gebhart/patrepeval huggingface dataset:
Converting cancer genes into killer genes. (1996)

Over the past decade, it has become clear that tumorigenesis is driven by alterations in genes that control cell growth or cell death. Theoretically, the proteins encoded by these genes provide excellent targets for new therapeutic agents. Here, we describe a gene therapy approach to specifically kill tumor cells expressing such oncoproteins. In outline, the target oncoprotein binds to exogenously introduced gene products, resulting in transcriptional activation of a toxic gene. As an example, we show that this approach can be used to specifically kill cells overexpressing a mutant p53 gene in cell culture. The strategy may be generally applicable to neoplastic diseases in which the underlying patterns of genetic alterations or abnormal gene expression are known.
RNAi‐based therapeutics–current status, challenges and prospects (2009)

RNA interference (RNAi) is a collection of small RNA directed mechanisms that result in sequence specific inhibition of gene expression. The notion that RNAi could lead to a new class of therapeutics caught the attention of many investigators soon after its discovery. The field of applied RNAi therapeutics has moved very quickly from lab to bedside. The RNAi approach has been widely used for drug development and several phase I and II clinical trials are under way. However, there are still some concerns and challenges to overcome for therapeutic applications. These include the potential for off-target effects, triggering innate immune responses and most importantly obtaining specific delivery into the cytoplasm of target cells. This review focuses on the current status of RNAi-based therapeutics, the challenges it faces and how to overcome them.
Review. Antioxidant gene therapeutic approaches to normal tissue radioprotection and tumor radiosensitization. (2007)

Administration of manganese superoxide dismutase-plasmid liposomes (MnSOD-PL) has been demonstrated to provide local radiation protection to the lung, esophagus, oral cavity, urinary bladder and intestine. Radiation protection has been shown to be mediated in part by MnSOD stabilization of the antioxidant pool including glutathione and total thiols within cells and in normal tissues. In experiments to determine whether organ-specific radioprotection would also protect orthotopic tumors, mice with Lewis lung carcinoma orthotopically placed at the carina or in other experiments with mice with cheek pouch placed SCCVII orthotopic squamous cell tumors demonstrated paradoxical and beneficial tumor radiosensitization following intratracheal or intraoral MnSOD-PL, respectively. The mechanism of MnSOD-PL tumor radiosensitization may involve a difference in redox balance between tumors and normal tissues. Differences in handling radiation-induced oxidative stress between tumors and normal tissues can provide a fundamental basis to design new cancer therapeutic agents which can exploit differences between normal tissue and tumor mechanisms of handling the oxidative stress of ionizing irradiation damage.
Use of PCR To Demonstrate Presence of Adenovirus Species B, C, or F as Well as Coinfection with Two Adenovirus Species in Children with Flu-Like Symptoms (2006)

Adenovirus (AdV) respiratory infections have usually been associated with species B, C, and E. In this study, we detected 9.4% of AdVs by PCR in 500 nasal swabs from 319 children with influenza-like symptoms. AdV typing by PCR with specific probes showed species C, B, and F as well as coinfection with two species. Coinfection with two AdV species and the presence of species F in respiratory samples are novel findings that should be further investigated.
Linear Expenditure Systems and Demand Analysis: An Application to the Pattern of British Demand (1954)

Journal Article Linear Expenditure Systems and Demand Analysis: An Application to the Pattern of British Demand Get access Richard Stone Richard Stone Department of Applied Economics, Cambridge Search for other works by this author on: Oxford Academic Google Scholar The Economic Journal, Volume 64, Issue 255, 1 September 1954, Pages 511–527, https://doi.org/10.2307/2227743 Published: 01 September 1954
MYB.Ph3 transcription factor from Petunia hybrida induces similar DNA‐bending/distortions on its two types of binding site (1995)

