gebhart/patrepeval huggingface dataset:
Improving PARP inhibitor efficacy in high-grade serous ovarian carcinoma: A focus on the immune system (2022)

High-grade serous ovarian carcinoma (HGSOC) is a genomically unstable malignancy responsible for over 70% of all deaths due to ovarian cancer. With roughly 50% of all HGSOC harboring defects in the homologous recombination (HR) DNA repair pathway (e.g., <i>BRCA1/</i>2 mutations), the introduction of poly ADP-ribose polymerase inhibitors (PARPi) has dramatically improved outcomes for women with HR defective HGSOC. By blocking the repair of single-stranded DNA damage in cancer cells already lacking high-fidelity HR pathways, PARPi causes the accumulation of double-stranded DNA breaks, leading to cell death. Thus, this synthetic lethality results in PARPi selectively targeting cancer cells, resulting in impressive efficacy. Despite this, resistance to PARPi commonly develops through diverse mechanisms, such as the acquisition of secondary <i>BRCA1/2</i> mutations. Perhaps less well documented is that PARPi can impact both the tumour microenvironment and the immune response, through upregulation of the stimulator of interferon genes (STING) pathway, upregulation of immune checkpoints such as PD-L1, and by stimulating the production of pro-inflammatory cytokines. Whilst targeted immunotherapies have not yet found their place in the clinic for HGSOC, the evidence above, as well as ongoing studies exploring the synergistic effects of PARPi with immune agents, including immune checkpoint inhibitors, suggests potential for targeting the immune response in HGSOC. Additionally, combining PARPi with epigenetic-modulating drugs may improve PARPi efficacy, by inducing a BRCA-defective phenotype to sensitise resistant cancer cells to PARPi. Finally, invigorating an immune response during PARPi therapy may engage anti-cancer immune responses that potentiate efficacy and mitigate the development of PARPi resistance. Here, we will review the emerging PARPi literature with a focus on PARPi effects on the immune response in HGSOC, as well as the potential of epigenetic combination therapies. We highlight the potential of transforming HGSOC from a lethal to a chronic disease and increasing the likelihood of cure.
Intermodal Auditory, Visual, and Tactile Attention Modulates Early Stages of Neural Processing (2008)

We used event-related potentials (ERPs) and gamma band oscillatory responses (GBRs) to examine whether intermodal attention operates early in the auditory, visual, and tactile modalities. To control for the effects of spatial attention, we spatially coregistered all stimuli and varied the attended modality across counterbalanced blocks in an intermodal selection task. In each block, participants selectively responded to either auditory, visual, or vibrotactile stimuli from the stream of intermodal events. Auditory and visual ERPs were modulated at the latencies of early cortical processing, but attention manifested later for tactile ERPs. For ERPs, auditory processing was modulated at the latency of the Na (29 msec), which indexes early cortical or thalamocortical processing and the subsequent P1 (90 msec) ERP components. Visual processing was modulated at the latency of the early phase of the C1 (62-72 msec) thought to be generated in the primary visual cortex and the subsequent P1 and N1 (176 msec). Tactile processing was modulated at the latency of the N160 (165 msec) likely generated in the secondary association cortex. Intermodal attention enhanced early sensory GBRs for all three modalities: auditory (onset 57 msec), visual (onset 47 msec), and tactile (onset 27 msec). Together, these results suggest that intermodal attention enhances neural processing relatively early in the sensory stream independent from differential effects of spatial and intramodal selective attention.
Selective JAK inhibition proves efficacious in epithelial cancer models (2008)

