gebhart/patrepeval huggingface dataset:
Autophagy and cancer (2012)

Basal autophagy plays a critical role in maintaining cellular homeostasis and genomic integrity by degrading aged or malfunctioning organelles and damaged or misfolded proteins. However, autophagy also plays a complicated role in tumorigenesis and treatment responsiveness. It can be tumor-suppressing during the early stages of tumorigenesis (i.e., it is an anti-tumor mechanism), as reduced autophagy is found in tumor cells and may be associated with malignant transformation. In this case, induction of autophagy would seem to be beneficial for cancer prevention. In established tumors, however, autophagy can be tumor- promoting (i.e., it is a pro-tumor mechanism), and cancer cells can use enhanced autophagy to survive under metabolic and therapeutic stress. The pharmacological and/or genetic inhibition of autophagy was recently shown to sensitize cancer cells to the lethal effects of various cancer therapies, including chemotherapy, radiotherapy and targeted therapies, suggesting that suppression of the autophagic pathway may represent a valuable sensitizing strategy for cancer treatments. In contrast, excessive stimulation of autophagy may also provide a therapeutic strategy for treating resistant cancer cells having high apoptotic thresholds. In order for us to develop successful autophagy- modulating strategies against cancer, we need to better understand how the roles of autophagy differ depending on the tumor stage, cell type and/or genetic factors, and we need to determine how specific pathways of autophagy are activated or inhibited by the various anti-cancer therapies.
Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice (1999)

Mice with a targeted mutation of the gastric inhibitory polypeptide (GIP) receptor gene (GIPR) were generated to determine the role of GIP as a mediator of signals from the gut to pancreatic beta cells. GIPR-/- mice have higher blood glucose levels with impaired initial insulin response after oral glucose load. Although blood glucose levels after meal ingestion are not increased by high-fat diet in GIPR+/+ mice because of compensatory higher insulin secretion, they are significantly increased in GIPR-/- mice because of the lack of such enhancement. Accordingly, early insulin secretion mediated by GIP determines glucose tolerance after oral glucose load in vivo, and because GIP plays an important role in the compensatory enhancement of insulin secretion produced by a high insulin demand, a defect in this entero-insular axis may contribute to the pathogenesis of diabetes.
Regulation of adhesion and growth of fibrosarcoma cells by NF-kappa B RelA involves transforming growth factor beta. (1994)

The NF-kappa B transcription factor is a pleiotropic activator that participates in the induction of a wide variety of cellular genes. Antisense oligomer inhibition of the RelA subunit of NF-kappa B results in a block of cellular adhesion and inhibition of tumor cell growth. Investigation of the molecular basis for these effects showed that in vitro inhibition of the growth of transformed fibroblasts by relA antisense oligonucleotides can be reversed by the parental-cell-conditioned medium. Cytokine profile analysis of these cells treated with relA antisense oligonucleotides revealed inhibition of transforming growth factor beta 1 (TGF-beta 1 to the transformed fibroblasts reversed the inhibitory effects of relA antisense oligomers on soft agar colony formation and cell adhesion to the substratum. Direct inhibition of TGF-beta 1 expression by antisense phosphorothioates to TGF-beta 1 mimicked the in vitro effects of blocking cell adhesion that are elicited by antisense relA oligomers. These results may explain the in vitro effects of relA antisense oligomers on fibrosarcoma cell growth and adhesion.
UDP-GlcNAc 2-Epimerase: A Regulator of Cell Surface Sialylation (1999)

Modification of cell surface molecules with sialic acid is crucial for their function in many biological processes, including cell adhesion and signal transduction. Uridine diphosphate-N-acetylglucosamine 2-epimerase (UDP-GlcNAc 2-epimerase) is an enzyme that catalyzes an early, rate-limiting step in the sialic acid biosynthetic pathway. UDP-GlcNAc 2-epimerase was found to be a major determinant of cell surface sialylation in human hematopoietic cell lines and a critical regulator of the function of specific cell surface adhesion molecules.
Pore-forming activity of OmpA protein of Escherichia coli. (1992)

Escherichia coli outer membrane protein OmpA was purified to homogeneity, as a monomer, from a K12 derivative deficient in both OmpF and OmpC porins. When proteoliposomes reconstituted from the purified OmpA, phospholipids, and lithium dodecyl sulfate were tested for permeability to small molecules by osmotic swelling, it was found that OmpA produced apparently nonspecific diffusion channels that allowed the penetration of various solutes. The pore-forming activity was destroyed by the heat denaturation of the OmpA protein, and the use of an OmpA-deficient mutant showed that the activity was not caused by copurifying contaminants. The size of the OmpA channel, estimated by comparison of diffusion rates of solutes of different sizes, was rather similar to that of E. coli OmpF and OmpC porins, i.e. about 1 nm in diameter. The rate of penetration of L-arabinose caused by a given amount of OmpA protein, however, was about a hundredfold lower than the rate produced by the same amount of E. coli OmpF porin. The addition of large amounts of lithium dodecyl sulfate to the reconstitution mixture increased the permeability through the OmpA channel, apparently by facilitating the correct insertion of OmpA into the bilayer.
Loss of N-glycolylneuraminic acid in humans: Mechanisms, consequences, and implications for hominid evolution (2001)