MYB.Ph3 from Petunia is a member of the MYB transcription factor family that recognizes two types of binding site, resembling direct and inverted repeats of the motif GTTA, respectively, and flanked on their 5' side by an A-rich sequence. In this study, it is shown that MYB.Ph3 induces similar conformational changes in both of its DNA-binding sites. Circular permutation assays indicate that the center of the distortions induced by MYB.Ph3 maps near the center of either MYB.Ph3-binding site. The degree of the distortion induced by MYB.Ph3 appears to be greatly affected by regions of the protein other than the DNA-binding domain, and differs from the distortion caused by animal c-MYB. Phasing analysis reveals that part of the distortion induced by MYB.Ph3 is DNA bending, oriented towards the minor groove, as is the case of its animal counterpart, c-MYB. DNA-binding by both MYB.Ph3 and animal c-MYB is more efficient in the presence of Ba2+, a divalent cation known to promote/stabilize DNA bending, than in the presence of other cations which do not favor this distortion, such as Na+ and Mg2+. In addition, both MYB proteins show higher affinity to selectively nicked DNA, which has increased DNA flexibility, strongly suggesting that DNA binding by these MYB proteins and DNA structural properties are mutually influenced.
The pgaABCD Locus of Escherichia coli Promotes the Synthesis of a Polysaccharide Adhesin Required for Biofilm Formation (2004)

Production of a polysaccharide matrix is a hallmark of bacterial biofilms, but the composition of matrix polysaccharides and their functions are not widely understood. Previous studies of the regulation of Escherichia coli biofilm formation suggested the involvement of an unknown adhesin. We now establish that the pgaABCD (formerly ycdSRQP) locus affects biofilm development by promoting abiotic surface binding and intercellular adhesion. All of the pga genes are required for optimal biofilm formation under a variety of growth conditions. A pga-dependent cell-bound polysaccharide was isolated and determined by nuclear magnetic resonance analyses to consist of unbranched beta-1,6-N-acetyl-D-glucosamine, a polymer previously unknown from the gram-negative bacteria but involved in adhesion by staphylococci. The pga genes are predicted to encode envelope proteins involved in synthesis, translocation, and possibly surface docking of this polysaccharide. As predicted, if poly-beta-1,6-GlcNAc (PGA) mediates cohesion, metaperiodate caused biofilm dispersal and the release of intact cells, whereas treatment with protease or other lytic enzymes had no effect. The pgaABCD operon exhibits features of a horizontally transferred locus and is present in a variety of eubacteria. Therefore, we propose that PGA serves as an adhesin that stabilizes biofilms of E. coli and other bacteria.
A Regulatory Gene as a Novel Visible Marker for Maize Transformation (1990)

The temporal and spatial patterns of anthocyanin pigmentation in the maize plant are determined by the presence or absence of the R protein product, a presumed transcriptional activator. At least 50 unique patterns of pigmentation, conditioned by members of the R gene family, have been described. In this study, microprojectiles were used to introduce into maize cells a vector containing the transcription unit from one of these genes (Lc) fused to a constitutive promoter. This chimeric gene induces cell autonomous pigmentation in tissues that are not normally pigmented by the Lc gene. As a reporter for gene expression studies in maize, R is unique because it can be quantified in living tissue simply by counting the number of pigmented cells following bombardment. R may also be useful as a visible marker for selecting stably transformed cell lineages that can give rise to transgenic plants.
Opening Platforms: How, When and Why? (2009)

Platform-mediated networks encompass several distinct types of participants, including end users, complementors, platform providers who facilitate users' access to complements, and sponsors who develop platform technologies. Each of these roles can be opened - that is, structured to encourage participation - or closed. This paper reviews factors that motivate decisions to open or close mature platforms. At the platform provider and sponsor levels, these decisions entail: 1) interoperating with established rival platforms; 2) licensing additional platform providers; or 3) broadening sponsorship. With respect to end users and complementors, decisions to open or close a mature platform involve: 1) backward compatibility with prior platform generations; 2) securing exclusive rights to certain complements; or 3) absorbing complements into the core platform. Over time, forces tend to push both proprietary and shared platforms toward hybrid governance models characterized by centralized control over platform technology (i.e., closed sponsorship) and shared responsibility for serving users (i.e., an open provider role).
Application of Photochemical Decarbonylation of Cyclopropenones for the in Situ Generation of Reactive Enediynes. Construction of a Cyclopropenone-Containing Enediyne Precursor by Using a Cyclopropenone Acetal Building Block (2005)