14592 Background: Signal transducers and activators of transcription (STATs) are a family of latent transcription factors that are aberrantly activated in a diverse spectrum of epithelial tumors. STATs can be activated through tyrosine phosyporylation by a number of kinases including Janus kinases (JAKs), Src, Abl, and EGFR. Phosphorylated STATs (pSTAT) contribute to oncogenesis by preventing apoptosis and stimulating proliferation and angiogenesis. With the evolution of novel targeted therapies, identification of the kinases responsible for STAT activation in cancer cells may help pinpoint sites of potential therapeutic intervention. Methods: A number of potent, selective, orally bioavailable JAK inhibitors were utilized to treat a series of human epithelial cancer cell lines and tumor xenografts derived from breast, head and neck, prostate, stomach, lung, and renal tumors. In doing so, the contribution of JAK signaling to STAT phosphorylation was investigated as were the sequela of such inhibition. Results: Selective JAK inhibition frequently reduced the basal and/or cytokine stimulated levels of phosphorylated STAT3/5 by > 90 %. Oral administration of JAK inhibitors was also sufficient to reduce phosphorylated STAT levels in tumor xenografts and impeded tumor growth, including tumor regression (e.g., BT-474 breast HER2+ breast cancer). Moreover, selective JAK inhibition dramatically improved the anti-tumor activities of various ancillary therapies including targeted and cytotoxic drugs. Conclusions: Aberrant STAT activation has been associated with epithelial cancers and contributes to oncogenesis. Here we utilized pharmacological tools to query the role of JAKs in STAT activation and demonstrated that selective JAK inhibition is sufficient to inhibit STAT phosphorylation in cell lines and xenograft tumors from a spectrum of human cancers. Selective JAK inhibition impeded the growth of xenograft tumors and markedly improved the anti-tumor activity of standard chemotherapies and molecularly targeted agents. As such, selective JAK inhibitors may prove to have clinical utility for the treatment of a number of common cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Incyte Incyte
Self-Organization and Formation of Liquid Crystal Phases by Molecular Templates Related to Membrane Components of Archaebacteria (1998)

Tubular supramolecular aggregates are formed from glycolipids 1, which are closely related to natural components of membranes of archaebacteria. The glycolipids exhibit disordered columnar thermotropic and hexagonal lyotropic liquid crystal phases. Whereas formation of the mesophases is insensitive to stereochemical factors, formation of the tubules is dependent on the configuration of the stereocenters that are shown in the picture but not specified.
Systemic Lupus Erythematosus (SLE) patients’ Peripheral Blood Mononuclear Cells (PBMCs) display an altered transcript isoform repertoire (2019)

Abstract Alternative splicing (AS) is a key mechanism of biological diversity in eukaryotes allowing a single gene to generate multiple mRNA transcript isoforms, yielding unique proteins that may have distinct or opposing functions. Alterations in AS have been associated with numerous diseases. SLE patients display autoantibodies to components of the spliceosome, chiefly anti-Sm/RNP, anti-Ro/La, and anti-dsDNA. We performed Long-Read sequencing using Pacific Biosciences equipment (LR-Seq), as well as short read RNA-Seq, from adolescent SLE patients’ and healthy controls’ PBMCs, to discover and quantitate splice junctions. A computational pipeline was built to differentially quantify splice junctions in the LR-Seq sequenced isoforms, both known and novel using rMATS (Multivariate Analysis of Transcript Splicing). Compared to Gencode, LR-Seq revealed ~9000 novel transcript isoforms. 55% of all transcripts were expressed in 2 or more samples. A majority of these transcripts belonged to genes associated with cell cycle, metabolism, and inflammation. Additionally, we interrogated our SLE LR-Seq generated transcriptome with publicly available RNA-Seq data from adult SLE and healthy donors. We observed 250 differential expression of exon skipping (ES) splice junctions in transcript isoforms of genes, a majority of which did not exhibit any significant change in gene expression. Of the 250 ES transcript isoforms, 160 exon inclusion events were observed in SLE PBMCs. Fifty percent of the exon inclusion events were found to be in novel transcript isoforms. Thus LR-Seq, besides revealing novel transcripts, allows us to study changes in transcript isoform expression.
Texture and stress of Ag films in Ag/Ti, Ag/Cr bilayers, and self-encapsulated structures (1997)

