julilili42/papers huggingface dataset:
Genetically engineered CAR NK cells display selective cytotoxicity against FLT3‐positive B‐ALL and inhibit in vivo leukemia growth
2019-03-12

Chimeric antigen receptor (CAR)‐engineered natural killer (NK) cells represent a promising effector cell type for adoptive cancer immunotherapy. Both, genetically modified donor‐derived NK cells as well as continuously expanding NK‐92 cells are currently under clinical development. To enhance their therapeutic utility for the treatment of pre‐B‐cell acute lymphoblastic leukemia (B‐ALL), we engineered NK‐92 cells by lentiviral gene transfer to express a FMS‐like tyrosine kinase 3 (FLT3)‐specific CAR that contains a composite CD28‐CD3ζ signaling domain. FLT3 has primarily been described as a therapeutic target for acute myeloid leukemia, but overexpression of FLT3 has also been reported in B‐ALL. Exposure of FLT3‐positive targets to CAR NK‐92 cells resulted in conjugate formation between NK and leukemia cells, NK‐cell degranulation and selective cytotoxicity toward established B‐ALL cell lines and primary blasts that were resistant to parental NK‐92. In a SEM B‐ALL xenograft model in NOD‐SCID IL2R γ null mice, treatment with CAR NK‐92 but not parental NK‐92 cells markedly inhibited disease progression, demonstrating high antileukemic activity in vivo . As FLT3 is known to be also expressed on precursor cells, we assessed the feasibility of incorporating an inducible caspase‐9 (iCasp9) suicide switch to enhance safety of our approach. Upon addition of the chemical dimerizer AP20187 to NK‐92 cells coexpressing the FLT3‐specific CAR and iCasp9, rapid iCasp9 activation was observed, precluding further CAR‐mediated cytotoxicity. Our data demonstrate that B‐ALL can be effectively targeted by FLT3‐specific CAR NK cells which may complement CD19‐directed immunotherapies, particularly in cases of inherent or acquired resistance to the latter.
Rationale for Combining Radiotherapy and Immune Checkpoint Inhibition for Patients With Hypoxic Tumors
2019-03-12

In order to compensate for the increased oxygen consumption in growing tumors, tumors need angiogenesis and vasculogenesis to increase the supply. Insufficiency in this process or in the microcirculation leads to hypoxic tumor areas with a significantly reduced pO2, which in turn leads to alterations in the biology of cancer cells as well as in the tumor microenvironment. Cancer cells develop more aggressive phenotypes, stem cell features and are more prone to metastasis formation and migration. In addition, intratumoral hypoxia confers therapy resistance, specifically radioresistance. Reactive oxygen species are crucial in fixing DNA breaks after ionizing radiation. Thus, hypoxic tumor cells show a two- to threefold increase in radioresistance. The microenvironment is enriched with chemokines (e.g., SDF-1) and growth factors (e.g., TGFβ) additionally reducing radiosensitivity. During recent years hypoxia has also been identified as a major factor for immune suppression in the tumor microenvironment. Hypoxic tumors show increased numbers of myeloid derived suppressor cells (MDSCs) as well as regulatory T cells (T<sub>reg</sub>s) and decreased infiltration and activation of cytotoxic T cells. The combination of radiotherapy with immune checkpoint inhibition is on the rise in the treatment of metastatic cancer patients, but is also tested in multiple curative treatment settings. There is a strong rationale for synergistic effects, such as increased T cell infiltration in irradiated tumors and mitigation of radiation-induced immunosuppressive mechanisms such as PD-L1 upregulation by immune checkpoint inhibition. Given the worse prognosis of patients with hypoxic tumors due to local therapy resistance but also increased rate of distant metastases and the strong immune suppression induced by hypoxia, we hypothesize that the subgroup of patients with hypoxic tumors might be of special interest for combining immune checkpoint inhibition with radiotherapy.
Clinical spectrum of STX1B-related epileptic disorders
2019-03-12