The surface of all mammalian cells is covered with a dense and complex array of sugar chains, which are frequently terminated by members of a family of molecules called sialic acids. One particular sialic acid called N-glycolylneuraminic acid (Neu5Gc) is widely expressed on most mammalian tissues, but is not easily detectable on human cells. In fact, it provokes an immune response in adult humans. The human deficiency of Neu5Gc is explained by an inactivating mutation in the gene encoding CMP-N-acetylneuraminic acid hydroxylase, the rate-limiting enzyme in generating Neu5Gc in cells of other mammals. This deficiency also results in an excess of the precursor sialic acid N-acetylneuraminic acid (Neu5Ac) in humans. This mutation appears universal to modern humans, occurred sometime after our last common ancestor with the great apes, and happens to be one of the first known human-great ape genetic differences with an obvious biochemical readout. While the original selection mechanisms and major biological consequences of this human-specific mutation remain uncertain, several interesting clues are currently being pursued. First, there is evidence that the human condition can explain differences in susceptibility or resistance to certain microbial pathogens. Second, the functions of some endogenous receptors for sialic acids in the immune system may be altered by this difference. Third, despite the lack of any obvious alternate pathway for synthesis, Neu5Gc has been reported in human tumors and possibly in human fetal tissues, and traces have even been detected in normal human tissues. One possible explanation is that this represents accumulation of Neu5Gc from dietary sources of animal origin. Finally, a markedly reduced expression of hydroxylase in the brains of other mammals raises the possibility that the human-specific mutation of this enzyme could have played a role in human brain evolution. Yrbk Phys Anthropol 44:54–69, 2001. © 2001 Wiley-Liss, Inc.
A hybrid technique based on combining ray tracing and FDTD methods for site-specific modeling of indoor radio wave propagation (2000)

The paper presents a hybrid technique based on combining ray tracing and finite-difference time-domain (FDTD) methods for site-specific modeling of indoor radio wave propagation. Ray tracing is used to analyze the wide area and FDTD is used to study areas close to complex discontinuities where ray-based solutions are not sufficiently accurate. The hybrid technique ensures improved accuracy and practicality in terms of computational resources at the same time since FDTD is only applied to a small portion of the entire modeling environment. Examples of applying the method for studying indoor structures and penetration of wave from outdoor to indoor are given at 2.4 GHz. Numerical results are compared with known exact solutions or results of the full wave analysis or traditional ray model to demonstrate the accuracy, efficiency, and robustness of the novel method. Numerical results are also compared with reported measurement results for waves at 1.29 GHz penetrating an external wall with metal-framed windows. Cumulative distributions of field envelope obtained from the hybrid method show close resemblance to the Rayleigh distribution, which conforms to the reported measurement results.
A subtype-specific peptide-based enzyme immunoassay for detection of antibodies to the G protein of human respiratory syncytial virus is more sensitive than routine serological tests (1997)

Peptides deduced from the central conserved region (residues 158 to 189) of protein G of human respiratory syncytial virus (HRSV) subtypes A and B were used as antigens in subtype-specific enzyme-linked immunosorbent assays (G-peptide ELISAs). These G-peptide ELISAs were compared with seven other serological assays to detect HRSV infection: ELISAs based on complete protein G, on fusion protein F, and on nucleoprotein N; a complement fixation assay; a virus neutralization test; and ELISAs for the detection of immunoglobulin A (IgA) or IgM antibodies specific for HRSV. In paired serum samples from patients with HRSV infection, more infections were diagnosed by the G-peptide ELISA (67%) than by all other serological tests combined (48%). Furthermore, for 16 of 18 patients (89%), the G-peptide ELISAs were able to differentiate between antibodies against HRSV subtypes A and B. This study shows that peptides corresponding to the central conserved region of the attachment protein G of HRSV can successfully be used as antigens in immunoassays. The G-peptide ELISA appeared to be more sensitive than conventional tests for the detection of HRSV antibody titer rises.
Regulation of Human Cystathionine β-Synthase by S-Adenosyl-l-methionine:  Evidence for Two Catalytically Active Conformations Involving an Autoinhibitory Domain in the C-Terminal Region (2001)