The texture of evaporated Ag films prepared on Ti or Cr underlayers before and after encapsulation process has been studied by x-ray diffraction. In addition, the stress state in self-encapsulated Ag/Ti structures has also been investigated using a “sin2 ψ” technique. Silver films deposited on Ti layers exhibit a strong 〈111〉 texture, which is in contrast to the nearly random orientation of Ag films on Cr underlayers. The minimization of interfacial energy with respect to lattice match can account for this underlayer dependence. After an encapsulation process involving Ti reactions in an ammonia ambient, the texture of Ag films in Ag/Ti bilayers is further enhanced. Highly textured Ag films may provide the basis for electromigration-resistant Ag metallization in integrated circuit devices. For the Ag/Ti bilayer structures, a low tensile stress of approximately 61 MPa arising from the nonequilibrium growth during the film deposition is present in the Ag films. This results in a lattice tension state in the film plane and a lattice compression state along the film normal. Thermal mismatch stress is produced by the encapsulation process at 600 °C. Most of this stress relaxes during the cooling stage and a residual tensile stress of ∼320 MPa in the film plane was determined.
Structural and functional analysis of lignostilbene dioxygenases from Sphingobium sp. SYK-6 (2021)

Lignostilbene-α,β-dioxygenases (LSDs) are iron-dependent oxygenases involved in the catabolism of lignin-derived stilbenes. Sphingobium sp. SYK-6 contains eight LSD homologs with undetermined physiological roles. To investigate which homologs are involved in the catabolism of dehydrodiconiferyl alcohol (DCA), derived from β-5 linked lignin subunits, we heterologously produced the enzymes and screened their activities in lysates. The seven soluble enzymes all cleaved lignostilbene, but only LSD2, LSD3, and LSD4 exhibited high specific activity for 3-(4-hydroxy-3-(4-hydroxy-3-methoxystyryl)-5-methoxyphenyl) acrylate (DCA-S) relative to lignostilbene. LSD4 catalyzed the cleavage of DCA-S to 5-formylferulate and vanillin and cleaved lignostilbene and DCA-S (∼10<sup>6</sup> M<sup>-1</sup> s<sup>-1</sup>) with tenfold greater specificity than pterostilbene and resveratrol. X-ray crystal structures of native LSD4 and the catalytically inactive cobalt-substituted Co-LSD4 at 1.45 Å resolution revealed the same fold, metal ion coordination, and edge-to-edge dimeric structure as observed in related enzymes. Key catalytic residues, Phe-59, Tyr-101, and Lys-134, were also conserved. Structures of Co-LSD4·vanillin, Co-LSD4·lignostilbene, and Co-LSD4·DCA-S complexes revealed that Ser-283 forms a hydrogen bond with the hydroxyl group of the ferulyl portion of DCA-S. This residue is conserved in LSD2 and LSD4 but is alanine in LSD3. Substitution of Ser-283 with Ala minimally affected the specificity of LSD4 for either lignostilbene or DCA-S. By contrast, substitution with phenylalanine, as occurs in LSD5 and LSD6, reduced the specificity of the enzyme for both substrates by an order of magnitude. This study expands our understanding of an LSD critical to DCA catabolism as well as the physiological roles of other LSDs and their determinants of substrate specificity.
Analysis of the volatile constituents of cooked petai beans (Parkia speciosa) using high‐resolution GC/ToF–MS (2008)

Abstract The volatile compounds from cooked petai beans ( Parkia speciosa ) were isolated by hydrodistillation under reduced pressure followed by solvent extraction. The organic extract was analyzed by classical single quadrupole GC/MS and by high resolution GC/ToF‐MS. Cyclic polysulphides were the major components of petai. New sulphur minor compounds were also identified and some of them were synthesised. 1,3‐Dithiabutane was found for the first time in a natural product whereas 2,4‐dithiapentane, 2,3,5‐trithiahexane and 2,4,6‐trithiaheptane for the first time in Parkia speciosa . GC/O analyses showed that these linear polysulphides have an important contribution to the flavour of cooked petai beans. Copyright © 2008 John Wiley &amp; Sons, Ltd.
Representative Measurement Point Selection to Monitor Software-defined Networks (2018)