[reaction: see text] A cyclopropenone-containing enediyne photoprecursor, 6-tert-butyldimethylsilyloxy-3-(alpha-hydroxybenzyl)bicyclo[8.1.0]undeca-1(10),2-diene-4-yn-11-one (1), was prepared in 10 steps by sequential modification of the cyclopropenone 2,2-dimethyl-1,3-propanediyl acetal (5). The crucial cyclization step was achieved under Nozaki conditions, while the endocylic double bond has been introduced by the allylic rearrangement. UV irradiation of the cyclopropenone 1 results in efficient decarbonylation and the formation of the reactive enediyne 2. The latter undergoes Bergman cycloaromatization with a half-life of 12 h at 40 degrees C and in the presence of 1,4-dihydrobenzene quantitatively produces corresponding tetralin 29.
Inferring the molecular and phenotypic impact of amino acid variants with MutPred2 (2020)

Identifying pathogenic variants and underlying functional alterations is challenging. To this end, we introduce MutPred2, a tool that improves the prioritization of pathogenic amino acid substitutions over existing methods, generates molecular mechanisms potentially causative of disease, and returns interpretable pathogenicity score distributions on individual genomes. Whilst its prioritization performance is state-of-the-art, a distinguishing feature of MutPred2 is the probabilistic modeling of variant impact on specific aspects of protein structure and function that can serve to guide experimental studies of phenotype-altering variants. We demonstrate the utility of MutPred2 in the identification of the structural and functional mutational signatures relevant to Mendelian disorders and the prioritization of de novo mutations associated with complex neurodevelopmental disorders. We then experimentally validate the functional impact of several variants identified in patients with such disorders. We argue that mechanism-driven studies of human inherited disease have the potential to significantly accelerate the discovery of clinically actionable variants.
Cancer Gene Therapy Using Plasmid DNA: Pharmacokinetic Study of DNA Following Injection in Mice (1995)

The fate of plasmid DNA complexed with cationic lipids delivered intravenously in mice was evaluated at selected timepoints up to 6 months postinjection. Blood half-life and tissue distribution of plasmid DNA and potential expression in tissues were examined. Southern blot analyses of blood indicated that intact plasmid DNA was rapidly degraded, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. Southern analyses of tissue demonstrated that intact DNA was differentially retained in the lung, spleen, liver, heart, kidney, marrow, and muscle up to 24 hr postinjection. After 7 days, no intact plasmid DNA was detectable by Southern blot analysis; however, the plasmid was detectable by the polymerase chain reaction (PCR) in all tissues examined at 7 and 28 days postinjection. At 6 months postinjection, femtogram levels of plasmid were detected only in muscle. Immunohistochemical analyses did not detect encoded protein in the tissues harboring residual plasmid at 1 or 7 days postinjection.
Complement activation and antibody binding by pneumolysin via a region of the toxin homologous to a human acute‐phase protein (1991)

Pneumolysin, a membrane-damaging toxin, is known to activate the classical complement pathway. We have shown that 1 microgram ml-1 of pneumolysin can activate complement, which is a much lower level than observed previously. We have identified two distinct regions of pneumolysin which show homology with a contiguous sequence within acute-phase proteins, including human C-reactive protein (CRP). Site-directed mutagenesis of the pneumolysin gene was used to change residues common to pneumolysin and CRP. Some of the modified toxins had a reduced ability both to activate complement and bind antibody. We suggest that the ability of pneumolysin to activate complement is related to its ability to bind the Fc portion of immunoglobulin G.
The role of (111)In Capromab Pendetide (Prosta-ScintR) immunoscintigraphy in the management of prostate cancer. (2002)

(111)In Capromab Pendetide (ProstaScintR) is a whole murine antibody that is reactive with prostate specific membrane antigen (PSMA), a glycoprotein on the surface of normal and abnormal prostate epithelium. It has proven to be of great value in assisting management decisions in prostate cancer patients who initially present with high risk for metastatic spread, or who develop a picture of recurrent disease after surgery or radiation therapy. Patterns of metastatic lymphatic spread have correlated well with autopsy reports in the literature. Unfortunately, other imaging study and/or histologic confirmation of scintigraphic findings has been difficult to obtain. Prostascint's role in predicting durable complete response (DCR) in postoperative patients having salvage radiotherapy to their prostate fossa is very promising. Further investigative work in larger patient populations is needed to confirm these early results.
Antiphospholipid antibody syndrome (1992)