Cystathionine beta-synthase (CBS), condensing homocysteine and serine, represents a key regulatory point in the biosynthesis of cysteine via the transsulfuration pathway. Inherited deficiency of CBS causes homocystinuria. CBS is activated by S-adenosyl-L-methionine (AdoMet) by inducing a conformational change involving a noncatalytic C-terminal region spanning residues 414-551. We report the purification of two patient-derived C-terminal mutant forms of CBS, S466L and I435T, that provide new insight into the mechanism of CBS regulation and indicate a regulatory function for the "CBS domain". Both of these point mutations confer catalytically active proteins. The I435T protein is AdoMet inducible but is 10-fold less responsive than wild-type (WT) CBS to physiologically relevant concentrations of this compound. The S466L form does not respond to AdoMet but is constitutively activated to a level intermediate between those of WT CBS in the presence and absence of AdoMet. Both mutant proteins are able to bind AdoMet, indicating that their impairment is related to their ability to assume the fully activated conformation that AdoMet induces in WT CBS. We found that I435T and WT CBS can be activated by partial thermal denaturation but that the AdoMet-stimulated WT, S466L, and a truncated form of CBS lacking the C-terminal region cannot be further activated by this treatment. Tryptophan and PLP fluorescence data for these different forms of CBS indicate that activation by AdoMet, limited proteolysis, and thermal denaturation share a common mechanism involving the displacement of an autoinhibitory domain located in the C-terminal region of the protein.
A phase I study of CS-1008 (humanized monoclonal antibody targeting death receptor 5 or DR5), administered weekly to patients with advanced solid tumors or lymphomas (2008)

3537 Background: CS-1008 is an IgG1 agonistic humanized monoclonal antibody targeting the human death receptor 5 (DR5). CS- 1008 triggers apoptosis after binding to DR5 resulting in death of targeted cells; it has demonstrated cytotoxic activity against DR5-positive human tumor cell lines in vitro, and in vivo it has shown significant anti-tumor activity against human tumor xenografts in nude mice. Methods: A phase I trial in patients with relapsed/refractory solid tumors and lymphomas was designed to determine the maximal tolerated dose (MTD), pharmacokinetics, immunogenicity, and safety profile of CS-1008 administered intravenously every week (a cycle was defined as 3 consecutive weeks). Three to six patients were enrolled in successive dose escalating cohorts at doses from 1 to 8 mg/kg weekly (1, 2, 4 and 8). The MTD was defined as the highest dose at which 0/3 or 1/6 patients experience dose limiting toxicities (DLT). Results: Seventeen patients were enrolled, with a median age of 57 years (range, 31–88 years). Nine patients were enrolled in the 1, 2, and 4 mg/kg dose cohorts (3 in each one) and 8 patients in the 8m/kg dose cohort. CS-1008 was well tolerated, with no DLTs observed and the MTD was not reached. There were no infusion related toxicities, grade 3 or 4 toxicities related with CS-1008, or renal/ hepatic/hematological toxicities. Nine non-related severe adverse events were reported, all of them related to the primary tumor or disease progression. PK results demonstrated a half-life of 8 to 16 days. Seven patients had stable disease: 2 in the 1 mg/kg dose cohort (hepatocellular carcinoma 497+ days, head and neck cancer 225 days), 1 in the 2 mg/kg cohort (colon cancer 77 days), 2 in the 4 mg/kg dose cohort (colon cancer 78 days, cholangiocarcinoma 155 days), and 2 in the 8 mg/kg dose cohort (colon cancer 79 days, hepatocellular carcinoma 78 days). Conclusions: CS-1008 is well tolerated, and the MTD was not reached. The high number of patients with stable disease in this phase I trial suggests anti-tumor activity. Clinical trials of CS-1008 in combination with chemotherapy for the treatment of DR5 positive epithelial tumors have been initiated. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Daiichi Sankyo Pharma Daiichi Sankyo Pharma Daiichi Sankyo Pharma
G-CSF rescues the memory impairment of animal models of Alzheimer's disease (2007)

Most of the current clinical treatments for Alzheimer's disease (AD) are largely symptomatic and can have serious side effects. We have tested the feasibility of using the granulocyte colony-stimulating factor (G-CSF), which is known to mobilize hematopoietic stem cells (HSCs) from the bone marrow into the peripheral blood, as a therapeutic agent for AD. Subcutaneous administration of G-CSF into two different beta-amyloid (Abeta)-induced AD mouse models substantially rescued their cognitive/memory functions. The rescue was accompanied by the accumulation of 5-bromo-2'deoxyuridine-positive HSCs, as well as local neurogenesis surrounding the Abeta aggregates. Furthermore, the level of acetylcholine in the brains of Tg2576 mice was considerably enhanced upon G-CSF treatment. We suggest that G-CSF, a drug already extensively used for treating chemotherapy-induced neutropenia, should be pursued as a novel, noninvasive therapeutic agent for the treatment of AD.
Pd-Catalyzed N-Arylation of Secondary Acyclic Amides: Catalyst Development, Scope, and Computational Study (2009)