Network state monitoring is a fundamental task for network management. However, determining the full network state in Software defined Networks requires disproportionately too many resources. This stems from the discrepancy between the established methods used for state monitoring compared to the varying contribution in terms of information obtained from every additionally monitored network node. This relationship may even become more complicated depending on the network state information of interest. One solution to overcome bottlenecks by reducing the overall monitoring footprint is the use of spatial sampling, which allows the estimation of the network state based a fraction of the overall state. In this work, we propose schemes to place a small number of measurement points in the SDN network to maximize the obtained network state information. Considering different conditions, we utilize routing information and graph theoretic centrality metrics, respectively, to estimate the amount of information a node provides. Based on this knowledge, we, furthermore, develop a mechanism to place multiple measurement points while avoiding redundant measurements. For demonstration purpose, we use the developed mechanisms to estimate the Flow Size Distribution in SDN environments. An emulative evaluation taking several known topologies shows the effectiveness of spatial sampling using the proposed scheme.
ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma (2023)

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS. The target recognition element of the second-generation CAR construct is based on two antibodies, previously shown to react against OS. T cells transduced with these CAR constructs mediate efficient and effective cytotoxicity against ALPL-positive cells in in vitro settings and in state-of-the-art in vivo orthotopic models of primary and metastatic OS, without unexpected toxicities against hematopoietic stem cells or healthy tissues. In summary, CAR-T cells targeting ALPL-1 show efficiency and specificity in treating OS in preclinical models, paving the path for clinical translation.
CB1 receptor antagonist AVE1625 affects primarily metabolic parameters independently of reduced food intake in Wistar rats (2007)

The objective of the present study was to investigate in fed Wistar rats whether the cannabinoid-1 (CB1) receptor antagonist AVE1625 causes primary effects on metabolic blood and tissue parameters as well as metabolic rate, which are independent of reduced caloric intake. After single administration to rats postprandially, AVE1625 caused a slight dose-dependent increase in basal lipolysis. Six hours after single administration, liver glycogen content was dose-dependently reduced to ∼60% of that of untreated controls. These findings demonstrate a primary acute effect of AVE1625 on induction of 1) lipolysis from fat tissue (increased FFA) and 2) glycogenolysis from the liver (reduced hepatic glycogen). Measured by indirect calorimetry, AVE1625 caused an immediate increase in total energy expenditure, a long-lasting increase of fat oxidation, and a transient increase of glucose oxidation, which were consistent with the acute findings on metabolic blood and tissue parameters. We conclude that, in addition to the well-investigated effects of CB1 receptor antagonists to reduce caloric intake and subsequently body weight, this pharmacological approach is additionally linked to inherently increased lipid oxidation. This oxidation is driven by persistently increased lipolysis from fat tissues, independently of reduced caloric intake, and might significantly contribute to the weight-reducing effect.
Analysis of Near Infrared Spectra during Methyl methacrylate (MMA) Suspension Polymerizations (2011)

Abstract Near infrared spectroscopy (NIRS) provides means for real‐time monitoring of polymerization reactors. Previous experimental studies report successful implementations of NIR‐based monitoring techniques for styrene, vinyl chloride and acrylic acid / vinyl acetate suspension polymerizations; however, no information is available in the literature for methyl methacrylate (MMA) polymerizations. For this reason, the main objective of this paper was analyzing the NIR spectra obtained in‐line and in situ during MMA suspension polymerizations and observing whether NIR spectra may be used for in‐line monitoring and control of the average particle size in these systems. Particularly, NIR spectral responses to changes of the average particle size were analyzed in poly(vinyl chloride), polystyrene and PMMA suspensions, showing that the NIR spectra of distinct reacting systems respond differently to modification of the suspended particle sizes. Finally, it was observed that the control of average particle sizes and particle size distributions in MMA suspension polymerizations requires that control actions be taken at the initial polymerization stages, when monomer conversion is below 30 wt%.
A Whole Cell E. coli Display Platform for Artificial Metalloenzymes: Poly(phenylacetylene) Production with a Rhodium–Nitrobindin Metalloprotein (2018)