<h3>CASE PRESENTATION</h3> At the age of 15 years, 4 years before consultation, a white woman had a sudden onset of right hemiplegia. High-titer immunoglobulin G (IgG) and immunoglobulin M (IgM) antiphospholipid antibody and lupus anticoagulant were found, and prednisone, 60 mg/d, and aspirin, 325 mg/d, were prescribed. Prednisone was discontinued after 1 year. At the age of 18 years, mild proteinuria, arthralgia, and chorea developed, and after magnetic resonance imaging, were attributed to a new stroke. The patient became pregnant for the first time at the age of 19 years and developed urinary protein (2 g/d) without hypertension at 14 weeks. Prednisone, aspirin, and heparin were administered, but because of a rise of blood pressure to 160/ 90 mm Hg, an increase in urinary protein to 10 g/d, and vaginal bleeding, a cesarean section was performed at 28 weeks and a boy weighing 680 g was delivered. While taking heparin
Stroke and Vascular Cognitive Impairment (2007)

Advances in stroke are occurring at an unprecedented pace, but often in disciplinary isolation and without optimal mechanisms for systematically translating, integrating and applying the findings. Knowledge accrues in pieces, but is understood in patterns. To optimize knowledge acquisition and application, infrastructures and systems need to be set up along with appealing incentives. The approach needs to be transdisciplinary, going beyond the bounds of any given discipline, reciprocally translational, and transactional, meaning that the interchanges have to yield previously agreed benefits to the parties (The Triple T Approach). A new breed of leaders needs to be developed and nurtured to catalyze the process. Opportunities abound. Stroke and most brain diseases share the same pathophysiological fundamental mechanisms. An integrated, systematic approach to these processes could yield not only greater understanding but new, common therapeutic targets for several diseases. Biphasic clinical trials could combine the best features of pragmatic and explanatory, randomized clinical trials. The greatest opportunity of all may be the largely under-explored and under-exploited borderlands between cerebrovascular and Alzheimer disease. One in three of us will have a stroke, become demented, or both. For each person who has a stroke or Alzheimer disease, two have some cognitive impairment short of dementia, often subclinical cerebrovascular disease on a substrate of Alzheimer changes. The fact that cerebrovascular and Alzheimer disease share the same risk factors, provide a great opportunity for prevention, if implemented at the "brain at risk" stage. Systematically integrating what we know and evaluating what we do could spur progress. Research is not only an activity but an attitude. Making evaluation and incentives to excel part of the funding of all stroke activities would yield far ranging cumulative improvements in all aspects of stroke. No system can replace the individual initiative, creativity and insights that lead to the great discoveries, but progress is not made by breakthroughs alone. No one's work is so exalted that it cannot be improved, nor so humble that it has no value. We can all make a difference.
Dry Etching Characteristics of Zinc Oxide Thin Films in Cl2-Based Plasma (2011)

We investigated the etching characteristics of zinc oxide (ZnO) and the effect of additive gases in a <TEX>$Cl_2$</TEX>-based inductively coupled plasma. The inert gases were argon, nitrogen, and helium. The maximum etch rates were 44.3, 39.9, and 37.9 nm/min for <TEX>$Cl_2$</TEX>(75%)/Ar(25%), <TEX>$Cl_2$</TEX>(50%)/<TEX>$N_2$</TEX>(50%), and <TEX>$Cl_2$</TEX>(75%)/He(25%) gas mixtures, 600 W radiofrequency power, 150 W bias power, and 2 Pa process pressure. We obtained the maximum etch rate by a combination of chemical reaction and physical bombardment. A volatile compound of Zn-Cl. achieved the chemical reaction on the surface of the ZnO thin films. The physical etching was performed by inert gas ion bombardment that broke the Zn-O bonds. The highly oriented (002) peak was determined on samples, and the (013) peak of <TEX>$Zn_2SiO_4$</TEX> was observed in the ZnO thin film sample based on x-ray diffraction spectroscopy patterns. In addition, the sample of <TEX>$Cl_2$</TEX>/He chemistry showed a high full-width at half-maximum value. The root-mean-square roughness of ZnO thin films decreased to 1.33 nm from 5.88 nm at <TEX>$Cl_2$</TEX>(50%)/<TEX>$N_2$</TEX>(50%) plasma chemistry.
Effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites in patients with schizophrenia (1998)