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.
Students’ perspectives on the use of digital versus conventional dental impression techniques in orthodontics
2019-03-12

Dental students were able to practice both conventional alginate and modern digital impressions without prior knowledge of intraoral impression techniques after basic training and an introduction from dentists. Students reported a preference for the digital technique. Implementing digital intraoral impressions into undergraduate training is recommended to familiarise students with this rapidly developing digital technique at an early stage.
The molecular pathogenesis of superoxide dismutase 1-linked ALS is promoted by low oxygen tension
2019-03-12

Mutations in superoxide dismutase 1 (SOD1) cause amyotrophic lateral sclerosis (ALS). Disease pathogenesis is linked to destabilization, disorder and aggregation of the SOD1 protein. However, the non-genetic factors that promote disorder and the subsequent aggregation of SOD1 have not been studied. Mainly located to the reducing cytosol, mature SOD1 contains an oxidized disulfide bond that is important for its stability. Since O<sub>2</sub> is required for formation of the bond, we reasoned that low O<sub>2</sub> tension might be a risk factor for the pathological changes associated with ALS development. By combining biochemical approaches in an extensive range of genetically distinct patient-derived cell lines, we show that the disulfide bond is an Achilles heel of the SOD1 protein. Culture of patient-derived fibroblasts, astrocytes, and induced pluripotent stem cell-derived mixed motor neuron and astrocyte cultures (MNACs) under low O<sub>2</sub> tensions caused reductive bond cleavage and increases in disordered SOD1. The effects were greatest in cells derived from patients carrying ALS-linked mutations in SOD1. However, significant increases also occurred in wild-type SOD1 in cultures derived from non-disease controls, and patients carrying mutations in other common ALS-linked genes. Compared to fibroblasts, MNACs showed far greater increases in SOD1 disorder and even aggregation of mutant SOD1s, in line with the vulnerability of the motor system to SOD1-mediated neurotoxicity. Our results show for the first time that O<sub>2</sub> tension is a principal determinant of SOD1 stability in human patient-derived cells. Furthermore, we provide a mechanism by which non-genetic risk factors for ALS, such as aging and other conditions causing reduced vascular perfusion, could promote disease initiation and progression.
PGRMC1 can trigger estrogen-dependent proliferation of breast cancer cells: estradiol vs. equilin vs. ethinylestradiol
2019-03-12

<b>Objective:</b> Previous studies have shown that progesterone receptor membrane component 1 (PGRMC1) expressed in breast cancer tissue can predict a worse prognosis for breast cancer patients. Moreover, we demonstrated that PGRMC1 can increase the proliferation of progestogens. However, the role of PGRMC1 in terms of estrogen-induced proliferation and comparing different estrogens is still unclear. <b>Methods:</b> Non-transfected and PGRMC1-transfected T-47D cells were stimulated with estradiol (E2), with equilin (EQ), or with ethinylestradiol (EE) at 1, 10, and 100 nmol/l. Increase of proliferation was compared with a control (without estrogens) and with the estrogen-induced stimulation in empty vector cells vs. PGRMC1-transfected cells. <b>Results:</b> The empty vector cells showed significant proliferation (12-15%) with all three estrogens only at the highest concentration, with no relevant differences between the estrogens. PGRMC1-transfected cells showed about three-fold higher proliferation (29-66%), whereby E2 elicited the strongest and EE the lowest proliferating effects, significantly lower compared to E2 and also compared to EQ. No significant differences were seen between E2 and EQ. <b>Conclusions:</b> PGRMC1 increases strongly the estrogen-dependent breast cell proliferation. The proliferating effects of EE may be lower compared to E2 and EQ. This could have importance in comparing hormone therapy and contraception. Thus, PGRMC1 not only could predict the risk using progestogens but also of different estrogens.
ATG-18 and EPG-6 are Both Required for Autophagy but Differentially Contribute to Lifespan Control in Caenorhabditis elegans
2019-03-12