Whole cell catalysis is, in many cases, a prerequisite for the cost-effective production of chemicals by biotechnological means. Synthetic metal catalysts for bioorthogonal reactions can be inactivated within cells due to abundant thiol derivatives. Here, a cell surface display-based whole cell biohybrid catalyst system (termed ArMt bugs) is reported as a generally applicable platform to unify cost-effective whole cell catalysis with biohybrid catalysis. An inactivated esterase autotransporter is employed to display the nitrobindin protein scaffold with a Rh catalyst on the E. coli surface. Stereoselective polymerization of phenylacetylene yielded a high turnover number (TON) (39 × 106 cell–1) for the ArMt bugs conversion platform.
Behavioral Effects of Continuously Administered Bergamot Essential Oil on Mice With Partial Sciatic Nerve Ligation (2020)

Neuropathic pain is an intractable chronic pain condition that is mainly caused by allodynia. We had previously reported that intra-plantar administration of bergamot essential oil (BEO) containing an aromatic compound significantly suppressed partial sciatic nerve ligation (PSNL)-induced mechanical allodynia <i>via</i> opioid mu receptors in mice. However, it has also been reported that the inhalation of BEO reduced formalin-induced nociceptive responses. Therefore, we aimed to elucidate whether the analgesic action of BEO is mediated by olfactory stimulation through volatile components. In the current study, BEO was continuously administered with an osmotic pump during PSNL surgery, and the effects on mice behavior were examined pharmacologically using a double activity monitoring system, which can detect two-dimensional planar motion in a cage with an infrared beam sensor as well as active motion with a running wheel. Here, we report that the two-dimensional planar activity significantly increased in mice with PSNL in the light phase (from 8 o'clock to 20 o'clock) but not in the dark phase (from 20 o'clock to 8 o'clock) from the second day after surgery. However, this increase was not observed when BEO was continuously administered. The effect of BEO on the two-dimensional planar counts in mice with PSNL was antagonized by naloxone hydrochloride. Regarding the running wheel activity, the number of rotations decreased by PSNL in the dark phase from the 8th day after surgery. However, this was not apparent with BEO use. The effect of BEO on the number of rotations was also antagonized by naloxone hydrochloride. Furthermore, inhalation of BEO in PSNL mice did not affect mechanical allodynia or the two-dimensional planar motion or running wheel activities. These findings indicate that BEO exhibits an analgesic action, which is mediated by opioid receptors and not by the olfactory system.
Can We Sample the Complete Geological Uncertainty Space in Reservoir-Modeling Uncertainty Estimates? (2000)

Summary The method by which the space of uncertainty should be sampled in reservoir models is an essential point of discussion that can have a major impact on the appraisal, development and economics of hydrocarbon fields. Usually, uncertainty is assessed by way of many realizations of a given stochastic model with fixed parameters but this does not adequately sample the complete geological uncertainty space and it underestimates the uncertainty. To improve the uncertainty assessment, in this article we propose a classification and hierarchy of the sources of internal reservoir architecture uncertainty. The impact of the different levels and sources of uncertainty on elements such as original hydrocarbons in place or final recovery is quantified. In this article we demonstrate that decisions as significant as stationarity, organization of reservoir heterogeneity, choice of the global statistics and variogramme range are of prime importance in relation to the other parameters. Furthermore, we also prove that the relative importance of any parameter in assessing the uncertainty depends on the type of result—volumetric or dynamic—on which the uncertainty calculation is computed. Uncertainty of the global mean provided by hard data is assessed using sampling techniques. The coefficients of variation obtained from many field cases allow a comparison between the different distributions. It lends support to the hierarchy of the sources of geological uncertainty into six levels. The evolution of this uncertainty with the quantity of hard data, wells, and the quality of knowledge, zoning, has been quantified using synthetic models and a field case. Both a general function for the decrease of uncertainty with the quantity of the data, and a possible increase—for some parameters—of uncertainty estimates with knowledge development are demonstrated herein.