inductions of TNF-alpha and IGTP, IIGP by structurally diverse classic and non-classic lipopolysaccharides (2005)

The innate immune system recognizes microbes by characteristic molecules like the Gram-negative lipopolysaccharide (LPS). Lipid A (the LPS bioactive moiety) signals through toll-like receptors (TLRs) to induce pro-inflammatory molecules and small GTPases of the p47 family involved in intracellular pathogen control. We tested TNF-alpha and p47-GTPase induction in macrophages using classical LPSs [lipid As with glucosamine backbones, ester- and amide-linked C14:0(3-OH) and C12 to C16 in acyloxyacyl groups] of wild type and mutant Escherichia coli and Yersinia species and non-classical LPSs [lipid As with diaminoglucose, ester-linked 3-OH-fatty acids and C28:0(27-OH) and C23:0(29-OH) in acyloxyacyl groups] of plant endosymbionts (Rhizobium), intracellular pathogens (Brucella and Legionella) and phylogenetically related opportunistic bacteria (Ochrobactrum). Classical but not non-classical LPSs efficiently induced TNF-alpha, IIGP and IGTP p47-GTPase expression. Remarkably, the acyloxyacyl groups in classical LPSs necessary to efficiently induce TNF-alpha were not necessary to induce p47-GTPases, suggesting that different aspects of lipid A are involved in this differential induction. This was confirmed by using PPDM2, a non-endotoxic lipid A-structurally related synthetic glycolipid. Despite their different bioactivity, all types of LPSs signalled through TLR-4 and not through TLR-2. However, whereas TNF-alpha induction was myeloid differentiation factor 88 (MyD88)-dependent, that of p47-GTPases occurred via a MyD88-independent pathway. These observations show that different aspects of the LPS pathogen-associated molecular pattern may be triggering different signalling pathways linked to the same TLR. They also reinforce the hypothesis that non-classical lipid As act as virulence factors by favouring the escape from the innate immune system.
Tumor necrosis factor-alpha induction of novel gene products in human endothelial cells including a macrophage-specific chemotaxin. (1990)

Cytokines such as tumor necrosis factor alpha (TNF) profoundly affect endothelial cell function, promoting for example interaction with leukocytes and inducing a procoagulant phenotype. Changes of this nature are likely to be central to the proinflammatory effects of TNF. In order to elucidate molecular mechanisms by which TNF alters endothelial cell function we utilized differential plaque hybridization to identify TNF-responsive genes. Forty TNF-inducible cDNAs were identified which on cross-hybridization were found to arise from six unique genes. DNA sequencing of these cDNAs revealed two encoded known cytokine-induced genes, endothelial leukocyte adhesion molecule 1 and neutrophil chemotactic factor. One of the cDNAs encodes a recently described monocyte-specific chemotactic factor not previously associated with endothelium. The production of a monocyte chemotaxin by cytokine-activated endothelium has important implications for understanding the role of the vessel wall in disease states such as atherosclerosis and may also in part explain the indirect angiogenic activity of TNF. The three other cDNAs are completely novel as judged by data bank searches of partial DNA sequences and remain unidentified. On exposure of endothelial cells to TNF there is a rapid and substantial increase in levels of mRNA encoding the six genes, which are further superinduced by cycloheximide. Thus these represent primary response genes as their induction does not depend on protein synthesis. Interleukin-1 beta and lipopolysaccharide are also potent inducers. Nuclear run-on studies revealed that in most cases induction by TNF is mediated largely at the transcriptional level.