During macroautophagy, the human WIPI (WD-repeat protein interacting with phosphoinositides) proteins (WIPI1–4) function as phosphatidylinositol 3-phosphate effectors at the nascent autophagosome. Likewise, the two WIPI homologues in Caenorhabditis elegans, ATG-18 and EPG-6, play important roles in autophagy, whereby ATG-18 is considered to act upstream of EPG-6 at the onset of autophagy. Due to its essential role in autophagy, ATG-18 was found to be also essential for lifespan extension in Caenorhabditis elegans; however, this has not yet been addressed with regard to EPG-6. Here, we wished to address this point and generated mutant strains that expressed the autophagy marker GFP::LGG-1 (GFP-LC3 in mammals) and harbored functional deletions of either atg-18 (atg18(gk378)), epg-6 (epg-6(bp242)) or both (atg-18(gk378);epg-6(bp242)). Using quantitative fluorescence microscopy, Western blotting, and lifespan assessments, we provide evidence that in the absence of either ATG-18 or EPG-6 autophagy was impaired, and while atg-18 mutant animals showed a short-lived phenotype, lifespan was significantly increased in epg-6 mutant animals. We speculate that the long-lived phenotype of epg-6 mutant animals points towards an autophagy-independent function of EPG-6 in lifespan control that warrants further mechanistic investigations in future studies.
Synthetic Adventures with 2‐C‐Branched Carbohydrates: 4‐C‐Formyl Branched Octoses with Structural Analogy to Bradyrhizose
2019-03-12

The synthesis of three 4‐ C ‐formyl branched octoses with variable stereoconfiguration at the C‐2 and C‐3 stereogenic centers is described. This class of compounds is of interest due to potential structural analogies to the naturally occurring bradyrhizose monosaccharide. Branched key sugar intermediates of the synthesis are 2‐ C ‐(1,2,3‐trihydroxyprop‐1‐yl)‐β‐ d ‐mannosides. A new mild oxidation protocol using known TEMPO/trichloroisocyanuric acid in ethyl acetate/toluene, buffered with 3‐( N ‐morpholino)propanesulfonic acid, is described as a valuable reaction for selective primary alcohol oxidation and, hence, the formation of 2‐(spirofuranose)pyranoses. Upon global deprotection these spirofuranoses give complex mixtures of diverse hemiacetal forms of the liberated 4‐ C ‐formyl octoses. As revealed by detailed NMR studies, the bradyrhizose‐type annulated forms do not represent the major isomers. For each of the target octoses, these potential neighboured acetal‐hemiacetal‐forms (9,7‐pyranose‐1,9‐pyranoses) seem to be unfavorable, and instead remote bis(hemiacetals) are formed (1,5‐pyranose‐9,7‐pyranoses or 1,4‐furanose‐9,7‐pyranoses) as the major species.
Are Automatic Methods for Cognate Detection Good Enough for Phylogenetic Reconstruction in Historical Linguistics?
2019-03-12

We evaluate the performance of state-of-the-art algorithms for automatic cognate detection by comparing how useful automatically inferred cognates are for the task of phylogenetic inference compared to classical manually annotated cognate sets. Our findings suggest that phylogenies inferred from automated cog- nate sets come close to phylogenies inferred from expert-annotated ones, although on average, the latter are still superior. We con- clude that future work on phylogenetic reconstruction can profit much from automatic cognate detection. Especially where scholars are merely interested in exploring the bigger picture of a language family's phylogeny, algorithms for automatic cognate detection are a useful complement for current research on language phylogenies.
Does evaluative learning depend on the statistical relationship between stimuli? On the sensitivity of evaluative cue conditioning to ecological contingencies
2019-03-12