We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the "top ring" ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.
IoT-OAS: An OAuth-Based Authorization Service Architecture for Secure Services in IoT Scenarios (2014)

Open authorization (OAuth) is an open protocol, which allows secure authorization in a simple and standardized way from third-party applications accessing online services, based on the representational state transfer (REST) web architecture. OAuth has been designed to provide an authorization layer, typically on top of a secure transport layer such as HTTPS. The Internet of Things (IoTs) refers to the interconnection of billions of resource-constrained devices, denoted as smart objects, in an Internet-like structure. Smart objects have limited processing/memory capabilities and operate in challenging environments, such as low-power and lossy networks. IP has been foreseen as the standard communication protocol for smart object interoperability. The Internet engineering task force constrained RESTful environments working group has defined the constrained application protocol (CoAP) as a generic web protocol for RESTful-constrained environments, targeting machine-to-machine applications, which maps to HTTP for integration with the existing web. In this paper, we propose an architecture targeting HTTP/CoAP services to provide an authorization framework, which can be integrated by invoking an external oauth-based authorization service (OAS). The overall architecture is denoted as IoT-OAS. We also present an overview of significant IoT application scenarios. The IoT-OAS architecture is meant to be flexible, highly configurable, and easy to integrate with existing services. Among the advantages achieved by delegating the authorization functionality, IoT scenarios benefit by: 1) lower processing load with respect to solutions, where access control is implemented on the smart object; 2) fine-grained (remote) customization of access policies; and 3) scalability, without the need to operate directly on the device.
Biological significance of fluorine-18-α-methyltyrosine (FAMT) uptake on PET in patients with oesophageal cancer (2014)

The uptake of (18)F-FAMT within tumour cells is determined by the LAT1 expression and correlated with cell proliferation and angiogenesis in oesophageal cancer. The present experiments also confirmed the presence of LAT1 as an underlying mechanism of (18)F-FAMT accumulation.
Fast parsing using pruning and grammar specialization (1996)

We show how a general grammar may be automatically adapted for fast parsing of utterances from a specific domain by means of constituent pruning and grammar specialization based on explanation-based learning. These methods together give an order of magnitude increase in speed, and the coverage loss entailed by grammar specialization is reduced to approximately half that reported in previous work. Experiments described here suggest that the loss of coverage has been reduced to the point where it no longer causes significant performance degradation in the context of a real application.
Significance of Diagnostic Parameters in [13C]Octanoic Acid Gastric Emptying Breath Tests* (1998)

Abstract Two novel characteristic parameters, the latency time (t (lat)) and the ascension time (t (asc)), are proposed for evaluation of non-invasive [(13)C]octanoic acid breath tests for assessment of the gastric emptying of solids. In breath tests performed in control subjects (n = 30) and diabetic patients (n = 100), the usefulness of these parameters was compared to conventional parameters, i.e., gastric half emptying-time t (1/2,b )) and lag phase (t (lag,b )). The proposed parameters were only loosely correlated (controls, r = 0.199; diabetics, 0.616). A strong correlation was found between the conventional parameters (controls, r = 0.891; diabetics, r = 0.962). Based on the conventional method, 36 patients were suspicious of delayed gastric emptying including 24 patients which exhibited a simultaneous delay in both parameters. Using the new parameters, a total of 46 patients were suspicious of delayed gastric emptying with 15 and 20 having isolated delay in t (lat) and t (asc), respectively. We conclude that the novel parameters may be more appropriate for examination of the different phases of gastric emptying and for evaluation of gastric emptying disturbances in diabetic patients than the parameters conventionally used for this purpose.
Semantic Scene Completion from a Single Depth Image (2017)

This paper focuses on semantic scene completion, a task for producing a complete 3D voxel representation of volumetric occupancy and semantic labels for a scene from a single-view depth map observation. Previous work has considered scene completion and semantic labeling of depth maps separately. However, we observe that these two problems are tightly intertwined. To leverage the coupled nature of these two tasks, we introduce the semantic scene completion network (SSCNet), an end-to-end 3D convolutional network that takes a single depth image as input and simultaneously outputs occupancy and semantic labels for all voxels in the camera view frustum. Our network uses a dilation-based 3D context module to efficiently expand the receptive field and enable 3D context learning. To train our network, we construct SUNCG - a manually created largescale dataset of synthetic 3D scenes with dense volumetric annotations. Our experiments demonstrate that the joint model outperforms methods addressing each task in isolation and outperforms alternative approaches on the semantic scene completion task. The dataset and code is available at http://sscnet.cs.princeton.edu.