The effect of fluoxetine on the plasma concentrations of clozapine and its major metabolites was studied in 10 schizophrenic patients with residual negative symptoms. Patients stabilized on clozapine therapy (200-450 mg/day) received additional fluoxetine (20 mg/day) for eight consecutive weeks. During fluoxetine administration, mean plasma concentrations of clozapine, norclozapine and clozapine N-oxide increased significantly by 58%, 36% and 38%, respectively. There was no difference in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, and the drug combination was generally well tolerated. The concomitant elevation in plasma levels of clozapine and its major metabolites suggests that fluoxetine inhibits the metabolism of clozapine by affecting pathways other than N-demethylation and N-oxidation. Close monitoring of clinical response and, possibly, plasma clozapine levels is recommended whenever fluoxetine is given to patients stabilized on clozapine therapy.
Temperature-sensitive polymer-nanoshell composites for photothermally modulated drug delivery (2000)

Composites of thermally sensitive hydrogels and optically active nanoparticles have been developed for the purpose of photothermally modulated drug delivery. Copolymers of N-isopropylacrylamide (NIPAAm) and acrylamide (AAm) exhibit a lower critical solution temperature (LCST) that is slightly above body temperature. When the temperature of the copolymer exceeds the LCST, the hydrogel collapses, causing a burst release of any soluble material held within the hydrogel matrix. Gold-gold sulfide nanoshells, a new class of nanoparticles designed to strongly absorb near-infrared light, have been incorporated into poly(NIPAAm-co-AAm) hydrogels for the purpose of initiating a temperature change with light; light at wavelengths between 800 and 1200 nm is transmitted through tissue with relatively little attenuation, absorbed by the nanoparticles, and converted to heat. Significantly enhanced drug release from composite hydrogels has been achieved in response to irradiation by light at 1064 nm. We have investigated the release of methylene blue and proteins of varying molecular weight. Additionally, the nanoshell-composite hydrogels can release multiple bursts of protein in response to repeated near-IR irradiation.
Receptor-associated Protein Is a Folding Chaperone for Low Density Lipoprotein Receptor-related Protein (1996)

The 39-kDa receptor-associated protein (RAP) is a receptor antagonist that inhibits ligand interactions with the receptors that belong to the low density lipoprotein receptor gene family. Our previous studies have demonstrated that RAP interacts with the low density lipoprotein receptor-related protein (LRP) within the endoplasmic reticulum and prevents premature interaction of ligands with the receptor. To analyze whether RAP is also involved in the folding of LRP during receptor biosynthesis, we generated anchor-free, soluble minireceptors that represent each of the four putative ligand-binding domains of LRP (SLRP1, -2, -3, and -4, corresponding to the clusters with 2, 8, 10, and 11 cysteine-rich complement-type repeats, respectively). When these SLRPs were overexpressed by cell transfection, only SLRP1 was secreted. Little or no secretion was observed for SLRP2, -3, and -4. However, when RAP cDNA was cotransfected with SLRP2, -3, and -4 cDNAs, each of these SLRPs was secreted. The cellular retention of SLRPs in the absence of RAP coexpression appeared to be a result of the formation of SDS-resistant, oligomeric aggregates observed under nonreducing conditions. Such oligomers of the SLRPs likely resulted from formation of intermolecular disulfide bonds since they were reduced to monomers when analyzed under reducing conditions. The oligomers were formed not only among molecules of a given SLRP, but also between different SLRPs. The role of RAP in the process of LRP folding was shown by the reduction in aggregated SLRP oligomers upon RAP coexpression. A similar role of RAP in preventing the aggregation of newly synthesized receptor was also observed using membrane-containing minireceptor of LRP. Coimmunoprecipitation and ligand binding studies demonstrated that RAP binds avidly to SLRP2, -3, and -4, but not to SLRP1. These results suggest that these interactions may be important for proper folding of LRP by ensuring the formation of proper intradomain, but not intermolecular or interdomain, disulfide bonds. Thus, our results strongly suggest that, in addition to the prevention of premature binding of ligands to LRP, RAP also plays an important role in receptor folding.