Evaluative conditioning (EC) is concerned with the transfer of valence from an unconditioned stimulus (US) to a conditioned stimulus (CS). Only recently the notion of EC was extended from individual CSs to categories of CSs that share certain cues. That research shows that a contingency implemented between a cue dimension and US valence has a direct effect on the evaluation of stimuli carrying values of this cue dimension. This phenomenon was coined “evaluative cue conditioning” (ECC). The present research tests whether ECC is sensitive to the contingency between a cue dimension and US valence. The present work thereby investigates the impact of ecological contingencies that define contingency by reference to all other CS-US pairings in the learning environment. Two experiments demonstrate that ECC effects are sensitive to the strength of the ecological contingency, suggesting that ECC is a relative phenomenon that depends on the valence of the CS-US pairings in the reference set. Moreover, these findings call for more research on the contingency sensitivity of standard EC effects using this revised definition of contingency.
Does evaluative learning depend on the statistical relationship between stimuli? On the sensitivity of evaluative cue conditioning to ecological contingencies
2019-03-12

&lt;p&gt;Evaluative conditioning (EC) is concerned with the transfer of valence from an unconditioned stimulus (US) to a conditioned stimulus (CS). Only recently the notion of EC was extended from individual CSs to categories of CSs that share certain cues. That research shows that a contingency implemented between a cue dimension and US valence has a direct effect on the evaluation of stimuli carrying values of this cue dimension. This phenomenon was coined &ldquo;evaluative cue conditioning&rdquo; (ECC). The present research tests whether ECC is sensitive to the contingency between a cue dimension and US valence. The present work thereby investigates the impact of ecological contingencies that define contingency by reference to all other CS-US pairings in the learning environment. Two experiments demonstrate that ECC effects are sensitive to the strength of the ecological contingency, suggesting that ECC is a relative phenomenon that depends on the valence of the CS-US pairings in the reference set. Moreover, these findings call for more research on the contingency sensitivity of standard EC effects using this revised definition of contingency.&lt;/p&gt;
Impaired ABCA1/ABCG1-mediated lipid efflux in the mouse retinal pigment epithelium (RPE) leads to retinal degeneration
2019-03-13

Age-related macular degeneration (AMD) is a progressive disease of the retinal pigment epithelium (RPE) and the retina leading to loss of central vision. Polymorphisms in genes involved in lipid metabolism, including the ATP-binding cassette transporter A1 ( ABCA1 ), have been associated with AMD risk. However, the significance of retinal lipid handling for AMD pathogenesis remains elusive. Here, we study the contribution of lipid efflux in the RPE by generating a mouse model lacking ABCA1 and its partner ABCG1 specifically in this layer. Mutant mice show lipid accumulation in the RPE, reduced RPE and retinal function, retinal inflammation and RPE/photoreceptor degeneration. Data from human cell lines indicate that the ABCA1 AMD risk-conferring allele decreases ABCA1 expression, identifying the potential molecular cause that underlies the genetic risk for AMD. Our results highlight the essential homeostatic role for lipid efflux in the RPE and suggest a pathogenic contribution of reduced ABCA1 function to AMD.
Intraoral scanning to fabricate complete dentures with functional borders: a proof-of-concept case report
2019-03-13

Abstract Background The utilization of intraoral scanning for manufacturing of complete dentures (CD) has been reported recently. However, functional border molding still cannot be supported digitally. A proof-of-concept trial shows two possible pathways to overcome this limitation by integrating a relining procedure into the digital workflow for CD manufacturing. Case presentation Intraoral scans and additional facial scans were performed with two various scanning systems for the rehabilitation of an edentulous male patient. The obtained raw data was aligned and used for the computer aided design (CAD) of the CD. The virtually constructed dentures were materialized in two various ways, considering rapid manufacturing and digital relining approaches in order to apply functionally molded borders. Conclusion The use of intraoral edentulous jaws scans in combination with the digital relining procedure may allow for fabrication of CD with functional borders within a fully digital workflow.
Non-invasive functional molecular phenotyping of human smooth muscle cells utilized in cardiovascular tissue engineering
2019-03-13

Smooth muscle cell (SMC) diversity and plasticity are limiting factors in their characterization and application in cardiovascular tissue engineering. This work aimed to evaluate the potential of Raman microspectroscopy and Raman imaging to distinguish SMCs of different tissue origins and phenotypes. Cultured human SMCs isolated from different vascular and non-vascular tissues as well as fixed human SMC-containing tissues were analyzed. In addition, Raman spectra and images of tissue-engineered SMC constructs were acquired. Routine techniques such as qPCR, histochemistry, histological and immunocytological staining were performed for comparative gene and protein expression analysis. We identified that SMCs of different tissue origins exhibited unique spectral information that allowed a separation of all groups of origin by multivariate data analysis (MVA). We were further able to non-invasively monitor phenotypic switching in cultured SMCs and assess the impact of different culture conditions on extracellular matrix remodeling in the tissue-engineered ring constructs. Interestingly, we identified that the Raman signature of the human SMC-based ring constructs was similar to the one obtained from native aortic tissue. We conclude that Raman microspectroscopic methods are promising tools to characterize cells and define cellular and extracellular matrix components on a molecular level. In this study, in situ measurements were marker-independent, fast, and identified cellular differences that were not detectable by established routine techniques. Perspectively, Raman microspectroscopy and MVA in combination with artificial intelligence can be suitable for automated quality monitoring of (stem) cell and cell-based tissue engineering products. STATEMENT OF SIGNIFICANCE: The accessibility of autologous blood vessels for surgery is limited. Tissue engineering (TE) aims to develop functional vascular replacements; however, no commercially available TE vascular graft (TEVG) exists to date. One limiting factor is the availability of a well-characterized and safe cell source. Smooth muscle cells (SMCs) are generally used for TEVGs. To engineer a TEVG, proliferating SMCs of the synthesizing phenotype are essential, whereas functional, sustainable TEVGs require SMCs of the contractile phenotype. SMC diversity and plasticity are therefore limiting factors, also for their quality monitoring and application in TE. In this study, Raman microspectroscopy and imaging combined with machine learning tools allowed the non-destructive, marker-independent characterization of SMCs, smooth muscle tissues and TE SMC-constructs. The spectral information was specific enough to distinguish for the first time the phenotypic switching in SMCs in real-time, and monitor the impact of culture conditions on ECM remodeling in the TE SMC-constructs.
Safety and Toxicology of Ocular Gene Therapy with Recombinant AAV Vector rAAV.hCNGA3 in Nonhuman Primates
2019-03-13

The purpose of this study was to examine the toxicity and side effects of a recombinant adeno-associated virus 8 (AAV8) vector, aimed to treat cyclic nucleotide gated channel alpha 3 (<i>CNGA3</i>)-linked achromatopsia, after a single subretinal administration in cynomolgus macaques. Animals were followed in two studies: a 13-week study with 22 animals and a 28-day study with 12 animals. Both groups were divided into subgroups receiving either vehicle only, a low (1 × 10<sup>11</sup> vector genomes (vg)), or a high dose (1 × 10<sup>12</sup> vg) of rAAV.hCNGA3. In the 13-week study, an extra group received single high-dose intravitreal injections. Here we present the group results of the histological examinations carried out after necropsy from the 28-day study, the retinal functional (electroretinography) in the 13-week study, and clinical observations from both studies. Treatment-related adverse effects were not found, and parameter changes were mostly related to the surgical procedure. The treatment of achromatopsia with rAAV.hCNGA3 is therefore deemed safe to apply to humans.
Parton-shower effects on Higgs boson production via vector-boson fusion in association with three jets
2019-03-13

We present an implementation of Higgs boson production via vector-boson fusion in association with three jets at hadron colliders in the POWHEG BOX, a framework for the matching of NLO-QCD calculations with parton-shower programs. Our work provides the means to precisely describe the properties of extra jet activity in vector-boson fusion reactions that are used for the suppression of QCD backgrounds by central jet veto techniques. For a representative setup at the CERN LHC we verify that uncertainties related to parton-shower effects are mild for distributions related to the third jet, in contrast to what has been observed in calculations based on vector-boson fusion induced Higgs production in association with two jets.